Tackling the Diabetes Puzzle

Diabetes has a substantial impact on every category of human being; and its infiltration into our communities continues at an alarming rate. As diabetes and its precursors sweet talk their way into our lives, scientists and health officials struggle to define all the parameters and find solutions, and people at risk or in early stages of the disease struggle to accept and adapt to the disease and the need for lifestyle and diet changes. As a decently preventable or manageable disease, diabetes seems to respond to dietary intervention, including supplementation, which has been researched for improvements to risk factors and symptoms of diabetes.

The basis of diabetes is the inability to either produce or utilize insulin, a hormone needed to convert sugar, starches and other food into energy. In healthy individuals, glucose is absorbed in the bloodstream and transported from the pancreas to body cells by insulin. In the cells, glucose is used to produce energy, with any leftover glucose then stored in the liver. In type 1 diabetespreviously known as juvenile diabetes due to its typical child-aged suffererthe pancreatic cells do not produce insulin to handle the normal glucose load. This accounts for only a small percentage of total diabetes cases, and insulin therapy is the usual treatment. In type 2 diabetes, the predominant form of the disease, the body either doesnt produce enough insulin or the cells receiving glucose are not able to convert glucose to energy. The build-up of glucose in the system can cause all sorts of complications, including vascular problems, chronic inflammation and nutrient deficiencies.

Diabetes by Numbers

The most recent data (2007) from the American Diabetes Association (ADA) reveals around 25 million Americans suffer from diabetes, with around 6 million of these people yet undiagnosed. It afflicts men about as much as it does women, and it cuts across every age group, with the over-60s having the highest rate (23 percent), followed by the under-60 /over-20s (11 percent) and the under-20s (less than 1 percent). The disease also hits all races, although blacks and Hispanics have relatively high rates of the disease.

Overall, diabetes is the seventh leading cause of death in the United States, with heart disease factoring in 68 percent of those deaths, and stroke featured in 16 percent. In fact, ADA reports people with diabetes are 2- to 4-times more likely to develop heart disease or stroke. The diabetic devastation starts well before death, with nerve-artery damage in 60 to 70 percent of diabetics and 50 percent of non-traumatic lower limb amputations occurring in diabetes patients. Unfortunately, diabetes is also the leading cause of blindness and kidney failure.

The wake of carnage is not only made of human suffering, but also of financial woe. ADA placed annual direct medical costs at about $116 billion for those diagnosed with diabetes, with indirect costs (disability, work, premature mortality, etc.) at $58 billion per year.  Overall, U.S. diabetes costs total $218 billion, factoring in undiagnosed diabetics. Breaking it down to a personal level, the average cost per person with diabetes is about 2.3-times higher than it would be if without diabetes.

Despite the dire numbers, one statistic presents an opportunity to slow the scourge of diabetes: between 57 million and 75 million Americans are thought to have pre-diabetes, depending on whom you ask. ADA defines pre-diabetes as a condition in which blood glucose levels are higher than normal, but are not high enough for a diagnosis of diabetes.

The Road to Diabetes

ADA warned research has shown some long-term damage to the body, especially the heart and circulatory system, may already occur during pre-diabetes. It advises at-risk people to consider modifying risk factors such as increased blood glucose, blood pressure, low-density lipoprotein (LDL) cholesterol and triglyceride levels, as well as lifestyle factors, including body weight, diet and exercise. It also recommends people consider ordering a fasting plasma glucose test (FPG) or oral glucose tolerance test (OGTT) to determine pre-diabetes.

Another focal point of diabetes prevention is metabolic syndrome, also known as syndrome X, a grouping of major risk factors that increase the risk of developing heart disease, stroke and type 2 diabetes. However, experts have yet to agree on a specific definition for this elusive condition. The idea of metabolic syndrome is at least a half-century old, originally linking obesity to atherosclerosis and diabetes. Over the next few decades, scientists added hypercholesterolemia to the list of associations, and in 1988, Gerald M. Reaven, M.D., Stanford University Medical Center, added insulin resistance and coined the term Syndrome X. The American Heart Association (AHA) subsequently defined metabolic syndrome by the presence of several risk factors, including elevated triglycerides, reduced high-density lipoprotein (HDL), increased blood pressure (BP), elevated fasting glucose and waist circumference, and an increased pro-inflammatory state.

