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Fenugreek, A Potent Hypoglycaemic Herb Can Cause Central Hypothyroidism Via Leptin - A Threat To Diabetes Phytotherapy
Abstract
Introduction
Fenugreek (Trigonella foenum graecum), a medicinal herb with potent antihyperglycaemic and hypoglycaemic effects, is used to treat diabetes. This study is aimed to explore the interaction of fenugreek seed extract (FSE) and HPT (hypothalamic-pituitary-thyroid) axis in context of leptin secretion which have important role in normal and type-1 diabetic subjects.
Materials and Methods
FSE (confirmed to contain trigonelline, diosgenin, 4 hydroxyisoleucine) was gavaged (0.25 gm/kg body weight/day) to normal and alloxan-induced type-1 diabetic rats for 4 weeks. Expression of hypothalamic prepro-TRH (Thyrotropin releasing hormone) mRNA, serum levels of TRH, TSH (Thyroid stimulating hormone), fT3, fT4, insulin, leptin, glucose; thyroperoxidase activity and growth of thyroid gland, food intake, adiposity index were also studied
Results
FSE significantly down regulated prepro-TRH mRNA expression; decreased serum TRH, TSH, fT3, fT4 levels, and regressed thyroid gland in FSE-fed normal and diabetic rats than those observed in normal diet-fed control and diabetic rats. FSE decreased (p<0.005–0.001) adiposity index and leptin secretion, increased food intake and body weight in all FSE-fed rats.
Conclusion
FSE improved insulin secretion, decreased glucose level but impaired HPT axis in diabetic rats, indicating insulin-independent central hypothyroidism. Results suggested that the dominant signal to hypothalamus suppressing HPT axis is the fall in leptin level which i resulted from decreased adiposity index following FSE feeding. Fenugreek simultaneously having hypoglycaemic and hypothyroidal actions raises questions whether it can be safely used to treat diabetes and/or hyperthyroidism as was suggested by many workers.
... However, there was a marginal increase in levels of TSH, although within clinical range. Several studies have been conducted so far to search for the fenugreek genera with the maximum content of active ingredients (52). Although acid hydrolysis can substantially improve the yield of saponin-rich extracts from this plant, it renders subsequent development of orally administrative therapeutics challenging (53). ...
Background: Fenugreek plant (Trigonella foenum-graecum) constitutes a traditionally acclaimed herbal remedy for many human ailments including diabetes, obesity, neurodegenerative diseases, and reproductive disorders. It is also used as an effective anti-oxidative, anti-inflammatory, antibacterial, and anti-fungal agent. The seed of the plant is especially enriched in several bioactive molecules including polyphenols, saponins, alkaloids, and flavonoids and has demonstrated potential to act as an antidiabetic phytotherapeutic. A novel patented formulation (Fenfuro®) was developed in our laboratory from the fenugreek seeds which contained >45% furostanolic saponins (HPLC). Objective: A placebo-controlled clinical compliance study was designed to assess the effects of complementing Fenfuro® on a randomized group of human volunteers on antidiabetic therapy (Metformin and sulphonylurea) in controlling the glycemic index along with simultaneous safety assessment. Study methodology and trial design: In a randomized double-blind, placebo-controlled trial, 42 individuals (21 male and 21 female volunteers) in the treatment group (out of 57 enrolled) and 39 individuals (17 male and 22 female volunteers) in the placebo group (out of 47 enrolled), all on antidiabetic therapy with Metformin/Metformin with sulphonyl urea within the age group of 18–65 years were administered either 1,000 mg (500 mg × 2) (Fenfuro®) capsules or placebo over a period of 12 consecutive weeks. Fasting and postprandial glucose along with glycated hemoglobin were determined as primary outcomes to assess the antidiabetic potential of the formulation. Moreover, in order to evaluate the safety of the formulation, C-peptide and Thyroid Stimulating Hormone (TSH) levels as well as immunohematological parameters were assessed between the treatment and placebo groups at the completion of the study. Results: After 12 weeks of administration, both fasting as well as postprandial serum glucose levels decreased by 38 and 44% respectively in the treatment group. Simultaneously, a significant reduction in glycated hemoglobin by about 34.7% was also noted. The formulation did not have any adverse effect on the study subjects as there was no significant change in C- peptide level and TSH level; liver, kidney, and cardiovascular function was also found to be normal as assessed by serum levels of key immunohematological parameters. No adverse events were reported. Conclusion: This clinical compliance study re-instated and established the safety and efficacy of Fenfuro® as an effective phytotherapeutic to treat hyperglycemia.
... 34 Among its side effects, fenugreek seeds extract causes hypothyroidal effect. 35 In humans, chronic administration of fenugreek seeds to diabetic patients caused transient diarrhea and excess of flatulence, 36 dyspepsia and mild abdominal distension. 37 It was demonstrated that fenugreek extract may cause a slight stomach discomfort. ...
Fenugreek (Trigonella-foenum-graecum.L) seeds are commonly utilized in cuisine as spices, in the traditional treatment and in the prevention of various troubles. This study attempts to assess the acute and subacute toxicity of its extract in wistar rats. In the acute toxicity, single oral administration of four doses (0,05 g, 0,3 g, 2 g and 5 g /kg.bw) to wistar rats was tested and to test subacute toxicity, quotidian oral administration of fenugreek seed extract at dosages of 1, 2 and 3 g/kg.bw was used for 28 days. The results of acute toxicity did not show any deaths and no indication of intoxication was observed in the rats for 14 days following receipt of the various doses of the extract. The subacute toxicity results demonstrated that repeated administration of the extract led to a significant weight gain (p<0.05) in treated rats in comparison to control rats. Treatment of rats with fenugreek seed extract did not cause any signs of intoxication and did not affect the hematological parameters of the rats compared to control rats (p>0.05). Gross examination revealed that the appearance of vital organs was not altered and histological examination revealed steatosis and an increase in the nuclei of hepatocytes in rats given a repeated dose of 3 g /kg of fenugreek seed extract. Fenugreek seeds extract is generally tolerated by rats even at high doses but more care should be taken at chronic use.
... Mathern et al 58 postulated that galactomannan present in seeds flushes out the sugars from the body before it enters the blood stream, thus resulting in weight loss. Furthermore it has been suggested that weight loss induced by fenugreek may be due to reduction of intestinal fat absorption or inhibition of pancreatic lipase activity 59 or reducing appetite by decreasing the levels of leptin in the adipose tissue 60 . Also, it was reported that saponins present in fenugreek suppressed the appetite signals in the hypothalamus leading to reduced food intake and body weight gain 61,62 . ...
