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Non-Pharmaceutical Interventions for Type 2 Diabetes: Diets, Botanicals, Antioxidants, Minerals, and Other Dietary Supplements

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This is a up-to-date, comprehensive review of natural product-based dietary interventions for type 2 diabetes.
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Chapter 16- NON-PHARMACEUTICAL INTERVENTION OPTIONS FOR
TYPE 2 DIABETES:
Diets and Dietary Supplements (Botanicals, Antioxidants, and Minerals)
Joseph L. Evans, Ph.D., , P & N Development Ventures, Saint Louis, MO USA
: jevansphd@earthlink.net
Mi-Kyung Bahng, Ph.D., ESM Technologies, Springfield, MO USA mikyung.bahng@gmail.com
Chapter revised: February 5, 2014
INTRODUCTION
Diabetes has reached epidemic proportions throughout the world: 8.3% of adults – 382 million
people have diabetes, and the number of people with the disease is set to rise beyond 592 million
in less than 25 years (http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf). Furthermore,
the prevalence of insulin resistance, a major causative factor in the early development of type 2
diabetes (T2D) and an independent risk factor for cardiovascular disease and the insulin resistance
syndrome (also known as the metabolic syndrome), is even more widespread [1-3]. Recent data
(1999-2010) indicate that the prevalence of the insulin resistance syndrome among US adults (≥20
years of age) is approximately 25% of the population [4]; the International Diabetes Federation has
reported an identical figure for the worldwide prevalence in adults (http://www.idf.org/metabolic-
syndrome).
This situation is further exacerbated by obesity, a major risk factor for developing T2D and
cardiovascular disease. Results from the 2009–2010 National Health and Nutrition Examination
Survey (NHANES), using measured heights and weights, indicate that an estimated 33.0% of U.S.
adults aged 20 and over are overweight, 35.7% are obese, and 6.3% are extremely obese
(http://www.cdc.gov/nchs/data/hestat/obesity_adult_09_10/obesity_adult_09_10.pdf). According to
the World Health Organization (WHO), the worldwide prevalence of obesity has nearly doubled
between 1980 and 2008. In 2008, 10% of men and 14% of women in the world were obese (BMI
≥30 kg/m2), compared with 5% for men and 8% for women in 1980. An estimated 205 million men
and 297 million women over the age of 20 were obese – a total of more than half a billion adults
worldwide (http://www.who.int/gho/ncd/risk_factors/obesity_text/en/). Since dietary modification
and increased physical activity provide insufficient glucose control over the long-term course of the
disease, the vast majority of patients require some type of pharmacological intervention [5;6].
Pharmacological options for the management of T2D have been increasing, and will continue to do
so [5;7;8], (http://www.ncbi.nlm.nih.gov/pubmed/24278998).The cost of prescription medications
may exceed the financial capacity of older citizens, those without adequate health insurance, and
those living in poverty [9;10]. Certain ethnic groups who are at increased risk for developing
diabetes (e.g. Asians, Hispanics, and Native Americans), come from cultures with a long history of
use of traditional medicines, and are likely to employ one or more folk (botanical) treatments rather
than prescription medications [11-20]. Though a majority of diabetic patients are being treated,
many are unable to achieve the current American Diabetes Association-recommended goal of
HbA1c < 7%. For these reasons, it is appropriate to identify and evaluate adjunctive options in the
light of available evidence, as to whether they are safe and to any extent effective. This
presentation does not recommend or endorse their use. We emphasize that almost no data is
available on long-term outcomes (safety or efficacy) with these agents or on their cost
effectiveness.
Regulatory Overview
Botanical extracts, vitamins, antioxidants, minerals, amino acids, and fatty acids (natural products
collectively and interchangeably referred to here as dietary supplements or nutraceuticals) are a
potential source of therapies for T2D and insulin resistance (http://nccam.nih.gov/health/diabetes/).
These agents are marketed in the US as specified by the Dietary Supplement Health and
Education Act (DSHEA), passed by the US Congress in 1994. DSHEA defined a new category of
food for regulatory purposes, termed dietary supplements, one that also includes concentrates,
metabolites, constituents, extracts, and combinations, and has resulted in major changes in the
marketing and use of dietary supplements in the US (see below).
From a regulatory perspective, nutraceuticals are treated differently compared to either over-the-
counter (OTC) or prescription pharmaceuticals [21-23]. DSHEA strictly requires manufacturers of
botanicals and nutraceuticals to clearly state on all product labels that it is not intended to
diagnose, treat, cure, or prevent any disease. Statements can be made to suggest that a dietary
supplement enhances general health, or refers to a documented biochemical or physiological
mechanism whereby a supplement affects a structure or function. These claims are commonly
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referred to as structure/function claims (e.g. supports cardiovascular health, supports immune
function, supports joint function, etc.). In contrast to the regulatory requirements for OTC and
prescription pharmaceuticals, manufacturers of dietary supplements are not required, under
DSHEA, to submit evidence of safety or efficacy prior to marketing. Although a dietary supplement
manufacturer is ultimately responsible for the safety of its products, the US Food and Drug
Administration (FDA) bears the burden of proof to show that a product is unsafe. To remove a
product from the market, the FDA must be convinced and show evidence that the product (or
ingredient contained in a product) possesses an undue risk of harm at the indicated dose [24].
For example, the increased risk for adverse events by ephredra-containing products compared
with other botanicals and nutraceuticals resulted in the FDA’s decision to remove ephredra-
containing products from the market in 2004 [22;24-26]. More recently (2013), the FDA announced
a ban on all products containing DMAA (also known as 1,3-dimethylamylamine, methylhexanamine
or geranium extract), a thermogenic agent. Ingestion of DMAA can elevate blood pressure and
lead to cardiovascular problems ranging from shortness of breath and tightening in the chest to
heart attack
(http://www.fda.gov/food/dietarysupplements/qadietarysupplements/ucm346576.htm).
A detailed comparison of the regulatory requirements of dietary supplements, OTC, and
prescription medications has been published [23]. In addition to market withdrawal, FDA frequently
takes action to prevent makers of these “supplements” from advertising unproven benefits.
Dietary Supplement Market
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Figure 1. Demograpic profile of US adults reporting taking dietary supplements.
Source: Council of Responsible Nutrition (CRN) Market Research Report (September 20, 2013).
Despite the caveat emptor atmosphere surrounding dietary supplements [21], they are
enthusiastically used by more than 68% of American adults (Figure 2) .
Dietary supplements are a $35 billion market that's growing at a rate of 7.6 percent. Common
motivations are to stay healthy (e.g. multi-vitamins, vitamin D, calcium and omega-3 fatty acids)
lose weight, and to avoid the use of prescription medications. Recent surveys indicate that
individuals are attracted to lower-calorie diets (especially less carbohydrates), less gluten, less
meat, more exercise, more self-care, fewer doctor visits, and less reliance on conventional
medicine. In response to these current trends, there has been a measurable increase in new
product launches and product development activities and continued growth in gut health
(especially probiotics) and omega-3 fatty acids http://www.nutraceuticalsworld.com/issues/2012-
12/view_features/state-of-the-industry-review-forecast/). The emerging areas of bone/joint health
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and glycemic control remain strong, and are poised to be significant categories for years to come.
According to Nutrition Business Journal (NBJ), dietary supplements accounted for one-fourth of all
of the U.S. nutrition industry sales in 2010. The dietary supplement industry experienced a growth
rate of ~5% from 2000 to 2010 and has added over $10 billion dollars in annual sales over that
period of time (http://newhope360.com/site-
files/newhope360.com/files/uploads/2013/04/TOC_Global_final.pdf). Consumer sales of dietary
supplements were $23.7 billion in 2007, $26.7 billion in 2009, and surpassed $30 billion in 2011
sales, growing 7% annually in a return to performance levels not seen since before the economic
downturn. This represents $2 billion in incremental sales in 2011 from year-ago levels and points
toward the escalating interest in supplementation. Overall, the dietary supplement industry has
continued to show growth despite a generally weak economy, and continued regulatory issues
have been a major influence in 2012. NBJ predicts that the market will continue to grow as shown
in Figure 2, although growth rates for many product categories within the dietary supplement
industry experienced diminished growth from previous years.
Figure 2. U.S. Dietary Supplement Sales & Growth, 2000-2017e.
Source: Nutrition Business Journal estimates. ($mil., consumer sales) "Global Supplement &
Nutrition Industry Report," Nutrition Business Journal, pp. 1-15, 2012.
Figure 3 shows U.S. dietary supplement sales (2011) broken out by product categories: it consists
of 34% Vitamins, 17% Herbs and Botanicals, 12% Sports Nutrition, 10% Meal Replacements, 8%
Minerals, and 19% Specialty and Others. Two categories, sports nutrition and meal replacements,
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clearly outperformed the other categories, as both exhibited double-digit growth during 2011. The
unifying theme here is that protein has successfully averted the slings and arrows levied against its
peers, fats and carbs, over recent years. The ‘specialty ingredient’ category of dietary supplements
also experienced respectable growth in 2011 thanks to continued advances from the industry’s
major archetype ingredients—Omega-3s and Probiotics. The dietary supplement represents about
25% of the total U.S. nutrition industry, as shown in Table 1 below.
Figure 3. U.S. Dietary Supplement Sales (% of total) in 2011 by Product Categories.
Source: Nutrition Business Journal estimates (http://newhope360.com/2012-supplement-business-
report).
Table 1. U.S. Dietary Supplements vs. Total Nutrition Industry, 2000-20
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Source: Nutrition Business Journal estimates ("Global Supplement & Nutrition Industry Report,"
Nutrition Business Journal, pp. 1-15, 2012.).
In 2010, almost 23 million households in the US had a member coping with diabetes, according to
Symphony IRI’s 2010 “OTC Medication Report,” which estimated the annual sales potential for
diabetes related OTC, drugs, and dietary supplements at $3.4 billion (M. Becker, "The Blood
Sugar Market Goes Boom!," Nutraceutical World Magazine, 1 October 2012). The dietary
supplement share of this impressive market has been estimated at $126 million (2012) with a
predicted growth to $240 million by 2019. Furthermore, the ADA estimates that there are 19 million
Americans who have been diagnosed with either T1D or T2D (Table 2). Those people, along with
the estimated 7 million who are undiagnosed, are costing the U.S. $116 billion annually to treat.
According to Escondido, CA-based Sloan Trends.
Table 2. Diabetes & Prediabetes Cases in the U.S.
Source: American Diabetes Association [27]
A nationally (US) representative survey has reported that over 30% of patients with diabetes used
complementary and alternative medicine (CAM) to manage their condition [28]; in certain ethnic
populations with diabetes (Navajo, Vietnamese, Hispanic), the percentages are even higher (40-
66%)[18;29-31]. A more recent study has reported that the prevalence of pharmacologic and non-
pharmacologic CAM among 806 participants with diabetes patients was 81.9% and 80.3%,
respectively [32]. Overall, CAM prevalence was similar for Caucasians (94.2%), African Americans
(95.5%), Hispanics (95.6%) and Native Americans (95.2%) and lower in Pacific Islanders/others
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(83.9%) and Asians (87.8%). Pharmacologic CAM prevalence was positively associated with
education (P=0.001). The presence of diabetes was a powerful predictor of CAM use. Several
significant ethnic differences were observed in specific forms of CAM use. Hispanics reported
using frequently prickly pear (nopal; see below) to complement their diabetes treatment, while
Caucasians more commonly used multivitamins.
In response to the increasing use of CAM by the general public [33] and by patients with diabetes
[28], the American Diabetes Association has issued a ‘position paper’ calling on health care
providers to ask their patients about their use of CAM [34]. The National Center of Complementary
and Alternative Medicine website (part of the US National Institutes of Health) is an excellent
source of credible information regarding the use of dietary supplements in individuals with T2D
(http://nccam.nih.gov/health/diabetes).
Due to the increasing use of dietary supplements and functional foods by individuals with diabetes
along with the potential for positive (and negative) impact, it is important, therefore, that diabetes
health care professionals increase their knowledge of these agents [21;35]. To this end, several
recent comprehensive reviews have focused on the use of botanicals and dietary supplements for
diabetes [17;36-39]. The overall objective of this chapter is to provide a concise, comparative
overview of those botanicals and other dietary supplements that have received the most scientific
and, especially, clinical attention.
DIETARY INTERVENTIONS
Dietary modification is universally recognized by caregivers as an initial intervention and mainstay
for the treatment of overweight patients with T2D [40] [41-43]. The other side of the non-
pharmacological intervention ‘coin’ involves changes in lifestyle, usually consisting of increased
physical activity [44], smoking cessation, and reduced intake of alcohol. The overall objectives of
these approaches are 1) weight loss and exercise training both resulting in improved insulin action,
2) improved glycemic and lipid control (both short-term and chronic), 3) reduced likelihood of
developing microvascular and macrovascular complications, and 4) improved quality of life. It is
important to remember that patients do not have to achieve their ideal body weight to reap
significant health benefit. It has been reported that a loss of 10-20 lb (4.5-9 kg) will be helpful, as
long as the weight loss and exercise programs are maintained [45-47].
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In patients with impaired glucose tolerance, dietary changes to ensure some degree of weight loss
coupled with physical activity, is clinically effective and cost effective in reducing the progression to
T2D [48].
The recommendations of the American Diabetes Association [49], the American Association of
Clinical Endocrinologists [50], along with those from several other professional organizations
(http://www.ndei.org/treatmentguidelines.aspx) for the nutritional management of patients with
T2D are provided elsewhere and will not be discussed in detail herein. The key to successful
dietary intervention is to ensure that caloric intake is less than caloric output. For long-term
success, this should be coupled with education designed to improve the patient’s understanding of
the beneficial effects of dietary modification on blood glucose, lipids, blood pressure, and overall
quality of life. Some successful dietary approaches have included those designed to limit intake of
saturated fats (< 7% of total caloric intake), and spreading the nutrient load. Dietary factors that are
able to spread the nutrient load include increased frequency of food intake, increased intake of
soluble fiber, legumes, and increased intake of foods with a low glycemic index. The beneficial role
that supplements and foodstuffs high in soluble fiber play in the conventional dietary management
of patients with T2D is well documented [51-54].
According to the ADA, it is unlikely that there is an optimal mix of macronutrients for the ‘diabetic
diet’. The best mix of carbohydrate, protein, and fat appears to vary depending on individual
circumstances. The best mix should provide a total caloric intake that facilitates, at the very
minimum, weight maintenance and ideally weight loss. The average daily intake of carbohydrates
recommended for patients with diabetes is approximately 45-65% of total caloric intake; low or
restricted carbohydrate diets are not recommended in the management of diabetes. Intake of fat
should be limited to approximately 20-35%; and dietary cholesterol should be < 200 mg/day. In
patients with dyslipidemia, a special effort should be made to limit saturated fat and to substitute
unsaturated or monounsaturated fat, especially omega-3 fatty acids. To reduce the risk of stroke
and cardiovascular disease, diets high (3-6 servings per day) in fruits and vegetables are highly
recommended [55-57]. Emerging epidemiological data suggests that higher coffee intake may
reduce the risk for the development of T2D [58]. Protein intake (in patients with normal renal
function) should be limited to 10-20% of total caloric intake, and reduced to 10-15% at the onset of
macroalbuminuria. In addition to their beneficial effects on plasma lipids, a meta-analysis of
randomized controlled clinical trials concluded that diets high in soluble fiber provided by either
whole foods (up to 43 g/d) or dietary supplementation (up to 15 g/d) reduced absolute values of
glycated HbA1c by 0.55%, and fasting plasma glucose by ~ 10.0 mg/dl [59].
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With regard to micronutrient supplementation, the ADA does not recommend routine
supplementation with any vitamin, mineral, or antioxidant in patients with diabetes who do not have
an underlying deficiency [49]. The basis for this position is the lack of clear evidence of efficacy
and, in some cases, a concern related to long-term safety [57;60-63]. With regard to alcohol intake,
patients with diabetes are advised to follow the same precautions as the general population. Daily
intake should be limited to a moderate amount (one drink per day or less for women, and two
drinks per day or less for men). In those patients using insulin or insulin au alcohol should be
consumed with food to reduce the risk of nocturnal hypoglycemia. Alcohol alone does not acutely
affect blood glucose or insulin but, if co-ingested with carbohydrate, could raise glucose [49].
The ADA has recently released (October 10, 2013) a new position statement regarding the
nutritional management of adults with diabetes [64]. This statement provides an updated set of
recommendations based on a review of recent scientific and clinical evidence. Briefly, the updated
recommendations call for all adults diagnosed with diabetes to consume a variety of nutrient-dense
foods in appropriate portion sizes as part of individualized eating plans that takes into account
personal nutrition preferences, lifestyle, culture, religion, and metabolic goals. In selecting
personalized eating plan, people with diabetes should be sure to consider individual metabolic
goals, including their glucose and lipid levels, along with their blood pressure. According to the
ADA, current evidence does not conclusively support one type of diet over another (e.g.,
Mediterranean, vegetarian, low carbohydrate). A primary objective is to identify an eating pattern
that fits an individual’s food preferences and lifestyle, that can be followed consistently, and offers
macro- and micronutrients necessary for good health [64]. Importantly, people with diabetes are
advised to limit or avoid altogether intake of sugar-sweetened beverages (especially those
containing high-fructose corn syrup) to reduce the risk for weight gain and worsening of the
cardiovascular profile.