From this cauldron of knowledge comes the basis of dietary intervention, which includes a litany of supplement ingredients researched for beneficial actions on endpoints related to the various risk factors of pre-diabetes and metabolic syndrome.

Nutraceutical Research

Of the micronutrients, minerals appear to offer the strongest actions against diabetes and metabolic syndrome risk factors. A 2002 study showed low serum magnesium levels, which had already been linked to diabetes, are common in people with metabolic syndrome and correlate to increased blood pressure and dyslipidemia, including fasting triglyceride levels.¹  In 2004, Japanese research reviewers from Kansai Medical University reported magnesium is a cofactor of many enzymes involved in glucose metabolism, and insulin stimulates magnesium uptake in insulin-sensitive tissues.² They further noted intracellular magnesium concentration is low in type 2 diabetes mellitus and in hypertensive patients, and patients with type 2 diabetes show an inverse association between the plasma magnesium and insulin resistance due to intracellular changes. They concluded magnesium is required for both proper glucose utilization and insulin signaling, adding, Metabolic alterations in cellular magnesium, which may play the role of a second messenger for insulin action, contribute to insulin resistance.

A 2005 study of data on middle-aged and older American women found lower intake of the mineral was linked to systemic inflammation and prevalence of metabolic syndrome.³  Then in 2006, Ka He , M.D., Sc.D., and his team from Northwestern University, IL, investigated the relationship between metabolic syndrome and magnesium intake in young adults free of diabetes.⁴ The 15-year study involving 4,637 Americans aged 18 to 30 years found those with higher magnesium intake had a lower risk of developing metabolic syndrome, in noting the preliminary findings showing magnesiums affect on enzymes that regulate cellular glucose metabolism, as well as its possible influence on insulin secretion via interaction with cellular calcium homeostasis.

A 2004 review indicated the mineral zinc may form a complex with insulin, together improving insulins solubility in the pancreatic beta cells and also increasing its ability to bind to its insulin receptors.⁵ Most recently, a 2009 study found zinc supplementation in obese Iranian children significantly decreased mean fasting plasma glucose (FPG), insulin and insulin resistance, although the intervention failed to impact body mass index (BMI), waist circumference, LDL and triglycerides.⁶

The mineral vanadium has promisingly shown the ability to reduce FGT and OGTT compared to placebo, despite earlier research showing no effect on insulin in overweight/obese patients with impaired glucose, actually raising triglycerides.⁷ Further evidence of a benefit from vanadium in diabetes cases came from a 2009 animal study, in which diabetic rats treated with an organic vanadium had significantly lower blood glucose, total cholesterol and triglycerides, compared to diabetic rats left untreated.⁸ Their tests demonstrated organic vanadium was possibly more effective than inorganic vanadium salt at alleviating diabetes symptoms.

The crux of attention in the mineral category has been paid to chromium, which has become quite popular for its ability to reduce insulin resistance and to help reduce the risk of cardiovascular disease (CVD) and type 2 diabetes.⁹ A 2008 review of several supplements and type 2 diabetes reported 16 of the 50 studies included in the review were on chromium, most of which found a positive effect of chromium on fasting plasma glucose.¹⁰ In 2010, a Toronto General Hospital, Ontario, trial in HIV patients, who are prone to metabolic abnormalities, resulted in improved insulin resistance and other metabolic parameters, such as insulin and triglyceride levels.¹¹

There are various forms of chromium on the supplement market. A 2007 Louisiana State University, Shreveport, research comparison found chromium nicotinate (as ChromeMate®, from InterHealth USA) more effective than chromium picolinate in improving glucose controls via decreased HbA1 levels (indicator of glucose control and long-term blood sugar status), as well as in reducing specific CVD risk factors, including inflammatory biomarkers and cytokines, triglycerides and total cholesterol in a diabetic animal model.¹²

Among basic dietary nutrients, fiber can help improve blood glucose levels and weight parameters influential in diabetes. Results from a 2007 research report detailed the ability of a patented lipophilic fiber derived from Opuntia ficus-indica cactus leaves (as NeOpuntia®, from Bio Serae Labs) to balance blood lipid levels and improve HDL cholesterol in overweight females.¹³ Women taking NeOpuntia had increased HDLl and decreased triglycerides, compared to the placebo group; in the end, 39 percent of those taking the cactus supplement were no longer diagnosed with metabolic syndrome.

