Fenugreek: Overview of Potential Health Benefits : Nutrition Today

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Fenugreek

Overview of Potential Health Benefits

Singletary, Keith W. PhD

Author Information

Keith W. Singletary, PhD, is professor emeritus of nutrition in the Department of Food Science and Human Nutrition at the University of Illinois. From 2001 to 2004, he was the director of the Functional Foods for Health Program, an interdisciplinary program between the Chicago and Urbana-Champaign campuses of the University of Illinois. Dr Singletary received bachelor and master's degrees in microbiology from Michigan State University and his PhD in nutritional sciences from the University of Illinois. Dr Singletary's primary research interests are in molecular carcinogenesis and cancer chemoprevention, specifically identifying and determining the mechanism of action of phytochemicals in fruits, vegetables, and spices as cancer protective agents. He has been recognized with the Senior Faculty Award for Excellence in Research by the College of Agricultural, Consumer and Environmental Sciences at the University of Illinois. Dr Singletary currently resides in Florida.

Funds for the preparation of this manuscript were provided by McCormickInc.

The author has no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.nutritiontodayonline.com).

Correspondence: Keith W. Singletary, PhD, Department of Food Science and Human Nutrition, University of Illinois, 260 Bevier Hall, 905 S Goodwin Ave, Urbana, IL 61801 ([email protected]).

Nutrition Today 52(2):p 93-111, 3/4 2017. | DOI: 10.1097/NT.0000000000000209

Abstract

The objectives of this article are to provide a brief overview of the scientific literature regarding the use of fenugreek in the management of hyperglycemia and dyslipidemia and suggest recommendations for additional research. Fenugreek (Trigonella foenum-graecum L., family Fabaceae) is an annual herb with triangular yellow flowers and seed-containing pods that grows in countries of the Mediterranean, Middle East, India, China, and, more recently, Canada. Fenugreek seed or its extracts are found in food products such as frozen dairy products, gelatin puddings, candy, and gravy sauces and in alcoholic and nonalcoholic beverages. An extract of fenugreek also is used as a flavoring ingredient in imitation maple syrup. Fenugreek has a history of use in traditional medicine in India and China. Its uses include as a treatment of weakness and leg edema, as a lactation and appetite stimulant, and as a remedy for indigestion, baldness, and fever. Some have used it topically for myalgia, wound treatment, and cellulitis. One potential benefit of fenugreek is improving elevated blood glucose and lipid levels associated with chronic conditions such as diabetes and obesity. Human investigations suggest that fenugreek can be beneficial as an adjunct in controlling high blood glucose and lipid levels in people with diabetes. However, larger, adequately powered, randomized, placebo-controlled, double-blind trials examining multiple measures of carbohydrate and lipid metabolism and insulin homeostasis are needed.

Fenugreek (Trigonella foenum-graecum L., family Fabaceae) is an annual herb with triangular yellow flowers and seed-containing pods that grows in countries of the Mediterranean, Middle East, India, China, and, more recently, Canada. The Greek word Trigonella refers to the flowers' “3-angled” shape, and the term foenum-graecum means “Greek hay.” The hard, yellow-brown mature seeds possess an unusual aromatic odor and are used in curry recipes, chutney, spice blends, and some vegetable soups. Fenugreek seed or its extracts are in food products such as frozen dairy products, gelatin puddings, candy, and gravy sauces and in alcoholic and nonalcoholic beverages. An extract of fenugreek also is used as a flavoring ingredient in imitation maple syrup. Pastourma, a Greek and Middle Eastern meat dish, has a substantial crust containing garlic and fenugreek, and hebleh or hulba is a fenugreek olive oil cake. Hebleh is the Arabic word for fenugreek, also known as methi in Hindi. In Greece, the seeds, either boiled or raw, may be eaten with honey.