Mediterranean Diet
Perhaps the most widely recognized diet with health promoting benefits is the so-called
Mediterranean Diet. Around 50 years ago, it was recognized by Keys and associates that very low
incidences of cardiovascular disease in the areas around Naples, Italy, were associated with what
was soon to be termed the Mediterranean Diet [65]. The heart of this diet is mainly vegetarian, and
differs from North American and Western European diets in that it is much lower in meat and dairy
products, and frequently contains fruits for dessert. This diet reflects a pattern of eating most highly
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associated with olive growing areas of the Mediterranean. Olive oil is a critical component of this
diet both because of its inherent benefits (presence of mono unsaturated fat, i.e. oleic acid) along
with allowing for the consumption of high quantities of fruits and vegetables in salads and other
prepared foods. Other essential components of this diet are fish (a rich source of omega-3 fatty
acids; see Polyunsaturated Fatty Acids in Fatty Acid section below), nuts, wheat, grapes, and
derived products including wine [66]. Many studies have convincingly demonstrated that this
dietary pattern plays an important role in the prevention of cardiovascular disease [67-74].
Chocolate—What’s for Dessert?
As discussed above, there is a growing body of epidemiological evidence supporting the idea that
diets rich in fruits and vegetables reduce or delay the onset of many chronic diseases, including
cardiovascular and related metabolic diseases [75]. A major class of compounds present in fruits
and vegetables that is associated with cardio-protective effects is the flavanols [76]. Cocoa is also
rich source of flavanols, a class of polyphenolic antioxidant compounds (e.g. (-)-epicatechin, (+)-
catechin, procyanidins) found in plants [76]. In addition to their antioxidant activity, flavanols have
also been associated with increased in nitric oxide bioavailability [77;78]. Consumption of
chocolate can result in significant increases in plasma epicatechin concentrations and decreases in
plasma baseline oxidation products [79]. Since nitric oxide bioavailability deeply influences insulin-
stimulated glucose uptake and vascular tone, flavanols have been evaluated for potential positive
metabolic and pressor effects. Flavanoid-rich dark chocolate (100g) improved endothelial function
and was associated with an increase in plasma epicatechin concentrations in healthy adults
[79;80].
The effects of either dark or white chocolate bars on blood pressure and glucose and insulin
responses to an oral-glucose-tolerance test in healthy subjects was compared [81]. After a 7-day
cocoa-free run-in phase, 15 healthy subjects were randomly assigned to receive for 15 days either
100 g dark chocolate bars, which contained approximately 500 mg polyphenols, or 90 g white
chocolate bars, which contained no polyphenols. Successively, subjects entered a further cocoa-
free washout phase of 7 days, and then were crossed over to the other condition. Oral glucose
tolerance tests were performed at the end of each period to calculate the homeostasis model
assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index
(QUICKI); blood pressure was measured daily. HOMA-IR was significantly lower after dark than
after white chocolate ingestion (0.94 ± 0.42 compared with 1.72 ± 0.62; P < 0.001), and QUICKI
was significantly higher after dark than after white chocolate ingestion (0.398 ± 0.04 compared with
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0.356 ± 0.02; P = 0.001). Although within normal values, systolic blood pressure was lower after
dark than after white chocolate ingestion (107.5 ± 8.6 compared with 113.9 ± 8.4 mm Hg; P <
0.05). These results suggest that dark but not white chocolate decreases blood pressure and
improves insulin sensitivity in healthy persons.
These same researchers have also evaluated the effects of dark chocolate (DC) consumption on
blood pressure (BP), flow-mediated dilation (FMD), oral glucose tolerance (OGTT), and insulin
sensitivity in patients with essential hypertension (EH) [82]. After a 7-day chocolate-free run-in
phase, 20 never-treated, grade I patients with EH (10 males; 43.7 ± 7.8 years) were randomized to
receive either 100 g per day DC (containing 88 mg flavanols) or 90 g per day flavanol-free white
chocolate (WC) in an isocaloric manner for 15 days. After a second 7-day chocolate-free period,
patients were crossed over to the other treatment. Noninvasive 24-hour ambulatory BP, FMD,
OGTT, serum cholesterol, and markers of vascular inflammation were evaluated at the end of each
treatment. The HOMA-IR, QUICKI, and insulin sensitivity index (SI) were calculated from OGTT
values. Ambulatory BP decreased after DC (24-hour systolic BP -11.9 ± 7.7 mm Hg, P < 0.0001;
24-hour diastolic BP -8.5 ± 5.0 mm Hg, P < 0.0001), but not WC. DC but not WC decreased
HOMA-IR (P < 0.0001), and it improved QUICKI, SI, and FMD. DC also decreased serum LDL
cholesterol (from 3.4 ± 0.5 to 3.0 ± 0.6 mmol/L; P<0.05). In summary, DC decreased BP and serum
LDL cholesterol, improved FMD, and enhanced insulin sensitivity in patients with EH. Additional
studies in larger groups and in individuals with T2D will be needed to confirm these results.
BOTANICAL INTERVENTIONS
Botanicals have been used for medicinal purposes since the dawn of civilization [83]. It is well
documented [20] that many pharmaceuticals commonly used today are structurally derived from
natural compounds found in traditional medicinal plants. The development of the anti-
hyperglycemic drug metformin (dimethlybiguanide; Glucophage®) can be traced to the traditional
use of Galega officinalis to treat diabetes, and the subsequent search to identify active compounds
with reduced toxicity [84-86]. G. officinalis is far from the only botanical to have been used as a
treatment for diabetes. Chinese medical books written as early as 3000 B.C. spoke of diabetes and
described therapies for this disease [87;88]. These historical accounts reveal that T2D existed long
ago, and medicinal plants have been used for many millennia to treat this disease. To date, the
anti-diabetic activities of well over 1200 traditional plants has been reported, although scant few
have been subjected to rigorous scientific evaluation for safety and efficacy in humans [87;89-93].
This section will provide a brief overview of those botanicals used for diabetes that have received
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the most scientific attention, have been evaluated for their anti-diabetic effects in individuals with
diabetes, and are deserving of additional evaluation. See Table 3 for a summary of this
information.
Ipomoea batatas (Caiapo)
Caiapo is derived from the skin of a variety of white sweet potato of South American origin,
Ipomoea batatas, which is cultivated in a mountainous region in Kagawa Prefecture, Japan. It has
been eaten raw for centuries in the belief that it is effective for anemia, hypertension, and diabetes.
Caiapo is commercially available throughout Japan without prescription, and used for the
prevention and treatment of T2D. In rodents, caiapo exhibits anti-diabetic activity, and the active
component is thought to be a high-molecular weight acid glycoprotein [94;95].
A beneficial effect of caiapo on glycemic control has been reported in several clinical studies. In a
pilot study, a total of 18 male patients with T2D (age: 58 ± 8 years; weight: 88 ± 3 kg; BMI: 27.7 ±
2.7 kg/m2; means ± SEM) treated by diet alone were randomized to receive placebo (n = 6) or 2
(low dose; n = 6) or 4 g (high dose; n = 6) caiapo (four tablets each containing 168 or 336 mg
powdered white-skinned sweet potato, respectively) before breakfast, lunch, and dinner for 6 weeks
[96]. At the end of treatment, no statistically significant changes in fasting glucose, insulin, or lipids
occurred in either the low-dose caiapo or placebo groups. In the group treated with the high dose
caiapo, fasting plasma glucose (-13%) as well as cholesterol [total (-10.5%) and LDL (-13%)
cholesterol] were significantly decreased (P < 0.05, compared to baseline). Body weight and blood
pressure remained unchanged in all three groups. In patients receiving low-dose caiapo, insulin
sensitivity (SI) increased by 37% (2.02 ± 0.70 vs. 2.76 ± 0.89 104 min-1 · µU–1 · ml–1, P < 0.05); in
those on high-dose caiapo, the FSIGT demonstrated an increase of SI by 42% (1.21 ± 0.32 vs. 1.73
± 0.40 104 min-1 · µU–1 · ml–1, P < 0.03). No changes were seen for SI in patients receiving placebo
(1.52 ± 0.28 vs. 1.35 ± 0.21 104 min-1 · µU–1 · ml–1). Glucose tolerance was significantly increased
(~72%; P < 0.02) in the high-dose group [97]. No adverse events were reported.
The results of this pilot study have been confirmed in a randomized, double-blind placebo
controlled trial [98]. A total of 61 patients with T2D treated by diet were given 4 g caiapo (n = 30;
mean age 55.2 ± 2.1 years; BMI 28.0 ± 0.4 kg/m2) or placebo (n = 31; mean age 55.6 ± 1.5 years;
BMI 27.6 ± 0.3 kg/m2) once daily for 12 weeks. Each subject underwent a 75-g oral glucose
tolerance test (OGTT) at baseline and after 1, 2, and 3 months to assess 2-h glucose levels.
Additionally, fasting blood glucose, HbA1C, total cholesterol, and triglyceride levels were measured.
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Fasting blood glucose levels decreased in the caiapo group (143.7 ± 1.9 vs. 128.5 ± 1.7 mg/dl; P <
0.001), and remained unchanged in the placebo group (144.3 ± 1.9 vs. 138.2 ± 2.1 mg/dl; P =
0.052). In the caiapo group, HbA1C decreased significantly (-0.53%; P < 0.001) from 7.21 ± 0.15 to
6.68 ± 0.14%, and remained unchanged in the placebo group (7.04 ± 0.17 vs. 7.10 ± 0.19%; P =
0.23). Two-hour glucose levels were significantly (P < 0.001) decreased in the caiapo group (193.3
± 10.4 vs. 162.8 ± 8.2 mg/dl) compared with the placebo group (191.7 ± 9.2 vs. 181.0 ± 7.1 mg/dl).
Mean cholesterol at the end of the treatment was significantly lower in the caiapo group (214.6 ±
11.2 mg/dl) than in the placebo group (248.7 ± 11.2 mg/dl; P < 0.05). A decrease in body weight
was observed in both the placebo group (P = 0.0027), and in the caiapo group (P < 0.0001); in the
caiapo group, body weight was related to the improvement in glucose control (r = 0.618; P <
0.0002). No significant changes in triglyceride levels or blood pressure were observed.
Unfortunately, possible effects on fasting insulin, C-peptide, or insulin sensitivity were not reported
in this study. Caiapo was well tolerated without significant adverse effects. This study confirms the
results of the pilot with regard to the beneficial effects of caiapo on short-tem glycemic control (as
well as cholesterol levels) and documents the efficacy of caiapo on long-term glycemic control in
patients with T2D. The magnitude of the effect of caiapo at reducing HbA1c (-0.53% absolute
decrease) is comparable with that of Acarbose, an approved oral anti-hyperglycemic medication
[99], although it falls short of what has been suggested as the minimal acceptable level for a new
anti-hyperglycemic medication (-0.7% absolute decrease) [100]. It will be of interest and important
to see if the results of this outcome with caiapo can be confirmed in other well designed clinical
trials, and to establish that caiapo does not exhibit any adverse interaction with existing anti-
hyperglycemic medication.
More recent work evaluating individuals with T2D using a randomized, placebo-controlled clinical
trial design has shown that Caiapo exerted beneficial effects on glycemic control (including HbA1c)
in patients with T2DM after 5 months follow-up. Improvement of insulin sensitivity was
accompanied by increased levels of adiponectin and a decrease in fibrinogen. Thus, Caiapo may
be considered as natural insulin sensitizer with potential but so far unproven anti-atherogenic
properties [101].
Trigonella foenum-graecum (Fenugreek)
Trigonella foenum-graecum, also known as fenugreek, is an herb native to southeastern Europe,
northern Africa, and western Asia, but is also widely cultivated in other parts of the world [102].
Fenugreek has a long history of traditional use in both Ayurvedic [holistic system of healing which
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originated among the Brahmin (Hindu priestly caste) sages of ancient India and Nepal
approximately 3000 - 5000 years ago] and Chinese medicine [103], and has been widely used for
the treatment of diabetes [104] [91]. The defatted seeds of the fenugreek plant contain ~50% fiber
(similar to guar gum), along with a variety of bioactive saponins, alkaloids, coumarins, and 4-
hydroxyisoleucine, the principle bioactive compound [90;91]. This latter compound exhibits
insulinotropic activity [105-107]; following a 6-day sub-chronic administration, 4-hydroxyisoleucine
(50 mg/kg/day) reduced fasting hyperglycemia, insulinemia, and improved glucose tolerance in
diabetic rats [107]. In addition, fenugreek, along with several other botanicals commonly used as
interventions for T2D, contains biguanide-related compounds [108]. The identification of guanidine
and related biguanide compounds in French lilac plant (Galega officinalis L.) led to the
development of metformin, the most widely used anti-diabetic compound through the world.
The clinical studies that have evaluated the efficacy of fenugreek in individuals with both type 1 and
T2D have recently been reviewed [17]. In one study, 17 of 21 patients with T2D showed a
reduction in 2-hour post-prandial glucose averaging 30 mg/dl following administration of 15 g of
ground fenugreek seed [109]. In a crossover, placebo-controlled trial with 60 individuals with type 2
diabetes, the treatment group received 12.5 mg defatted fenugreek at lunch and dinner with
isocaloric diets for 24 weeks [110]. Fasting blood glucose was 151 mg/dl at baseline, and reduced
to 112 mg/dl after 24 weeks (P < 0.05). Fenugreek also caused a significant decrease in the area
under the glucose curve by approximately 40%.
In a small study, the effects of fenugreek seeds on glycemic control and insulin resistance in mild-
to-moderate T2D was performed using a double-blind, placebo-controlled design [111]. Twenty-five
newly diagnosed patients with T2D (fasting glucose < 200 mg/dl) were randomly divided into two
groups. Group I (n = 12) received 1 g/day of fenugreek seeds and Group II (n = 13) received
standard care (dietary control, exercise) plus placebo capsules for two months. After two months,
fasting blood glucose and two-hour post-glucose load blood glucose were not significantly different.
However, following an oral glucose challenge, the area under the curve (AUC) for blood glucose
(2375 ± 574 vs 27597 ± 274) and insulin (2492 ± 2536 vs. 5631 ± 2428) was significantly lower (P
< 0.001), as was the HOMA-IR index (112.9 ± 67 vs 92.2 ± 57; P < 0.05) in the treatment group
compared to control. Serum triglycerides were decreased and HDL cholesterol increased
significantly (both P < 0.05) following fenugreek treatment. Significant reductions in total cholesterol
and triglycerides have also been reported in other studies following fenugreek treatment [17].
15
In an open label pilot study, fenugreek seeds were evaluated in combination with M. charantia and
jamun seeds (Syzigium cumini) for effects on glycemic control in patients with T2D [112]. The
patients were divided into two groups of 30 each. The patients of group I were given the raw
powdered mixture in the form of capsules; the patients of group II were given this mixture in the
form of salty biscuits. Daily supplementation of 1 g of this powered mixture for a 1.5-month period
and increased to 2 g for another 1.5 months significantly reduced the fasting as well as the
postprandial glucose level of the diabetic patients. A significant decrease in oral hypoglycemic drug
intake and decline in percentage of the subjects who were on hypoglycemic drugs were found after
the 3-month feeding trial. The authors concluded that 2 g of this powdered mixture of traditional
medicinal plants in either raw or cooked form can be successfully used for lowering blood glucose
in diabetics.
The doses of fenugreek used in clinical studies have ranged from 2.5 grams to 15 grams daily of
the crushed and defatted seeds. Crushing is important in order to release the viscous gel fiber,
which presumably contributes to the efficacy of fenugreek. Typical doses of seeds are in the range
of 1-3 grams mixed with food and taken at mealtime. The most common side effects are
gastrointestinal upset (diarrhea and flatulence), which often can be alleviated by dose-titration.
Since the fenugreek fiber might absorb other oral medications, fenugreek should be taken
independently (e.g. 1-2 h) of other medications. Due to its ability to lower blood glucose, individuals
should monitor their glucose levels carefully if used in combination with insulin or other glucose-
lowering agents. Fenugreek can exhibit anti-coagulant activity; it should not be used with other
anti-coagulating agents due to the increased risk for bleeding.
The potential genotoxicity of a fenugreek seed extract (THL), containing a minimum of 40% 4-
hydroxyisoleucine, was evaluated using the panel of assays recommended by US Food and Drug
Administration for food ingredients (i.e. reverse mutation assay; mouse lymphoma forward
mutation assay; mouse micronucleus assay). THL was determined not to be genotoxic under the
conditions of the tested genetic toxicity battery [113]. An updated review regarding the beneficial
effects of fenugreek on both glucose and lipid control has recently been published [114]. No long
term studies on outcome, and cost- effectiveness, have been presented.
Cinnamomum cassia (Cinnamon)
Anderson and colleagues have previously reported that an ammonium hydroxide extract of
cinnamon potentiated the effect of insulin on glucose oxidation in isolated rat adipocytes [115;116].
16
Close evaluation of these in vitro data reveals that the cinnamon extract actually possessed insulin
mimetic activity, since the stimulatory effects were independent of insulin concentration and no
added insulin was required to achieve maximal glucose oxidation [116]. A water-soluble
polyphenolic polymer from cinnamon has been isolated, and shown to have insulin-like activity as
well as antioxidant activity in vitro [113]. Additionally, enzyme inhibition studies done have shown
that the bioactive compound(s) isolated from cinnamon can stimulate autophosphorylation of a
truncated form of the insulin receptor and can inhibit PTP-1, the rat homolog of the tyrosine
phosphatase PTP-1B that inactivates the insulin receptor [117;118].