Fiber-rich salba, a whole grain also rich in alpha lipoic acid (ALA) and minerals, has turned in some positive results on various cardiovascular risk factors in diabetes. A 2007 Canadian trial featured type 2 diabetics taking either 37 g/d salba (intervention) or wheat bran (control) for 12 weeks while maintaining their conventional diabetes therapies.¹⁴ Compared to the control diet, salba reduced systolic blood pressure (SBP) by 6.3 mmHg and inflammatory marker C-reactive protein (CRP) by 40 percent, without affecting safety parameters such as liver, kidney and hemostatic function, or body weight. Plasma ALA and omega-3 eicosapentaenoic acid (EPA) were increased two-fold in the salba group.

Then in 2010, another St Michael's Hospital, Toronto, study sought to determine the mechanisms behind salbas cardioprotective effects in diabetes patients.¹⁵  Healthy men and women received various doses (0, 7, 15 or 24 g) of salba in white bread, and capillary samples and appetite ratings were taken two hours after consumption. The three highest doses of salba resulted in a dose-response reduction in postprandial glycemia; appetite decreased at 60 minutes for the highest dose, 90 minutes for the highest two doses and 120 minutes for all three positive doses.

Finnish researchers reported in 2009 a comparison of normal fat-free milk, lactose-free milk and a milk fortified with a novel fiber ingredient on serum glucose, insulin and satiety in healthy adults resulted in a lower insulin response in the fiber-rich milk group.¹⁶ Then in 2010, researchers from the University of Hawaii, Honolulu, discovered an association between total fiber intake and reduced diabetes risk among all male subjects, whereas high intake of grain fiber reduced diabetes risk significantly in  both men and women.¹⁷ They noted high-vegetable fiber intake lowered risk by 22 percent in all men ,but not women, while magnesium lowered risk in  both genders and possibly be the key to the effectiveness of fiber on these endpoints.

Other research on fiber has shown beta-glucan can help improve postprandial insulin responses in obese women at risk for insulin resistance,¹⁸ and the addition of maize-based fibers  (as PROMITOR Soluble Corn Fiber or PROMITOR Resistant Starch, from Tate & Lyle) to healthy beverages significantly lowered glycemic and insulinemic responses, compared with the controlbeverages.¹⁹

On other beverages, a collaborative international review of coffee and tea consumption data from more than 30 studies and almost a million subjects revealed people who drank higher than average amounts of either beverage found an inverse association between consumption and diabetes risk; they noted each additional cup of coffee consumed per day further decreased risk by 7 percent.²⁰ They noted three to four cups per day equaled a 25-percent decrease in risk, compared to drinking two or fewer cups, while included studies involving decaffeinated coffee and tea showed similarly positive results. Thus, the scientists speculated the benefits might be due to compounds other than caffeine, including antioxidant phytochemicals and magnesium.

A 2009 Chinese study reported various polysaccharides in oolong, green and black teas may benefit people with diabetes because they help retard absorption of glucose.²¹ Of the teas, black tea polysaccharides exhibited the strongest glucose-inhibiting properties. 

Phyto-Relief

InSea2, from Innovactiv, combines polyphenols from two types of brown seaweed. These phytochemicals improved diabetes and metabolic syndrome risk factors in a 2009 trial.²² Researchers from Laval University, Quebec, reported 500 mg of InSea2 given to healthy volunteers induced a 44-percent decrease in the glycemic response that normally occurs following ingestion of a standardized mea, in addition to reducing initial insulin production and overall insulin response. In fact, the ingredient improved insulin sensitivity by 6.9 percent after just one dose.

The leaves of the loquat plant (Eriobotrya japonica) contain a phytochemical known to activate blood glucose transporters, according to OptiPure, which makes the Loquoro brand extract from this plant.

