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Hannon et al. Nutrition and Diabetes (2020) 10:14
https://doi.org/10.1038/s41387-020-0117-6 Nutrition & Diabetes
REVIEW ARTICLE Open Access
Use and abuse of dietary supplements in persons
with diabetes
Bridget A. Hannon
1
, William D. Fairfield
2
, Bryan Adams
3
, Theodore Kyle
4
, Mason Crow
3
and Diana M. Thomas
3
Abstract
The dietary supplement industry has estimated sales of over $30 billion in the US and over $100 billion globally. Many
consumers believe that dietary supplements are safer and possibly more effective than drugs to treat diabetes. The
sheer volume of the literature in this space makes compiling them into one review challenging, so much so that
primarily narrative reviews currently exist. By applying the interactive database supplied by the Office of Dietary
Supplements at the National Institutes of Health, we identified the top 100 ingredients that appeared most often in
dietary supplement products. One-hundred different keyword searches using the ingredient name and the word
diabetes were performed using a program developed to automatically scrape PubMed. Each search was retained in a
separate Excel spreadsheet, which was then reviewed for inclusion or exclusion. The studies that met the inclusion
criteria were evaluated for effect of reducing and controlling diabetes. The PubMed scrape resulted in 6217 studies. For
each keyword search only the most recent 100 were retained, which refined the total to 1823 studies. Of these 425
met the screening criteria. The ingredients, fiber, selenium and zinc had the most studies associated with
improvement in diabetes. Several popular supplement ingredients (phosphorus, pantothenic acid, calcium,
magnesium, glutamine, isoleucine, tyrosine, choline, and creatine monohydrate) did not result in any studies meeting
our screening criteria. Our study demonstrates how to automate reviews to filter and collapse literature in content
areas that have an enormous volume of studies. The aggregated set of studies suggest there is little clinical evidence
for the use of dietary supplements to reduce or control diabetes.
Introduction
Dietary supplements comprise a vibrant market in the
United States (US) and around the world. Industry esti-
mates suggest that sales of such products for all indica-
tions amount to more than $30 billion in the US
1
, and
estimates for global sales exceed $100 billion
2
. Supple-
ment use remains popular among consumers, despite the
lack of evidence for many popular supplements on the
market. Consumers may use supplements in hopes of
improving or maintaining their health, to correct a dietary
deficiency, or more therapeutically for a specific health
condition.
US regulatory oversight for dietary supplements is dis-
tinctly different from the framework for pharmaceuticals
3
.
Makers of a new drug must submit evidence for safety and
efficacy to the US Food and Drug Administration (FDA)
for prior review and approval before it can be used on the
market. The same standard does not apply to dietary
supplements. Dietary supplements, by law, are not
intended to diagnose, treat, prevent, or cure any disease.
Therefore, FDA-approved evidence of safety and efficacy
for supplements is not needed prior to their appearance
on the market. Likewise, there are no regulations
regarding the validity of products claims that can be
made, with the exception that claims cannot state that a
supplement may treat, prevent, or cure a disease
4
. For
example, a supplement maker cannot claim that their
product is intended for diabetes treatment. They can,
however, claim that a product helps to maintain healthy
blood sugar levels, so long as they are not suggesting that
© The Author(s) 2020
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, whi ch permits use, sharing, adaptation, distribution and reproduction
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Correspondence: Diana M. Thomas (diana.thomas@westpoint.edu)
1
Division of Nutritional Sciences, University of Illinois at Urbana-Champaign,
Urbana, IL, USA
2
Department of Kinesiology and Community Health, University of Illinois at
Urbana-Champaign, Urbana, IL, USA
Full list of author information is available at the end of the article.
Nutrition and Diabetes
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the product can help a consumer with elevated blood
sugar. In practice, delineating these distinctions can be
very difficult to make for consumers to interpret the
potential consequences of a supplement
5
.
Another difference between dietary supplements and
pharmaceuticals is the regulation of their manufacturing.
Both drugs and supplements must be manufactured
according to good manufacturing practices (GMPs).
However, supplements must meet the different and gen-
erally lower standard for GMPs that applies to drugs
6
. The
stringent requirements for active drug ingredients do not
apply to supplements. Because a new supplement product
is not subject to FDA approval, an FDA manufacturing
inspection is not required, and the FDA does not routi-
nely analyze the content of dietary supplements.
Responsibility for enforcement regarding potentially
deceptive claims about dietary supplements falls princi-
pally to the Federal Trade Commission (FTC). But the
volume of potential violations far exceeds the capacity of
FTC to take enforcement actions
3
. Claims of potential
efficacy of dietary supplements for preventing or con-
trolling diabetes mellitus are common and may easily be
found from sources that consumers might consider to be
authoritative. For instance, Healthline lists 10 supple-
ments to help lower blood sugar
7
.