Three small studies have evaluated the use of cinnamon in T2D. The effects of cinnamon on blood
glucose, triglyceride, total cholesterol, HDL cholesterol, and LDL cholesterol levels was evaluated
in patients with T2D [119]. A total of 60 people with T2D (30 men and 30 women aged 52.2 ± 6.32
years) were divided randomly into six groups. Groups 1, 2, and 3 consumed 1, 3, or 6 g of
cinnamon daily, respectively, and groups 4, 5, and 6 were given placebo capsules corresponding to
the number of capsules consumed for the three levels of cinnamon. The cinnamon was consumed
for 40 days, followed by a 20-day washout period. After 40 days, all three doses of cinnamon
significantly reduced the mean fasting serum glucose (18-29%), triglyceride (23-30%), LDL
cholesterol (7-27%), and total cholesterol (12-26%) levels; no significant changes were noted in the
placebo groups. Changes in HDL cholesterol were not significant, and no significant adverse
events were reported. The results of this interesting study suggest that intake of 1, 3, or 6 g of
cinnamon per day reduces serum glucose, triglyceride, LDL cholesterol, and total cholesterol.
A more recent trial has evaluated an aqueous-purified cinnamon extract on long-term glycemic
control and lipids in patients with T2D with equivocal results [120]. A total of 79 patients on insulin
therapy but treated with oral anti-diabetics or diet were randomly assigned to take either cinnamon
extract or a placebo capsule three times a day for 4 months in a double-blind study. The amount of
aqueous cinnamon extract corresponded to 3 g of cinnamon powder per day. The mean absolute
and percentage differences between the pre- and post-intervention fasting plasma glucose level of
the cinnamon and placebo groups were significantly different. There was a significantly higher
reduction in the cinnamon group (10.3%) than in the placebo group (3.4%). No significant intra-
group or inter-group differences were observed regarding HbA1c, lipid profiles or differences
between the pre- and post-intervention levels of these parameters The decrease in plasma glucose
correlated significantly with the baseline concentrations, indicating that subjects with a higher initial
plasma glucose level exhibited a greater response more from cinnamon intake [100]. No adverse
17
effects were observed.
In a third study, a total of 25 postmenopausal patients with T2D (aged 62.9 ± 1.5 y, BMI 30.4 ± 0.9
kg/m2) participated in a 6-wk intervention, during which they were supplemented with either
cinnamon (1.5 g/d) or a placebo [121]. Before and after 2 and 6 wk of supplementation, arterialized
blood samples were obtained and oral glucose tolerance tests were performed. Blood lipid profiles
and multiple indices of whole-body insulin sensitivity were determined. There were no time x
treatment interactions for whole-body insulin sensitivity or oral glucose tolerance. The blood lipid
profile of fasting subjects did not change after cinnamon supplementation. These results showed
that cinnamon supplementation (1.5 g/d) did not improve whole-body insulin sensitivity or oral
glucose tolerance, and did not modulate blood lipid profile in postmenopausal patients with T2D.
Thus, the ability of cinnamon to improve long-term glycemic control has yet to be confirmed.
Recently, an updated systematic review and meta-analysis of RCTs evaluating cinnamon's effect
on glycemia and lipid levels has been published [122].In this meta-analysis, Embase and Cochrane
Central Register of Controlled Trials (CENTRAL) were searched through February 2012. Included
RCTs evaluated cinnamon compared with control in patients with type 2 diabetes and reported at
least one of the following: HbA1c, fasting plasma glucose, total cholesterol, low-density lipoprotein
cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), or triglycerides. Weighted mean
differences (with 95% confidence intervals) for endpoints were calculated using random-effects
models. In a meta-analysis of 10 RCTs (n = 543 patients), cinnamon doses of 120 mg/d to 6 g/d for
4 to 18 weeks reduced levels of fasting plasma glucose (-24.59 mg/dL; 95% CI, -40.52 to -8.67
mg/dL), total cholesterol (-15.60 mg/dL; 95% CI, -29.76 to -1.44 mg/dL), LDL-C (-9.42 mg/dL; 95%
CI, -17.21 to -1.63 mg/dL), and triglycerides (-29.59 mg/dL; 95% CI, -48.27 to -10.91
mg/dL). Cinnamon also increased levels of HDL-C (1.66 mg/dL; 95% CI, 1.09 to 2.24 mg/dL). No
significant effect on HbA1c levels (-0.16%; 95%, CI -0.39% to 0.02%) was seen. High degrees of
heterogeneity were present for all analyses except HDL-C (I(2) ranging from 66.5% to 94.72%).
The authors concluded that the consumption of cinnamon was associated with a statistically
significant decrease in levels of fasting plasma glucose, total cholesterol, LDL-C, and triglyceride
levels, and resulted in increased HDL-C levels. However, no significant effect on HbA1c was found.
Mormordica charantia (Bitter melon)
Mormordica charantia is reported to be the most popular plant used worldwide to treat diabetes
[90;91]. It has many names depending on the geographic location of origin: in India, where it is
18
widely used for diabetes [19], M. charantia is known as karela, bitter melon, and bitter gourd. In
other parts of the world, it is also known as wild cucumber, ampalaya, and cundeamor [17]. The
glucose-lowering activity of M. charantia (administered as both fresh juice and unripe fruit) has
been well documented in animal models of diabetes [19;123]. Compounds possessing anti-diabetic
activity include charantin and vicine [36;91;124]. In addition, other bioactive components of bitter
melon extract appear to have structural similarities to animal insulin (e.g. polypeptide-p) [123;124].
Several modes of action have been proposed to account for the anti-diabetic activity of M.
charantia including inhibition of glucose absorption in the gut, stimulation of insulin secretion, and
the stimulation of hepatic glycogen synthesis [17;123]. Four clinical trials have reported bitter
melon juice, fruit, and dried powder to have a moderate hypoglycemic effect [17;36;125]. However,
these studies were small and were not randomized or double-blind, and of insufficient quality to
recommend the use of M. charantia . When used at typical doses, 300-600 mg of juice extract or 1-
2 g of powdered leaf daily, M. charantia is generally well tolerated, although it should not be used
by children or pregnant women [17;125].
A recent assessment of four randomized controlled trials with up to three months duration and
investigating 479 subjects concluded that there is insufficient evidence regarding the effects of M.
charantia for improving glycemic control compared to placebo for T2D [126].
Gymnema sylvestre (Gurmar)
Gymnema sylvestre (also called gurmar), a woody plant that grows wild in India, has a long history
of use in Ayurvedic medicine [19]. The leaves of G. sylvestre contain glycosides and the peptide
gurmarin [90;91]. Other plant constituents include resins, gymnemic acids, saponins, stigmasterol,
quercitol, and several amino acid derivatives. A water-soluble acidic fraction called GS4 has been
used in most clinical studies (see below). Several modes of action have been proposed to account
for the anti-diabetic activity of G. sylvestre including increased glucose uptake and utilization,
increased insulin secretion, and increased -cell number [36].
There have been several small clinical studies in individuals with type 1 and T2D (reviewed in [17]).
These studies have reported that G. sylvestre decreases fasting glucose and HbA1c, lowered
insulin requirements in individuals with type 1 diabetes, and lowered the dose of anti-
hyperglycemic medications in individuals with T2D. G. sylvestre also appears to facilitate
endogenous insulin secretion, but it is not a substitute for insulin. There are no data from double-
blind, placebo-controlled studies in humans that validate the efficacy of G. sylvestre in type 1 or
19
type 2 diabetes. The extract (~400 mg daily) of G. sylvestre is well tolerated, and no significant side
effects have been reported.
A recent review of the effects of the various extracts of G. sylvestre in the regulation of
carbohydrate and lipid metabolism in both animal and clinical studies has been published [127].
Nothing in this paper changes the original evaluation of this ingredient.
Opuntia (fuliginosa, streptacantha) (Prickly pear cactus; Nopal)
Nopal, a member of the Opuntia genus, is widely used in Mexico as a treatment for glucose control
[128]. It grows in arid regions throughout the Western hemisphere, and is known in the United
States as prickly pear cactus. This plant produces both a vegetable, called nopal, and a red egg-
shaped fruit called tuna. Nopal is a common component of every day foods including soups,
salads, sandwiches, and blended in drinks. When used for glucose control, nopal is prepared as a
food, and is available as in bulk, dried powder form or in capsules. The glucose-lowering activity of
nopal is likely due to its very high soluble fiber and pectin content [90;91;129], although its ability to
reduce fasting glucose is suggestive of additional modes of action [128].
The results of most human studies of this plant have been reported in Spanish-language journals
[36;128]; two studies evaluating the acute effects of nopal have been published in English by Frati
et al [130;131]. Both studies used Opuntia streptacantha Lemaire, and reported improved glycemic
control (decreased serum glucose) and improved insulin sensitivity (decreased serum insulin)
following a single-dose (500 g of broiled or grilled nopal stems) in patients with type 2 diabetes (n=
14 and n = 22). No effect was observed in healthy individuals [130], nor were any adverse effects
reported. The potential clinical efficacy of this plant warrants further study.
In 2010, a study designed to evaluate the acute and chronic effects of OpunDia (Opuntia ficus-
indica) in obese pre-diabetic men and women was published [132]. This double-blind placebo
controlled study included participants (age range of 20-50 years) randomly assigned to one of the
two groups and given a 16-week supply of either the 200 mg OpunDia (n=15), or placebo (n=14).
The acute phase of the study consisted of an oral glucose tolerance test (OGTT) with a 400 mg
bolus of OpunDia given 30 min before orally ingesting a 75 g glucose drink. Baseline and post 16-
week concentrations of glucose, insulin, hsCRP, adiponectin, proinsulin, Hb1Ac, cholesterol, and a
comprehensive metabolic panel were collected along with body composition. There was a
statistically significant decrease in blood glucose concentrations at the 60 (205.92+/-36.90 and
20
188.84+/-38.43 mg/dL, respectively), 90 (184.55+/-33.67 and 169.74+/-35.16 mg/dL, respectively)
and 120 min (159.24+/-17.85 and 148.89+/-24.86 mg/dL, respectively) time points with the pre-
OGTT compared to the OpunDia bolus trial. There were no between-group differences found with
the OGTT time points, area under the curve, blood chemistry variables (insulin, hsCRP,
adiponectin, proinsulin, Hb1Ac), diet analysis variables (carbohydrates, fat, protein and total kcals),
body composition variables (fat mass, fat free mass, percent body fat and total body weight), or
blood chemistry safety parameters (comprehensive metabolic panel) pre-to-post 16-week
intervention. There are no long term studies on outcomes, or cost effectiveness.
Coccinia indica and Coccinia cordifolia
Coccinia indica is a creeper plant (one that spreads by means of stems that creep) that grows
wildly in Bangladesh and in many other parts of the Indian sub-continent. Although C. indica has a
long history of use as an antidiabetic treatment in Ayurvedic medicine [19], it has not been
subjected to the number of clinical trials that have evaluated M. charantia, fenugreek, or G.
sylvestre (based on published reports). Neither the bioactive compounds nor mode of action C.
indica have been well-characterized, but there is some suggestion that a component(s) of the plant
possesses insulin-mimetic activity [36].
A double blind, placebo-controlled trial in which a preparation from the leaves of the plant was
administered to patients with uncontrolled T2D for 6 weeks [133]. Of the 16 patients who received
the experimental preparations, 10 showed significant improvement in their glucose tolerance (P <
0.001), while none out of the 16 patients in the placebo group showed improvement. Several other
studies also offered supporting evidence of the beneficial effect of this treatment (reviewed in [36]).
No adverse effects were reported. The potential clinical efficacy of this plant warrants further study.
This study aimed to evaluate the effectiveness of Coccinia cordifolia on blood glucose levels of
incident type 2 diabetic patients requiring only dietary or lifestyle modifications [134]. The study
was a double-blind, placebo-controlled, randomized trial. Sixty incident type 2 diabetic subjects
(aged 35-60 years) were recruited from St. Johns Medical College Hospital, Bangalore, India. The
subjects were randomly assigned into the placebo or experimental group and were provided with 1
g alcoholic extract of the herb for 90 days. Anthropometric, biochemical, dietary, and physical
activity assessment were carried out at baseline and were repeated at days 45 and 90 of the study.
All subjects were provided with standard dietary and physical activity advice for blood sugar
control. There was a significant decrease (P < 0.05) in the fasting, postprandial blood glucose and
21
HbA1C (~0.6%) of the experimental group compared with that of the placebo group. The fasting
and postprandial blood glucose levels of the experimental group at day 90 significantly decreased
by 16 and 18%, respectively. There were no significant changes observed in the serum lipid levels.
This study suggests that C. cordifolia extract has a potential hypoglycemic action in patients with
mild diabetes. However, further studies are needed to confirm these results and to elucidate the
mode(s) of action of Coccinia.
Panax (ginseng, japoncicus, quinquefolius, eleutherococcus)
Ginseng, a member of the plant family Aaraliaceae, has been used in traditional Chinese medicine
for thousands of years [83;88;135]. The botanical names for Asian ginseng (Chinese or Korean) is
Panax ginseng; Japanese ginseng is known as Panax japonicus; American ginseng is Panax
quinquefolius. Siberian ginseng belongs to the genus Eleutherococcus. Many therapeutic claims
have been ascribed to the use of ginseng root extract including improved vitality and immune
function, along with beneficial effects on cancer, diabetes, cardiovascular disease, and sexual
function [136]. Bioactive compounds that have been identified in ginseng species include
ginsenosides, polysaccharides, peptides, and fatty acids [90;91]. Most pharmacological actions are
attributed to the ginsenosides, a family of steroids named saponins [90;91]. A comprehensive
review of the randomized controlled trials (RCTs) evaluating ginseng extracts (mostly Panax
ginseng and Panax quinquefolius ) has been performed, and it was concluded by the authors that
there was insufficient evidence to support efficacy for any of the above indications [136]. However,
in light of the extreme compositional variability of ginsenoside concentrations reported in a
sampling of 32 studies, it is possible that the anti-hyperglycemic efficacy might be as variable as its
ginsenoside content [137;138].
Two small studies have evaluated the use of ginseng in diabetes. In a double-blind, placebo
controlled study, 36 patients with T2D were treated for 8 weeks with ginseng extract (species not
specified) at 100 (n =12) or 200 (n = 12) mg/day, or with a placebo (n =12) [139]. Ginseng (100 and
200 mg/day) but not placebo lowered fasting blood glucose by approximately 0.5-1 mmol/l (P <
0.05). Eight subjects who were given ginseng and two who were given placebo achieved normal
fasting blood glucose. In response to an oral glucose challenge, the area under the 2-h blood
glucose curve was reduced approximately 16% (P < 0.001) in the eight ginseng-treated patients
who had normalized fasting blood glucose, without any concomitant change in immunoreactive
insulin or C-peptide. The 200 mg dose improved HbA1c (~0.5% decrease; P < 0.05) and physical
activity compared to placebo. Ginseng had no effect on plasma lipids. Another small study reported
22
the acute effects of Panax quinquefolius administration (single dose on four separate occasions; 3
g/treatment) or placebo on glucose tolerance in patients with T2D (n = 9) and in non-diabetic
subjects (n = 10) [140]. In both groups, ginseng caused a significant reduction (P < 0.05) in the
area under the blood glucose curve by approximately 20% compared to placebo. The potential
clinical efficacy of this plant warrants further study using a standardized extract.
In another study, the clinical efficacy of Korean red ginseng (Panax ginseng), as assessed by
HbA1c, was not demonstrated, although its safety was acceptable.[141]. A recent review has
evaluated the efficacy and safety of American ginseng on glycemic control in patients with.T2D
[142],
Aloe vera
The dried sap of the aloe plant (aloes) is a traditional botanical remedy frequently used to treat
dermatitis, burns and to enhance wound healing [143], and one of a variety of plants used for
diabetes in India [19] and the Arabian peninsula [144]. Its ability to lower the blood glucose was
studied in 5 patients with T2D [145]. Following the ingestion of aloe (one-half a teaspoonful daily
for 4-14 weeks), fasting serum glucose level decreased in every patient from a mean of 273 ± 25
(SE) to 151 ± 23 mg/dl (P < 0.05) with no change in body weight. This glucose-lowering activity has
been confirmed in two other studies which reported that oral administration of the aloes juice (1
tablespoon twice daily) reduced fasting glucose and triglycerides in subjects with type 2 diabetes
both in the absence and presence of concomitant sulfonylurea therapy [146;147]. No adverse
effects were reported in these studies. Aloe gel also holds the potential for glucose-lowering
activity, as it contains glucomannan, a water soluble fiber that reportedly has glucose-lowering and
insulin sensitizing activities [52;148]. The potential clinical efficacy of this plant warrants further
study.
More recently, in a randomized double-blind placebo-controlled clinical trial with hyperlipidemic
(hypercholesterolemic and/or hypertriglyceridemic) patients with T2D aged 40 to 60 years not using
other anti-hyperlipidemic agents and resistant to daily intake of two 5 mg glyburide tablets and two
500 mg metformin tablets [149]. The efficacy and safety of taking aloe gel (one 300 mg capsule
every 12 hours for 2 months) combined with the aforementioned drugs in treatment of 30 patients
were evaluated and compared with the placebo group (n = 30). The aloe gel lowered fasting blood
glucose, HbA1c, total cholesterol, and LDL levels significantly without any significant effects on the
23
other blood lipid levels and liver/kidney function tests compared with the placebo at the endpoint.
