Addressing Metabolic Syndrome

References

Metabolic syndrome is a convergence of cardiovascular disease (CVD) and diabetes risk factors—including being overweight/obese, high blood pressure, abnormal blood lipids and blood glucose abnormalities—connected by insulin resistance. While a relatively new term, and one that is still not officially recognized in some mainstream medical circles, its profile is rising with mainstream media attention.

Researchers from the University of Minnesota recently reported not only does the Western dietary pattern—high intakes of refined grains, fried foods and red meat—significantly increase the risk of developing the disorder (by 18 percent), but drinking diet soda raised the risk by 34 percent.¹ In their study, 60.5 percent of the population (n=9,514; ages 40 to 64 at baseline) had metabolic syndrome at baseline or developed it during the nine-year followup. It’s not only adults who are facing rising rates of metabolic syndrome; new research suggests about 9 percent of U.S. teenagers have metabolic syndrome, with incidence rising to one in four obese teens.²

A recent study from the Joslins Diabetes Center, Boston, specifically identified insulin resistance in the liver as a key factor in the development of metabolic syndrome and the associated cardiac pathologies.³ Using liver insulin receptor knockout (LIRKO) mice, which have pure hepatic insulin resistance, the researchers found an atherogenic diet caused LIRKO mice to develop severe atherosclerosis, beyond the dyslipidemia developed on a standard chow diet.

In insulin resistance, there is a reduction in the number of insulin receptors sites on the cell wall. The result of this, according to a review of the etiology of metabolic syndrome, produced by Albion Advanced Nutrition, is that glucose cannot be efficiently transferred by insulin through these receptor sites from the bloodstream into the cell to be burned as energy. This causes elevated blood sugar levels. This blood sugar is carried into the liver, where it is converted to fat that can be transferred and stored throughout the body, the end result being weight gain. Additionally, the conversion of these sugars to triglycerides leads to unhealthy blood lipid levels, which can lead to CVD.

The American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) recommend metabolic syndrome be identified as the presence of three or more of the following components: elevated waist circumference; elevated triglycerides; reduced high-density lipoprotein (HDL) cholesterol; elevated blood pressure; and elevated fasting glucose. Lifestyle therapies are considered first-line interventions for managing both long- and short-term risk, including fat loss, increased physical activity, and following a healthy diet with a reduced intake of saturated fat and cholesterol, and an emphasis on whole grains, fruits and vegetables, fish and lean protein, and low-fat dairy.

Obesity appears to be one of the driving forces behind metabolic syndrome. Italian researchers reported a literature review found the most striking resolution of metabolic syndrome based on different approaches was with weight-reduction surgery, in which 93 percent of cases were resolved.⁴ At the same time, the researchers acknowledged it is likely a more Mediterranean-style diet may be a less drastic intervention, while offering a workable dietary pattern: lower content of refined carbs, high fiber, moderate intake of fat (mostly unsaturated), and a moderate-to-high content of vegetable proteins. Spanish researchers seconded the use of a Mediterranean-style diet to address not only fat loss, but also to help control inflammation.⁵

A one-year trial out of Italy supports this suggestion, as adults who followed a lifestyle intervention with diet and exercise (n=169) significantly reduced metabolic syndrome incidence, central obesity and diabetes risk, compared to control subjects who were only given general information.⁶ Data from the Framingham-Offspring study concluded women with higher nutritional risk profiles (more total fats, more alcohol, less fiber, less micronutrients) had a two- to three-fold risk of developing abdominal obesity and metabolic syndrome.⁷

Whole grains and fiber are particularly cited by researchers for health benefits that translate into the area of metabolic syndrome. A review out of the University of Granada, Spain, noted dietary fiber could play a key role in managing metabolic syndrome through multiple mechanisms of action, including aiding weight management, supporting glucose and lipid homeostatus, enhancing insulin control, and regulating inflammatory markers.⁸ Italian researchers found in a cohort of 1,653 adults, prevalence of metabolic syndrome significantly decreased from the lowest to the highest tertile of fiber and magnesium intake, with subjects in the lowest tertiles three- to four-times as likely to have metabolic syndrome.⁹ Further, an intervention study at Pennsylvania State University College of Medicine, Hershey, involving 50 obese adults with metabolic syndrome, concluded a hypocaloric diet with an emphasis on whole grain intake had greater reductions in inflammatory markers and abdominal fat, compared to those consuming refined grains.¹⁰