What is the evidence for supplements as a benefit for
patients with diabetes? The American Diabetes Associa-
tion Standards of Medical Care in Diabetes states that
there is insufficient evidence to support a benefit from
supplements for patients with diabetes who have no
underlying deficiencies. Thus, they are not recommended
for glycemic control
8
. Despite this, there have been several
narrative reviews highlighting the potential benefits of
various supplements for diabetes-related outcomes
9–11
.
However, many of the studies that have been reviewed
may not be of appropriate design or quality to provide
strong evidence for or against supplement use.
Examining reviews of supplements and their benefits is
challenging, because searching directly using key words,
such as “diabetes”and “dietary supplement”within pubmed.
gov or other medically related search engines results in an
unmanageable set of publications that are incomplete and
difficult to organize. In addition, the active ingredients
within a supplement serve as the basis of many studies and
would not be captured in the search results. The objective
of this review was to identify supplement ingredients
commonly used for diabetes management and evaluate the
scientific evidence supporting their use in patients with type
1 (T1D) and type 2 (T2D) diabetes mellitus.
Methods
Dietary supplement ingredient list
The Office of Dietary Supplements (ODS) at the
National Institutes of Health developed a searchable
database, the Dietary Supplement Label Database (DSLD)
available at the URL https://dsld.nlm.nih.gov/dsld/
12
. The
database houses information from approximately 76,000
dietary supplement products commercially available in
the US. Within the advanced search, we selected an
option to search “by Label Statement or Health Claims
contains”. In this we input the key word diabetes. The
ingredient list for the resulting search was downloaded as
a.csv file and retained. Code was written in the statistical
software R (RCore Team (2013)) to count the number of
times the ingredient appeared in a product.
The ingredients were sorted in descending order by the
number of times the ingredient appeared on a product
label. Spurious information that were not specific ingre-
dients, like “total calories”were removed from the list.
From the remainder of the list the top 100 ingredients
based on how often they appeared in products were
retained (see Supplemental Materials).
Web-scraping program developed to search pubmed.gov
We then used the RSelenium
13
package to create a
program in the statistical software package R (RCore
Team (2013)) to automatically collect or “scrape”infor-
mation from listings and abstracts in the PubMed data-
base pertaining to both the ingredients on our ingredient
lists and diabetes research. The program automatically
combined each ingredient in the final retained database
derived from the ODS website with “(ingredient) AND
Diabetes”when searched on PubMed, e.g. “(Potassium)
AND Diabetes.”Additional searches were not made for
diabetes comorbidities or T1D versus T2D. The program
then automated the search with these key words using
PubMed built in filters to filter articles that contained an
abstract and gathered pertinent article information from
PubMed for up to the 100 most recent articles. The
information the program scraped included the title,
author, journal, year, URL, DOI, and abstract. Addition-
ally, the program removed any redundant articles that
may have existed on PubMed. The search also allowed for
flagging of certain words in the title and abstract. The
following phrases were flagged and counted for each
ingredient: cohort, observational, randomized control trial
(RCT), meta-analysis, systematic review, clinical trial,
HbA1c, fasting glucose, and insulin. Results were auto-
matically retained in separate spreadsheets by ingredient
name.
Article screening
Two members of the research team (BAH and WDF)
screened the 100 most recent abstracts from the included
ingredients. The following information was extracted
from every article: was the study conducted in individuals
with diabetes (yes/no), was the study conducted in an
animal model (yes/no), does the study meet inclusion
Hannon et al. Nutrition and Diabetes (2020) 10:14 Page 2 of 12
Nutrition and Diabetes
criteria (yes/no). Inclusion criteria involved a study
examining the role of the individual ingredient on out-
comes related to diabetes (including glucose, insulin,
HbA1c, diabetes-related complications, etc.) in animal or
human subjects. Exclusion criteria involved studies
examining the effects of a multi-nutrient supplement or
co-nutrients, cross-sectional or observational studies,
studies relying on self-reported dietary or supplement
intake, studies that included caloric restriction, or studies
with an outcome not related to diabetes. If an abstract was
found to meet inclusion criteria, the following informa-
tion was extracted: study type (RCT, single-arm trial,
crossover, meta-analysis, narrative review, etc.), outcome,
and whether results support the use of that ingredient for
T1D or T2D. If a study did not meet inclusion criteria, the
reason for exclusion was noted.
Cross checking and discrepancy resolution
After the first pass of article screening, four members of
the research team (BAH, WDF, DMT, MWC) cross-
checked the initial abstract screen. Data extracted from
this step included confirmation that the study examines
the effect of a supplement on diabetes-related outcomes
in either a human or animal model and if a discrepancy is
present between the original screener and the cross-
checker. If there was a discrepancy identified, notes were
retained on the reason for the discrepancy. Finally, all
discrepancies were reviewed by DMT for validity. Studies
that had been flagged as a discrepancy were reviewed and
discarded or retained after cross-checking retainment
criteria.