No adverse effects were reported. There is insufficient data to reach a conclusion about this
product.
Allium (sativum and cepa) (Garlic)
Allium sativum (garlic) has been used as a medicinal herb by the ancient Sumarians, Egyptians,
Greeks, Chinese, Indians, and later the Italians and English [150]. The leading Indian ancient
medical text, Charaka-Samhita recommended garlic for the treatment of heart disease and arthritis
for over many centuries [150]. Compounds present in aqueous garlic extract or raw garlic
homogenate though to be the principle bioactive components include allicin (allyl 2-
propenethiosulfonate or diallyl thiosulfonate), allyl methyl thiosulfonate, 1-propenyl allyl
thiosulfonate, and γ-L-glutamyl-S-alkyl-L-cysteine.
In modern times, garlic preparations have been widely recognized as agents for prevention and
treatment of cardiovascular and other metabolic diseases, atherosclerosis, hyperlipidemia,
thrombosis, hypertension and diabetes [151-153]. Epidemiological evidence indicates an inverse
correlation between garlic consumption and the reduced risk of the development of cardiovascular
disease [154-156]. The efficacy of garlic in cardiovascular diseases has been more evident in non-
clinical models, thus prompting a variety of clinical trials [150]. Many of these trials have reported
beneficial effects of garlic on almost all cardiovascular conditions mentioned above [157]; however,
a number of studies have reported no beneficial effects, casting doubt on the reputed health
benefits of garlic. The glucose-lowering activity of garlic in humans with type 2 diabetes is not well
studied. In the studies that have evaluated garlic, the data have been conflicting [36;150]. Thus, the
role of garlic in glucose control has yet to be confirmed.
A recent study was conducted to assess the anti-hyperglycemic, lipid-lowering, anti-inflammatory,
and improving glycemic control of garlic in obese patients with T2D [158]. This was an open-label,
prospective, comparative study, conducted on 60 patients. The patients were divided into two
groups of 30 each, of either sex. Group 1 was given metformin tablets, 500 mg twice a day
(BD)/three times a day (TDS), after meals, and group 2 was given metformin tablets, 500 mg
BD/TDS, after meals, along with garlic (Allium sativum) capsules, 250 mg BD. Patients were
evaluated for fasting and postprandial blood glucose, HbA1c, serum adenosine deaminase levels
and lipid profile (serum cholesterol, high-density lipoprotein cholesterol, triglycerides and low-
density lipoprotein cholesterol) at the start of the study. Patients were followed up for 12 weeks,
24
with monitoring of fasting and postprandial blood glucose at 2 week intervals, and monitoring of the
other parameters at the end of study. Data obtained at the end of the study was statistically
analyzed using Student's t test. It was observed that both metformin alone and metformin
with garlic reduced fasting blood glucose and postprandial blood glucose significantly, with a
greater percentage reduction with metformin plus garlic; however, the change in HbA1c was not
significant. A fall in total cholesterol, triglyceride, and low-density lipoprotein and an increase in
high-density lipoprotein were more pronounced in patients treated with metformin plus garlic.
Similarly, a fall in C-reactive protein and adenosine deaminase levels was greater in patients taking
metformin with garlic than in patients taking only metformin. These promising effects of garlic
extract need to be confirmed in future clinical studies.
Traditional Chinese Medicine
A discussion of botanical interventions for T2D would not be complete without the thoughtful
consideration of Traditional Chinese Medicine. Over the centuries, Chinese herbal ‘drugs’ have
served as a primary source for the prevention and treatment of many diseases including diabetes.
Xiao-ke is a term used to refer to wasting and thirsting syndrome (T1D); the more modern term,
Tang-niao-bing, means ‘sugar urine illness’ (T2D)[159]. Unfortunately, a review of Traditional
Chinese Medicine in the context of T2D is beyond the scope of this chapter. However, a number of
excellent reviews on this subject are available, and will provide the reader with a more definitive
evaluation of this subject than what could be accomplished in this presentation [160-165]. A
systematic review of this topic concluded that the current state of the literature regarding the utility
of TCM for the treatment of T2D is inadequate [166].
25
Table 3. Major Botanicals Used for Type 2 Diabetes
Botanical Putative
Bioactives
Anti- Diabetic
Activity
Mode of
Action
Typical
Daily
Dose
Potential Side
Effects
I. batas
(Caiapo)
High-molecular
weight acid
glycoprotein
Glucose
control;
reduces HbA1c
Not well
characterized;
Possibly
increases
insulin
sensitivity
4 g of
white-skin
sweet
potato
(capsule)
None reported
T. foenum-
graecum
(Fenugreek)
Fiber, 4-
hydroxyisoleucine,
saponins,
coumarins,
alkaloids,
glycosides
Glucose
control; Anti-
hyperlipidemic
Delays gastric
emptying;
Inhibits
glucose
absorption in
gut; Enhances
insulin
secretion
2.5-15 g
(defatted
seeds)
Hypoglycemia;
Additive with
other glucose-
lowering
agents and
insulin; GI
irritation; Anti-
coagulant
C. cassia
(Cinnamon)
Methyl hydroxyl
chalcone polymer
(MHCP)
Glucose
control
Possibly
insulin
mimetic
3-6 g
(capsule)
None reported
M. charantia
(Bitter
melon)
Charantin, vicine,
mormordicine
(alkaloid),
polypeptide P
Glucose
control
Inhibits
glucose
absorption in
gut; Enhances
insulin
secretion;
increases
glucose
transport and
glycogen
synthesis
300-600
mg (juice
extract);
1.8 g
(capsule)
Hypoglycemia;
Additive with
other glucose-
lowering
agents and
insulin; GI
irritation
G. sylvestre
(Gurmar)
Gymnemic acids,
gymnemosides
Glucose
control
Inhibits
glucose
absorption in
gut; Enhances
insulin
secretion
200-600
mg
Hypoglycemia;
Additive with
other glucose-
lowering
agents and
insulin; GI
irritation
O.
streptacantha
(Nopal;
prickly pear)
Fiber, pectin Glucose
control; Anti-
hyperlipidemic
Delays gastric
emptying;
Inhibits
glucose
absorption in
gut
2.4 g None reported
(limited data)
26
C. indica Not yet
characterized
Glucose
control
Not
characterized;
possibly
insulin
mimetic
1.8 g
(powdered
leaves)
None reported
(limited data)
P.
quinquefolius
(American
ginseng)
Ginsenosides
(saponins),
polysaccharides,
peptides, fatty
acids
Glucose
control
Delays gastric
emptying;
Inhibits
glucose
absorption in
gut; Hormonal
& CNS
activity
100-200
mg
Estrogenic
effects;
Ginseng
abuse
syndrome;
Interacts with
many drugs
A. vera
(Aloe)
Fiber
(glucomannan),
aloins,
anthraquinones,
barbaloin,
polysaccharides,
salicylic acids
Glucose
control
Not
characterized;
possibly
delays gastric
emptying and
inhibits
glucose
absorption in
gut
1.2 g
(capsule)
None reported
(limited data)
A. sativum
(Garlic)
Allicin, allyl methyl
thiosulfonate, 1-
propenyl allyl
thiosulfonate, -L-
glutamyl- S-alkyl-
L- cysteine
Anti-
hyperlipidemic;
Anti-
hypertensive
Anti-
inflammatory
(Antioxidant)
600-1000
mg
GI irritation;
Anti-
coagulant;
heartburn;
garlic odor
Please see text for detailed comments on effectiveness, or lack thereof these non-botanical
interventions
Oxidative stress, resulting primarily from chronic hyperglycemia, is a major cause of the
complications of diabetes [167]. More recently, there is a growing appreciation of the role of
oxidative stress as a mediator of insulin resistance and β-cell dysfunction [168-170]. In this context,
there are a growing number of studies in humans that have reported beneficial effects of
antioxidants on various measures of abnormalities of diabetes [38;39;171;172]. In addition, it is
often reported that individuals with diabetes are deficient in one or more essential micronutrients,
and that supplementation often provides a significant improvement. This section will provide a
concise overview of those antioxidants, vitamins, minerals, and other dietary supplements
(collectively referred to here as nutraceuticals) that have received the most attention as potential
adjunct treatments for diabetes. See Table 4 for a summary of this information.
27
ANTIOXIDANTS AND VITAMINS
-Lipoic Acid
Alpha-lipoic acid [(LA), occasionally referred to as thioctic acid], is a biologically active, eight-
carbon disulfide containing a single chiral center [173]. In vivo, LA is reduced to its dithiol form,
dihydrolipoic acid, a compound that also possesses biological activity. LA is synthesized de novo in
organisms ranging from bacteria to man. In humans, it is synthesized in liver and other tissues,
where it functions as a co-factor in multi-enzyme dehydrogenase complexes, such as pyruvate
dehydrogenase (PDH) and α-ketoglutarate dehydrogenase. Thus, LA plays an essential role in
mitochondrial-specific pathways that generate energy from glucose. More recently, LA has been
shown to regulate transcription via modulation of thiol/disulfide exchange reactions on several
transcription factors including NRF2, a major protein that binds to the anti-oxidant response
element [174]. Lipoic acid also has beneficial effects on lipid metabolism, via its ability to stimulate
AMP-activated protein kinase and sirtuin 1 [175]. When used as a nutritional supplement in
humans, LA is an effective anti-oxidant, increases intracellular glutathione, has anti-inflammatory
activity, and counteracts oxidative stress. Due its established record of safety and efficacy, LA has
become one of the most widely used nutritional supplements in the world.
In Western countries, LA has been used to reduce the symptoms of peripheral diabetic neuropathy.
LA has been prescribed in Germany for over thirty years for the treatment of diabetes-induced
neuropathy [176-178]. Results from several controlled clinical studies evaluating the effects of LA
on diabetic neuropathy indicate that this compound is safe, well tolerated, and efficacious when
administered intravenously [178-181]. Other work indicates that LA is also efficacious at improving
symptoms of diabetic neuropathy when administered orally [182].
A recently published meta-analysis of fifteen clinical studies reported that treatment with LA (300-
600 mg/d, iv, for 2-4 weeks) was safe and significantly improved both nerve conduction velocity
and the symptoms of diabetic peripheral neuropathy [183]. LA also increases insulin sensitivity and
improves glucose control in a variety of clinical contexts [184-186]. Controlled release lipoic acid
has been reported to increase insulin sensitivity in women with polycystic ovary syndrome, and to
reduce plasma triglycerides [184].
Oral administration of LA (1800 mg/d) was associated with modest (~2%) but statistically significant
weight loss in patients with body mass index > 27 [187]; LA (1200 mg/d) was also associated with
28
weight loss in non-diabetic schizophrenia patients taking antihistaminic antipsychotics [188]. In
Japan, LA is prescribed for hearing impairment, Leigh syndrome, and sub-acute necrotizing
encephalopathy prior to its designation as a food supplement [189-191].
In addition to the beneficial effects of LA on diabetes-induced neuropathy, several clinical studies
have reported an improvement in insulin sensitivity and whole-body glucose metabolism in patients
with type 2 diabetes after continuous intravenous (iv) infusion of LA [173;192-194]. Investigators
have reported that a continuous infusion iv of LA substantially increases insulin-mediated glucose
disposal (~30-50%) [192;193]. Oral administration of LA (enteric-coated tablet) exerts a smaller
(~20%) but nonetheless significant effect on insulin sensitivity [195;196]. To overcome the
abbreviated half-life of LA in plasma, a controlled release formulation of LA (CRLA) has been
developed [197]. The pharmacokinetics, safety, and tolerability of CRLA were evaluated in healthy
individuals and in patients with type 2 diabetes, and this agent was found to be safe, well-tolerated,
and significantly reduced plasma fructosamine in patients with type 2 diabetes [197]. Also, non-
controlled release LA recently has been reported to increase insulin mediated glucose disposal in
patients with type 2 diabetes [198]. Controlled release lipoic acid has also been shown to increase
insulin sensitivity in women with polycystic ovary syndrome, and to reduce plasma triglycerides
[184].
29
Although the exact mechanism of action of LA is unknown, in vitro data from the laboratories of
Rudich and others have indicated that LA pretreatment maintains the intracellular level of reduced
glutathione (the major intracellular antioxidant) in the presence of oxidative stress, and blocks the
activation of serine kinases that could potentially mediate insulin resistance [199-202]. Thus, one
potential explanation for the protective effects of LA might be related to its ability to preserve the
intracellular redox balance (acting either directly or through other endogenous antioxidants such as
glutathione), thereby blocking the activation of inhibitory stress-sensitive serine kinases including
IKKβ [168]. This stress-sensitive kinase is a crucial regulator of the transcription factor nuclear
factor-κB (NF-κB), a major target of hyperglycemia, cytokines, reactive oxygen species, and
oxidative stress [203-205]. The aberrant regulation of NF-κB is associated with a number of chronic
diseases including diabetes and atherosclerosis [203;205]. The ability of LA to block the activation
of NF-κB is well established in vitro and in vivo [201;206-209]. Recent evidence has linked the
activation of NF-κB with insulin resistance [169;210]. Activation of IKKβ inhibits insulin action.
Salicylates, which inhibit IKKβ activity and block NF-κB activation [211], restore insulin sensitivity
both in vitro and in vivo [212;213].Treatment of nine patients with type 2 diabetes for two weeks
with high-dose aspirin (7 g/day) resulted in a significant reduction in hepatic glucose production
and fasting hyperglycemia, and increased insulin sensitivity [214]. The potential for toxicity
associated with such a high dose of salicylate administered chronically precludes consideration of
this agent for therapy, but the results support the rationale that IKKβ inhibition could be a useful
pharmacological approach to increase insulin sensitivity. Furthermore, LA and other agents that
interfere with the persistent activation of the NF-κB pathway appear to be promising approaches to
increase insulin sensitivity, and perhaps even as treatments for complications of diabetes in which
NF-κB activation has been implicated [178;204]. Despite its long history of safety, in very rare
cases involving genetically susceptible individuals, lipoic acid intake can be associated with acute
hypoglycemia [215]. This condition is known as insulin autoimmune syndrome or Hirata Disease.
30
L-Arginine
L-Arginine is classified as a ‘semi-essential’ amino acid utilized by all cells [216-218].
It plays a critical role in cytoplasmic and nuclear protein synthesis, biosynthesis of
other amino acids and derivatives, and in the urea cycle. In this essential biochemical
pathway, urea is synthesized from arginine to enable the body to remove excess
ammonia, which is toxic to cells. L-arginine is classified as a glucogenic amino acid
because it can be metabolized into α-ketoglutarate, and enter the citric acid cycle
(Kreb’s Cycle). In one of its most important roles, L-arginine serves as a direct
precursor for the biosynthesis of NO [219]. Although this reaction was originally
discovered to occur in endothelial cells, the generation of NO from L-arginine occurs
in a variety of other cell types including skeletal muscle [217;220;221]. NO is
produced endogenously from L-arginine in a complex reaction that is catalyzed by the
enzyme nitric oxide synthase (NOS). The other product that is formed in this reaction
is citrulline. NO serves as a second messenger to trigger blood vessel dilation and
increase blood flow. L-arginine is the only physiological substrate that the NOS
enzymes use as a nitrogen donor. Thus, under certain conditions, it may be rate
limiting for NO production.
It is well established that aging leads to the deterioration of the vasculature and increased risk for
cardiovascular disease [222-224]. Circulatory diseases account for considerable morbidity and
almost half of all deaths in people over the age of 75 years. A major abnormality of the vasculature
present in individuals with type 2 diabetes is endothelial dysfunction, or reduced blood flow
capacity. As discussed above, NO is a major regulator of the blood flow. Basal release of NO from
the vascular endothelium maintains a constant vasodilating tone. Impaired NO-mediated
vasodilatation has been described in hypertension, diabetes, cardiovascular disease, and aging
[225;226].
In atherosclerosis, the endothelium has a reduced capacity to produce NO and target cells are
relatively insensitive to it [226]. The ability of NO to cause vasodilation provides an explanation for
the mechanism of action of nitroglycerin, which has been used for over 100 years to treat patients
with angina (pain due to inadequate blood flow to the heart) [227]. NO is produced following
administration of nitroglycerin and other NO donors, such as L-arginine [227;228]. In particular, L-
arginine is a substrate for NOS, which is responsible for the endothelial production of NO.
31
Therefore, many investigators have evaluated the usefulness of L-arginine supplementation in
animals and in humans in increasing NO production and improving cardiovascular health. The
results of these studies have been summarized in several recent books [218;229] and a review
[230]. Results of oral L-arginine supplementation in hypercholesterolemic animals have
consistently shown beneficial effects. L-arginine appears to inhibit the progression of
atherosclerotic plaques and preserve endothelial function [230]. In addition, L-arginine affects other
mediators of atherosclerosis, including circulating inflammatory cells and platelets [230].
On balance, the data in humans have also been positive, although more variable [231-242]. Five of
the 17 studies showed no cardiovascular health benefit from oral L-arginine supplementation [230].
The remaining 12 studies demonstrated beneficial effects as evidenced by decreased platelet
aggregation and adhesion, decreased monocyte adhesion, or improved endothelium-dependent
vasodilation [230]. Taken together, these studies provide some evidence for the idea that treatment
with an exogenous NO donor could have a beneficial effect on cardiovascular health.