Background: Frequent consumption of western diet containing saturated fatty acids and increase risk of metabolic
syndrome (MS). Features of MS include visceral obesity, insulin resistance, dyslipidemia, cardiovascular complication
and hypertension. The aim of this study was to investigate the role of Nigella sativa and ginger in ameliorating features of
MS. Methods: Induction of MS in rats by high‐fructose high‐fat fed diet was certain after 8 weeks. Animals were
alienated into four groups: normal control, MS control group given saline, MS groups given fenugreek oil (4 ml/kg), and
omega-3 (260 mg/kg) daily for 4 weeks. Parameters chosen for assessment included effect on body weight gain, glucose,
insulin, adiponectin levels, and lipid profile. Also, peroxisome proliferator‐activated receptor‐gamma (PPARγ) protein
expressions and glucose transporter 4 (GLUT4) content were estimated. In addition, Blood pressure, heart rate, CK-MB,
and LDH were estimated. Also renal function tests and antioxidant activity were evaluated. Additionally, CRP, and
fibrinogen were determined. Results: Fenugreek oil and omega-3 caused decrease in both MS‐induced increase in body
weight and glucose. They reduced insulin level and resistance with increased adiponectin, and correction of MS‐induced
hyperlipidemia. Drugs also increased GLUT4 and PPARγ protein expression compared with MS control group.
Furthermore, both drugs caused decrease in both MS‐induced increase in blood pressure and heart rate. They reduced
creatinine, BUN, uric acid, albumin, and MDA with increased GSH, and SOD. Also, both fenugreek and omega3decreased CRP, and fibrinogen compared with MS control group. Conclusion: Fenugreek oil and omega-3ameliorate
cardiac and renal complication of MS via their antioxidant activity and increase in GLUT4 and PPARγ expression.
... Mathern et al. [38] postulated that galactomannan present in seeds flushes out the sugars from the body before it enters the blood stream, thus resulting in weight loss. Furthermore it has been suggested that weight loss induced by fenugreek may be due to reduction of intestinal fat absorption or inhibition of pancreatic lipase activity [39] or reducing appetite by decreasing the levels of leptin in the adipose tissue [40]. Also, it was reported that saponins present in fenugreek suppressed the appetite signals in the hypothalamus leading to reduced food intake and body weight gain [41,42]. ...
ABSTRACT
Current trials to the treatment of coronavirus disease 2019 should open new prospects in the search for novel drugs from
medicinal plants and other natural products. This paper provides details of some nutraceuticals that inhibit human
coronavirus entry into cells, general replication, and specific chymotrypsin-like protease (3CLpro)-mediated replication.
Many non-pharmaceutical interventions were approved by countries worldwide in the fight against the COVID-19
pandemic with adverse socioeconomic side effects, which raises the question about their differential effectiveness. We
estimate the effect of each intervention on the incidence of COVID-19. In recent years, there has been a growing interest in
nutraceuticals, which are those nutrients in foods that have beneficial effects on health. There has been extensive interest in
the antiviral properties of nutraceuticals, which are especially topical in the context of the ongoing COVID-19 pandemic.
The Prophet Mohamed may God’s prayers and peace be upon him, came with the religion and assistance to the world as he
urged what is in the benefit of the bodies and prohibited everything that spoils them, so he commanded and desired
medication. Many quranic verses in the Book of God Almighty talk about the bliss of paradise and what God has prepared
for his pious servants. Therefore, the aim of this review is to evaluate the main nutraceuticals to which antiviral roles have
been attributed (either by direct action on viruses or by modulating the immune system), with a focus on what was
mentioned in the Holy Quran and Sunnah. Furthermore, the possible use of these substances against SARS-CoV-2.
Fenugreek seed extract (FSE) is known to possess antidiabetic properties. The current study evaluated the comparative potency of 4 different components of FSE (Trigonelline, 4-Hydroxyisoleucine, Diosgenin, and Galactomannan) in amelioration of diabetes-induced hyperglycaemia; metabolic and stress disorders. FSE and the four bioactives were fed to normal and alloxan-induced type-1 diabetic rats for four weeks. Changes in pancreatic hormones, lipid profile, antioxidant enzymes, and expression of Glucose transporter-2 (GLUT-2) and Glucagon-like peptide-1 receptor (GLP-1R) were evaluated. Key findings revealed the highest levels of serum insulin and GLP-1; islet cell regeneration, increased Dipeptidyl peptidase-IV enzyme inhibition, significant recovery of GLUT-2 and GLP-1R expression, and maximum levels of low-density lipoprotein receptors (LDLR) in trigonelline fed diabetic rats. The same bioactive also caused the maximum increase in various antioxidant enzymes with decreased serum malondialdehyde (MDA) levels in diabetic rats. The 4-Hydroxyisoleucine showed antidiabetic properties either equal to or less significantly as compared to trigonelline. Diosgenin on the other hand caused maximum stimulation only in lipid metabolism whereas galactomannan couldn’t produce significant changes in any parameters over the other 3 components. The results indicated trigonelline is the most desirable component of FSE and may be used as a phytotherapeutic agent for the holistic management of type-1 diabetes.
This case report discusses a 48-year-old Ethiopian patient with Graves’ ophthalmopathy who turned to an Ethiopian folk remedy involving medicinal smoke, leading to the exacerbation of Graves’ ophthalmopathy. Her condition deteriorated, resulting in severe visual impairment, proptosis, and spontaneous corneal perforation. This resulted in bilateral severe visual loss and evisceration of one eye. The case underscores the unique challenges of treating people of traditional cultures. Potential pathophysiological mechanisms are discussed. Physicians must be vigilant about patients’ use of traditional medicine.
Since ancient times, fenugreek has been utilized as a dietary condiment as well as for its various therapeutic properties. The goal of this study is to look at the function of fenugreek in regulating obesity metabolism by providing a global picture of gene networks and pathways. The buildup of fat in adipose tissue and other internal organs is a hallmark of obesity, a long-term carbohydrate and lipid metabolic disorder. The fenugreek plant grows up to 60 cm tall, with golden-yellow rhomboidal seeds. Though the seeds of fenugreek are more well-known, the leaves and stems have also been suggested to have therapeutic properties. Various studies have shown that the secondary metabolites in the fenugreek plant are responsible for these properties. Several studies have shown that fenugreek has anti-obesity properties, making it a good plant candidate with a high prospect of being used to treat obesity. This review paper discusses the use of combinatorial analytic approaches to better understand the medicinal uses of fenugreek. Combinatorial analytical methods that use functional modulation and modelling may make it easier to come up with research strategies to fill in research gaps and find possible research niches.