Evidence grading
Each included study was assigned to one of the fol-
lowing evidence grades: 1: meta-analysis of human RCTs,
2: human or animal RCT, 3: human or animal single arm
trial, 4: narrative review, position statement, or case
report
14
.
Results
The Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) flow chart for article
screening is provided in Fig. 1. There were 2086 ingre-
dients on the ODS website included the word diabetes in
PRISMA 2009 Flow Diagram
Records idenfied through PubMed
web scrape
(
n =6217
)
Screening Included Eligibility Idenficaon
Records aer truncaon of 100
(n =1823)
Records screened in first review
(
n =1823
)
Records excluded
(n =1398)
Arcles assessed in cross-check
(n =425)
Arcles excluded in cross-
check
(
n = 185
)
Studies included in qualitave synthesis
(n = 240)
Fig. 1 PRISMA Flow Diagram. Article screening process depicted in the preferred reporting items for systematic reviews and meta-analyses
(PRISMA) flow chart.
Hannon et al. Nutrition and Diabetes (2020) 10:14 Page 3 of 12
Nutrition and Diabetes
their label statement or claim. From the 100 most com-
mon ingredients, there were 6,217 articles in PubMed
found in the searches from each ingredient and the key-
word diabetes (Table 1). If ingredients had greater than
100 articles, the 100 most recent were included for
screening. From the remaining 1823 abstracts, 425 were
retained for full text screening. Many studies were
excluded at this phase for evaluation of multinutrient
supplements, observational study design, or outcomes not
related to diabetes. After the 425 articles were evaluated
and discrepancies were resolved, 240 studies remained.
Common reasons for exclusion at this stage included the
use of multinutrient supplementation, reliance on self-
report dietary measures, or outcome not related to dia-
betes. The 240 included studies examined over 100 dif-
ferent diabetes-related comorbidities, including outcomes
related to insulin dynamics (secretion, production, resis-
tance, sensitivity, HOMA-IR, and HOMA-B), glucose
metabolism (postprandial, fasting, oral tolerance, two-
hour oral tolerance, glycemic response, and HbA1c), and
hepatic and pancreatic morphology and function (liver
function tests, steatosis, beta cell function, and histology).
Other studies examined outcomes related to oxidative
stress (antioxidant enzyme activity, antioxidant capacity,
endothelial dysfunction, reactive oxidative species for-
mation, glutathione activity, endoplasmic reticulum
stress, etc.) or molecular and microbial changes (expres-
sion of genes such as GLUT4,NFkB,PI3K,mTOR,TNFα,
TGFβ, and VEGF, gut microbial diversity, microbial dys-
biosis, and concentration of lipopolysaccharide binding
protein). Outcomes related to complications of chronic
hyperglycemia (advanced glycation end product forma-
tion, retinopathy, neuropathy, nephropathy, kidney func-
tion, wound healing, vascular function, immune function,
etc.) and comorbidities of diabetes (body composition,
waist circumference, blood lipid concentrations, blood
pressure, bone integrity, C-reactive protein concentra-
tions, incidence of the Metabolic Syndrome, mortality,
etc.) were also explored. A final ingredient list with
included studies are outlined below and in Table 2.
References for all included studies are available in the
Supplementary Information.
Water-soluble vitamins
Water-soluble vitamins that had relevant studies
included vitamin C
15
, folate/folic acid
6
, vitamin B12
5
,
vitamin B6
4
, biotin
4
, and niacin
3
. Meta-analyses examin-
ing vitamin C supplementation and diabetes-related out-
comes concluded that supplementation may improve
fasting blood glucose but not HbA1c in individuals with
T2D
15–17
. Findings from human and animal clinical trials
were mixed. Three meta-analyses of folate or folic acid
supplementation had conflicting findings
18–20
. Relevant
studies examining effects of B12 supplementation were
limited to individuals taking Metformin, as this drug can
deplete serum B12 levels. Human studies on both B6 and
biotin were extremely limited, with narrative reviews on
both vitamins concluding a lack of evidence for their
benefit among T2D patients
21
. One meta-analysis on
niacin supplementation was found, which concluded an
increased risk of T2D onset following supplementation
22
.
Fat-soluble vitamins
Vitamin E
22
was the only fat-soluble vitamin with
relevant studies. Included meta-analyses displayed no
benefit to measurements of glucose or insulin with the
exception of one showing improvements in HbA1C in
individuals with uncontrolled glycemia and low serum
vitamin E at baseline. Human and animal trials displayed
mixed results on fasting glucose, insulin, and markers of
inflammation. Results of human clinical trials were not
dose dependent, exhibiting variability regardless of dose.