In ancient Egypt, fenugreek was used in incense and mummy embalming and is considered one of the oldest medicinal plants. It has a history of use in traditional medicines in India and China. Its uses include as a treatment of weakness and leg edema, as a lactation and appetite stimulant, and as a remedy for indigestion, baldness, and fever. Some have used it topically for myalgia, wound treatment, and cellulitis. One of the potential benefits of fenugreek receiving substantial research interest is counteracting hyperglycemia and dyslipidemia associated with such chronic conditions as diabetes and obesity. The medicinal uses of fenugreek seeds have been evaluated in numerous human and animal studies particularly in India and the Middle East.1–6 It even has been proposed as a functional food and nutraceutical.7

The objectives of this article are to provide a brief overview of the scientific literature regarding the use of fenugreek in the management of hyperglycemia and dyslipidemia and suggest recommendations for additional research.

METHODS

A search of the PubMed and EBSCO host literature databases identified more than 200 relevant reports published between 1948 and 2016. Search terms included Trigonella foenum graecum, fenugreek, and methi. The search also included the terms 4-hydroxyisoleucine, trigonelline, and diosgenin because they were identified as major components of fenugreek seed responsible for some of its biological actions. Full reports of English-language publications and English-language abstracts of foreign-language articles from peer-reviewed journals were the primary sources of information. Commercial and governmental reports also were supplementary sources. On the basis of the subjects' characteristics, soundness of experimental methodologies (eg, sample size, blinding, randomization), adequate description of test samples (eg, composition, daily dose, duration of use), outcomes measured (eg, blood glucose, insulin, lipoprotein-cholesterol levels, HbA1c), and thoroughness of data analyses, the quality of human studies varied considerably. Nonetheless, all published human investigations were included in this discussion so that the totality and diversity of information can be evaluated and issues for future research can be identified.

COMPOSITION

Fenugreek seeds are composed of 20% to 30% protein, 45% to 60% carbohydrates (mainly the galactomannan, mucilaginous fibers in the cell walls), and 5% to 10% lipids. Other important components include pyridine-type alkaloids (mostly trigonelline), free amino acids (most notably 4-hydroxyisoleucine), saponins, and glycosides that produce upon hydrolysis steroidal sapogenins, such as diosgenin.8 In the Figure, the structures of several bioactive phytochemicals in fenugreek are represented. Detailed compositions of separate seed fractions, such as husk and endosperm, and their chemical constituents were reported, along with variations in biochemical composition due to different genotypes and environmental conditions.9–14 In human and animal studies, the biological actions of different forms of fenugreek (eg, defatted or germinated seed) were evaluated including water and organic solvent extracts predominantly from the seed powder. Not all reports provide the specific composition of these samples and extracts examined, although general information about their constituents can be obtained from analyses of similar samples.15–21

F1
FIGURE:
Structures of select fenugreek constituents diosgenin (top), 4-hydroxyisoleucine (center), and trigonelline (bottom).

ANIMAL STUDIES OF HYPOGLYCEMIC AND HYPOLIPIDEMIC EFFECTS OF FENUGREEK

To date, dozens of in vivo experimental studies have evaluated the capacity of fenugreek to counteract the dysregulation of glucose and lipid metabolism and explored possible mechanisms of action. These are summarized in the Appendix.

HUMAN STUDIES OF HYPOGLYCEMIC AND HYPOLIPIDEMIC EFFECTS OF FENUGREEK

Since the 1980s, dozens of human studies, many from India and Iran, have evaluated the effects of fenugreek seed or leaf powders and their extracts on carbohydrate and lipid homeostasis (Table). These products were administered alone or incorporated into foods and beverages and were examined in trials differing substantially in numbers and health status of subjects, amounts and forms of fenugreek provided, lengths and outcomes of treatment protocols, and completeness of experimental designs. Specifically, many studies recruited a relatively small number of subjects (<20 per treatment group) and were not randomized, double blinded, or placebo controlled or of sufficiently long duration. Collectively, evidence suggests that the consumption of this plant can improve blood glucose in those with type 2 diabetes, but many studies are of poor quality, and substantial heterogeneity of outcomes is apparent. When measured in published studies, serum insulin levels and measures of insulin resistance in response to fenugreek administration did not consistently correspond to treatment-induced improvements in blood glucose. Similar heterogeneity in outcomes is seen with measurements of lipid status, in which specific blood lipid fractions (eg, total cholesterol, very low–density lipoprotein [VLDL], low-density lipoprotein [LDL], high-density lipoprotein) do not show consistent patterns of improvement among studies.