Fenugreek (Trigonella foenum graecum) seed extract is a bioactive ingredient of many food supplements. Hence, there is a need for systematic assessment of the quality of published toxicological studies for its use in human health, hazard consideration, and risk assessment. The aim of the present investigation was to determine the reliability of published toxicological studies of fenugreek seed by using ToxRTool (Toxicological data reliability assessment tool). A comprehensive systematic literature search was conducted in PubMed, EMBASE, Cochrane Library, CPCI-S, ICTRP, Ovid, and Google Scholar till October 2018. Each identified study was evaluated for its quality using the ToxRTool with outcomes such as combined score, weighted score, and reliability category by three independent raters. Correlations of various criteria groups with the combined score were evaluated by Pearson correlation and Kendall rank correlation coefficient. Inter-rater consistency was measured by Cronbach's alpha coefficient. The database searches initially yielded 436 results, of which 391 (89.67%) studies were “not assignable”. The remaining 45 studies were included for quantitative analysis by ToxRTool. Based on the weighted score, 17 in-vivo, and 3 in-vitro studies were determined to be “Reliable Without Restriction” which were conducted according to international guidelines such as GLP. These studies have a significant difference (p < 0.05) for the combined and weighted score as compared to non-GLP studies. Remaining 28 in-vivo and 2 in-vitro studies were determined to be “Not Reliable.” The GLP studies conducted with “identified study material” have a significant difference (p < 0.0001) between combined and weighted score as compared to studies which used “non-identified study material”. For criteria group of ToxRTool I, III and V, the Pearson correlation with the combined score was found to be 0.875, 0.734 and 0.905, respectively and Kendall rank correlation coefficient was found to be 0.764, 0.551 and 0.752, respectively. Cronbach's alpha coefficient for combined score and weighted score were 0.920 and 0.887, respectively. In conclusion, the ToxRTool was found useful to identify seventeen toxicity studies of fenugreek seeds as “Reliable without Restrictions”. These studies showed a broad margin of safety for the standardized extract of fenugreek seeds and can form a basis for toxicological risk assessment with reasonable certainty.
Abstract Nitrate has described as an endocrine
disruptor that promotes onset of diabetes. This study
was undertaken to evaluate diabetic effect of high
nitrate intake in young and adult male rats and its
amelioration by fenugreek administration. The study
revealed significant increase in serum glucose and
blood glycosylated hemoglobin (HbA1c%), while
serum insulin and liver glycogen were decreased
among nitrate exposed animals, in particular the young
group. A significant reduction in the body weight gain
and serum thyroid hormones (T4 & T3) was also
recorded. Further reduction in serumlevels of urea and
creatinine, as well as total protein in serum, liver and
pancreas was demonstrated, with elevation in their
levels in the urine of all nitrate exposed groups.
Meanwhile, the activity of serum transaminases (ALT
and AST) was increased, with decline in their activity
in the liver tissue. In addition, an elevation in serum
total bilirubin, tissues (liver and pancreas) nitric oxide
and lipid profile, as well as liver activity of glucose-6-phosphatase was recorded. Fenugreek administration
to nitrate exposed rats was found to be effective in
alleviating hyperglycemia and other biochemical
changes characterizing nitrate-induced diabetes. So,
fenugreek can be considered to possess potent activity
against onset of nitrate induced-diabetes.
In experimental studies, several parameters, such as body weight, body mass index, adiposity index, and dual-energy X-ray absorptiometry, have commonly been used to demonstrate increased adiposity and investigate the mechanisms underlying obesity and sedentary lifestyles. However, these investigations have not classified the degree of adiposity nor defined adiposity categories for rats, such as normal, overweight, and obese. The aim of the study was to characterize the degree of adiposity in rats fed a high-fat diet using cluster analysis and to create adiposity intervals in an experimental model of obesity. Thirty-day-old male Wistar rats were fed a normal (n=41) or a high-fat (n=43) diet for 15 weeks. Obesity was defined based on the adiposity index; and the degree of adiposity was evaluated using cluster analysis. Cluster analysis allowed the rats to be classified into two groups (overweight and obese). The obese group displayed significantly higher total body fat and a higher adiposity index compared with those of the overweight group. No differences in systolic blood pressure or nonesterified fatty acid, glucose, total cholesterol, or triglyceride levels were observed between the obese and overweight groups. The adiposity index of the obese group was positively correlated with final body weight, total body fat, and leptin levels. Despite the classification of sedentary rats into overweight and obese groups, it was not possible to identify differences in the comorbidities between the two groups.
The present study was conducted to assess the effect of fenugreek, insulin and glimepiride alone and their combination in diabetic rat liver. Fifty six male Sprague dawley rats of uniform age were randomly divided into seven groups. Group 1: Non-diabetic control; Group 2: Streptozotocin (40 mg/Kg i/p single dose)-induced diabetic control; Group 3: Insulin (4 U/kg once daily for 8 weeks) treatment in diabetic rats; Group 4: Glimepiride (4 mg/Kg orally once daily for 8 weeks) treatment in diabetic rats; Group 5: Fenugreek seed powder treatment (1 g/kg orally once daily for 8 weeks) in diabetic rats; Group 6: Insulin + Fenugreek seed powder treatment (once daily for 8 weeks) in diabetic rats; Group 7: Glimepiride + Fenugreek seed powder treatment (once daily for 8 weeks) in diabetic rats. Livers were collected at the end of experiment for histopathology and estimation of reduced glutathione (GSH), thiobarbituric acid reacting substances (TBARS), protein carbonyls, glutathione S-transferase (GST), glucose-6-phosphate dehydrogenase (G6PD), Na(+)/K(+) ATPase and Mg(2)+ ATPase, cytochrome P450 (CYP) and glycogen. There was an increase in the concentration of TBARS and protein carbonyls, and decrease in the concentration of GSH and glycogen, and the activity of GST, G6PD, Na(+)/K(+) ATPase and Mg(2)+ ATPase in diabetic livers, while treatment groups showed significant (P < 0.05) increase in the above parameters. The histology of liver revealed marked changes in diabetic rats and mild changes in combination treatment groups. The treatment with fenugreek, insulin and glimepiride improved the liver parameters in diabetic rats and their combination showed a beneficial effect on liver.
Obesity and diabetes mellitus are great public health concerns throughout the world because of their increasing incidence and prevalence. Leptin, the adipocyte hormone, is well known for its role in the regulation of food intake and energy expenditure. In addition to the regulation of appetite and satiety that recently has attracted much attentions, insight has also been gained into the critical role of leptin in the control of the insulin-glucose axis, peripheral glucose and insulin responsiveness. Since the discovery of leptin, leptin has been taken for its therapeutic potential to obesity and diabetes. Recently, the therapeutic effects of central leptin gene therapy have been reported in insulin-deficient diabetes in obesity animal models such as ob/ob mise, diet-induced obese mice, and insulin-deficient type 1 diabetes mice, and also in patients with inactivating mutations in the leptin gene. Herein, we review the role of leptin in regulating feeding behavior and glucose metabolism and also the therapeutic potential of leptin in obesity and diabetes mellitus.
4-Hydroxyisoleucine (4HI) isolated from seeds of fenugreek produced antihyperglycaemic effects in diabetic mice. However, its role in pancreatic regeneration is not well understood. The objective of the present study was to evaluate the antihyperglycaemic, pancreatic regenerative potential of 4HI and compare it with pioglitazone. Alloxan (80 mg/kg, i.v.) induced diabetic mice were fed orally with 4HI (40 mg/kg) once a day for consecutive 28 days with or without pioglitazone (Pgz, 10 mg/kg). Serum glucose levels and body weight were measured every 7 days whereas on 35th day; pancreatic, serum insulin levels and glycosylated haemoglobin levels were estimated. On 35th day mice were sacrificed, pancreas removed and histological studies were done. Potential for islet neogenesis and adipogenisis of 4HI and Pgz were also observed against in pancreatic ductal stem cell culture in vitro. 4HI treated group showed gradual decrease in serum glucose levels and attended normoglycemia at the end of treatment. Histopathological picture of the pancreas in 4HI treated mice exhibited presence of tiny islets indicating islet neogenesis from pancreatic duct/ progenital cells. This observation was further strengthened by in vitro islet neogenesis and adipogenesis obtained after treating the pancreatic ductal stem cells with 4HI. The higher levels of pancreatic and serum insulin observed in 4HI treated animals further supports the regenerative potential of 4HI. Glycosylated haemoglobin levels were significantly reduced by 4HI. Thus, the present data demonstrates for the first time the pancreatic regenerative potential of 4HI and also provides evidence for its known antihyperglycaemic activity compared to untreated diabetic mice which showed uncontrolled hyperglycaemia.