University of Innsbruck, Austria, researchers investigated loquat leaves as a promising strategy to treat symptoms of the metabolic syndrome, including obesity and type 2 diabetes.²³ Their 2010 report noted corsolic acid (CA) and other triterpene constituents of loquat leaves inhibited 11beta-HSD1, a glucocorticoid-activating enzymeelevated glucocorticoids is a key risk factor for metabolic disease.²⁴

The leaves of banaba (Lagerstroemia speciosa L.) also contain anti-diabetic corosolic acid. A 2008 Japanese study examined the effect of CA on blood glucose levels and the hydrolysis of disaccharides in the small intestine in mice.²⁵ Banaba-derived CA at a does of 10 mg/kg body weight improved hypoglycemia, due partly to the inhibition of the hydrolysis of sucrose.

Another leaf-based herbal extract indicated for glucose control in diabetes comes from Gymnema sylvestre, an herb used in Ayurveda traditional medicine. In 2009, Holy Cross College, India, scientists aimed to isolate and identify gymnemas anti-diabetic compound using bioassay-guided fractionation.²⁶ They isolated dihydroxy gymnemic triacetate and administered this phytochemical to rats for 45 days at a dose of 20mg/kg body weight. Compared to the control group, the gymnema-treated animals experienced significant improvements to various diabetes parameters, including plasma glucose, insulin, glycated hemoglobin (HbA1c), tissue glycogen, lipid parameters such as triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol and activities of hepatic marker enzymes. Another Indian study looked at the effects of several plant extracts on diabetic rats.²⁷ They found the ethanol extracts of both gymnema and E. jambolana, as well as the water extract of bitter melon exhibited the highest hypoglycemic and antihyperglycemic activity, while hexane extracts had the lowest such activities.

Derived from the carob pod, D-chiro-inositol structural similarity to glucose provides promising benefits to glucose control in diabetes. A Brazilian study published in 2000 showed D-Chiro-inositol (as Chriositol, from Cyvex Nutrition) reduced glucose concentrations when co-administered with manganese in rats.²⁸ In 2002, researchers noted data showing humans and animals with type 2 diabetes typically have decreased chiro-inositol levels in tissues and in urine, which also exhibited increased myo-inositol.²⁹ In animals, this chiro-inositol decrease correlated with the severity of underlying insulin resistance determined by five separate assays. Researchers suggested a decreased conversion of myo- to chiro-inositol in vivo is the causative factor.

Maitake mushrooms (Grifola frondosa) offer another botanical remedy for glucose control. Noting maitake lowered blood glucose in diabetic animal models, Japanese researchers published 2001 study results showing substances in maitake can ameliorate symptoms of diabetes including insulin concentration changes.³⁰ A year later, Georgetown University Medical Center, Washington, study on whole mushroom powder and two maitake extracts on insulin resistance in a hypertensive and Zucker (obese) animal models revealed improvements to certain diabetic and metabolic factors.³¹ Only the ether soluble extract decreased SBP in hypertensive rats, while the water soluble extract and whole powder both lowered SBP in Zucker rats, in addition to lowering triglycerides in the hypertensive rats.  Among the other actions reported, circulating insulin and HbA1C were significantly decreased in whole powder and ether extract groups.

A 2008 comparison study of three fungal mushroom ingredients rich in vanadium in hyperglycemic and normal mice.³² Administration of Coprinus comatus decreased blood glucose in hyperglycemic mice and improved sugar tolerance in normal mice. Maitake and Ganoderma lucidum did not produce the same result.³³ However, in a 2009 Chinese study, fermented maitake rich in vanadium decreased blood glucose and HbA1c levels in hyperglycemic mice.³⁴

Another Asian-inspired botanical for diabetes is Phellodendron amurense tree bark extract coupled with polymethoxylated flavones extracted from Citrus sinensis to lower fasting glucose in overweight subjects.³⁵ The combination (as Flavoxine, from Next Pharamceuticals) also significantly lowered triglycerides and LDL  in both overweight and normal weight subjects; HDL was concurrently increased.

A fellow tree bark ingredient making inroads to management of diabetes parameters is French maritime pine bark extract (as Pycnogenol®, from Horphag Research).  Supplementation with 100 mg of Pycnogenol for 12 weeks in type 2 diabetes patients significantly lowered plasma glucose levels as compared to placebo.³⁶ A decrease in glycated hemoglobin was only relevant compared to placebo for the first month of intervention.