T1
TABLE:
Chronological Listing of Human Studies on Fenugreek and Glucose/Lipid Dysregulation

Several issues are likely contributing to this variability in the human study outcomes. One major contributor is the dose of and duration of exposure to the fenugreek samples. Those investigations of longer duration are more consistently effective in improving blood glucose or lipid values. Considering that HbA1c changes are often used as a measure of hypoglycemic action and that the life span of a red blood cell is 120 days, sufficient trial length is necessary to adequately monitor this important outcome.64 In general, the provision of fenugreek doses greater than 5 g/d was more likely to demonstrate fenugreek activity.

The diets of patients may also affect the benefits of fenugreek intake. The magnitude of an effect is unclear because the compositions of patient diets were not consistently evaluated. Some studies provided both control and treatment groups with isocaloric diets so that any effect of dietary caloric intake on blood glucose or lipid levels is minimized. In 1 publication, fenugreek seed powder (10 g/d), when consumed in yogurt by subjects with diabetes, was ineffective in lowering blood VLDL and serum triglyceride (TG) levels but, in contrast, was effective when given in hot water.53 Fenugreek also was administered in baked goods with inconsistent effects.27,44,47,49,60 The reasons for differences are not clear but suggest that the influence of dietary factors and methods of intake on fenugreek's actions need to be more closely examined.

Another factor affecting fenugreek activity is the severity of the patients' type 2 diabetes. For example, in a placebo-controlled investigation, patients with coronary artery disease exhibiting different degrees of type 2 diabetes symptoms were provided 5-g/d seed powder for 1 month.34 Whereas those patients considered to have severe type 2 diabetes showed no effects on fasting blood glucose (FBG) and postprandial blood glucose (PBG), those individuals determined to have mild type 2 diabetes demonstrated significant decreases in FBG and PBG when compared with initial values. These preliminary results suggest that more research is needed to elucidate how the magnitude of glucose dysregulation and insulin resistance affect responses to fenugreek dose. In this same report, a separate group of healthy individuals given the seed powder for 3 months showed no effects on FBG and PBG, when differences between the initial and final values were evaluated. This lack of effect in individuals without diabetes underscores the inconsistent influence observed in some investigations of fenugreek intake on those with normal glucose homeostasis. In addition, there were differences in the use, type, and dosing regimen of oral hypoglycemic drugs of patients with type 2 diabetes receiving fenugreek. Details of use are not consistently provided and should be more carefully described.

Fenugreek sample preparation can be a major source of variability in study outcomes. For example, seed and leaf powders and defatted/debitterized, boiled, degummed, and hydroalcoholic extracts of fenugreek have been administered to patients. A treatment effect was most consistently observed with whole-seed and defatted seed samples. The removal or modification of water-soluble gummy fiber may have contributed to the inconsistent effects of degummed and boiled seed samples. Hydroalcoholic extracts of seeds yielded inconsistent improvements in blood glucose and lipid levels when given to healthy, diabetic, and hypercholesterolemic individuals.40,41,52,55,56,62,63 The dose of extracts and their content of saponins may have contributed to these inconsistencies because, in those with type 2 diabetes, 1-g saponin powder was effective in correcting aberrant FBG, PBG, and HbA1c levels,45 as was a propriety hydroalcoholic extract enriched in furostanolic saponins.63