In this study, we aimed to evaluate the possible relations of serum leptin and thyroid hormones on insulin treatment of surgically thyroidectomized and streptozotosin induced diabetic group of rats and whether the thyroid hormones control the leptin levels or leptin levels affect the thyroid hormones in DM. The Sprague-Dawley rats were assigned to eight groups: group 1, control; group 2, diabetes (injected intraperitoneally (i.p.) with streptozotocin (stz) 55 mg/kg); group 3, diabetes + insulin (rats were treated with insulin, 7-10 U/kg/day, subcutaneously); group 4, surgically thyroidectomized control; group 5, thyroidectomized + diabetes (3 weeks after the surgical operation, injected i.p. with stz); group 6, thyroidectomized + diabetes + insulin; group 7, thyroidectomized + diabetes + insulin + thyroid hormone (after diabetes induction, rats were treated with insulin and thyroid hormone, levothyroxin sodium (T4; 2.5 microg/kg); group 8, thyroidectomized + diabetes + insulin + thyroid hormone (T4; 5 microg/kg). The free and total T3 and T4 levels were measured in serum samples by otoanalyzer, and leptin levels were determined by ELISA method. The main finding of our recent study is that the decreased levels of serum leptin during the diabetes, hypothyroidism, and hypothyroidism with diabetes can be regulated in different percentages with the treatment of insulin and various doses of thyroid hormone. The observations in our study suggest the idea that during diabetic hypothyroidism, without thyroid hormone treatment, insulin is not sufficient to balance the metabolic pathways so mediated effects of insulin in leptin regulation via thyroid hormones are an increased possibility.
The safety and efficacy of Trigonella foenum-graecum extract was investigated using 20 male volunteers aged 20-30 years. They were randomly treated with either 40 mg/kg aqueous extract powder in 10 mL distilled water or 10 mL distilled water in which coffee simulated the extract. The extract significantly lowered blood glucose level by 13.4% 4 hours after ingestion. A significant change of 14.1% was observed in potassium levels. No significant alteration in serum cholesterol, total serum protein and blood urea occurred. Approximately one-third experienced feelings of hunger, frequency of micturition or dizziness during the 24 hours after ingestion. The aqueous extract effectively reduced blood glucose in normal subjects safely. Its hypokalaemic effect merits further investigation.
Fenugreek (Trigonella foenum-graecum L. seed) is a food with traditional medicinal use in diabetes. Beneficial effects have been demonstrated in diabetic animals and both insulin-dependent and non-insulin-dependent diabetic subjects. Effects of a lipid extract A, crude ethanolic extract B, further sub-fractions of B (saponin-free C, saponin D and sapogenin E) and a gum fibre fraction F on intestinal sodium-dependent glucose uptake were investigated in vitro using rabbit intestinal brush border membrane vesicles. All fractions except A inhibited glucose-uptake at 0.33 and/or 3.3 mg/mL (p < 0.001). Greatest inhibition was observed with fractions D and E. Diosgenin and trigonelline (compounds reported in fenugreek) also inhibited glucose-uptake (IC50 values approximately 3 mg/ml, equivalent to 8 mM and 19 mM respectively) but did not account for the activity of the crude extracts. Fenugreek extracts had no effect on basal levels of glycogen phosphorylase a (HGPa) activity in rat hepatocyte suspensions. However fractions C and E caused a marginal but statistically significant inhibition (18.9 and 15.1% respectively, p < 0.05) of glucagon induction of this enzyme suggesting a glucagon-antagonist effect. Diosgenin (1.65 mg/ml; 4 mM) inhibited glucagon-induced HGPa activity by 20% (p < 0.05), and was more effective than trigonelline (non significant inhibition of 9.4% at 1.65 mg/ml, 10 mM).
The regulation of TRH gene expression in the paraventricular nucleus of the hypothalamus (PVH) by leptin is critical for normal function of the thyroid axis in rodents and humans. The TRH neuron in the PVH expresses both leptin and melanocortin-4 receptors, suggesting that both signaling systems may regulate TRH gene expression in vivo. Indeed, the TRH promoter responds to both of these signaling pathways in cell culture through identified cis-acting elements, which include signal transducer and activator of transcription (STAT) 3 and cAMP-response element binding protein binding sites that mediate leptin and melanocortin responses, respectively. To determine whether leptin signaling can directly target the TRH promoter in vivo, we developed a chromatin immunoprecipitation assay to use on leptin-treated animals. After a single injection of leptin in fasting animals, we could detect a significant increase in TRH gene expression in the PVH that correlated well with the induction of phosphorylated-STAT3 in the hypothalamus. Furthermore, using a STAT3 antibody, we could immunoprecipitate the STAT-binding site containing regions of both the TRH promoter and the promoter of the suppressor of cytokine signaling-3 gene, another well-defined target of leptin action. In contrast, upstream regions of these promoters that lack STAT sites were not precipitated. Taken together these experiments demonstrate that STAT3 mediates transcriptional effects of leptin in vivo and that the TRH promoter is a likely direct site of leptin action. In addition, these experiments demonstrate that chromatin immunoprecipitation can be used to characterize leptin-signaling in vivo.
In obesity-related hypertension, activation of the renin-angiotensin system (RAS) has been reported despite marked fluid volume expansion. Adipose tissue expresses components of the RAS and is markedly expanded in obesity. This study evaluated changes in components of the adipose and systemic RAS in diet-induced obese hypertensive rats. RAS was quantified in adipose tissue and compared with primary sources for the circulating RAS. Male Sprague-Dawley rats were fed either a low-fat (LF; 11% kcal as fat) or moderately high-fat (32% kcal as fat) diet for 11 wk. After 8 wk, rats fed the moderately high-fat diet segregated into obesity-prone (OP) and obesity-resistant (OR) groups based on their body weight gain (body weight: OR, 566 +/- 10; OP, 702 +/- 20 g; P < 0.05). Mean arterial blood pressure was increased in OP rats (LF: 97 +/- 2; OR: 97 +/- 2; OP: 105 +/- 1 mmHg; P < 0.05). Quantification of mRNA expression by real-time PCR demonstrated a selective increase (2-fold) in angiotensinogen gene expression in retroperitoneal adipose tissue from OP vs. OR and LF rats. Similarly, plasma angiotensinogen concentration was increased in OP rats (LF: 390 +/- 48; OR: 355 +/- 24; OP: 530 +/- 22 ng/ml; P < 0.05). In contrast, other components of the RAS were not altered in OP rats. Marked increases in the plasma concentrations of angiotensin peptides were observed in OP rats (angiotensin II: LF: 95 +/- 31; OR: 59 +/- 20; OP: 295 +/- 118 pg/ml; P < 0.05). These results demonstrate increased activity of the adipose and systemic RAS in obesity-related hypertension.