Recently, a study assessed the efficacy of long-term L-arginine (L-arg) therapy in preventing or
delaying type 2 diabetes mellitus [243]. A mono-centre, randomized, double-blind, parallel-group,
placebo-controlled, phase III trial (L-arg trial) was conducted on 144 individuals with impaired
glucose tolerance (IGT) and metabolic syndrome (MS). L-Arg/placebo was administered (6.4
g/day) on a background structured lifestyle intervention for 18 months plus a 12-month extended
follow-up period after study intervention termination. Fasting glucose levels and glucose tolerance
after oral glucose tolerance test were evaluated throughout the study. After 18 months, L-arg as
compared with placebo did not reduce the cumulative incidence of diabetes [21.4 and 20.8%,
respectively, hazard ratio (HR), 1.04; 95% confidence interval (CI), 0.58-1.86] while the cumulative
probability to become normal glucose tolerant (NGT) increased (42.4 and 22.1%, respectively, HR,
2.60; 95% CI, 1.51-4.46, p < 0.001). The higher cumulative probability to become of NGT was
maintained during the extended period in subjects previously treated with L-arg (HR, 3.21; 95% CI,
1.87-5.51; p < 0.001). At the end of the extended period, the cumulative incidence of diabetes in
subjects previously treated with L-arg was reduced as compared with placebo (27.2 and 47.1%,
respectively, HR, 0.42; 95% CI, 0.24-0.75, p < 0.05). During both periods, L-arg significantly
improved insulin sensitivity and β-cell function. These results support the consideration of L-
arginine intervention for those individuals with are classified as having the metabolic syndrome with
impaired glucose tolerance. More definitive studies are needed.
32
Vitamin C
Epidemiological evidence suggests that a high dietary intake of vitamin C, a marker of fruit and
vegetable intake, is associated with a reduced risk for the development of cardiovascular disease
[244;245]. Plasma vitamin C, fruit intake, and dietary vitamin C intake is significantly and inversely
associated with mean concentrations of C-reactive protein and tissue plasminogen activator (t-PA)
antigen, a marker of endothelial dysfunction, suggesting that vitamin C has anti-inflammatory
effects and is associated with lower endothelial dysfunction in men with no history of
cardiovascular disease or diabetes [246;247]. However, a high vitamin C intake from supplements
has been reported to be associated with an increased risk of cardiovascular disease mortality in
postmenopausal women with diabetes [60].
The normal functions of vascular endothelial tissue include regulation of vasomotor tone, inhibition
of platelet activity, and regulation of recruitment of inflammatory cells into the vasculature [248]. A
damaged endothelium (‘endothelial dysfunction’) is a key event in the development of diabetic
macroangiopathy, and is associated with the oxidative stress-mediated blunting of nitric oxide
action [226;249;250]. Endothelial dysfunction has been documented in individuals who are insulin
resistant and in those at risk for developing T2D [250-252].
The data as to whether vitamin C treatment (either acute or sub-chronic) exerts a beneficial effect
on endothelial dysfunction in individuals with T2D is conflicting. Acute treatment with vitamin C
improved endothelial function in obese subjects [253], in patients with type 1 and T2D, and in
women with gestational diabetes [254-256].
In patients with cardiovascular disease including endothelial dysfunction, both acute (single dose, 2
g) and chronic treatment with vitamin C (30 days, 500 mg/d) reverses the vasomotor defect, as
judged by increased flow-mediated dilation of the brachial artery [257;258]. All of the above studies
involved relatively small populations (< 75) and used acute treatment except one, which was for 30
days [258]. Nonetheless, the persistent finding of a beneficial effect of antioxidant treatment on
endothelial function (flow-mediated dilation) in individuals with demonstrated endothelial
dysfunction is encouraging. It is likely that these results will stimulate additional clinical studies of
larger size and longer duration to evaluate the efficacy of vitamin C and perhaps other antioxidants.
In addition to playing a major role in the etiology of diabetic macroangiopathy, endothelial
dysfunction could promote insulin resistance [251]. It is possible that oxidative stress-mediated
33
blunting of nitric oxide action indirectly affects insulin sensitivity (e.g. reduced peripheral blood flow,
increased peroxynitrite formation, others) consequently reducing insulin-stimulated glucose
transport in skeletal muscle.
Cigarette smoking impairs endothelial function, and is one of the major risk factors for
hypertension, atherosclerosis, and coronary heart disease. The effects of vitamin C (infusion) on
insulin sensitivity and endothelial function (measured by flow-mediated dilation of brachial artery;
FMD) were evaluated in smokers, non-smokers with impaired glucose tolerance, and non-smokers
with normal glucose tolerance [259]. Both insulin sensitivity and FMD were blunted in smokers and
nonsmokers with IGT, compared with controls. In smokers and in non-smokers with impaired
glucose tolerance, vitamin C significantly improved FMD, increased insulin sensitivity, and
decreased plasma thiobarbituric acid-reactive substances, an index of oxidative stress. In contrast,
vitamin C had no effect on these parameters in non-smokers with normal glucose tolerance. In
patients with coronary spastic angina and endothelial dysfunction, vitamin C infusion augmented
FMD and increased insulin sensitivity [260]. In contrast, vitamin C had no effect in healthy controls.
More recent studies have reported that vitamin C treatment significantly increased forearm
vasodilatory response to reactive hyperemia only in patients with combined T2D and
cardiovascular disease [261], and improved endothelial dysfunction and attenuated post-prandial
lipemia-induced oxidative stress in subjects with T2D [262].
To test the hypothesis that the vitamin C influences microcirculatory function in patients with T2D,
subjects were treated with 1 g of vitamin C three times a day for 2 weeks in a randomized placebo-
controlled double-blind cross-over design. Microvascular reactivity was assessed by vital
capillaroscopy and post-occlusive reactive hyperemia. High-sensitivity(hs)-CRP (C-reactive
protein), IL-6 (interleukin-6), IL-1ra (interleukin-1 receptor antagonist), and ox-LDL (oxidized low-
density lipoprotein) were analyzed. The results showed no significant change in microvascular
reactivity assessed after 2 weeks of vitamin C treatment. IL-1ra, IL-6, hs-CRP and ox-LDL did not
change significantly, neither as absolute or relative values. In conclusion, in contrast with some
studies reported previously, this study did not demonstrate an effect of continuous oral treatment
with vitamin C on microvascular reactivity assessed at the level of individual capillaries, nor any
indication of an effect on inflammatory cytokines or ox-LDL.
34
Using an excellent study design, the effects of high-dose oral vitamin C to alter endothelial
dysfunction and insulin resistance in T2D was investigated [263]. Thirty-two diabetic subjects with
low plasma vitamin C were enrolled in a randomized, double-blind, placebo-controlled study of
vitamin C (800 mg/day for 4 wk). No significant changes in fasting glucose, insulin, SI (determined
by glucose clamp), or forearm blood flow in response to ACh, SNP, or insulin were observed after
vitamin C treatment. These results indicate that that high-dose oral vitamin C therapy, resulting in
incomplete replenishment of vitamin C levels, is ineffective at improving endothelial dysfunction
and insulin resistance in T2D.
Recent work regarding the benefit of vitamin C for T2D (or prevention of cardiovascular
complications) remains conflicted. A major study reported no benefit of intervention with either
vitamin C (ascorbate, 500 mg every day), vitamin E RRR-alpha-tocopherol acetate, 600 IU every
other day), or beta-carotene (50 mg every other day) on the risk of developing T2D in women at
high risk for cardiovascular disease [264]. In contrast, epidemiological evidence suggests that
higher plasma vitamin C and, to a lesser degree fruit and vegetable intake, was associated with a
substantially decreased risk of diabetes [265]. Clearly, it is advisable, in most cases, to continue to
pursue reduced calorie diets with a high intake of fiber, fruits, and vegetables to reduce the risk for
developing type 2 diabetes and its complications.,
Coenzyme Q10
Another antioxidant reported to have beneficial effects for diabetes is coenzyme Q10. Coenzyme Q
is a vitamin-like molecule that has is frequently used in the treatment of several disorders primarily
related to suboptimal cellular energy metabolism and oxidative stress [266]. The effects of orally
administered coenzyme Q10 were evaluated in a double-blind, placebo-controlled study of 30
patients with coronary heart disease [267]. Following 8 weeks of treatment with coenzyme Q10 (60
mg twice daily), patients exhibited reduced plasma levels of glucose, insulin, (fasting and 2 hour),
and lipid peroxides (a marker of oxidative stress) compared to controls. These results indicate that
coenzyme Q10 decreased oxidative stress and improved insulin sensitivity. Additional evaluation of
coenzyme Q10 is clearly warrented.
To improve their lipid profiles, many patients with T2D are taking one of the HMG-CoA reductase
inhibitors (i.e. statin class of drugs). Statins can reduce serum levels of coenzyme Q10 by up to
40% [268;269]. The logical option is supplementation with coenzyme Q10 as a routine adjunct to
any treatment that may reduce the endogenous production of coenzyme Q10, based on a balance
of likely benefit against very small risk. This has not been evaluated.
35
In a recently published study, the effects of coenzyme Q10 versus placebo on glycemic control and
lipid profile in patients with T2D was evaluated. In this randomized, double-blind, placebo-
controlled trial, 64 type patients with T2D were randomly assigned to receive either 200 mg
coenzyme Q10 or placebo daily for 12 weeks. Fasting blood samples were obtained and fasting
plasma glucose (FPG), HbA1c, total cholesterol (TC), triglycerides (TG), LDL-C and HDL-C were
measured. At baseline, no significant differences in age, body mass index (BMI), diabetes duration,
FPG, HbA1c, TC, TG, LDL-C and HDL-C existed between two groups. Serum HbA1c
concentration decreased in the coenzyme Q10-treated group (8% ± 2.28 vs. 8.61 ± 2.47%) with no
significant effect in the placebo group. In addition, mean differences of TC and LDL-C level were
reduced between two groups (P value=0.027 and 0.039, respectively). Following intervention, no
differences were observed regarding FPG, TG and HDL-C in the coenzyme Q10-treated group.
Since this is the first report of the beneficial effects of coenzyme Q10 glycemic or lipid control, this
study requires confirmation .
36
Vitamin E
Cardiovascular disease is the leading cause of morbidity and mortality in the Western world, and
the major macrovascular complication of diabetes [270]. It is associated with increased oxidative
stress [271], and studies both in vitro and in vivo have provided the rationale for numerous
prospective clinical studies evaluating the effects of vitamin E (α-tocopherol) on diabetes and
cardiovascular events in different populations [272;273](see below). A review of these data by Jialal
and colleagues has led to the overall conclusion that four of the five major prospective trials (data
reported through 2001) have reported a beneficial effect on cardiovascular end-points, including
cardiovascular death, nonfatal myocardial infarction, ischemic stroke, peripheral vascular disease,
and others [273]. The one major study (HOPE Study [274]) that was negative for all end-points,
had three limitations [273]. It was terminated early due to the overwhelming positive effects of the
angiotensin-converting enzyme ramipril, it lacked data on the dietary intake of other antioxidants,
and only evaluated synthetic vitamin E (a mixture of tocopherols and tocotrienols) and not α-
tocopherol, the most potent and effective tocopherol.
In a study in patients with T2D evaluating the effects of vitamin E on biochemical risk factors for the
development of cardiovascular disease, vitamin E treatment significantly reduced low-density
lipoprotein oxidizability and soluble cell adhesion molecules [275]. Taken together, the evidence
suggests a beneficial effect of vitamin E in patients with pre-existing cardiovascular disease, and in
those who are at a greater risk for its development.
Oral vitamin E treatment appears to be effective in normalizing abnormalities in retinal
hemodynamic, and improving renal function in patients with type 1 diabetes of short (disease)
duration [276]. Vitamin E was beneficial in those individuals with poorest glycemic control and the
most impaired retinal blood flow [276]. In a well-controlled study, short-term (4 weeks)
supplementation of patients with T2D with persistent micro/macroalbuminuria with both vitamins E
and C significantly lowered their urinary albumin excretion rate [277]. Four months treatment of
patients with T2D with autonomic neuropathy with vitamin E improved the ratio of cardiac
sympathetic to parasympathetic tone coincident with lowering of several indices of oxidative stress
[278]. Interestingly, the study also reported a lowering of glycated hemoglobin, insulin,
norepinephrine, and the homeoststatic model assessment index, indicative of increased insulin
sensitivity and glycemic control. These data suggest that vitamin E and perhaps other antioxidant
supplementation may provide a benefit in the treatment of microvascular complications of diabetes
including diabetic retinopathy or nephropathy.
37
Initial reports of a positive effect of vitamin E on insulin action in insulin resistant patients with T2D
were published almost ten years ago [279;280]. Twenty-five patients with T2D were treated with
vitamin E (d-α-tocopherol; 900 mg/day) or placebo for three months in a double-blind, crossover
design [281]. There was a trend in the reduction of plasma glucose, along with significant
reductions in HbA1c levels (7.8 vs. 7.1), triglycerides, free fatty acids, total cholesterol, low-density
lipoprotein cholesterol, and apoprotein B [280]. The β-cell response to glucose was unaffected.
These intriguing results prompted additional evaluations by Paolisso and colleagues using a more
sensitive technique to measure insulin sensitivity, the euglycemic-hyperinsulinemic clamp.
Ten healthy subjects and 15 patients with T2D underwent an oral glucose tolerance test and
euglycemic-hyperinsulinemic clamp before and after vitamin E supplementation (900 mg/d for 4
mo) [282]. In patients with T2D, vitamin E supplementation significantly increased both whole-body
glucose disposal (i.e. insulin sensitivity) by approximately 50% and non-oxidative glucose disposal
by approximately 60%. Vitamin E also improved insulin action in the healthy subjects.
Vitamin E also improved insulin action in elderly people [283]. Twenty elderly, non-obese subjects
with normal glucose tolerance were submitted to euglycemic-hyperinsulinemic clamp in a double-
blind, crossover, and randomized study after 4 months treatment with either vitamin E (900 mg/d)
or placebo. Whole-body glucose disposal was significantly potentiated by vitamin E compared to
placebo. Furthermore, plasma vitamin E concentrations were correlated with net changes in
insulin-stimulated whole-body glucose disposal.
In a 4-week, double-blind, randomized study of vitamin E administration (600 mg/d) versus placebo
in 24 hypertensive patients, whole-body glucose disposal was measured by the euglycemic-
hyperinsulinemic clamp [284]. In hypertensive subjects, vitamin E administration significantly
increased whole-body glucose disposal, along with the ratio of reduced glutathione/oxidized
glutathione in plasma. Four months treatment of patients with T2D with cardiac autonomic
neuropathy with vitamin E lowered of glycated hemoglobin, insulin, norepinephrine, and the
homeoststatic model assessment index, indicative of increased insulin sensitivity and improved
glycemic control [278].
The results from a large number of major intervention studies have all concluded that treatment
with vitamin E is ineffective at improving glycemic control or endothelial function, altering the
development of T2D, or at preventing cardiovascular disease [57;61-63;285-288]; some studies
38
have even raised questions of its safety [62;287]. In light of these results, the use of supplemental
vitamin E (mixture or an individual isomer) for diabetes or cardiovascular health is no longer
recommended.
This conclusion is supported, to a certain extent, by a recent meta-analysis that included 50
randomized controlled clinical trials with approximately 295,000 participants, which concluded that
the efficacy of vitamin and antioxidant supplements [289] were ineffective for the prevention of
cardiovascular disease. However, recent clinical data pertaining to Vitamin E are not universally
negative. For example, Montero et al performed a systematic review on endothelial function in
individuals with T2D [290]. They searched for randomized controlled trials assessing the effects of
antioxidant vitamin E and/or C supplementation on endothelial function in T2DM subjects. They
included ten randomized controlled trials comparing antioxidant vitamin-supplemented and control
groups (overall n = 296). Post-intervention standardized mean difference (SMD) in endothelial
function did not reach statistical significance between groups (0.35; 95% confidence interval =
-0.17, 0.88; P = 0.18). In subgroup analysis, post-intervention endothelial function was significantly
improved by antioxidant vitamin supplementation in T2DM subgroups with body mass index (BMI)
</= 29.45 kg m-2 (SMD = 1.02; P < 0.05), but not in T2DM subgroups with BMI > 29.45 kg m-2
(SMD = -0.07; P = 0.70). In meta-regression, an inverse association was found between BMI and
post-intervention SMD in endothelial function (B = -0.024, P = 0.02). Prolonged antioxidant vitamin
E and/or C supplementation could be effective to improve endothelial function in non-obese T2DM
subjects. Obviously, it cannot be concluded if the benefit on endothelia function could be attributed
to vitamin E alone, or due to a combination of vitamins E and C.
As we move into the era of more customized patient treatment protocols (personalized medicine), it
is important to realize that some patients are more likely to benefit from a particular intervention
than others. For example, Suksomboon et al reported that vitamin E supplementation had not
effect at improving glycemic control in unselected patients with T2D, but that it deceased HbA1c
(~0.6%) in patients with low serum levels of vitamin E (below the typical normal range) [291].
Another example of the possible importance of patient selection in the context of vitamin E
intervention is provided by Vardi et al, who have reported that patients with type 2 diabetes
possessing the haptoglobin type 2-2 have a higher risk (odds ratio = 2.03) for cardiovascular
events, compared to patients with other haptoglobin types. This risk was reduced in patients
treated with vitamin E (odds ratio = 0.66) [292;293].
39
Niacin
Niacin (nicotinic acid) has been used for many years to reduce elevated cholesterol and
triglycerides. In addition, niacin has been shown to decrease cardiovascular events and mortality
[294]. Some degree of angiographic regression has also being shown with niacin when used with
other cholesterol medications. However, the use of niacin for the treatment of dyslipidemia-
associated T2D has been limited, due to the adverse effect of high doses on glycemic control.