Pycnogenols biggest impact may be in diabetic retinaopathy, damage to the retinal vessels. A 2006 African trial showed Pycnogenol plays a role in antioxidant defense and anti-hyperglycemia efforts, ultimately reducing risk of diabetic retinopathy and cataract formation.³⁷ Then, a late-2009 research report highlighted Pycnogenols improvements to microcirculation, retinal edema and visual acuity in the early stages of diabetic retinopathy.³⁸ The G D'Annunzio University, Italy, trial involved patients previously diagnosed with diabetes for at least four years prior to the study, who also had retinopathy characterized by leaky capillaries causing swellings. After intervention with three 50 mg of Pycnogenol tablets or placebo tablets for three months, visual improvements in 75 percent in the Pygnogenol group abased on perception and improved visual acuity based on testing compared favorably to placebo, which showed no such improvements.

The antioxidant botanical ingredient resveratrol found in many plants, including  grapes, has been shown to reduce metabolic disturbances and lower BP in obese Zucker rats after long-term supplementation.³⁹ In 2008, French scientists reported resveratrol appears to impact metabolic pathways in humans, which helps the development of diet-induced obesity and obesity-dependent metabolic disorders .⁴⁰ Non-toxic and easily absorbed by humans, resveratrols bioavailability is limited by metabolic interactions in plasma, they concluded improved bioavailability would increase the botanicals therapeutic potential.

Then in 2010, researchers at China Pharmaceutical University, Nanjing, investigated whether resveratrols anti-inflammatory actions play a part in its amelioration of diabetes or insulin resistance.⁴¹ This in vitro study found resveratrol improved insulin sensitivity in adiposities after modulating insulin signaling transduction, all relative to inhibiting inflammatory response.

Still more herbal ingredients have generated positive research results on diabetes and metabolic syndrome. Adding another bark-based ingredient to the category, cinnamon was found to activate certain receptors which serve as transcriptional factors in the regulation of insulin resistance and adipogenesis.⁴² A 2006 trial featured subjects with pre-diabetes and metabolic syndrome randomly assigned to receive  either 500 mg/d of Cinnulin PF (from Integrity Nutraceuticals International), a water-soluble cinnamon extract or a placebo for 12 weeks.⁴³ Those taking Cinnulin PF group tested for significant decreases in fasting blood glucose and  SBP, while lean mass increased, compared with the placebo group. The researchers noted there was a slight, but statistically significant decrease in body fat in the Cinnulin PF group.

In another study, participants were randomized to take either daily oral cinnamon or a placebo for eight weeks, and researchers compared post-treatment insulin sensitivity indices to baseline data.⁴⁴ They found significant reductions in insulin resistance in the cinnamon group, but not in the placebo group.

Most recently, a 2009 study involving healthy subjects found 3 g of cinnamon consumed in rice pudding decreased postprandial serum insulin and increased glucagon-like peptide 1 (GLP-1) concentrations without significantly affecting blood glucose, glucose-dependent insulinotropic polypeptide (GIP), the ghrelin concentration, satiety or gastric emptying rate (GER).⁴⁵ Researchers noted the results indicate a dose-dependent decrease in insulin concentration by cinnamon.

With so many wide-reaching risk factors and consequences, diabetes and its preceding pre-diabetes and metabolic syndrome can benefit from many different remedies that target the various endpoints. Nonetheless, a solid line-up of nutrients and herbs have been studied for specific impact on insulin, glucose and cardiovascular parameters of this pervasive disease.

References on the next page...

References for "Tackling the Diabetes Puzzle"

1. Guerrero-Romero F and Rodríguez-Morán M. Low serum magnesium levels and metabolic syndrome. Acta Diabetol. 2002 Dec;39(4):209-13.

2. Takaya J et al. Intracellular magnesium and insulin resistance. Magnes Res. 2004 Jun;17(2):126-36.

3. Song Y et al. Magnesium intake, C-reactive protein, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care. 2005 Jun;28(6):1438-44.

4. He K et al. Magnesium intake and incidence of metabolic syndrome among young adults. Circulation. 2006 Apr 4;113(13):1675-82.