REVIEWS OF CLINICAL TRIALS

More than a dozen reviews have evaluated select clinical trials in which fenugreek feeding was used to manage obesity or control high blood glucose and cholesterol levels.64–79 These reviews also underscored the considerable heterogeneity and incompleteness in experimental design among trials. In particular, there often was a lack of adequate description of blinding, use of medications, controls, baseline patient characteristics, statistical analyses, washout periods when used, and methods of randomization. In some cases, the preparation of fenugreek samples was not well described, and doses varied considerably, which limited the interpretation of data and clinical applicability.65,71,74 Despite these concerns, 2 recent systematic reviews72,75 highlighted the potential use of fenugreek in glycemic control. On the basis of their analysis of 10 selected trials, Neelakantan et al72 determined that fenugreek significantly lowered FBG, 2-hour postload blood glucose levels, and HbA1c concentrations, compared with controls, and that these changes were limited to those studies providing medium to high doses of fenugreek powder (>5 g/d) to individuals with diabetes. Trials evaluating lower doses of hydroalcoholic extracts (<2 g) were without effect. Fenugreek was generally without effect on measures of blood glucose in nondiabetic subjects at the doses and durations studied. In general, it was concluded that whole raw seeds, extracted powder, gum isolates of seeds, and cooked whole seeds were effective in lowering blood glucose, whereas degummed seeds and cooked leaves were not.22,67

CONCLUSIONS

Taken together, the outcomes from human investigations suggest that fenugreek can be beneficial as an adjunct in controlling high blood glucose and lipid levels in people with diabetes. However, larger, adequately powered, randomized, placebo-controlled, double-blind trials examining multiple measures of carbohydrate and lipid metabolism and insulin homeostasis are needed. Furthermore, in future investigations, dose-dependent outcomes from chronic feeding of lower levels of powdered fenugreek seed would be helpful in confirming the range of effective doses and in assessing whether fenugreek's routine inclusion in the diet can impact glucose and insulin regulation. A better understanding of the bioavailability and disposition of putative bioactive constituents in fenugreek and the characterization of their biological actions and adverse effects warrants additional examination.80,81 In light of some reports that fenugreek samples significantly decreased fat and food intake,51,52,55 the effects of fenugreek intake on satiety and food consumption would be of interest. Moreover, the preliminary observation in people with type 2 diabetes57 that fenugreek can significantly affect serum levels of adiponectin, a hormone influencing glucose and lipid metabolism and insulin resistance, needs to be confirmed. An emerging and understudied research area is fenugreek's influence on health through its impact on the gut microbiome.80–82

SAFETY

Fenugreek extracts, oleoresins, and oils are approved as generally recognized as safe for typical use as a seasoning or flavoring agent by the US Food and Drug Administration. Generally, the studies cited in the literature report minor to no adverse effects of fenugreek intake. Human adverse effects are mainly temporary gastrointestinal disturbance and discomfort.70,83–85 In patients with diabetes, the long-term provision of gram quantities of fenugreek seed was not associated with any clinical hepatic or renal abnormalities.32 In light of the negative outcomes in genotoxicity assays for fenugreek, intake of this herb is likely to be safe at doses typically used in foods to modulate blood glucose and lipid levels.86,87

In rats, a safe and tolerable dietary dose of fenugreek seed was 2.5% w/w,88 and even higher amounts (20% w/w) given for 90 days showed no adverse effects. Debitterized fenugreek seed powder evaluated in acute and subchronic toxicity tests in mice and rats produced no significant toxicity at doses up to 5 g/kg.89 Similarly, in vivo evaluation of fenugreek-derived samples for adverse effects identified no safety concerns.90–92

Caution, nonetheless, has been recommended for fenugreek use. Pregnant women should exercise care because there is evidence of the historical use of fenugreek in inducing childbirth and it has elicited uterine stimulatory properties in animal studies.71,83,93,94 In addition, developmental toxicity was reported in offspring of female mice given a lyophilized aqueous extract of fenugreek seeds (0.5 and 1.0 g/kg of body weight [bw]) during pregnancy,95 and fetal toxicity was observed in rats injected (0.8–3.2 g/kg) with a decoction of fenugreek.96 The relevance of these high doses to the chronic, dietary use of fenugreek by humans is not known.