Niacin is a B-vitamin (B-3), but when used in the doses necessary for blood cholesterol control, it
should be considered a drug and not a vitamin. Recently, it has been reported that niacin has the
potential ability, when given in low doses, to be well tolerated and efficacious. In this study,
treatment of individuals with dyslipidemia-associated T2D with extended-release niacin
(Niaspan™) led to significantly improved lipid levels and minimal changes in glycemic control [295].
The extended-release form was designed to circumvent the bothersome side effects of regular
niacin, such as flushing of the skin.
In this 16-week, double-blind, placebo-controlled trial, 148 patients were randomized to placebo (n
= 49) or 1000 (n = 45) or 1500 milligrams per day (n = 52) of Niaspan™. About half of the study
participants continued taking their prescribed statin drugs for cholesterol lowering during the trial,
and 81 percent continued their medications for diabetes. Dose-dependent increases in high-
density lipoprotein cholesterol levels (+19% to +24%; P < 0.05) vs. placebo for both niacin
dosages) and reductions in triglyceride levels (-13% to -28%; P < 0.05) vs. placebo for the 1500-
mg Niaspan™) were observed. Baseline and week 16 values for glycosylated hemoglobin levels
were 7.13% and 7.11%, respectively, in the placebo group; 7.28% and 7.35%, respectively, in the
1000-mg Niaspan™ group (P < 0.16 vs. placebo); and 7.2% and 7.5%, respectively, in the 1500-
mg Niaspan™ group (P < 0.048 vs placebo). Four patients discontinued participation because of
inadequate glucose control. Rates of adverse event rates other than flushing were similar for the
niacin and placebo groups. Four patients discontinued participation owing to flushing (including 1
receiving placebo). No hepatotoxic effects or myopathy were observed. The authors concluded that
low doses of Niaspan™ (1000 or 1500 mg/d) are a treatment option for dyslipidemia in patients
with T2D.
Patients with diabetic dyslipidemia are commonly treated with triglyceride-lowering fibrate drugs,
but niacin appears more effective than the fibrates for raising HDL. Since most patients with
diabetes will require lipid-lowering therapy, the use of statins to lower LDL cholesterol has become
routine therapy for the majority of patients. This study suggests that the addition of extended
40
release low-dose niacin to statin therapy could provide an additional benefit for improvement of
blood lipids and lipoproteins in patients with diabetes. However, the impact of niacin on glycemic
control in patients with T2D will still require regular monitoring.
In 2011, the Aim-High Trial was published with great fanfare and reported that among patients with
atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter
(1.81 mmol per liter), there was no incremental clinical benefit from the addition of niacin to statin
therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol
and triglyceride levels [296]. It was thought to place a dagger in the heart of those advocating
niacin therapy. However, niacin exerts many other effects that are viewed as being beneficial
and/or protective in the context of cardiovascular disease. These include its ability to reduce
lipoprotein(a), C-reactive protein, platelet-activating factor acetylhydrolase, plasminogen activator
inhibitor 1 and fibrinogen [297]. Interestingly, aside from aerobic exercise, niacin is also the most
effective intervention at raising the level of circulating adiponectin [298], Adiponectin is one of the
adipocyte-derived hormones (adipokines), and well known for its effect in improving insulin
sensitivity in liver and skeletal muscle [299]. Unlike most other adipocyte-derived hormones,
adiponectin gene expression and blood concentration are inversely associated with adiposity.
Despite the discouraging results from the Aim-High Trial, niacin therapy should not be uniformly
discarded. A recent meta-analysis evaluating the effects of niacin on cardiovascular events
identified eleven trials including 9,959 subjects [300]. The authors reported that niacin use was
associated with a significant reduction in the composite endpoints of any CVD event (OR: 0.66;
95% confidence interval [CI]: 0.49 to 0.89; p = 0.007) and major coronary heart disease event (OR:
0.75; 95% CI: 0.59 to 0.96; p = 0.02). No significant association was observed between niacin
therapy and stroke incidence (OR: 0.88; 95% CI: 0.5 to 1.54; p = 0.65). The magnitude of on-
treatment high-density lipoprotein cholesterol difference between treatment arms was not
significantly associated with the magnitude of the effect of niacin on outcomes. The authors
concluded that the consensus perspective derived from available clinical data supports that niacin
reduces CVD events and, further, that this may occur through a mechanism not reflected by
changes in high-density lipoprotein cholesterol concentration. Results from a single study should
not be used to base one’s entire judgment regarding any aspect of an intervention. In contrast, the
totality of the evidence should be considered. In the case of niacin, we agree that it should remain
on the list and be considered as a safe and effective intervention, under appropriate conditions
[301], but its value has not been verified by long term studies.
41
Resveratrol
It has long been known that the French consume a much greater amount of saturated fats in their
diet, yet suffer from a lower incidence of cardiovascular disease. This phenomenon has been
termed ‘The French Paradox’. It has been proposed that the greater amount of red wine consumed
by the French protects them against the development of cardiovascular disease [302-304]. The
intensive search for the actual molecule(s) that could be responsible for this almost miraculous
activity led researchers to a compound identified as resveratrol. Resveratrol is a polyphenolic
compound (a stillbenol) found in plants, especially red grapes and peanuts [305]. Red wine,
produced from red grapes, contains the highest amount, on a percentage basis, of resveratrol
ranging from 0.1 – 14.3 mg per liter. The more resveratrol is investigated, the more its diverse
health benefits emerge. In animals, resveratrol has been associated with anti-cancer activity,
cardioprotective activity, antioxidant and glutathione-sparing activities, anti-inflammatory activity,
anti-viral activity, and anti-neurodegenerative activity [305-307]. But without a doubt, the activities
that affords resveratrol the most notoriety, is its ability to increase lifespan and delay age-related
deterioration in a variety of experimental models [308;309]. In experiments using yeast, nematodes
(roundworms), fruit flies, and fish, resveratrol has been shown to increase mean lifespan by 18-
70%, and maximum lifespan by 15-66%. While resveratrol has not yet been shown to increase
lifespan in mammals, it has been consistently shown in mice to delay age-related diseases,
improve metabolic efficiency, including a reduction in body weight and blood glucose, and largely
mimic the biochemical and physiologic effects of caloric restriction, qualifying it, to a degree, as a
caloric restriction mimetic [310;311].
What does resveratrol do at the mechanistic level that has led to its being the most widely
recognized polyphenolic? The striking similarities of the benefits of caloric restriction and
resveratrol led researchers to evaluate the effects of resveratrol on SIRT1 activation. These
experiments have conclusively shown that resveratrol does, indeed, activate SIRT1 and its
signaling partner, PGC-1 [312-314]. While there might be (and are) other important molecular
targets of resveratrol including AMPK [315], none are more important than SIRT1 and PGC-1 . In
light of the critical roles played by SIRT1 and PGC-1 in mitochondrial biogenesis, the obvious
question is what does resveratrol do, in this regard? Treatment of mice with resveratrol significantly
increased their aerobic capacity, judged by their increased running time and oxygen consumption
in their muscles [312]. Resveratrol induced the genes for oxidative phosphorylation and
mitochondrial biogenesis, effects largely explained by the resveratrol-mediated decrease in PGC-
42
1 acetylation and an increase in PGC-1 activity. This mechanism is consistent with resveratrol
being a known activator of SIRT1, and by the lack of effect of resveratrol in cells lacking SIRT1.
Importantly, resveratrol treatment protected mice against diet-induced-obesity and insulin
resistance [313;316;317]. If there was any doubt, these results obtained with resveratrol clearly
implicate SIRT1 and PGC-1 as key regulators of energy and metabolic homeostasis.
Since 2009, there has been an ever growing number of clinical assessments of various
preparations of resveratrol in a variety of clinical contexts, including obesity [318-322], impaired
glucose tolerance [323], T2D [324;325], cardiovascular disease [319;326-329], primary
cardiovascular disease prevention [330-333], mild hypertension [321], metabolic syndrome [334],
and cancer [335]. When used in the context of the metabolic and cardiovascular diseases, all
studies except one [319] have reported beneficial effects of resveratrol on one or more clinically
meaningful outcome measures.
Table 4. Major Non-Botanical Dietary Supplements Used for Type 2 Diabetes
Botanical Anti-Diabetic
Activity
Mode of
Action
Typical
Daily Dose
Potential
Side Effects
Omega-3
PUFAs
Anti-
hyperlipidemic
PPARα,γ, ō
agonists
0.65-1.2 g
(EPA +
DHA); 2.4
g ALA
GI irritation;
halitosis
α-Lipoic
acid
Insulin
sensitizer; Anti-
neuropathy
Anti-
inflammatory
(Antioxidant)
900-1800
mg
GI irritation
Chromium Glucose
control
Enhances
insulin action
200-400
µg
Potential for
renal toxicity
(rare)
Magnesium Insulin
sensitizer;
Glucose
control; Anti-
hypertensive
Not
characterized;
Possibly
enhances
insulin action
300-400
mg; (2.5 g
used for
glucose
control)
Diarrhea
Resveratrol Insulin
sensitizer;
Glucose
control
Sirt 1
activator; Anti-
inflammatory
(Antioxidant)
100-250
mg
Allergic
dermatitis,
diarrhea, and
immune
changes
Zinc Glucose Anti- 30-80 mg GI irritation;
43
control inflammatory
(Antioxidant);
insulin
binding
metallic taste;
headache
L-Arginine Improves
endothelial
dysfunction
Nitric oxide
donor
3-6 g None
reported
Vitamin C Insulin
sensitizer;
Improves
endothelial
dysfunction
Anti-
inflammatory
(Antioxidant)
500-2000
mg
None
reported
Coenzyme
Q10
Insulin
sensitizer
Anti-
inflammatory
(Antioxidant)
100-150
mg
GI irritation
Vitamin E Insulin
sensitizer
Anti-
inflammatory
(Antioxidant)
600-900
mg
None
reported
Vanadium Insulin
sensitizer;
Glucose
control
Insulin
mimetic; Pan-
tyrosine
phosphatase
inhibitor
100-150
mg
GI irritation;
tissue
accumulation;
Uncertain
long-term
safety profile
Not
recommended
for long term
human use
CLA Anti-obesity PPAR
agonist
2-4 g GI irritation;
Increased
inflammation
and oxidative
stress
Niacin Anti-
hyperlipidemic
Anti-lipolytic;
decreases
rate of hepatic
synthesis of
VLDL and
LDL
1000-1500
mg
Impaired
glucose
tolerance;
flushing
Available as
Rx
44
MINERALS AND TRACE ELEMENTS
Chromium
Second only to calcium, chromium is very popular mineral supplement in the US, with over 10
million individual users; in 2005, retail sales of chromium picolinate-containing products totaled
over $130 million, and represent approximately 20% of the total market for chromium-containing
products. Several authors, mostly on the basis of small studies of short duration, have suggested
dietary trivalent chromium supplementation as an attractive option for the management of T2D and
for glycemic control in persons at high risk for T2D [267;336]. Thus, chromium has emerged as the
most widely used dietary supplement for the treatment of T2D in the US. The link between
chromium and carbohydrate metabolism was proposed over 40 years ago, when it was identified
as a component of the biologically active ‘glucose tolerance factor’ [337]. Chromium deficiency has
been associated with decreased insulin action in both diabetic animals and humans [338-340].
Some but not all human studies have found that chromium supplementation has beneficial effects
in individuals with impaired glucose tolerance and diabetes [341-345]. Oral administration of
trivalent chromium is associated with favorable safety profile in animals and in humans [346;347].
To critically evaluate the clinical studies with chromium-treatment reported to date, a systematic
review and meta-analysis of the RCTs were performed [348]. The objective was to determine the
effect of chromium on glucose and insulin responses in healthy subjects and in individuals with
glucose intolerance or T2D. The authors identified 20 reports of RCTs assessing the effects of
chromium on glucose, insulin, or HbA1c. Their analyses summarized data on 618 participants from
the 15 trials that reported adequate data: 193 participants had T2D and 425 were in good health or
had impaired glucose tolerance. The meta-analysis showed no association between chromium and
glucose or insulin concentrations among non-diabetic subjects. A study of 155 diabetic subjects in
China reported that chromium reduced glucose and insulin concentrations [349]; the combined
data from the 38 diabetic subjects in the other studies did not. Three trials reported data on HbA1c:
one study each of persons with T2D [349], persons with impaired glucose tolerance [350], and
healthy subjects [351]. The study of diabetic subjects in China was the only one to report that
chromium significantly reduced HbA1c [349]. Thus, this meta-analysis of RCTs showed no effect of
chromium on glucose or insulin concentrations in non-diabetic subjects, and data for persons with
diabetes are inconclusive.
More recent reports suggest that the ability of chromium to improve glycemic control and/or
increase insulin sensitivity is better observed in subjects with glucose intolerance, insulin
45
resistance, type 1 diabetes, T2D, or gestational diabetes, rather than in healthy normal subjects
[352]. Furthermore, these studies suggest that the form of chromium influences the study results,
and that the picolinate form provides greater efficacy [353]. Absorption and bioavailability studies of
the various forms of commercially available chromium have shown that chromium picolinate is
more readily absorbed and is more bioavailable than the other forms of chromium that have been
clinically tested in subjects with diabetes [354;355]. This may account for some of the disparity
seen in the glycemic response observed in the clinical studies conducted to date.
In contrast to the results reported by others [345;352], a recent study has found that chromium
picolinate (500 and 1000 μg daily for 6 months) was ineffective at reducing HbA1c in obese, poorly-
controlled, insulin-dependent individuals with T2D [342]. Possibilities to explain this contrasting
result are the limited statistical power to detect a significant change due to the small number of
subjects (n = 17 for placebo group; n = 14 for 500 μg group; n = 15 for 1000 μg group), greater
degree of obesity (and insulin resistance) at baseline (BMI = 33-35 kg/m2), and the severity of
diabetes control at baseline (HbA1c = 9.4-9.7%). Furthermore, these subjects were unable to
achieve adequate glycemic control even with anti-hyperglycemic medication, and required a very
high dose of insulin.
Although the exact mechanism of chromium action has not been definitively established, data from
a recent in vivo study suggest that chromium might exhibit its insulin sensitizing effect by reducing
the content and activity of the tyrosine phosphatase PTP-1B [356]. PTP-1B has long been
implicated in the regulation of insulin receptor tyrosine phosphorylation and tyrosine kinase activity
[357], and has been validated as a bona fide pharmacological target for increasing insulin
sensitivity [117;358-361]. In animals, small molecules that inhibit PTP-1B increase insulin
sensitivity and lower plasma glucose [362-364]. Alternatively, chromium might act directly on the
insulin receptor, and increase its tyrosine kinase activity [365], as has been observed with other
small molecules [366;367].
Additional RCTs in well-characterized, at-risk populations are necessary to determine whether
chromium has any significant long term effects on glucose, insulin, and HbA1c. To this end, the
Office of Dietary Supplements (ODS), the National Center for Complementary and Alternative
Medicine (NCCAM), and the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invited basic and clinical applications to study the role of chromium as adjuvant therapy in
46
T2D and/or impaired glucose tolerance (http://grants1.nih.gov/grants/guide/pa-files/PA-01-114.html;
program announcement expired 10/1/2004).
Magnesium
Magnesium, the fourth most abundant cation in humans, is an essential mineral in human nutrition,
and is required for wide array of biological functions [368;369]. It is a cofactor in over 300
enzymatic reactions, and is important for the electrical stability of cells, maintenance of membrane
integrity, muscle contraction, nerve conduction and vascular tone. Magnesium deficiency is linked
to a number of clinical disorders including insulin resistance, T2D, hypertension, and
cardiovascular disease [368;370-376]. Epidemiological studies strongly indicate that high daily
magnesium intake is predictive of a lower risk for T2D in both men and women [375;377-379]. The
plasma magnesium level is inversely related to insulin sensitivity in adults [380-382] and obese
children [383], and parenteral magnesium supplementation improves insulin sensitivity as well as
insulin secretion in patients with T2D [384-386]. However, until recently (see below), no beneficial
effect of oral magnesium supplementation has been demonstrated on glycemic control either in
patients with type 1 or T2D. Nonetheless, RCTs in well-characterized, at-risk populations are
warranted to see whether magnesium replacement therapy will prove efficacious in the treatment
of T2D.
To this end, it has recently been reported that oral magnesium supplementation (as a solution of
magnesium chloride, MgCl2) restores serum magnesium levels, and improves insulin sensitivity
and metabolic control in patients with T2D [387]. This study was a randomized double-blind
placebo-controlled design, in which 63 subjects with decreased serum magnesium (≤ 0.74 mmol/l)
treated by glibenclamide received either 50 ml of MgCl2 solution (50 g/l) or placebo daily for 16
weeks. At the end of the study, MgCl2–treated subjects showed a significantly higher serum
magnesium concentration (0.74 ± 0.10 vs. 0.65 ± 0.07 mmol/l, P < 0.02) and lower HOMA-IR index
(3.8 ± 1.1 vs. 5.0 ± 1.3, P < 0.005), fasting glucose levels (8.0 ± 2.4 vs. 10.3 ± 2.1 mmol/l, P <
0.01), and HbA1c (8.0 ± 2.4 vs. 10.1 ± 3.3%, P < 0.04) compared to placebo-treated subjects.