The reductions in circulating levels of leptin, insulin, and glucose with fasting serve as important homeostasis signals to neurons of the hypothalamic arcuate nucleus that synthesize neuropeptide Y (NPY)/agouti-related protein (AGRP) and alpha-MSH/cocaine and amphetamine-regulated transcript. Because the central administration of leptin is capable of preventing the inhibitory effects of fasting on TRH mRNA in hypophysiotropic neurons primarily through effects on the arcuate nucleus, we determined whether the continuous administration of 30 mU/d insulin or 648 microg/d glucose into the cerebrospinal fluid by osmotic minipump might also have similar effects on the hypothalamic-pituitary-thyroid axis. As anticipated, the intracerebroventricular infusion of leptin reduced fasting-induced elevations in NPY and AGRP mRNA and increased proopiomelanocortin and cocaine and amphetamine-regulated transcript mRNA in the arcuate nucleus. In addition, leptin prevented fasting-induced reduction in pro-TRH mRNA levels in the paraventricular nucleus and in circulating thyroid hormone levels. In contrast, whereas insulin increased proopiomelanocortin mRNA and both insulin and glucose reduced NPY mRNA in arcuate nucleus neurons, neither prevented the fasting-induced suppression in hypophysiotropic TRH mRNA or circulating thyroid hormone levels. We conclude that insulin and glucose only partially replicate the central effects of leptin and may not be essential components of the hypothalamic-pituitary-thyroid regulatory system during fasting.
Hypothalamic thyrotropin-releasing hormone (TRH) stimulates thyroid-stimulating hormone (TSH) secretion from the anterior pituitary. TSH then initiates thyroid hormone (TH) synthesis and release from the thyroid gland. Although opposing TRH and TH inputs regulate the hypothalamic-pituitary-thyroid axis, TH negative feedback is thought to be the primary regulator. This hypothesis, however, has yet to be proven in vivo. To elucidate the relative importance of TRH and TH in regulating the hypothalamic-pituitary-thyroid axis, we have generated mice that lack either TRH, the beta isoforms of TH receptors (TRbeta KO), or both (double KO). TRbeta knock-out (KO) mice have significantly higher TH and TSH levels compared with wild-type mice, in contrast to double KO mice, which have reduced TH and TSH levels. Unexpectedly, hypothyroid double KO mice also failed to mount a significant rise in serum TSH levels, and pituitary TSH immunostaining was markedly reduced compared with all other hypothyroid mouse genotypes. This impaired TSH response, however, was not due to a reduced number of pituitary thyrotrophs because thyrotroph cell number, as assessed by counting TSH immunopositive cells, was restored after chronic TRH treatment. Thus, TRH is absolutely required for both TSH and TH synthesis but is not necessary for thyrotroph cell development.
The identification and sequencing of the ob gene and its product, leptin, in 1994 opened new insights in the study of the mechanisms controlling body weight and led to a surge of research activity. Since its discovery, leptin has been the subject of an enormous amount of work especially within the fields of nutrition, metabolism and endocrinology. Leptin is accepted as an adipose signal, and even though the underlying mechanisms are not fully clarified, leptin, in addition to the thyroid hormones, is believed to be involved in regulation during the switch from the fed to the starved state. It is not clear whether leptin and the melanocortin pathways interact with the thyroid axis under physiological conditions other than during starvation or in response to severe illness, both states in which the hypothalamo-pituitary-thyroid axis may be severely suppressed. In addition to the suggested central relationship between leptin and thyroid hormones, there might also be a peripheral relationship although this effect is not clear. Both thyroid hormones and leptin might be involved in the adaptive thermogenesis through mitochondrial uncoupling proteins and heat production because both thyroxine and triiodothyronine are involved in the starvation-induced decrease in thermogenesis. Both rodent and human studies of leptin have failed to show any consistent relationship between thyroid function and serum leptin concentrations. However, leptin might have an important role in thyroid pathophysiology due to thyroid hormone involvement in thermogenesis and regulation of uncoupling proteins. In this review, we have focused on leptin in relation to thyroid pathophysiology.
Thyrotropin‐releasing hormone (TRH) synthesized in hypothalamic paraventricular nucleus directs hypothalamus‐pituitary‐thyroid (HPT) axis function, regulating thyrotropin release from adenohypophysis and thyroid hormones serum concentration. Pyroglutamyl aminopeptidase II (PPII), a Zn‐dependent metallopeptidase located in adenohypophysis and medial‐basal‐hypothalamus degrades TRH released from the median eminence and participates in HPT axis function by regulating TRH‐induced thyrotropin release from adenohypophysis. It is unknown whether dietary Zn deficiency down‐regulates PPII. Our aim was to compare adenohypohyseal and medial‐basal‐hypothalamic PPII activity and expression of adult rats fed a Zn‐deficient diet (2 ppm) throughout their lifespan (DD), prenatally (DC) or after weaning (CD) vs. that of animals fed a control diet (20 ppm:CC).
Female rats consumed a Zn‐deficient or control diet from two weeks before gestation and up to the end of lactation. We analyzed adenohypophyseal and medial‐basal‐hypothalamic PPII activity of dams and male offspring when adults; its relation to median eminence TRH, serum thyrotropin, leptin and thyroid hormones concentration. Offspring ate the same diet as their dams (CC, DD) or were switched from dietary regime after weaning (CD, DC) and until 2.5 months of age. DD males showed decreased adenohypophyseal and medial‐basal‐hypothalamic PPII activity, along with high thyrotropin serum concentration. Post‐weaning Zn‐deficiency (CD) decreased PPII activity only in adenohypophysis and increased thyrotropin circulating levels. Zn‐replenishment (DC) normalized PPII activity in both regions and serum thyrotropin concentration. Adenohypophyseal PPII activity decreased and prolactin levels increased in Zn‐deficient dams. We concluded that long‐term changes in dietary Zn down‐regulate PPII activity independently of T 3, increasing thyrotropin serum concentration, overall resembling sub‐clinical hypothyroidism.