Minerals
Minerals were the most widely studied category in this
review, accounting for 106 studies. Included minerals
were chromium
23
, potassium
1
, selenium
24
, sodium
7
, and
zinc
25
. Chromium is well studied in relation to diabetes,
and one notable review highlighted the potential asso-
ciation between chromium deficiency and hyperglycemia
and impaired glucose tolerance
26
. However, results from
supplementation trials in both humans and animals were
mixed. One study on potassium supplementation was
conducted in individuals with prediabetes and concluded
that potassium supplementation improved fasting blood
glucose despite weight gain, but no significant effects were
observed for oral glucose tolerance test or insulin
sensitivity.
Selenium accounted for 25 studies with mostly positive
results. The two meta-analyses investigated risk of dia-
betes following supplementation, but concluded no ben-
efit
24,27
. Human clinical trials found improvements in
measurements of glucose, insulin, insulin resistance, and
blood lipids, and markers of inflammation. Results from
animal trials include improvements in anti-oxidant
enzyme activity, blood glucose, and insulin sensitivity.
However, one review cites the positive correlation
between selenium and diabetic risk as well as its hyper-
glycemic effects in rats
28
.
Evidence on sodium supplementation was unsub-
stantial. No meta-analyses were included, and the only
human clinical trial found an improvement in GLP-1
expression with no improvements on glycemia, insulin, or
anthropometric measurements.
Thirty-six studies on zinc supplementation met inclusion
criteria, and thirty of those reported positive results. Three
meta-analyses found improvements in fasting glucose,
HbA1c, and insulin
29–31
.Anotherfoundimprovementsin
Hannon et al. Nutrition and Diabetes (2020) 10:14 Page 4 of 12
Nutrition and Diabetes
Table 1 Top 100 most common ingredients in the Office of Dietary Supplements database that list “diabetes”on their label or health claim.
Ingredient Number of Articles in PubMed Terms extracted from abstracts
Cohort Observational RCT Meta-analysis Systematic review Clinical trial HbA1c Fasting Glucose Insulin
Protein 2067 4 3 7 2 2 6 9 4 39
“Total Carbohydrate”493 8 5 14 12 8 20 30 11 52
Calcium 397 10 12 6 4 2 6 3 3 11
Dietary fiber 351 6 4 3 2 7 10 7 4 27
Vitamin E 244 4 4 4 2 0 9 4 4 29
Vitamin C 199 7 3 6 5 4 8 6 3 21
Chromium 184 4 0 6 5 2 8 11 7 52
Zinc 182 1 3 5 8 8 11 12 5 43
Folic acid 166 9 6 6 5 5 4 6 4 11
Magnesium 147 8 3 11 5 4 8 7 5 30
Sodium 140 2 3 3 2 2 7 3 2 19
Selenium 120 4 7 8 5 2 13 3 4 28
Potassium 91 2 2 2 1 3 4 1 1 18
Vitamin B12 88 8 3 2 0 4 7 1 2 14
Phosphorus 51 3 6 3 1 1 1 2 0 6
Vitamin B6 48 5 2 1 0 0 4 3 1 6
Trans fat 45 2 2 0 0 0 2 1 0 15
L-Tyrosine 44 1 0 1 0 1 0 2 1 25
Taurine 42 0 0 0 0 1 1 0 0 15
L-Leucine 41 1 1 0 1 1 2 0 0 23
L-Glutamine 38 0 0 1 0 0 0 3 1 12
Caffeine 28 5 0 0 0 1 0 1 0 9
Choline Bitartrate 23 0 0 0 0 0 0 0 0 4
Niacin 21 2 1 0 0 0 2 0 1 5
Biotin 17 0 0 1 1 1 3 1 1 9
Beta-Alanine 15 0 0 0 0 0 0 2 1 5
Beta-Alanine 15 0 0 0 0 0 0 2 1 5
L-Isoleucine 5 1 0 0 0 0 0 0 0 2
L-Valine 4 1 0 0 0 0 0 0 0 2
Creatine Monohydrate 3 0 0 0 1 0 1 0 0 0
“Strength Matrix”2000000000
Pantothenic acid 2 0 1 1 0 1 0 0 0 0
Caffeine Anhydrous 0 0 0 0 0 0 0 0 0 0
Agmatine Sulfate 0 0 0 0 0 0 0 0 0 0
N-Acetyl-L-Tyrosine 0 0 0 0 0 0 0 0 0 0
Creatine Nitrate 0 0 0 0 0 0 0 0 0 0
L-Citrulline Aspartate 0 0 0 0 0 0 0 0 0 0
Vinpocetine 0 0 0 0 0 0 0 0 0 0
Each ingredient was searched in PubMed using the ingredient name and supplement and506 diabetes. The terms listed above were extracted from the abstract and counted above507 using R.