There is potential for fenugreek to interact with certain medications. For example, increased blood-thinning action may occur when fenugreek is taken with warfarin or other anticoagulants, and an excessive fall in blood glucose may result when taken by people with diabetes along with hypoglycemic agents.79,97–99 Fenugreek may possibly contribute to hypokalemia when consumed with diuretics or other hypokalemic agents.66 Fenugreek seed extracts and trigonelline have minimal potential to inhibit CYP2D6 and CYP3A4, suggesting that the traditional use of this herb is likely to be safe in the context of drugs metabolized by these cytochrome P450s.100 On the other hand, it was reported that fenugreek taken concurrently with theophylline can change the pharmacokinetic behavior of this drug in dogs, which suggests that fenugreek may modulate CYP1A2-mediated hepatic oxidation.101 Similar interactions could occur with CYP2C11 substrate drugs with low therapeutic indices.102 Only indirect evidence exists that fenugreek intake may enhance the effects of β-blockers, calcium-channel blockers, and cardiac glycosides.74 More long-term evaluations in larger numbers of patients are needed to better confirm any potential drug interactions and the doses of fenugreek involved. The fiber-dense fenugreek seeds may interfere with the absorption of oral medications, which should be taken 2 hours before fenugreek consumption.65,84

Allergic reactions to this spice have been documented in humans. Specifically, caution needs to be exercised by individuals allergic to other plants of the Fabaceae family (eg, chickpeas, peanuts, soybeans) because of potential cross-reactivity.65,103 Similarly, fenugreek has been identified as a significant source of fermentable oligosaccharides, disaccharides, and monosaccharides and polyols in certain ethnic foods, which should be considered by those managing functional bowel disorders.104 These issues are relevant because fenugreek is marketed commercially in encapsulated forms and is prescribed by practitioners of complementary and alternative medicine for the management of hypercholesterolemia and diabetes.105

An interesting consequence of fenugreek intake is that sotolon, a lactone derivative present in the seeds, has an unusual aroma and may cause a maple syrup odor in the sweat and urine of fenugreek consumers.73

Typical intakes of fenugreek for traditional and culinary uses have not been well documented. There is 1 report that an average portion (100 g) of fenugreek-containing ethnic foods yields approximately 1.2 g of fenugreek.104 The usual daily intake of fenugreek seed in India was noted to be 0.3 to 0.6 g per adult.106 Doses of fenugreek-containing supplements by humans were reported to be as high as 100 g,66 although typical daily intakes are 1 to 5 g.84,107 One report94 suggested that 21 g/d of fenugreek per 60-kg adult human is a recommended intake limit to prevent accidental overdose by oral administration.

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                      APPENDIX

                      ANIMAL STUDIES OF HYPOGLYCEMIC AND HYPOLIPIDEMIC EFFECTS OF FENUGREEK

                      To date, dozens of in vivo experimental studies have evaluated the capacity of fenugreek to counteract the dysregulation of glucose and lipid metabolism. These are summarized in the Table, Supplemental Digital Content 1, https://links.lww.com/NT/A19.