Subsequently, in a smaller pilot study (n = 9), the effects of magnesium (Mg) supplementation on
patients with T2D with stable glycemic control were investigated [388]. Water from a salt lake with a
high natural Mg content (7.1%) (MAG21) was used for supplementation after dilution with distilled
water to 100mg/100mL; 300mL/day was given for 30 days. Fasting serum immunoreactive insulin
level decreased significantly, as did HOMA-IR (both P < 0.05). There was also a marked decrease
47
of the mean triglyceride level after supplementation. The patients with hypertension showed
significant reduction of systolic (P < 0.01), diastolic (P = 0.0038), and mean (P < 0.01) blood
pressure. Taken together, these results support the use of oral magnesium supplementation only in
patients with T2D who are magnesium-depleted.
Zinc
Zinc is another essential mineral in human nutrition with a wide range of biological functions. Zinc
fulfills catalytic, structural, or regulatory roles in more than 200 zinc-requiring metalloenzymes
[369]. The interaction of zinc with insulin induces conformational changes and enhances binding to
the insulin receptor [389;390]. Zinc ions possess insulin mimetic activity, perhaps through their
ability to inhibit protein tyrosine phosphatases, including PTP-1B [391]. With regard to glucose
metabolism, zinc is a co-factor of several key enzymes. Zinc is an activator of fructose-1-6-
bisphosphate aldolase, and an inhibitor of fructose-1-6-biphosphatase [392]. Zinc can also exert
antioxidant activity [393], and is a cofactor in copper/zinc superoxide dismutase, a major
antioxidant enzyme [394].
Some studies have reported zinc deficiency along with alterations in zinc metabolism in patients
with diabetes [392;393;395]. Zinc supplementation studies in patients with diabetes are few, and
have yielded contradictory results with regard to effects on glycemic control [392;395]. Interestingly,
a recent study has confirmed previous reports that diabetic patients (both Type 1 and T2D) have
significantly lower mean serum zinc levels compared with healthy controls [395], and that zinc
supplementation (30 mg/day for 12 weeks) in the patients with T2D elevated their serum zinc level
and significantly decreased HbA1c. In a 12-week randomized, double-blind placebo controlled study
(n =18 per group) designed to evaluate the effects vitamin/mineral combination therapy on indices
of nephropathy in patients with T2D, zinc (30 mg /day), when used in combination with magnesium
(200 mg/day), vitamin C (200 mg), and vitamin E (100 IU/day) decreased the level of urinary
albumin excretion (P = 0.005, respectively), without affecting urinary N-acetyl-beta-d-
glucosaminidase activity [396]. The combination also resulted in a significant decrease in fasting
serum glucose (P = 0.035) and malondialdehyde (P = 0.004)[396], along with an increase in HDL
cholesterol and apolipoprotein A1 levels (P = 0.019)[397]. While these results provide some
evidence for the beneficial effects of combination of magnesium, zinc, and vitamins C and E
supplementation on improving glomerular (but not tubular) renal function in type 2 diabetic patients,
and on metabolic control, they do not provide adequate proof of efficacy of these materials alone or
together.
48
Vanadium
Vanadium is a transition metal that can exist in several oxidation states (-1 to +5), and is widely
present in nature in the form of minerals [398]. It is also found in animals and humans, primarily as
the tetravalent vanadyl cation (VO2+) and the pentavalent vanadate (VO3). The tetravalent form is
the most common intracellular form whereas the pentavalent form predominates in extracellular
body fluids. Animals fed vanadium-deficient diets exhibited an increased rate of spontaneous
abortion, depressed milk production, decreased growth, and premature death. The nutritional
necessity in humans has not been established. The ‘average’ diet in the US supplies approximately
15-60 micrograms of vanadium daily. Foods relatively rich in vanadium include black pepper,
mushrooms, shellfish, parsley, and dill seed. Fresh fruits, vegetables, and oils contain little or no
vanadium.
In vitro and in vivo, vanadium-containing compounds exhibit insulin-mimetic activity primarily due to
their ability to inhibit tyrosine phosphatase activity [117;399-401] and activate a cytosolic tyrosine
kinase [402]. Many of the metabolic effects of insulin including the stimulation of glucose transport,
glycogen synthesis, glucose oxidation, and lipogenesis and anti-lipolysis are mimicked by
vanadate and related peroxovanadium compounds [401;403;404]. In vivo, vanadate and
peroxovanadium compounds significantly lower blood glucose in insulin-dependent and insulin-
resistant diabetic animals in the absence of overt toxicity [405-409]. The glucose-lowering effect of
vanadate is achieved without elevating serum insulin, indicating an insulin mimetic effect and, in
some cases, an insulin sensitizing effect.
In humans with T2D, several small studies of 2-4 weeks duration have indicated small but
significant beneficial effects of vanadate treatment on various indicators of glucose metabolism
[410-415]. The most common side effects were gastrointestinal disturbances: nausea, vomiting,
diarrhea, and cramps. In the study from Cusi et al [415], eleven patients with T2D were treated with
vanadyl sulfate (VS) at a higher dose (150 mg/day) and for a longer period of time (6 weeks) than
in the previous studies. Before and after treatment insulin secretion during an oral glucose
tolerance test, and hepatic glucose production (HGP) along with whole body insulin-mediated
glucose disposal were measured. Treatment significantly improved glycemic control: fasting
plasma glucose (FPG) decreased from 194 ± 16 to 155 ± 15 mg/dl, fructosamine decreased from
348 ± 26 µmol/l to 293 ± 12 µmol/l, and HbA1C decreased from 8.1 ± 0.4 to 7.6 ± 0.4% (all P < 0.01)
without any change in body weight. Subjects had an increased rate of HGP compared with non-
diabetic controls (4.1 ± 0.2 vs. 2.7 ± 0.2 mg/kg lean body mass/min; P < 0.001), which was closely
49
correlated with FPG (r = 0.56; P < 0.006). Vanadyl sulfate reduced HGP by about 20% (P < 0.01),
and the decline in HGP was correlated with the reduction in FPG (r = 0.60; P < 0.05). VS also
caused a modest increase in insulin-mediated glucose disposal (from 4.3 ± 0.4 to 5.1 ± 0.6 mg/kg
lean body mass/min; P < 0.03), although the improvement in insulin sensitivity did not correlate
with the decline in FPG after treatment (r = -0.16; P = NS). Thus, VS at a dose of 150 mg/day for 6
weeks improves hepatic and muscle insulin sensitivity in patients with T2D. The glucose-lowering
effect of VS correlated well with the reduction in HGP, but not with insulin-mediated glucose
disposal, suggesting that liver, rather than muscle, is the primary target of VS action at therapeutic
doses.
Vanadium has a poor therapeutic index, and attempts have been made to reduce the dose of
vanadium required for therapeutic effectiveness [398]. Organic forms of vanadium, as opposed to
the inorganic VS, are appear to be safer (in animal studies), more absorbable, and able to deliver a
therapeutic effect up to 50% greater than the inorganic forms [409;416]. An ongoing goal has been
to provide vanadium with increased bioavailability, and in a form that is best able to produce the
desired biological effects [416;417]. As a result, numerous organic complexes of vanadium have
been developed including bis(maltolato)oxovanadium (BMOV), bis(cysteinamide N-
octyl)oxovanadium known as Naglivan, bis(pyrrolidine-N-carbodithioato)oxovanadium, vanadyl-
cysteine methyl ester, and bis-glycinato oxovanadium (BGOV) [409;416;418]. Other forms of
vanadium, including polyoxovanadium [419] and vanadylpicolinate complexes [420] have also
been proposed. The usefulness of these newer formulations as clinical agents for T2D remains to
be determined. Despite the encouraging results of the clinical studies published to date, the safety
of larger doses and use of vanadium salts (or related compounds) for longer periods is unknown
[421]. Thus, the use of supplemental vanadium for the management of diabetes or impaired
glucose tolerance is not recommended at this time.
FATTY ACIDS
Polyunsaturated Fatty Acids
Dietary
-3 polyunsaturated fatty acids (
-3 PUFAs) exhibit a broad array of biological activities in
health and disease, including anti-inflammatory, lipid-lowering, and the prevention of coronary heart
disease [422-427]. The most prominent dietary sources of
-3 PUFAs include fish oils abundant in
eicosapentanoic (EPA) and docosahexanoic (DHA) acids along with plants rich in -linolenic acid.
A primary mechanism of action of
-3 PUFAs is achieved by altering gene expression mediated by
the regulation of the activities or abundance of four families of transcription factors [428-431].
50
These include the peroxisome proliferator activated receptor (PPAR ), liver X receptors (,),
hepatic nuclear factor-4, and the sterol regulatory element binding proteins 1 and 2. These
transcription factors play major roles in the regulation of hepatic carbohydrate, fatty acid,
triglyceride, cholesterol and bile acid metabolism.
A large body of epidemiological and clinical trial data suggests that
-3 PUFAs play a significant
role in the prevention of coronary artery disease [424-426]. The most convincing evidence is
derived from four major intervention trials evaluating either fish meal, fish oil, or an -linolenic acid-
enriched spread on hard clinical end-points including myocardial infarction, death from coronary
heart disease, and total mortality [432-435]. In essence, these studies found that supplementation
significantly reduced cardiovascular events (cardiovascular death, non-fatal myocardial infarction
and stoke)[433-435] and total mortality [432]. The average recommended intake by an expert panel
of US nutritional scientists is 2.2 g/d of -linolenic acid and 0.65 g/d of EPA plus DHA [436], while
the British Nutrition Foundation has recommended 2.4 g/d of -linolenic acid and 1.2 g/d of EPA
plus DHA [437].
An interim report from The Japan EPA Lipid Intervention Study (JELIS) was presented at the
American Heart Association Meeting in November 2005
(http://www.americanheart.org/presenter.jhtml?identifier=3035468)[438]. Of 18,645 eligible
participants, 9,326 were given 1,800 milligrams (mg)/day of highly purified EPA capsules as add-on
therapy to a statin. The primary endpoint of the study was experiencing any one of a group of
outcomes that included sudden cardiac death, heart attack, unstable angina (sustained chest pain
due to the heart’s oxygen starvation), or undergoing procedures to reopen blocked arteries, such
as angioplasty/stents or coronary artery bypass surgery. After more than 4.5 years of follow-up, the
primary endpoint was seen in 2.8 percent of patients treated with statins plus EPA compared to 3.5
percent in the statin-only group, represents an approximate 20 percent reduction in risk EPA plus
statin treatment compared to statin treatment alone.
Conflicting results have been reported regarding the effects of fish oil supplementation on glycemic
control in those with glucose intolerance including individuals with T2D. Several early studies
reported detrimental effects [439;440], but subsequent studies with improved design have not
replicated the earlier findings [441-444]. Results from a meta-analysis of pooled data from all RCTs
in which fish oil supplementation was the only intervention in subjects with T2D was recently
published [444]. Eighteen trials including 823 subjects followed for a mean of 12 weeks were
51
included. Doses of fish oil used ranged from 3 to 18 g/day. The outcomes studied were glycemic
control and lipid levels. Meta-analysis demonstrated a statistically significant effect of fish oil on
lowering triglycerides (-0.56 mmol/l) and raising LDL cholesterol (0.21 mmol/). No statistically
significant effect was observed for fasting glucose, HbA1c, total cholesterol, or HDL cholesterol. The
triglyceride-lowering effect and the elevation in LDL cholesterol were most evident in those trials
that recruited hypertriglyceridemic subjects and used higher doses of fish oil. Thus, this meta-
analysis of RCTs showed that fish oil supplementation in T2D lowers triglycerides, raises LDL
cholesterol, and has no statistically significant effect on glycemic control. There is no evidence that
fish oil supplementation adversely effects glucose tolerance, insulin action, or insulin secretion in
non-diabetic individuals [369]. There is some evidence that fish oil may improves defects in insulin
action and prevent alterations in glucose homeostasis and the further development of T2D [445].
A recent report has shown that, in individuals with T2D but without hypertriglyceridemia, fish oil
supplementation for 9 weeks moderately increased blood glucose and decreases insulin sensitivity
[446].
Conjugated Linoleic Acid (CLA)
Conjugated linoleic acid (CLA) refers to a group of polyunsaturated fatty acids that are positional
and geometric conjugated dieonic isomers of linoleic acid [447]. The biological activity of CLA was
originally discovered due to its ability to inhibit chemically induced carcinogenesis in rodents
[448;449]. Subsequently, numerous health benefits have been attributed to CLA including activity
as an anti-obesogenic, anti-diabetogenic, and anti-atherosclerotic agent [450;451]. The major
isomers of CLA are the cis-9,trans-11 and the trans-10, cis-12, with their biological activities being
isomer-specific [447]. The major dietary sources of CLA are meat and dairy products. CLA
concentrations in dairy products typically range from 2.8 to 7.0 mg/g fat (frozen yogurt and
condensed milk, respectively), of which the cis-9,trans-11 isomer comprises ~75%-95% of the total
CLA [451]. CLA concentrations in meat typically range from 0.6 to 5.8 mg/g fat (pork and lamb,
respectively), of which the cis-9,trans-11 isomer comprises ~55%-85% of the total CLA [451].
Similar to Ώ-3 PUFAs, CLA isomers are ligands and activators of PPARγ, but with an approximate
10-fold higher affinity (~140-260 nM) [452]. CLA isomers readily undergo extensive metabolism
including elongation and desaturation, yielding additional potential bioactive molecules [450].
In several animal models, CLA has been shown to reduce body fat accumulation, improve glucose
tolerance, and increase insulin sensitivity [453;454]. In individuals with T2D (n =12), plasma trans-
52
10, cis-12 but not cis-9,trans-11 CLA is inversely correlated with body weight (P < 0.05) and serum
leptin (P < 0.02) [455]. Thus, CLA supplementation has been suggested as a potential new
nutraceutical approach for obesity, a major risk factor for the development of T2D. However,
conflicting results have been reported regarding the beneficial effects of CLA supplementation on
adiposity and metabolism in humans [456-459]. In several studies, administration of CLA (1.8-4.2
g/day) for 12 weeks has been reported to decrease body fat mass (~4%; P < 0.001) in healthy
individuals [460;461] and in overweight and obese individuals [462]. There were no changes in
body weight, serum lipids, or glucose metabolism in these studies.
However, in another study, abdominally obese men (n = 60) were treated with 3.4 g/day CLA
(isomer mixture), purified trans-10, cis-12 CLA, or placebo [463]. Euglycemic-hyperinsulinemic
clamp, serum hormones, lipids, and anthropometry were assessed before and after 12 weeks of
treatment. Baseline metabolic status was similar between groups. Unexpectedly, trans-10, cis-12
CLA increased insulin resistance (19%; P < 0.01) and glycemia (4%; P < 0.001) and reduced HDL
cholesterol (-4%; P < 0.01) compared with placebo. Body fat, sagittal abdominal diameter, and
weight decreased versus baseline, but the difference was not significantly different from placebo.
The CLA mixture did not change glucose metabolism, body composition, or weight compared with
placebo but lowered HDL cholesterol (-2%; P < 0.05). Trans-10, cis-12 CLA also increases markers
of oxidative stress and inflammation [464], thus revealing important isomer-specific metabolic
actions of CLA in abdominally obese men.
The detrimental effect of the CLA mixture on insulin sensitivity was confirmed by another group.
The effect of CLA supplementation on markers of glucose and insulin metabolism, lipoprotein
metabolism, and inflammatory markers of CVD in subjects with T2D [465]. The study was a
randomized, double-blind, placebo-controlled trial. Thirty-two subjects with stable, diet-controlled
type 2 diabetes received CLA (3.0 g/d; 50:50 blend of cis-9, trans-11 CLA and trans-10, cis-12
CLA) or control for 8 wk. A 3-h 75-g oral-glucose-tolerance test was performed, and fasting plasma
lipid concentrations and inflammatory markers were measured before and after the intervention.
CLA supplementation significantly increased fasting glucose concentrations (6.3%; P < 0.05) and
reduced insulin sensitivity as measured by homeostasis model assessment, oral glucose insulin
sensitivity, and the insulin sensitivity index (composite) (P = 0.05). Total HDL-cholesterol
concentrations increased by 8% (P < 0.05), which was due to a significant increase in HDL(2)-
cholesterol concentrations (P < 0.05). The ratio of LDL to HDL cholesterol was significantly reduced
(P < 0.01). CLA supplementation reduced fibrinogen concentrations (P < 0.01), but had no effect on
53
inflammatory markers of CVD. Thus, supplementation with a CLA mixture had an adverse effect on
insulin and glucose metabolism.
The effects of trans-10, cis-12 CLA supplementation on plasma proinsulin, insulin, C-peptide and
adiponectin concentrations, including their associations with change in insulin sensitivity, has also
been evaluated [466]. The study was a randomized, double-blind, placebo-controlled trial. Fifty-
seven non-diabetic abdominally obese men received either 3.4 g trans-10, cis-12 CLA, CLA-isomer
mixture, or control oil for 12 weeks. Insulin sensitivity (hyperinsulinemic-euglycemic clamp), intact
proinsulin, insulin, the proinsulin: insulin ratio, C-peptide, glucose, and adiponectin were assessed
before and after supplementation. Supplementation with trans-10, cis-12 CLA increased proinsulin
(P < 0.01), the proinsulin : insulin ratio (P < 0.05) and C-peptide concentrations (P < 0.001) in
comparison with control subjects. Adiponectin did not change significantly. The change in
proinsulin, but not the proinsulin: insulin ratio, was related to impaired insulin sensitivity (r = -0.58;
P <0.0001), independently of changes in insulin, C-peptide, glucose, adiponectin and BMI. Thus, in
obese, non-diabetic men, trans-10, cis-12 CLA induced hyperproinsulinemia that was related to
impaired insulin sensitivity, independently of changes in insulin concentrations. These results are of
clinical interest, as hyperproinsulinemia predicts diabetes and cardiovascular disease. In light of
these results, the use of supplemental CLA (mixture or an individual isomer) for the management
of obesity, impaired glucose tolerance, or diabetes is definitely not recommended.