RCT randomized control trial, HbA1C hemoglobin A1C.
Hannon et al. Nutrition and Diabetes (2020) 10:14 Page 5 of 12
Nutrition and Diabetes
Table 2 Summary table containing number of studies in each study grade category (Meta-analyses =Grade 1, RCT =Grade 2, Single Arm or Cross-over =Grade,
narrative review or Case Study =Grade 4), support for diabetes benefit and overall description by supplement ingredient.
Nutrient Total
studies
Meta-
analyses
RCT Single
Arm or
cross-
over
Narrative
review or
case study
Do results support the use of this
supplement for diabetes
management? (Yes, No, Mixed)
Brief summary
Human Animal
Water-soluble vitamins
Niacin 3 1 –2–– Yes (1); No (2) Meta-analysis of human RCTs concluded that niacin supplementation resulted in
increased onset of T2DM cases; animal studies examined outcomes of oxidative
stress, glucose tolerance, and insulin sensitivity, with mixed results.
Vitamin B6 4 ––3–1 Yes (2); No (1); Mixed (1) Supplementation may improve diabetic neuropathy, fasting glucose, and
diabetes-related endothelial dysfunction in mice. Narrative review of human
studies concluded no benefit.
Biotin 4 ––1–3 Yes (2); No (1); Mixed (1) In animals, biotin was only effective when combined with exercise. Narrative
review of human trials concluded that high-dose biotin may improve fasting
glucose and glucokinase function.
Folate/
Folic Acid
63 2–1–Yes (2); No (1); Mixed (3) Meta-analyses concluded conflicting findings on folic acid supplementation for
fasting glucose and HOMA-IR. Supplementation did not result in improvements in
HbA1c or homocysteine, but did improve carotid intima media thickness in adults
with MetS and decreased risk of stroke in adults with T2DM when co-administered
with ACE inhibitor.
Vitamin B12
5–1–– 4 Yes (2); No (3) B12 supplementation may be important in individuals on Metformin, as this drug
reduces serum levels of the vitamin. Experimental evidence does not support
B12 supplementation for diabetes-related outcomes.
Vitamin C 15 5 4 5 –1 Yes (6); No (3); Mixed (6) Meta-analyses concluded that supplementation may improve fasting glucose and
diastolic blood pressure, but not HbA1c, in adults with T2DM. Human clinical trials
conclude no benefit of supplementation on fasting glucose, blood lipids, or onset
of T2DM, but may improve anxiety symptoms. Findings from animal models
indicate improvements in antioxidant capacity and T lymphocyte function.
Fat-soluble vitamins
Vitamin E 22 5 8 6 1 1 Yes (12); No (8); Mixed (2) Meta-analyses found no effect on markers of glucose or insulin dynamics with the
exception of one displaying improved HbA1C in subjects with uncontrolled
glycemia at baseline and low baseline Vitamin E levels. Improvements from
human clinical trials indicated mixed findings. A meta-analysis of animal trials
displayed significant improvements in wound healing.
Hannon et al. Nutrition and Diabetes (2020) 10:14 Page 6 of 12
Nutrition and Diabetes
Table 2 continued
Nutrient Total
studies
Meta-
analyses
RCT Single
Arm or
cross-
over
Narrative
review or
case study
Do results support the use of this
supplement for diabetes
management? (Yes, No, Mixed)
Brief summary
Human Animal
Minerals
Chromium 37 6 7 21 –3 Yes (17); No (8); Mixed (12) Meta-analyses display mixed results on glucose control, HbA1C, and TG
concentrations. Human and animal trials found mixed results on HbA1C, insulin,
and oxidative stress. One meta-analysis found that chromium deficiency was
associated with impaired glucose tolerance.
Potassium 1 –1–– – Yes (1); No (0) Single trial in humans concluded improvements in fasting glucose, but not OGTT
following supplementation, despite weight gain. weight gain
Selenium 25 2 10 7 2 4 Yes (15); No (5); Mixed (5) No improvement in risk of diabetes in meta-analyses. Human clinical trials suggest
improvements in glucose, insulin, insulin resistance, blood lipids, and
inflammation. Animal trials display improvements in anti-oxidant enzyme activity,
blood glucose, and insulin sensitivity.
Sodium 7 –153 –Yes (5); No (0); Mixed (2) In one human trial, GLP-1 was improved but no other measurements related to
diabetes. Animal trials display improvements in glucose control, insulin
measurements, and body weight.
Zinc 36 4 6 14 1 10 Yes (30); No (4); Mixed (2) Meta-analyses concluded improvements in fasting glucose, HbA1c, fasting insulin,
and markers of diabetic kidney injury. Human RCTs found mixed, but mostly
positive, effects of supplementation on reducted progression to diabetes in pre-
diabetes, improvements in fasting glucose, OGTT, insulin resistance, and blood
lipids. Animal trials suggest zinc’s potential to augment metformin treatment,
other positive effects on glucose control, insulin, and oxidative stress.