                      Effects on Glucose Homeostasis

                      The modulation of high blood glucose levels was examined in healthy and obese rodents and in several rodent models of diabetes induced by chemical damage to the pancreas (alloxan, streptozotocin, nitrate) or by feeding high-fat, high-sucrose, or high-cholesterol diets. One study showed that a fenugreek extract was effective when given intermittently.57 However, most studies reporting benefits continuously administered fenugreek seed powder mixed into the diet at concentrations ranging from 2.4% to 20% w/w for durations of treatment varying from 7 days to 4 months or gave fenugreek orally at doses of 1 to 8 mg/kg of bw/d for periods lasting 2 to 8 weeks. In some cases, fenugreek's actions were compared with those of insulin and other drugs. In 1 report, dietary fenugreek (5% w/w) given for 12 weeks was similar in effectiveness compared with daily metformin dosing (300 mg/kg orally [PO]).21 Fenugreek seed powder (500 mg/kg PO) for 2 weeks or 1 g/kg for 45 days was only as effective as glibenclamide (0.5 mg/kg) in lowering fasting blood glucose levels.34,35,43 Similar results were observed when fenugreek leaf powder was compared with glibenclamide.42 A study comparing fenugreek seed powder (1 g/kg PO), insulin of 4 U/kg, and glimepiride (4 mg/kg PO) treatments for 48 weeks showed that fenugreek was comparable with the 2 drugs in lowering fasting blood glucose in diabetic rats.31 Collectively considered, however, the reports of fenugreek's efficacy compared with insulin's efficacy are inconclusive. For example, fenugreek, often provided in the diet, was as effective as insulin dosing (2 IU/d) in reducing blood glucose levels in diabetic animals.3,4,6,11,12,20 Yet, in numerous other reports, fenugreek was less effective than insulin or another antidiabetic drug.5,7–9,13,15–17,19,42,43,55 Inconsistencies in the magnitude of fenugreek's hypoglycemic effects compared with those of insulin and other antidiabetic drugs are likely due to differences in experimental methods and specific fenugreek samples.

                      In 5 reports, fenugreek seed powder failed to affect blood glucose levels or other indicators of glucose homeostasis.2,26,27,29,41 The reasons for the lack of effects are not known. Differences in experimental methods may have been 1 contributor to this,2,29 and glycemic status also may be a contributing factor because, in several instances, no effect was seen in normoglycemic animals.29–31 In one of these studies, the amounts of fenugreek consumed by the diabetic rats in the supplemented diets were not described.26

                      Considering these effects on blood glucose homeostasis, these studies collectively demonstrate that dietary fenugreek seed can correct high blood glucose levels in diabetic rodents and lower concentrations of glycosylated hemoglobin where measured. It also may ameliorate diabetic symptoms (such as polydipsia and weight loss), normalize circulating levels of serum insulin, and counteract insulin resistance.

                      Overall, when measured against the efficacy of hypoglycemic drugs, the actions of fenugreek were modest and inconsistent. These results suggest that it has potential usefulness as a dietary adjunct in the control of hyperglycemia.

                      Effects on Lipid Homeostasis

                      Likewise, the treatment for hyperlipidemic animals with fenugreek was generally effective in counteracting elevated levels of blood lipids. Several early investigations provided initial scientific support for fenugreek as a dietary constituent capable of improving elevated concentrations of blood cholesterol, triglycerides, and lipoprotein-associated cholesterol in rats and rabbits.51,52,58–60 Subsequent studies during the next 3 decades confirmed fenugreek's antihyperlipidemic actions in a variety of rodent, rabbit, pig, and dog models in which lipid homeostasis was dysregulated after the administration of high-fat, high-cholesterol, high-sucrose, or high-bile salt diets or by diabetes-inducing agents. Fenugreek supplemented to diets at levels of at least 2.5% was most consistently hypolipidemic, although few reports examined lower dietary concentrations for extended periods. Similar effectiveness was observed in animals administered fenugreek orally in amounts of 0.5 to 1.0 g/kg of bw for periods of 1 to 2 months. The end points most consistently improved were blood levels of total cholesterol, triglycerides, and LDL cholesterol (LDL-C). In general, decreases in blood concentrations of total cholesterol were between 10% and 48%, triglycerides were between 14% and 53%, and LDL-C was between 14% and 44%. High-density lipoprotein cholesterol concentrations in the blood showed either no change or an increase, and where tested or calculated, blood concentrations of VLDL cholesterol and oxidized LDL, adipose tissue mass, and atherogenicity indexes decreased. As a reflection of improved kidney and liver tissue status, treatment with fenugreek generally counteracted elevated aspartate aminotransferase and alanine aminotransferase levels in the blood and tissues of diabetic and hyperlipidemic animals.