SUMMARY AND POSSIBILITIES FOR TREATMENT
Clearly, many natural products including botanicals and other nutraceuticals have hypoglycemic,
anti-hyperglycemic, insulin sensitizing, anti-hyperlipidemic, anti-hypertensive, and anti-
inflammatory activities. There are published studies reporting the anti-diabetic activity of well-over a
thousand different botanicals and nutraceuticals. The number of those treatments evaluated in
clinical trials is approximately 100 [36]. In the vast major of these trials, the botanicals and
nutraceuticals were evaluated as an adjunct to diet and prescription medications. Fifty-eight of the
trials were controlled, and conducted in individuals with diabetes or impaired glucose tolerance. Of
these, statistically significant treatment effects were reported in 88% of trials (23 of 26) evaluating a
single botanical, and 67% of trials (18 of 27) evaluating individual vitamin or mineral supplements
(reviewed in [36]). When reported, side effects were few and generally mild (gastrointestinal
irritation and nausea).
54
However, many of the studies suffered from design flaws including small (< 10 subjects) sample
sizes, heterogeneity of subjects, and short-duration of treatment. Furthermore, there is a lack of
multiple studies for many of the individual supplements. Despite the apparent lack of side effects of
these treatments, it would be prudent to be aware of the potential for dietary supplements,
especially botanicals, to interact with a patient’s prescription medication. One of the most important
potential botanical-drug interactions is that of garlic, Trigonella, and Ginkgo biloba with non-
steroidal anti-inflammatory drugs (including aspirin) or warfarin, as these botanicals possess limited
anti-coagulant activity [102;467]. Another potential interaction of concern is one involving G. biloba,
a botanical widely used for the treatment of memory and concentration problems, confusion,
depression, anxiety, dizziness, tinnitus, and headache [468;469]. Ingestion of G. biloba extract by
patients with T2D may increase the hepatic metabolic clearance rate of not only insulin but also
hypoglycemic medications, resulting in reduced insulin-mediated glucose metabolism and elevated
blood glucose [470]. Another issue to consider with botanicals is the potential for batch-to-batch
variation due to age of the plant, geographic source, time of harvest, and method of drying and
preparation, all of which can dramatically impact the purity and potency of active ingredients. None
of the agents discussed here is recommended for use in pregnant or lactating women, or in
children. Furthermore, patients should be advised on the proper use of any alternative treatment to
avoid the risk of hypoglycemia.
That being stated, several botanical and nutraceutical agents merit consideration as complimentary
approaches for use in patients with T2D. Botanical treatments with the strongest evidence of
clinical safety and efficacy include I. batas (caiapo), T. foenum-graecum (fenugreek), and C.cassia
(cinnamon). Non-botanical nutraceutical agents with promise for improving insulin sensitivity and
glycemic control include α-lipoic acid, chromium picolinate, magnesium, and resveratrol. In
addition, there is evidence that α-lipoic acid improves the symptoms of individuals with
microvascular complications, especially neuropathy. Clearly, Ώ-3 PUFAs (EPA, DHA, α-linolenic
acid) merit strong consideration for lipid lowering, and overall cardiovascular health.
The increasing movement for the public in general and patients with diabetes (and other diseases)
to self-treat using botanicals and nutraceuticals cannot be disputed and should not be ignored.
Health care professionals are urged to increase their knowledge base in this area on an ongoing
basis. They are also urged to pro-actively query patients on their use of these agents, and record
the information obtained in the patient record. Many patients are reluctant to discuss their use of
botanicals and nutraceuticals, so it is important for health care professionals to keep an open mind
55
and be non-judgmental. Since patients cannot be expected to distinguish between the marketing
hype of manufacturers and evidence derived from credible scientific studies, health care
professionals must be positioned to provide an informed opinion and recommendation (see Table 5
for a selected list of credible sources of information on the internet).
Table 5. Credible Internet Sources for Information on Botanicals, Dietary Supplements,
and other Integrative/Functional Medicine Interventions (Selected examples)
Source Website Address Thumbnail
Sketch
American
Botanical
Council
http://abc.herbalgram.org/site/PageServer The leading
independent,
non-profit,
international
member-based
organization
providing
education using
science-based
and traditional
information to
promote the
responsible use
of herbal
medicine
American
Society of
Pharmacognosy
http://www.phcog.org Professional
/scientific
organization
dedicated to
discipline of
pharmacognosy
(the science and
study of drugs
and natural
compounds with
medicinal
properties from
natural sources)
The Cochrane
Library
http://www.thecochranelibrary.com/ An electronic
database
designed to
provide high
quality scientific
evidence
Consumer
Lab.com
http://www.consumerlab.com Independent
product review
56
site that provides
information on
the content of
nutritional
products
including dietary
supplements
(Subscription
required for
access to some
content)
Diabetes.co.uk http://www.diabetes.co.uk/alternative-
treatment/alternative-treatment.html
An extensive
clearinghouse of
diabetes-related
information
including
integrative
approaches
MD Anderson
Complementary/
Integrative
Medicine
http://www.mdanderson.org/departments/CIMER/ Website of
prestigious
cancer treatment
center
National Center
for
Complimentary
and Alternative
Medicine
http://nccam.nih.gov;
http://nccam.nih.gov/health/diabetes/
National (US)
center that
supports and
disseminates
research results
on
complementary
and alternative
medicine;
NCCAM
research report
(2005): Treating
type 2 diabetes
with dietary
supplements
Natural
Medicines
Comprehensive
Database
http://www.naturaldatabase.com An extremely
comprehensive,
scientifically-
based, and
practical
database on
natural
medicines
(Subscription
required)
57
NIH Office of
Dietary
Supplements
(ODS)
http://ods.od.nih.gov/index.aspx National (US)
center that
supports and
disseminates
research results
on dietary
supplements
National Institute
of Diabetes&
Digestive &
Kidney
Diseases:
Alternative
Therapies for
Diabetes
http://diabetes.niddk.nih.gov/
dm/pubs/alternativetherapies/index.htm
Clearinghouse
(albeit abridged)
for some
alternative
treatments for
diabetes
Quackwatch http://www.quackwatch.org/ A non-profit
corporation
whose purpose
is to combat
health-related
frauds, myths,
fads, fallacies,
and misconduct
US FDA Office of
Nutritional
Products,
Labeling, and
Dietary
Supplements
http://www.fda.gov/Food/DietarySupplements/default.htm FDA office
responsible for
developing policy
and regulations
for dietary
supplements,
medical foods,
and related
areas, as well as
for their scientific
evaluation
WebMD Health http://diabetes.webmd.com/default.htm WebMD provides
comprehensive
health
information and
tools for
managing health
care. For health
care
professionals
and their patients
58
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... Its deficiency is associated with a number of clinical disorders, including insulin resistance, type 2 diabetes, hypertension, and cardiovascular disease. Magnesium supplementation has been reported to improve insulin sensitivity in patients with T2D [25]. Among the investigated samples, PV was the richest in this metal, and its content was two-fold higher than in MA, another sample rich in Mg. ...
... It is the activator of fructose-1-6-bisphosphate aldolase and the inhibitor of fructose-1-6bisphosphatase. It can also have antioxidant activity, and is a cofactor in copper/zinc superoxide dismutase, the major antioxidant enzyme [25]. Manganese aids in glucose metabolism and is required for normal synthesis and secretion of insulin. ...
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Type 2 diabetes (T2D) is a chronic disease with a growing prevalence worldwide. In addition to the conventional therapy, many T2D patients use phytotherapeutic preparations. In the present study, chemical composition, antioxidant, and α-glucosidase inhibiting activity of traditional antidiabetics from Croatian ethnomedicine (Achillea millefolium, Artemisia absinthium, Centaurium erythraea, Morusalba, Phaseolus vulgaris, Sambucus nigra, and Salvia officinalis) were assessed. The efficacy of water and 80% ethanol as extraction solvents for bioactive constituents was compared. HPLC analysis revealed that the prepared extracts were rich in phenols, especially rutin, ferulic, and chlorogenic acid. Antiradical (against DPPH and ABTS radicals), reducing (towards Mo6+ and Fe3+ ions), and enzyme inhibiting properties were in linear correlation with the content of phenolic constituents. Ethanolic extracts, richer in phenolic substances, showed dominant efficacy in those assays. Aqueous extracts, on the other hand, were better Fe2+ ion chelators and more active in the β-carotene linoleic acid assay. Extracts from S. officinalis and A. millefolium were particularly active antioxidants and α-glucosidase inhibitors. A. absinthium, another potent α-glucosidase inhibitor, contained chromium, a mineral that promotes insulin action. The investigated plants contained significant amounts of minerals useful in management of T2D, with negligible amounts of heavy metals deeming them safe for human use.
... Pravilna ishrana uz fizičku aktivnost predstavlja osnovu nefarmakoloških mera u prevenciji i kontroli dijabetesa [1]. Uzimajući u obzir da dijabetes predstavlja zdravstveni problem rastućih razmera, postoji sve veće interesovanje ka efektima suplementacije izolovanim nutrijentima i biološki aktivnim sastojcima u okviru medicinske nutritivne terapije dijabetesa [2]. Procenjuje se da više od polovine pacijenata sa dijabetesom koristi dijetetske suplemente [3]. ...
... S druge strane, postoje dokazi da suplementacija aminokiselinom leucinom može dovesti do sveukupnog poboljšanja homeostaze glukoze [16]. Takođe, utvrđeno je da suplementacija Largininom, kao prekursorom azot-monoksida, dovodi do povećanja osetljivosti β-ćelija pankreasa i poboljšanja endotelne funkcije kod osoba sa intolerancijom glukoze i metaboličkim sindromom [2]. ...
... Many pharmaceuticals commonly used today are structurally derived from the natural compounds that are found in traditional medicinal plants. For example, the development of the antihyperglycemic drug metformin can be traced to the traditional use of Galega officinalis to treat diabetes (Evans and Bahng, 2014). Botanicals that are most frequently promoted to help manage blood glucose levels include bitter melon (Momordica charantia), fenugreek (Trigonella foenum graecum), gurmar (Gymnema sylvestre), ivy gourd (Coccinia grandis), nopal (Opuntia spp.), ginseng, Russian tarragon (Artemisia dracunculus), cinnamon (Cinnamomum cassia), psyllium (Plantago ovata), and garlic (Allium sativum) (Cefalu et al., 2008). ...
... The prickly pear cactus is traditionally used to treat diabetes in the form of a blended "shake" that is prepared from young cladodes (Becerra-Jiménez and Andrade-Cetto, 2012). Nopal is rich in highly soluble fiber and pectin, which can affect intestinal glucose uptake, thus partly explaining its hypoglycemic actions (Frati et al., 1990;Evans and Bahng, 2014). Several studies have confirmed that a total extract and a juice from the plant can have antihyperglycemic effects (Ibañez-Camacho et al., 1983;Becerra-Jiménez and Andrade-Cetto, 2012). ...
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Diabetes mellitus is a common effect of uncontrolled high blood sugar and it is associated with long-term damage, dysfunction, and failure of various organs. In the adult population, the global prevalence of diabetes has nearly doubled since 1980. Without effective prevention and management programs, the continuing significant rise in diabetes will have grave consequences on the health and lifespan of the world population, and also on the world economy. Supplements can be used to correct nutritional deficiencies or to maintain an adequate intake of certain nutrients. These are often used as treatments for diabetes, sometimes because they have lower costs, or are more accessible or “natural” compared to prescribed medications. Several vitamins, minerals, botanicals, and secondary metabolites have been reported to elicit beneficial effects in hypoglycemic actions in vivo and in vitro; however, the data remain conflicting. Many pharmaceuticals commonly used today are structurally derived from natural compounds from traditional medicinal plants. Botanicals that are most frequently used to help manage blood glucose include: bitter melon (Momordica charantia), fenugreek (Trigonella foenum graecum), gurmar (Gymnema sylvestre), ivy gourd (Coccinia indica), nopal (Opuntia spp.), ginseng, Russian tarragon (Artemisia dracunculus), cinnamon (Cinnamomum cassia), psyllium (Plantago ovata), and garlic (Allium sativum). In majority of the herbal products and secondary metabolites used in treating diabetes, the mechanisms of action involve regulation of insulin signaling pathways, translocation of GLUT-4 receptor and/or activation the PPARγ. Several flavonoids inhibit glucose absorption by inhibiting intestinal α-amylase and α-glucosidase. In-depth studies to validate the efficacies and safeties of extracts of these traditional medicinal plants are needed, and large, well designed, clinical studies need to be carried out before the use of such preparations can be recommended for treatment and/or prevention of diabetes. The main focus of this review is to describe what we know to date of the active compounds in these, along with their glucose-lowering mechanisms, which are either through insulin-mimicking activity or enhanced glucose uptake.
... This is very important for those diagnosed with human immunodeficiency virus. since EGb761 may cause a viral outbreak in patients taking efavirenz, an antiretroviral that is metabolized by CYP3A4 [107]. Clinical cases indicate interactions of EGb with anti-epileptics, aspirin, diuretics, ibuprofen, risperidone, rofecoxib, trazodone and warfarin [97, 108]. ...
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Type 2 diabetes (T2DM) is characterized by increased circulating blood glucose levels. Several therapies are available to control glucose levels. However, nutritional choices play a major role in managing diabetes. Nutritional supplements can help in reducing the side effects of medicines on the individual so, this chapter will not only discuss several nutritional choices but also available nutritional supplements to control T2DM. Keeping in mind the traditional belief that food is medicine and as therapies are often associated with deleterious side effects, this chapter will discuss alternative and herbal medicines. In addition, life style alterations with proper nutritional choices is also important and will be touched upon in this chapter.
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Most physicians recommend the American Heart Association (AHA) Step I or Step 11 diet to patients at risk for heart disease and stroke, but recent studies suggest there might be a better approach. The Mediterranean diet, which has been around for thousands of years, offers a practical, effective, and enjoyable strategy that is relatively easy to adopt and more likely to be successful over the long term than most other heart-healthy diets. In this article, Drs Curtis and O'Keefe review the current understanding and scientific evidence related to cardioprotective diets and present practical ideas for implementation.
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In the first report (Journal of Clinical Pharmacology 2000:647-654), it was shown that ingestion of 120 mg of Ginkgo biloba extract (EGb 761) daily for 3 months by normal glucose-tolerant individuals caused a significant increase in pancreatic beta -cell insulin and C-peptide response, measured as the area under the curve (AUC(0 --> 120)) during a 2-hour standard (75 g) oral glucose tolerance test (OGTT). This follow-up study was designed to determine the effect of the same Ginkgo biloba treatment on glucose-stimulated pancreatic beta -cell function in non-insulin-dependent diabetes mellitus (NIDDM) subjects. In diet-controlled subjects (fasting plasma glucose [FPG] 117 +/- 36 mg/dl; fasting plasma insulin [FPI], 29 +/- 8 muU/ml; n = 6), ingestion of Ginkgo biloba produced no significant effect on the insulin AUC(0 --> 120) (193 +/- 53 vs. 182 +/- 58 muU/ml/h, before and after ingesting Ginkgo biloba, respectively). In hyperinsulinemic NIDDM subjects taking oral hypoglycemic medications (n = 6) (FPG 143 +/- 48 mg/dl; FPI 46 +/- 13 muU/ml), ingestion of Ginkgo biloba caused blunted plasma insulin levels from 30 to 120 minutes during the OGTT, leading to a reduction of the insulin AUC(0 --> 120) (199 +/- 33 vs. 147 +/- 58 muU/ml/h, before and after Ginkgo biloba, respectively). The C-peptide levels increased, and so the AUC(0 --> 120) did not parallel the insulin AUC(0 --> 120) creating a dissimilar insulin/C-peptide ratio indicative of an enhanced hepatic extraction of insulin relative to C-peptide. Thus, in pancreatic beta -cells that are already maximally stimulated, ingestion of Ginkgo biloba may cause a reduction in plasma insulin levels. Only in NIDDM subjects with pancreatic exhaustion (FPG 152 +/- 46 mg/dl; FPI 16 +/- 8 muU/ml; n = 8), who also took oral hypoglycemic agents, did Ginkgo biloba ingestion significantly increase pancreatic beta -cell function in response to glucose loading (insulin AUC(0 --> 120) increased from 51 +/- 29 to 98 +/- 20 muU/ml/h, p < 0.0001), paralleled by a C-peptide AUC(0 --> 120) increase from 7.2 +/- 2.8 to 13.7 +/- 6.8 (p < 0.0001). Whether this increase is due to "resuscitation" of previously exhausted islets or increased activity of only the remaining functional islets is unclear. However, not even in this group did increased pancreatic beta -cell activity cause a reduction of blood glucose during the OGTT It is concluded that ingestion of Ginkgo biloba extract by an NIDDM subject may increase the hepatic metabolic clearance rate of not only insulin but also She hypoglycemic agents. The result is reduced insulin-mediated glucose metabolism and elevated blood glucose. (C) 2001 the American College of Clinical Pharmacology.