5. Marreiro DN et al. [Role of zinc in insulin resistance] Arq Bras Endocrinol Metabol. 2004 Apr;48(2):234-9.

6. Hashemipour M et al. Effect of zinc supplementation on insulin resistance and components of the metabolic syndrome in prepubertal obese children. Hormones (Athens). 2009 Oct-Dec;8(4):279-85.

7. Jacques-Camarena O et al. Effect of vanadium on insulin sensitivity in patients with impaired glucose tolerance. Ann Nutr Metab. 2008;53(3-4):195-8.

8. Li M et al. Anti-diabetic effects of sodium 4-amino-2,6-dipicolinatodioxovanadium(V) dihydrate in streptozotocin-induced diabetic rats. J Inorg Biochem. 2009 Apr;103(4):585-9.

9. Hummel M et al. Chromium in metabolic and cardiovascular disease. Horm Metab Res. 2007 Oct;39(10):743-51.

10. Bartlett HE, Eperjesi F Nutritional supplementation for type 2 diabetes: a systematic review Ophthalmic Physiol Opt. 2008 Nov;28(6):503-23

11. Aghdassi E et al. In patients with HIV-infection, chromium supplementation improves insulin resistance and other metabolic abnormalities: a randomized, double-blind, placebo controlled trial. Curr HIV Res. 2010 Mar 1;8(2):113-20.

12. Jain SK et al. Effect of chromium niacinate and chromium picolinate supplementation on lipid peroxidation, TNF-alpha, IL-6, CRP, glycated hemoglobin, triglycerides, and cholesterol levels in blood of streptozotocin-treated diabetic rats. Free Radic Biol Med. 2007 Oct 15;43(8):1124-31.

13. Linarès E et al. The effect of NeOpuntia on blood lipid parameters--risk factors for the metabolic syndrome (syndrome X). Adv Ther. 2007 Sep-Oct;24(5):1115-25.

14. Vuksan V et al. Supplementation of conventional therapy with the novel grain Salba (Salvia hispanica L.) improves major and emerging cardiovascular risk factors in type 2 diabetes: results of a randomized controlled trial. Diabetes Care. 2007 Nov;30(11):2804-10.

15. Vuksan V et al. Reduction in postprandial glucose excursion and prolongation of satiety: possible explanation of the long-term effects of whole grain Salba (Salvia Hispanica L.). Eur J Clin Nutr. 2010 Jan 20, Epub ahead of print.

16. Lummela N et al. Effects of a fibre-enriched milk drink on insulin and glucose levels in healthy subjects. Nutr J. 2009 Oct 1;8:45.

17. Hopping BN et al. Dietary fiber, magnesium, and glycemic load alter risk of type 2 diabetes in a multiethnic cohort in Hawaii. J Nutr. 2010 Jan;140(1):68-74.

18. Kim H et al. Glucose and insulin responses to whole grain breakfasts varying in soluble fiber, beta-glucan: a dose response study in obese women with increased risk for insulin resistance. Eur J Nutr. 2009 Apr;48(3):170-5.

19. Kendall CW et al. Effect of novel maize-based dietary fibers on postprandial glycemia and insulinemia. J Am Coll Nutr. 2008 Dec;27(6):711-8.

20. Huxley R et al. Coffee, Decaffeinated Coffee, and Tea Consumption in Relation to Incident Type 2 Diabetes Mellitus. Arch Intern Med. 2009;169(22):2053-2063.

21. Chen H et al. Physicochemical properties and antioxidant capacity of 3 polysaccharides from green tea, oolong tea, and black tea. J Food Sci. 2009 Aug;74(6):C469-74.

22. Presented at the Experimental Biology meeting in Anaheim, Calif., April 2010.

23. Rollinger JM et al. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 by plant extracts used as traditional antidiabetic medicines. Fitoterapia. 2009 Jan 23, Epub ahead of print.

24. Rollinger JM et al. 11beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational approaches. Bioorg Med Chem. 2010 Feb 15;18(4):1507-15.

25. Takagi S et al. Effect of corosolic acid on the hydrolysis of disaccharides. J Nutr Sci Vitaminol (Tokyo). 2008 Jun;54(3):266-8.