                      Comparisons of fenugreek's efficacy with lipid-lowering drugs are limited. Dietary fenugreek (0.75% w/w) reduced blood total cholesterol levels in obese Zucker rats in a manner similar to rosuvastatin (10 mg/kg) and fenofibrate (30 mg/kg) and was better than fenofibrate in lowering LDL-C.44 However, in this study, fenugreek was much less effective in suppressing blood triglyceride amounts, compared with the 2 drugs. Similar trends were detected for kidney and liver lipid concentrations, where monitored. Atorvastatin (0.5 mg/kg) was more potent in suppressing hyperlipidemia in rabbits, compared with fenugreek seed powder (500-mg/kg bw) fed for 4 weeks.61

                      In 1 study with obese rats, a novel insight was offered to explain why fenugreek supplementation led to higher plasma TG levels, compared with controls.23 It was proposed that fenugreek-associated lowering of hepatic steatosis in the obese animals led to an enhanced but temporary release of hepatic TG into the blood system. Whether this phenomenon is encountered in humans, consuming fenugreek supplements is unknown, but in long-term studies, this temporal pattern of change in blood TG levels may not necessarily reflect detrimental health effects.23

                      Potential Mechanisms of Action
                      Effects on Carbohydrate Status

                      One mechanism of action involves adjusting or normalizing activities of enzymes catalyzing glycolysis, gluconeogenesis, and glycogen metabolism. These include glucokinase, hexokinase, lactate dehydrogenase, phosphofructokinase, glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, and fructose-1,6-bisphosphatase.3,9,14,35,42,62–65 There were a few reports that fenugreek administration lowers carbohydrate digestion and absorption and can modulate the activities of kidney and intestinal disaccharidases, possibly because of the galactomannan soluble fiber content.65–68 Normalization of membrane content and distribution of glucose transporter 4 were observed in the skeletal and heart muscles and in the brain.5,8,13,69,70 Although an in vivo study did not demonstrate the restoration of insulin signaling by a fenugreek extract, in vitro studies with 4-hydroxyisoleucine suggest that fenugreek's hypoglycemic action may involve enhancing insulin sensitivity by increasing glucose uptake and glucose transporter 4 translocation in the peripheral tissues, in part through stimulating the PI3K/Akt signaling pathway.71,72 Adipocytes and liver cells were identified as additional targets for the activation of insulin signaling pathways.73 Taken together, changes in glucose metabolism and absorption, as well as a decrease in insulin resistance, can explain the fenugreek-associated changes in plasma glucose observed.74 Actions of fenugreek on insulin secretion have not been well characterized and deserve closer scrutiny.75

                      Effects on Lipid Status

                      In animal models, fenugreek altered lipid metabolism in the kidney, liver, uterus, and white adipose tissues, through modulating activities of lipogenic enzymes such as fatty acid synthase, malic enzyme, glucose-6-phosphate dehydrogenase, and β-OH-butyrate dehydrogenase. Fenugreek's hypocholesterolemic activity also was associated with greater liver conversion of cholesterol to bile acids, which may be a consequence of increased fecal excretion of bile acids and sterols. Steroid saponins, sapogenins, and galactomannans are candidate fenugreek components for mediating these changes, but a mechanism is unclear.3,7,10,12,14,69,76–78 Elevated plasma free fatty acid levels are characteristic of prediabetes and diabetes. In this regard, a fenugreek seed extract suppressed plasma free fatty acid levels in high fructose–fed insulin-resistant rats.69 Moreover, this extract increased PPARγ protein levels in the liver, which could increase fatty acid and glucose uptake and improve insulin sensitivity. In vitro evidence also points to fenugreek's capacity to up-regulate LDL receptors and decrease the expression of sterol regulatory element binding protein 1 and CAAT element binding protein-α in target tissues.79 The administration of fenugreek samples altered circulating levels of leptin and adiponectin and lowered adipose tissue mass in animal studies.69,80–82 In light of the role of leptin in regulating energy balance and the potential of adiponectin to influence insulin resistance and atherosclerosis and regulate glucose and lipid metabolism, the impact of dietary fenugreek on these metabolic regulators should be further characterized.