Type 1 diabetes mellitus (DM1) and dysfunction of the thyroid gland (TG) are the most common endocrine diseases, which are interrelated. However, the molecular mechanisms of thyroid dysfunction in DM1 and the role of adenylyl cyclase signaling system (ACSS) in this process remain poorly understood. Typically for studying etiology and pathogenesis of thyroid diseases in DM1 the models of acute DM1 induced by high doses of streptozotocin (STZ) are used. At the same time, a suitable model for this purpose is the model of mild DM1 initiated by moderate doses of STZ, which more closely resembles human DM1. The aim of this study was a comparative study of the functional state of the thyroid gland in rats with 30-day acute DM1 induced by injection of STZ at a dose of 65 mg/kg, and in rats with 30- and 210-day mild DM1 induced by three consecutive injections of STZ at medium doses (30-40 mg/kg). For this purpose in diabetic animals the levels of thyroid hormones and TSH and the functional activity of hormone-sensitive ACSS in membranes isolated from thyroid gland were studied. It was shown that in blood of rats with acute DM1 the levels of fT(4), fT(3), and tT(3) were decreased by 45, 23 and 19%, respectively, while the level of TSH did not change significantly. In rats with the 30-day mild DM1 the concentration of fT(4) was decreased by 32%, while the levels of tT(4), tT(3), and TSH were similar to that in control. In rats with prolonged mild DM1 after 150 and 210 days following the first treatment with STZ the levels of tT(4), fT(4), and tT(3) were significantly reduced, but the concentration of TSH in rats with 210-day mild DM1 was increased by 119%. The results obtained in the study of thyroid status and TSH levels in rats with prolonged mild DM1 are in good agreement with the data obtained in the study of thyroid diseases in patients with DM1. It was found that the AC basal activity in the membranes isolated from the thyroid gland of diabetic rats did not change, except for the rats with the prolonged mild DM1 where this activity was increased by 21%. In all groups of diabetic rats the decrease of AC stimulating effects of GppNHp (10(-5) M) and TSH (10(-8) M) was found, and in the rats with prolonged mild DM1 the AC effect of PACAP-38 (10(-6) M) was also reduced. The decrease of AC effect of TSH varied among different groups of the diabetic animals: in the rats with acute DM1 this effect was reduced by 46% and in the rats with 30- and 210-day mild DM1-by 18 and 34%. Thus, it was concluded that the key cause of the thyroid resistance to TSH under conditions of DM1 is a weakening of the signal transduction generated by TSH via the ACSS.
Several studies support hypolipidemic effect of fenugreek in normal and diabetic subjects. However, very little is known about the possible direct action of fenugreek on adipose tissue. The present study was designed to investigate the effects of fenugreek seeds on adipogenesis and lipolysis. Preadipocytes were isolated from adipose tissue of normal rats and differentiated to adipocyte in the presence of ethanolic extract of fenugreek seeds. The effect of this extract on lipolysis was also evaluated in fat tissue isolated from diabetic rats. Fenugreek led to a significant reduction in lipid droplet accumulation as evaluated with Oil Red O staining. Incubation of preadipocytes with the extract for 24 h resulted in significant decrease in cell viability. The extract, even at high concentrations (up to 1000 μg mL(-1)), had virtually no significant effect on lipolysis. The present data demonstrated that fenugreek seed inhibits formation of new differentiated adipocytes from precursor cells through an anti-proliferative effect on preadipocytes.
The hypothalamus-pituitary-thyroid (HPT) axis represents a classical example of an endocrine feedback loop. Hypothalamic thyrotropin-releasing hormone (TRH) neurons were identified as key components of thyroid hormone (TH) setpoint regulation already in the 1980s, and this was followed by the demonstration of a pivotal role for the thyroid hormone receptor β (TRβ) in negative feedback of thyroid hormone on the hypothalamic and pituitary level. Gradually, the concept emerged of the HPT axis setpoint as a fixed entity, aiming at a particular thyroid hormone (TH) serum concentration. However, TH serum concentrations appear to be variable, and highly responsive to physiological and pathophysiological environmental factors, including the availability or absence of food, inflammation, and clock time. During food deprivation and inflammation, TH serum concentrations decrease without a concomitant rise in serum TSH, reflecting a deviation from negative feedback regulation in the HPT axis. Surprisingly, thyroid hormone action in peripheral organs in these conditions cannot be simply predicted by decreased serum TH concentrations. Instead, diverse environmental stimuli have differential effects on local thyroid hormone metabolism, e.g., in liver and muscle, occurring quite independently from decreased TH serum concentrations. The net effect of these differential local changes is probably a major determinant of thyroid hormone action at the tissue level. In sum, hypothalamic HPT axis setpoint regulation as well as TH metabolism at the peripheral organ level are flexible and dynamic, and may adapt the organism in an optimal way to a range of environmental challenges.
Protective effects of trigonelline (TRG) isolated from fenugreek seed were evaluated in isoproterenol (ISO)-induced myocardial dysfunctions in adult rats and a proteomic approach was applied to understand its mechanism of action.
In a preliminary experiment, effects of TRG at 20, 40, and 80 mg/kg for 20 d were studied in ISO-induced (100 mg/kg) adult rats. As 40 mg/kg was found the most effective concentration, in the final experiment, effects of 40 mg/kg of the test drug were investigated using different indices including cardiac marker enzymes, lipid peroxidation, antioxidants, cardiac histology, and electrocardiogram. Proteomic analyses were also done in cardiac myocytes.
ISO administration increased serum levels of cardiac markers (creatine kinase-MB, glutamate pyruvate transaminase, and lactate dehydrogenase) and exhibited a positive reaction in the TROP-T test. It also increased the cardiac lipid peroxidation and decreased the cellular antioxidants. Proteomic data revealed nine protein spots, seven were down-regulated and two up-regulated. The overexpressions of two small stress proteins, heat shock protein (Hsp)27 and αB crystallin were confirmed by Western blot analysis. All these alterations were restored to nearly normal values in 40 mg/kg of TRG-pretreated animals, suggesting its cardioprotective effects, which were further confirmed by histologic examinations and triphenyl tetrazolium chloride staining assay.
For the first time, our study revealed the down-regulation of Hsp27 and αB-crystallin and (CaMKII delta) isoform by TRG. As the test compound prevented the ISO-induced myocardial injury, its therapeutic use may further be explored.
Leptin has been shown to regulate the hypothalamus-pituitary-thyroid axis, acting primarily through the STAT3 pathway triggered through the binding of leptin to the long-chain isoform of the leptin receptor, ObRb. We previously demonstrated that although hyperthyroid rats presented leptin effects on TSH secretion, those effects were abolished in hypothyroid rats. We addressed the hypothesis that changes in the STAT3 pathway might explain the lack of TSH response to leptin in hypothyroidism by evaluating the protein content of components of leptin signalling via the STAT3 pathway in the hypothalamus and pituitary of hypothyroid (0.03% methimazole in the drinking water/21 days) and hyperthyroid (thyroxine 5 μg/100 g body weight /5 days) rats. Hypothyroid rats exhibited decreased ObRb and phosphorylated STAT3 (pSTAT3) protein in the hypothalamus, and in the pituitary gland they exhibited decreased ObRb, total STAT3, pSTAT3 and SOCS3 (P<0.05). Except for a modest decrease in pituitary STAT3, no other alterations were observed in hyperthyroid rats. Moreover, unlike euthyroid rats, the hypothyroid rats did not exhibit a reduction in food ingestion after a single injection of leptin (0.5 mg/kg body weight). Therefore, hypothyroidism decreased ObRb-STAT3 signalling in the hypothalamus and pituitary gland, which likely contributes to the loss of leptin action on food intake and TSH secretion, as previously observed in hypothyroid rats.