Amino acids
Beta-
Alanine
1–––– 1 Yes (1); No (0) May indirectly improve T2DM complications through increases in intramuscular
carnosine concentrations.
Taurine 17 ––12 3 2 Yes (9); No (3); Mixed (6) Human crossover trials found no effect on insulin sensitivity or platelet
aggregation. Animal work indicates potential benefit for complications including
diabetic retinopathy and endothelial dysfunction, but mixed results for fasting
glucose, beta cell function, and glucose tolerance. Narrative reviews cite the
potential of taurine yet the lack of clinical trials.
Hannon et al. Nutrition and Diabetes (2020) 10:14 Page 7 of 12
Nutrition and Diabetes
Table 2 continued
Nutrient Total
studies
Meta-
analyses
RCT Single
Arm or
cross-
over
Narrative
review or
case study
Do results support the use of this
supplement for diabetes
management? (Yes, No, Mixed)
Brief summary
Human Animal
L-Leucine 18 –111–6 Yes (11); No (4); Mixed (3) Only human RCT found no benefit on improvements in HbA1C or insulin
sensitivity. Animal studies evidenced improvements in fasting glucose and OGTT,
but mixed effects on insulin resistance. Supplementation did not improve
pancreatic insulin output. Narrative reviews concluded mixed results on glucose
homeostasis.
Other
Caffeine 3 –11–1 Yes (0); No (2); Mixed (1) Human RCT in T1DM patients concluded caffeine may attenuate post-exercise
drop in glycemia, but also may result in late-onset hypoglycemia. Animal study
showed no benefit on platelet aggregation or ATP signaling.
Dietary
fiber
26 1 6 10 1 8 Yes (18); No (2); Mixed (6) Many different fiber sources were tested. Meta-analysis results show
improvements in HbA1C, HOMA-IR, and insulin levels following soluble fiber
supplementation. Human RCTs demonstrated benefits of soluble fiber on
postprandial and fasting glucose, but not intravenous glucose tolerance. Animal
RCTs examined various soluble fibers and prebiotics and demonstrated benefits in
body weight, hyperglycemia, hyperinsulinemia, and microbial diversity. Several
narrative reviews on prebiotics suggest their benefit for microbial diversity, and
improvements in glucose and insulin concentrations.
Protein 4 –11–1 Yes (2); No (1); Mixed (1) Human RCT results in mixed effects on adipokine profiles. Animal trials suggest
benefits for insulin sensitivity following beta-conglycinin supplementation; but
glucosamine supplementation induced insulin resistance. A narrative review
suggests milk proteins may improve postprandial glucose.
Trans fat 6 –1 4 1 1 Yes (2); No (1); Mixed (2) CLA supplementation impaired insulin sensitivity in men with obesity, but
improved insulin secretion in animal studies, despite other mixed results. Trans-
vaccenic acid improved insulin sensitivity in rats.
Totals 240 27 50 103 13 47
ACE angiotensin converting enzyme, ATP adenosine triphosphate, CLA conjugated linoleic acid, GLP-1 glucagon-like peptide 1, HbA1C hemoglobin A1C, HOMA-IR homeostatic model of insulin resistance, MetS Metabolic
Syndrome, OGTT oral glucose tolerance test, RCT randomized control trial, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus, TG triglycerides.
Hannon et al. Nutrition and Diabetes (2020) 10:14 Page 8 of 12
Nutrition and Diabetes
markers of diabetic kidney injury
29
. Zinc supplementation
in a trial of pre-diabetic individuals reduced progression to
diabetes along with improvements in fasting glucose, oral
glucose tolerance test (OGTT) results, insulin resistance,
and blood lipids. Other included human trials display mixed
results with many showing improvements in similar mar-
kers. One trial in streptozotocin-induced diabetic rats, zinc
displayed the potential to augment metformin’s improve-
ments on glucose control
32
. Other animal trials show
mostly positive effects of zinc supplementation on glucose
control, insulin, and oxidative stress.
Amino acids
Eighteen studies on leucine, seventeen on taurine, and
one on Beta-Alanine supplementation met inclusion cri-
teria. Only one human RCT was found for leucine sup-
plementation, and concluded no effect on glucose or
insulin sensitivity
33
. Many potential articles were excluded
for examining multiple amino acids in conjunction. Ani-
mal studies in leucine supplementation indicated poten-
tial benefits for glycemia (fasting glucose, oral glucose
tolerance) and pancreatic insulin secretion, but no effect
on β-cell development, fasting insulin, or blood lipid
concentrations. Narrative reviews highlighted the role of
leucine as a potential insulin secretagogue to improve
glucose homeostasis, but the mechanism remains
unknown. Three human crossover trials were identified
for taurine supplementation, two of which concluded no
benefit on insulin sensitivity or platelet aggregation
34,35
.