                      Alleviating Complications of Diabetes and Obesity

                      Fenugreek exposure can lessen tissue damage and complications of diabetes, most notably by suppressing oxidative stress. For example, in a variety of tissues in diabetic animals, fenugreek dosing led to a drop in lipid peroxide and protein carbonyl levels, compared with controls. Frequently, this was due to increased content or activities of the enzymes superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and glutathione reductase and in tissue glutathione levels.4,9,13,15,17,21,24,25,32,33,41,48,83–92 Fenugreek treatment substantially decreased diabetes-associated pathology in such tissues as the kidney, heart, liver, and pancreas. Specifically, in the liver, steatosis was lowered, structural abnormalities were prevented, central vein and sinusoidal congestion were decreased, bile duct hyperplasia was lowered, and endoplasmic reticulum stress was normalized.10,88,93,94 The hypocholesterolemic effect of fenugreek also contributed to decreased cholesterol gallstone formation in mice.45 In the kidney of diabetic animals, fenugreek administration suppressed nephropathy by decreasing glomerular capillary endothelial swelling, endolysis, fatty infiltration, glomerular extracellular matrix accumulation, and thickening of the basement membrane, compared with controls.84,89,94,95 In 1 study, suppression of diabetic ultrastructural abnormalities in the kidney after fenugreek treatment was associated with reduced oxidative stress, lower TGF-β messenger RNA and protein levels, and lower connective tissue growth factor messenger RNA and protein content in glomeruli.95 In ocular tissue, a reversal of retinal damage followed fenugreek dosing along with decreased accumulation of fructose, glucose, and sorbitol in the lens and suppression of activities of polyol pathway enzymes.19,20 Fenugreek steroids lessened the development of diabetes-induced lesions in the testis and epididymis of rats.96 In the pancreas, fenugreek decreased acini congestion and suppressed β-cell degeneration possibly because of lowering of IL6 levels and suppression of autoimmune-associated inflammation.31,84,85 The treatment for hypercholesterolemic rabbits and rodents with fenugreek extract led to decreased congestion in the tunica intima of aorta and reduced aorta atheromatous lesions.31,97 In diabetic rats, it lowered aortic reactivity and improved hemorheological parameters.98,99 Of interest, in a rat model of isoproterenol-induced myocardial infarction, fenugreek treatment improved myocardial architecture, compared with controls, as evidenced by decreases in edema, inflammatory mononuclear cells, myocardial necrosis, and separation of myocardial fibers.50 In the brain of diabetic animals, fenugreek dosing was observed to restore synaptosomal membrane fluidity and intrasynaptosomal calcium homeostasis, compared with controls, and it suppressed the accumulation of neuronal neurolipofuscin and the activities of monoamine oxidase and Ca++/ATPase.5,15,17 In the sciatic nerves, fenugreek treatment decreased neuropathy as measured by diminished axonal loss and nerve fiber demyelination.18 Several inflammatory biomarkers were reported to be lowered in the serum of diabetic rodents, including IL6, IL1, TNF-α, and C-reactive protein.21,76,100 Taken together, these findings suggest that fenugreek has considerable potential to counteract numerous complications associated with diabetes.

                      Nonetheless, in animal studies, the doses studied were pharmacological, and even in humans, the amounts used were approximately 5 to 10 times the levels found in typical ethnic diets.77 In animal investigations, responses to chronic intake of lower dietary doses of fenugreek are needed. For these studies, standard animal models of diabetes can be used, as well as those more closely mimicking maturity onset, insulin-resistant diabetes, and obesity-induced diabetes.74,101

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