Thyroid hormone (TH) signaling plays an important role in development and adult life. Many organisms may have evolved under selective pressure of exogenous TH, suggesting that thyroid hormone signaling is phylogenetically older than the systems that regulate their synthesis. Therefore, the negative feedback system by TH itself was probably the first mechanism of regulation of circulating TH levels. In humans and other vertebrates, it is well known that TH negatively regulates its own production through central actions that modulate the hypothalamic-pituitary-thyroid (HPT) axis. Indeed, primary hypothyroidism leads to the up-regulation of the genes encoding many key players in the HPT axis, such as TRH, type 2 deiodinase (dio2), pyroglutamyl peptidase II (PPII), TRH receptor 1 (TRHR1), and the TSH α- and β-subunits. However, in many physiological circumstances, the activity of the HPT axis is not always a function of circulating TH concentrations. Indeed, circadian changes in the HPT axis activity are not a consequence of oscillation in circulating TH levels. Similarly, during reduced food availability, several components of the HPT axis are down-regulated even in the presence of lower circulating TH levels, suggesting the presence of a regulatory pathway hierarchically higher than the feedback system. This minireview discusses the neural regulation of the HPT axis, focusing on both TH-dependent and -independent pathways and their potential integration.
Thyroid disease and type 1 but also type 2 diabetes mellitus are strongly associated and this has important clinical implications for insulin sensitivity and treatment requirements. The pathophysiological basis of this association has only recently been better elucidated. It rests on a complex interaction of common signalling pathways and, in the case of type 1 diabetes and autoimmune thyroid disease, on a linked genetic susceptibility. The pathophysiological mechanisms underlying this linked regulation are increasingly being unravelled. They are exemplified in the regulation of 5' adenosine monophosphate-activated protein kinase (AMPK), a central target not only for the modulation of insulin sensitivity but also for the feedback of thyroid hormones on appetite and energy expenditure. The present review will discuss these concepts and their consequences for the clinical care of patients with diabetes mellitus and thyroid disorders. Moreover, it makes reference to the added effect of metformin in suppressing TSH.
Thyroid hormone (TH) plays a critical role in development, growth, and cellular metabolism. TH production is controlled by a complex mechanism of positive and negative regulation. Hypothalamic TSH-releasing hormone (TRH) stimulates TSH secretion from the anterior pituitary. TSH then initiates TH synthesis and release from the thyroid gland. The synthesis of TRH and TSH subunit genes is inhibited at the transcriptional level by TH, which also inhibits posttranslational modification and release of TSH. Although opposing TRH and TH inputs regulate the hypothalamic-pituitary-thyroid axis, TH negative feedback at the pituitary was thought to be the primary regulator of serum TSH levels. However, study of transgenic animals showed an unexpected, dominant role for TRH in regulating the hypothalamic-pituitary-thyroid axis and an unanticipated involvement of the thyroid hormone receptor ligand-dependent activation function (AF-2) domain in TH negative regulation. These results are summarized in the review.
The thyrotropin-releasing hormone neuron is well-positioned to integrate information about the environment as well as circulating TH levels and ultimately affect metabolism in response to these physiological changes.
Streptozotocin diabetes in rats is associated with reduced function of the hypothalamo-pituitary-thyroid axis. The structure and hormone secretion of the thyroid and pituitary glands were studied in adult male rats 1 month after streptozotocin injection. The thyroid of diabetic rats was characterized by decreased follicle area and epithelial thickness. By electron microscopy, thyroid epithelial cells were characterized by flattened and almost empty rough endoplasmic reticulum cisternae, scanty exocytotic apical and endocytotic vesicles as well as degenerate mitochondria and rough endoplasmic reticulum. By immunohistochemistry, intracolloidal thyroglobulin and T3 as well as intraepithelial thyroglobulin were reduced. Electron microscopic and immunohistochemical analysis of pituitary glands showed that in diabetic rats thyrotrophs were mostly of type II, and the number of thyrotrophs (type I + type II) was greater than in controls. By radioimmunoassay (RIA), plasma T3, T4, and TSH levels were markedly reduced, and the TSH response to TRH was deficient in diabetic animals. The pituitary TSH concentration was increased, as expected from the morphological data. This study demonstrates severe structural changes in the thyroid and pituitary glands of diabetic rats which are accompanied by marked alterations of their secretory activity.
1.1. The soluble supernatant fraction (105,000 g supernatant) of the pigeon and common myna thyroid gland showed high peroxidase activity. The peroxidase activity of the common myna was higher than that of the pigeon.2.2. The pH optimum of pigeon thyroid peroxidase was 5·5 whereas in the common myna it was 6·0.3.3. H2O2 (1·16 μmole/ml) was inhibitory to pigeon thyroid peroxidase whereas common myna thyroid peroxidase was not inhibited even at a concentration as high as 100 μmoles/ml.4.4. The effect of various inhibitors and stimulators on the peroxidase of the pigeon and common myna were studied and compared.
A modification of the TRI Reagent procedure has been elaborated for isolation of RNA from polysaccharide- and proteoglycan-rich material. In the modified procedure, RNA is precipitated from the aqueous phase by the combined action of isopropanol and a high-salt concentration. Under these conditions, RNA is effectively precipitated while contaminating polysaccharides and proteoglycans remain in the soluble form. The modified precipitation does not prolong or increase the complexity of the TRI Reagent procedure. The new procedure was tested by isolation of RNA from polysaccharide- and proteoglycan-rich tissues such as rat liver and aorta.
The mechanisms regulating leptin secretion were investigated in isolated rat white adipocytes. Insulin (1-100 nM) linearly stimulated leptin secretion from incubated adipocytes for at least 2 h. The adrenergic agonists norepinephrine, isoproterenol (two nonselective beta-agonists), or CL-316243 (potent beta3) all inhibited insulin (10 nM)-stimulated leptin release. The inhibitory effects of norepinephrine and isoproterenol could be reversed not only by the nonselective antagonist propranolol but also by the selective antagonists ICI-89406 (beta1) or ICI-118551 (beta2), the beta2-antagonist being less effective than the beta1. Insulin-stimulated leptin secretion could also be inhibited by a series of agents increasing intracellular cAMP levels, such as lipolytic hormones (ACTH and thyrotropin-stimulating hormone), various nonhydrolyzable cAMP analogs, pertussis toxin, forskolin, methylxanthines (caffeine, theophylline, IBMX), and specific inhibitors of phosphodiesterase III (imazodan, milrinone, and amrinone). Significantly, antilipolytic agents other than insulin (adenosine, nicotinic acid, acipimox, and orthovanadate) did not mimic the acute stimulatory effects of insulin on leptin secretion under these conditions. We conclude that norepinephrine specifically inhibits insulin-stimulated leptin secretion not only via the low-affinity beta3-adrenoceptors but also via the high-affinity beta1/beta2-adrenoceptors. Moreover, it is suggested that 1) activation of phosphodiesterase III by insulin represents an important metabolic step in stimulation of leptin secretion, and 2) lipolytic hormones competitively counterregulate the stimulatory effects of insulin by activating the adenylate cyclase system.