The third was conducted in patients with type 1 diabetes,
and showed benefits of supplementation for vascular
stiffness
36
. Among the 12 animal RCTs reviewed, there
were promising results for taurine supplementation on
diabetic retinopathy, endothelial dysfunction, insulin
sensitivity, and polydipsia/polyuria. There were mixed
results regarding beta cell function and glycemia. Narra-
tive reviews stated that taurine may be beneficial for
diabetes but cite a lack of clinical evidence.
Fiber, macronutrients, and caffeine
Twenty-six studies were reviewed on dietary fiber
supplementation. One meta-analysis of human RCTs
found beneficial effects of soluble fiber supplementation
on HbA1c, fasting glucose, and HOMA-IR
25
. Human
clinical trials conclude positive results following supple-
mentation of a wide range of fibers, including insoluble
fiber, galacto-oligosaccharides (GOS), chicory inulin, and
beta-glucan. Animal RCTs concluded beneficial effects of
soluble fiber supplementation (from wheat bran extract,
GOS, barley, and beta-glucan) on outcomes related to
glucose, HbA1c, and microbial diversity). There were
mixed effects of supplementation on insulin sensitivity.
Narrative reviews highlighted the potential benefits of
prebiotics on glycemic and microbial outcomes and
soluble fiber for glycemic response, insulin concentra-
tions, and body weight.
Additionally, there were six studies on trans-fat sup-
plementation, four on protein supplementation, and three
on caffeine supplementation that met inclusion criteria.
The most common trans-fat supplementation was con-
jugated linoleic acid (CLA), which negatively impacted
insulin sensitivity in prediabetic men, despite having
beneficial effects on insulin secretion in animals
23
. Trans-
vaccenic acid also improved insulin sensitivity and
secretion in animals. In humans, protein supplementation
had mixed effects on adipokine concentrations, yet
improved adiponectin and insulin concentrations in ani-
mals. One study found that glucosamine supplementation
induced insulin resistance in animals
37
. A narrative review
cited milk proteins to potentially improve postprandial
glucose, but more work is needed into the effects of iso-
lated milk proteins (whey, casein), rather than within the
dairy matrix, in order for conclusions to be made
38
.
Caffeine supplementation did not significantly affect pla-
telet aggregation of ATP signaling in animal studies. A
crossover trial investigated the effects of caffeine on post-
exercise glucose concentrations in individuals with T1D,
and found that it may contribute to late-onset hypogly-
cemia and should be used with caution
39
.
Discussion
This scoping review utilized the ODS Researcher
Database and a novel web-scraping program to sum-
marize existing evidence supporting dietary supplement
use for prevention and treatment of diabetes mellitus.
While there were several supplement ingredients that had
a larger volume of studies suggesting support of their use
(e.g. dietary fiber, selenium, and zinc), the overall results
were modest with few human RCTs or meta-analyses
(Table 2). In general, we found that most, but not all,
ingredients that are currently included in supplements for
diabetes had very little to no evidence supporting
their use.
Ingredients that had zero articles meeting our inclusion
criteria were phosphorus, pantothenic acid, calcium,
magnesium, glutamine, isoleucine, tyrosine, choline, and
creatine monohydrate. These ingredients are present in a
total of 1763 supplements in the ODS database that make
a health claim related to diabetes, despite limited evi-
dence. The ingredients with the greatest scientific evi-
dence, fiber, selenium and zinc, totaled 572 products in
the ODS database. It is evident that there is a need for
greater cohesion between scientific evidence and con-
sumption of dietary supplements.
Many studies were excluded for relying on self-reported
diet or supplement intake and associations with reduc-
tions in diabetes-related secondary symptoms or for
administering treatment as co-supplementation
17
.We
Hannon et al. Nutrition and Diabetes (2020) 10:14 Page 9 of 12
Nutrition and Diabetes
and other teams have shown the unreliability of self-
reported dietary intake, and its use can lead to the pub-
lishing of inaccurate diet-disease relationships
40,41
. In co-
supplementation, it is impossible to isolate individual
effects of one ingredient if it not examined separately. One
common co-supplementation was Vitamin C and Vitamin
E, which have been examined in a meta-analysis for their
effects on HOMA-IR but concluded no benefit. In the
case of reporting a reduction of secondary symptoms of
diabetes, such as improved glycemic control, we are
unsure if this was the primary goal of the study. It is
unclear why these secondary symptoms would be repor-
ted without reporting changes in standard measures for
presence of diabetes, such as insulin levels, fasting glu-
cose, and HbA1c. Clearly stated research questions a
statistical statement of the null and alternative hypothesis
and registration with clincialtrials.gov will eliminate these
doubts
42
.