26. Daisy P et al. A novel dihydroxy gymnemic triacetate isolated from Gymnema sylvestre possessing normoglycemic and hypolipidemic activity on STZ-induced diabetic rats. J Ethnopharmacol. 2009 Nov 12;126(2):339-44.

27. Yadav M et al. Complementary and Comparative Study on Hypoglycemic and Antihyperglycemic Activity of Various Extracts of Eugenia jambolana Seed, Momordica charantia Fruits, Gymnema sylvestre, and Trigonella foenum graecum Seeds in Rats. Appl Biochem Biotechnol. 2010 Apr;160(8):2388-400.

28. Fonteles MC et al. Antihyperglycemic effects of 3-O-methyl-D-chiro-inositol and D-chiro-inositol associated with manganese in streptozotocin diabetic rats. Horm Metab Res. 2000 Apr;32(4):129-32.

29. Sun TH et al. Both myo-inositol to chiro-inositol epimerase activities and chiro-inositol to myo-inositol ratios are decreased in tissues of GK type 2 diabetic rats compared to Wistar controls. Biochem Biophys Res Commun. 2002 May 10;293(3):1092-8.

30. Horio H and Ohtsuru M. Maitake (Grifola frondosa) improve glucose tolerance of experimental diabetic rats. J Nutr Sci Vitaminol (Tokyo). 2001 Feb;47(1):57-63.

31. 30. Talpur NA et al. Antihypertensive and metabolic effects of whole Maitake mushroom powder and its fractions in two rat strains Mol Cell Biochem. 2002 Aug;237(1-2):129-36

32. Han C and Liu T. Comparison of vanadium-rich activity of three species fungi of basidiomycetes. Biol Trace Elem Res. 2009 Mar;127(3):278-83.

33. Han C and Liu T. A comparison of hypoglycemic activity of three species of basidiomycetes rich in vanadium. Biol Trace Elem Res. 2009 Feb;127(2):177-82.

34. Cui B et al. Hypoglycemic activity of Grifola frondosa rich in vanadium. Biol Trace Elem Res. 2009 Nov;131(2):186-91.

35. Oben J et al. Phellodendron and Citrus extracts benefit cardiovascular health in osteoarthritis patients: a double-blind, placebo-controlled pilot study. Nutr J. 2008 May 20;7:16.

36. Liu X et al. Antidiabetic effect of Pycnogenol French maritime pine bark extract in patients with diabetes type II. Life Sci. 2004 Oct 8;75(21):2505-13.

37. Kamuren ZT et al. Effects of low-carbohydrate diet and Pycnogenol treatment on retinal antioxidant enzymes in normal and diabetic rats. J Ocul Pharmacol Ther. 2006 Feb;22(1):10-8.

38. Steigerwalt R et al. Pycnogenol improves microcirculation, retinal edema, and visual acuity in early diabetic retinopathy. J Ocul Pharmacol Ther. 2009 Dec;25(6):537-40.

39. Rivera L et al. Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem Pharmacol. 2009 Mar 15;77(6):1053-63.

40. Durand C et al. Metabolic effects of resveratrol in mammals--a link between improved insulin action and aging. Curr Aging Sci. 2008 Dec;1(3):145-51.

41. Kang L et al. Resveratrol modulates adipokine expression and improves insulin sensitivity in adipocytes: Relative to inhibition of inflammatory responses. Biochimie. 2010 Feb 25, Epub ahead of print.

42. Sheng X et al. Improved Insulin Resistance and Lipid Metabolism by Cinnamon Extract through Activation of Peroxisome Proliferator-Activated Receptors. PPAR Res. 2008;2008:581348.

43. Ziegenfuss TN et al. Effects of a water-soluble cinnamon extract on body composition and features of the metabolic syndrome in pre-diabetic men and women. J Int Soc Sports Nutr. 2006 Dec 28;3:45-53.

44. Wang JG et al. The effect of cinnamon extract on insulin resistance parameters in polycystic ovary syndrome: a pilot study. Fertil Steril. 2007 Jul;88(1):240-3.

45. Hlebowicz J et al. Effects of 1 and 3 g cinnamon on gastric emptying, satiety, and postprandial blood glucose, insulin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and ghrelin concentrations in healthy subjects. Am J Clin Nutr. 2009 Mar;89(3):815-21.