Researchers have also found benefits of specific types of fibers in addressing different aspects of metabolic syndrome. Oat beta-glucan (as Viscofiber®, from Natraceutical Canada) was the subject of two clinical studies at St. Michael’s Hospital, Toronto. In the first study, Viscofiber was compared to a less-viscous oat betaglucan and found to be more effective at suppressing postprandial glycemia in healthy individuals.¹¹ The second study, which is in preparation for publication, examined the effect of oat and barley Viscofiber on postprandial glycemia and plasma insulin in healthy individuals, and found a dose-dependent reduction in both indices. Studies have further found intervention with Viscofiber can assist in weight loss by increasing satiety;¹² and oat beta-glucan helps reduce serum cholesterol,¹³ and hypertension.¹⁴

A research review out of Pakistan reported guar gum may have a role to play in addressing metabolic syndrome, as its soluble dietary fiber content may improve cholesterol levels, aid in glycemic control and support weight management.¹⁵ Animal research out of Spain found long-term intake of guar by healthy rats improved glucose tolerance and insulin response to glucose absorption.¹⁶

The type of fat in the diet is also an important factor in managing metabolic syndrome. A review out of Cape Breton University, Nova Scotia, noted consumption of the long-chain omega-3 essential fatty acids (EFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) particularly benefits metabolic syndrome by impacting dyslipidemia and platelet aggregation, in addition to possibly reducing conversion of metabolic syndrome to type 2 diabetes.¹⁷ To wit, a population study in Alaska natives found consumption of long-chain omega-3 EFAs from fish were associated with lower blood pressure and triglyceride levels, as well as lower fasting insulin; higher consumption of saturated fat and trans fats increased triglyceride levels and blood pressure, with adverse effects on metabolic syndrome.¹⁸ Researchers from the University of Litoral, Santa Fe, Argentina, examined the impact of fish oil on dyslipidemia, insulin resistance and adiposity in rats.¹⁹

They found fish oil reversed dyslipidemia, improved insulin activity and reduced weight; part of its activity was linked to a reduction in adipocyte cell size, making them more insulin sensitive and reducing the release of fatty acids.

Nutritional Factors

As mentioned in the Italian study of fiber intake and metabolic syndrome, magnesium appears to also be a key compound in addressing the different factors of this condition. Researchers from the U.S. Centers for Disease Control and Prevention (CDC) reviewed data from the Third National Health and Nutrition Examination Sur vey (1988 to 1994) and found an inverse association between dietary magnesium intake and the prevalence of metabolic syndrome.²⁰ And a review out of Northwestern University, Chicago, noted studies indicate magnesium plays a pivotal role in glucose homeostasis and insulin secretion, and intake may be inversely related to the risk of hypertension and diabetes.²¹

The same research team from Northwestern examined the relationship of magnesium intake in young adults (n=4,637) to incidence of metabolic syndrome.²² During the course of 15 years of follow-up, there were 608 incidences of metabolic syndrome, with magnesium intake inversely associated with disease incidence. The researchers stated: “Experimental data suggests that magnesium may directly regulate cellular glucose metabolism through its role as a cofactor for a number of relevant enzymes and may influence insulin secretion by interacting with cellular calcium homeostasis. In addition, epidemiological studies and clinical trials indicate that magnesium intake may improve insulin sensitivity.”

Another important mineral in this arena is chromium, which reviewers note has been shown to facilitate insulin signaling, improve systemic insulin sensitivity and reduce CVD risk.²³ An animal study out of Louisiana State University, Shreveport, found niacin-bound chromium and chromium picolinate worked to lower pro-inflammatory cytokines, with the niacin-bound chromium also reducing lipid levels and oxidative stress.²⁴ A study conducted at the University of Vermont, Burlington, reviewed the effects of chromium picolinate on obese hyperinsulinemic rats and found intervention significantly lowered fasting insulin levels and improved glucose disappearance.²⁵ In addition, treated obese rats had lower plasma total cholesterol.

Follow-up work by the Vermont team involved 37 type 2 diabetics who were given sulfonylurea plus placebo or 1,000 mcg/d of chromium picolinate for six months.²⁶ Drug therapy alone resulted in a significant increase in body weight, which was attenuated by chromium supplementation. Intervention also significantly improved insulin sensitivity and glucose control.