Previous reviews on supplement use for diabetes mel-
litus have concluded mixed results. Twenty-seven meta-
analyses were identified in the current study, assessing
eight different ingredients. Supplementation of vitamin
B6, folate, vitamin C, vitamin E, chromium, and selenium
was found to have mixed or null effects on diabetes-
related outcomes in meta-analyses. Zinc and fiber were
the only two ingredients with consistent positive results in
meta-analyses.
There were many notable narrative reviews assessed in
the present study, which largely concluded a potential
benefit for a particular supplement yet acknowledged the
lack of clinical evidence to make such claims. We suspect
that the large volume of literature available in the field is
not conducive to standard systematic reviews.
Despite lack of clinical evidence, consumers will
continue to take dietary supplements for perceived
benefit regarding diabetes, thus it is important for
healthcare providers to be knowledgeable about com-
mon supplements and their potential effects. The role
of supplement use for diabetes management, and its
potential interactions with other medical treatment
approaches, have been reviewed from a pharmacy
standpoint and from that of complementary and alter-
native medicine
11
. As supplement use continues to
grow in the US, it is important for healthcare profes-
sionals to understand the evidence behind supplements
and their potential role as part of medical care. Current
supplement use in the US is around 52% of all adults,
but use increases with age and is more common among
womenthanmen
43
. Among individuals with diabetes,
theprevalenceisashighas59%, however this report is
from the 2014 NHANES cohort, and the current pre-
valence may be higher
44
. The most commonly used
supplements in this population were lycopene, vitamin
D, and vitamin B12.
This study had several strengths. The use of R and the
web scrape allowed for thousands of studies indexed in
PubMed to be searched based on inclusion of specific
keywords. This approach also decreases the potential for
human error as it relies on computer extraction of rele-
vant studies rather than manual. Using this method also
allows for a rigorous treatment of the which literature to
include by the applying the capacity to automatically
scrape abstracts. Another strength of this study design is
the broad inclusion criteria. As many included studies
were conducted in animal models, we were able to assess
the effects of supplementation on diabetes-related out-
comes in a preclinical model. This is important, as results
from animal models can still be used as background to
support a dietary supplement claim in conjunction with
results from human studies
45
. Finally, exclusion criteria
involved removing cross-sectional studies or those relying
on self-reported dietary or supplement intake. Self-report
dietary intake has been evidenced to be unreliable due to
reasons such as recall bias, misestimation of portion sizes,
and social desirability bias. To best infer causality between
supplement intake and diabetes-related health outcomes,
the decision was made to only include controlled
experimental trials.
This study is also not without limitations. Included
supplements were limited to those indexed in the ODS
DSLD. This resource is updated regularly and thoroughly
by the ODS and the National Library of Medicine, but it is
still possible that there may be relevant supplements that
were not found in the search strategy. Additionally, terms
related to diabetes (i.e., glycemic control, glucose, insulin,
blood sugar, etc.) or diabetes comorbidities were not
searched. The purpose of this review was to scope the
evidence of current products on the market for diabetes,
and not systematically review all supplements related to
glycemic control and insulin sensitivity. The effects of
individual supplements and diabetes-related outcomes
have been systematically reviewed and meta-analyzed
previously, including chromium
46,47
, magnesium
48–50
,
vitamin D
51
, and vitamin E
52
. Finally, the search for arti-
cles was limited to those indexed in PubMed. This
allowed our search to be limited to peer-reviewed articles
that are pertinent to biomedical sciences and could be
searched for pertinent keywords in the title and abstract.
However, the authors acknowledge that there may have
been potentially relevant studies that were not indexed in
PubMed.
In conclusion, there does not exist strong evidence to
support the use of many commercial supplements for
management of diabetes or its comorbidities. Even
existing support is limited due to poor study design and
uncontrolled study methods. Before recommendations
for supplement use to treat diabetes can be made, there
is a need for well-designed human clinical trials to
Hannon et al. Nutrition and Diabetes (2020) 10:14 Page 10 of 12
Nutrition and Diabetes
evaluate the role of these ingredients in diabetes-related
outcomes.
Author details
1
Division of Nutritional Sciences, University of Illinois at Urbana-Champaign,
Urbana, IL, USA.
2
Department of Kinesiology and Community Health, University
of Illinois at Urbana-Champaign, Urbana, IL, USA.
3
Department of Mathematical
Sciences, United States Military Academy, West Point, NY, USA.
4
ConscienHealth, Country Club Dr, Pittsburgh, PA, USA
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Supplementary Information accompanies this paper at (https://doi.org/
10.1038/s41387-020-0117-6).
Received: 15 October 2019 Revised: 2 March 2020 Accepted: 5 March 2020
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