Secretory activity of the pituitary-thyroid axis and thyroid hormone metabolism show characteristic changes in response to different stressors often referred to as the euthyroid sick syndrome. Hypoglycemia is an acute metabolic stressor inducing various neuroendocrine responses, the effects of which on pituitary-thyroid secretory activity so far have been entirely neglected. We performed stepwise hypoglycemic and euglycemic clamps each lasting 6 hours in 30 healthy men. To assess the potential influence of hyperinsulinemia on pituitary-thyroid hormone release, 2 different rates of insulin infusion were used for the clamps. During the hypoglycemic clamps, serum thyroid-stimulating hormone (TSH) concentration decreased in comparison to the euglycemic condition on average by 28% +/- 4% (P <.001), while serum concentration of free triiodothyronine (fT3), free thyroxine (fT4), and thyroxine-binding globulin (TBG) remained unchanged. The effect did not depend on the rate of insulin infusion. To assess the prolonged effect of acute hypoglycemia on pituitary-thyroid secretory activity, serum TSH and thyroid hormone concentrations were subsequently measured in another 15 healthy men before and 18 hours after 2 consecutive hypoglycemic clamps together lasting about 270 minutes. Compared with values before the hypoglycemic clamps, serum levels of TSH, fT3, and fT4 were found to be still reduced (by 44% +/- 6%, 12% +/- 2%, and 10% +/- 1%, respectively) 18 hours after the last hypoglycemic episode (P <.001 for all comparisons). The observed hormonal changes after hypoglycemia were not accompanied by any change in resting energy expenditure (REE). Data indicate acute as well as prolonged inhibitory influences of hypoglycemia on pituitary-thyroid secretory activity. The pattern of changes suggests that hypoglycemia exerts its influence primarily at a central, ie, pituitary and/or hypothalamic, site of the axis.
The combined effects of Trigonella foenum-graecum and Allium sativum extracts were evaluated for their ameliorative potential in the L-thyroxine-induced hyperthyroidic rat model to contribute to an understanding of interaction between the two extracts. The investigation was carried out using two different doses. A comparison was made with the response of individual plant extracts at the previously studied effective dose in adult Wistar rats rendered hyperthyroidic by daily injections of L-thyroxine (300 microg/kg body wt., s.c.). Propylthiouracil (PTU), an antithyroid drug, was used as a reference compound. Alterations in serum triiodothyronine (T3), thyroxine (T4), glucose, hepatic glucose-6-phosphatase (G-6-Pase) and oxygen consumption were studied as end parameters. Superoxide dismutase (SOD), catalase (CAT) activities, lipid peroxidation (LPO) and reduced glutathione (GSH) were examined to reveal any toxic effects of the drugs. The combined effects of Trigonella and Allium at 200 and 500 mg/kg body wt. respectively, were equipotent as compared to the individual extracts in lowering the serum concentrations of T3 and T4 in hyperthyroidic rats. Our findings reveal that some plant extracts in combination may not always prove to be synergistic. It is therefore suggested that Trigonella foenum-graecum and Allium sativum extracts may be used individually and not together in the regulation of hyperthyroidism.
Diabetes mellitus is a condition that is extremely serious from both clinical and public health standpoints. The traditional healthcare system of India, Ayurveda, offers a balanced and holistic multi-modality approach to treating this disorder. Many Ayurvedic modalities have been subjected to empirical scientific evaluation, but most such research has been done in India, receiving little attention in North America. This paper offers a review of the English language literature related to Ayurveda and diabetes care, encompassing herbs, diet, yoga, and meditation as modalities that are accessible and acceptable to Western clinicians and patients. There is a considerable amount of data from both animal and human trials suggesting efficacy of Ayurvedic interventions in managing diabetes. However, the reported human trials generally fall short of contemporary methodological standards. More research is needed in the area of Ayurvedic treatment of diabetes, assessing both whole practice and individual modalities.
The incidence of type 1 and type 2 diabetes mellitus in the pediatric population has increased over the past decade. The practitioner is often faced with the challenge of differentiating between type 1 and type 2 diabetes at the time of initial diagnosis because of the overlap of clinical and laboratory characteristics between these two entities. Adipokines are proteins secreted by the adipose tissue. Leptin and adiponectin are two adipokines that have been extensively studied in vitro, in animal studies, and in human subjects with type 1 and type 2 diabetes. Leptin and adiponectin play a significant role in the regulation of lipid and carbohydrate metabolism. Adiponectin increases insulin sensitivity in both the liver and skeletal muscle. Leptin decreases appetite, increases energy expenditure, suppresses insulin synthesis and secretion and increases insulin sensitivity. Changes in the secretion or sensitivity to leptin and adiponectin may contribute to the development of type 1 and type 2 diabetes. Adiponectin is higher in adult and pediatric patients with type 1 diabetes compared to those with type 2 diabetes. Data regarding leptin levels are contradictory. Most studies report decreased serum leptin at the time of diagnosis in type 1 diabetes compared to type 2 diabetes subjects and non-diabetic controls. This paper will review basic research and clinical evidence supporting the role of adiponectin and leptin in the development of type 1 and type 2 diabetes and discuss their potential use as tools in the differential diagnosis of pediatric diabetes.
A novel preparation of a dialysed aqueous extract of fenugreek seeds (FSE) that stimulates the insulin signalling pathway was reported previously (Vijayakumar et al., 2005). The present study was designed to investigate the long-term effects (multiple dose effect) of this FSE preparation on the blood glucose level and body weight, and a short-term effect (single dose effect) on serum insulin and hepatic enzymes, in experimentally induced diabetic conditions. The multiple dose effect of FSE on the glucose level and body weight was studied in alloxan (AXN)-diabetic mice in comparison with the vehicle treated control diabetic mice. Intraperitoneal (i.p.) administration of FSE (15 mg/kg body weight (BW)) for 5 consecutive days reduced hyperglycemia in AXN-diabetic mice on day 5 and this effect was further sustained for 10 days. The FSE-induced hypoglycemic effect was accompanied without any reduction in the body weight compared with the diabetic mice in which the body weight was reduced significantly. A single dose effect of FSE on hepatic glucokinase (GK) and hexokinase (HK) enzymes was studied in streptozotocin (STZ)-diabetic mice. Intraperitoneal administration of FSE (15 mg/kg BW) by 90 min decreased the blood glucose levels significantly (p < 0.01) in STZ-diabetic mice and the effect was comparable to that achieved by insulin (1.5 U/kg BW) injection. This effect was associated with a significant enhancement in the liver GK and HK activities on a par with that of insulin. In normal glucose loaded mice, FSE improved the intraperitoneal glucose tolerance accompanied by a reduction in serum insulin concentration. These results are indicative of an extra-pancreatic mode of action of FSE. The present study concludes that this novel FSE preparation corrects metabolic alterations associated with diabetes by exhibiting insulin-like properties and has a potential for clinical applications.
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