Two studies conducted at the Alpha Therapy Center, Corpus Christ y, Texas, examined the effects of a combination of chromium picolinate and biotin in type 2 diabetics. The first study, a double blind, placebo-controlled trial, involved 348 participants randomized to receive the combination supplement (600 mcg chromium and 2 mg biotin) or placebo for 90 days.²⁷ Intervention significantly lowered glucose levels in all participants, and lowered total cholesterol and the atherogenic index in patients with hypercholesterolemia. In the second trial, 447 type 2 diabetics received the same combination supplement or placebo for 90 days in combination with oral anti-diabetic agents; researchers found the supplement could improve glycemic control, particularly among patients with poor glycemic control strictly on oral therapy.²⁸

Vitamin E

is also important in addressing different aspects of metabolic syndrome. A recent population study out of Korea noted low vitamin E levels were inversely associated with incidence of metabolic syndrome.²⁹ Similarly, Finnish researchers reviewing a cohort of more than 4,200 adults over a 23-year follow-up found vitamin E intake was significantly associated with a reduced risk of type 2 diabetes.³⁰

Tocotrienols

may prove particularly efficacious in addressing cardiometabolic pathologies associated with metabolic syndrome. Providing rice bran oil containing tocotrienols to diabetic rats has been shown to decrease blood glucose levels,³¹ lower plasma triglyceride and cholesterol levels, and suppress hyperlipidemic and hyperinsulinemic responses.³² In clinical trials with diabetic patients, rice bran water solubles reduced hyperglycemia and glycosylated hemoglobin, and increased insulin levels.³³ In a two-month study in type 2 diabetics, tocotrienols decreased serum total lipids by 23 percent and total cholesterol by 30 percent.³⁴ Two open, company-sponsored studies from American River Nutrition found two months of annatto tocotrienol (75 mg/d) supplementation significantly reduced total and LDL cholesterol levels, while increasing HDL cholesterol.

Another antioxidant playing a role in metabolic syndrome is alpha-lipoic acid (ALA). At its most fundamental biological level, ALA breaks down glucose in every cell and converts it to energy. Animal studies have shown ALA may enhance weight loss, ameliorate insulin resistance and atherogenic dyslipidemia, and lower blood pressure, positioning it as a therapeutic agent for treating metabolic syndrome.³⁵ Such research suggests ALA may work in part by increasing fatty acid oxidation, preventing triglyceride accumulation in skeletal muscle that can lead to insulin resistance.³⁶ Further in vitro trials have found ALA may directly affect beta cell function, reducing insulin secretion, while also enhancing mitochondrial function and inhibiting AMP-activated protein kinase (AMPK), thereby preventing obesity.³⁷

Clinical research supports the initial findings. A study at Emory University School of Medicine, Atlanta, involved 58 subjects with metabolic syndrome; they were randomized to receive an angiotensin receptor blocker, lipoic acid (300 mg/d), both or neither for four weeks.³⁸ Treatment with both the pharmaceutical and/or ALA was associated with statistically significant reductions in inflammatory cytokines and improved endothelial function. Bulgarian researchers have further found ALA treatment can improve insulin sensitivity in type 2 diabetics.³⁹

Studies have also investigated the synergistic activities of ALA with acetyl-Lcarnitine (ALC), an acetylated form of the amino acid L-carnitine. Reviews suggest co-administration of ALA with ALC may have greater effects in reducing oxidative mitochondrial dysfunction.⁴⁰ Further, animal research suggests the combination of nutrients may work to maintain myocardial function,⁴¹ while also increasing oxygen consumption and fatty acid oxidation in adipocytes, enhancing fat metabolism.⁴²

On its own, the amino acid L-carnitine is well-known for the vital role it plays in fat metabolism, working to transport fatty acids into the mitochondria. In a review of the challenges with insulin resistance in obese adults, researchers at the University of Louisville, Ky., cited carnitine as one dietary agent that may help correct problems at the molecular level.⁴³ Animal studies, primarily using the high fructose-fed Wistar rat, have shown L-carnitine may operate on a number of levels in fighting metabolic syndrome. Researchers from Annamalai University, Annamalai Nagar, India, examined the effect of L-carnitine on lipid accumulation and peroxidative damage in skeletal muscle.⁴⁴ Intervention ameliorated the insulin resistance seen in the fructosefed animals, normalizing oxidative stress levels and avoiding antioxidant depletion. The same researchers reported L-carnitine (300 mg/Kg) could lower blood pressure in rats by increasing nitric oxide availability and providing antioxidant protection,⁴⁵ and counter progressive renal disturbances seen in this model of metabolic syndrome.⁴⁶

Conjugated linoleic acid

(CLA), like L-carnitine, is known primarily for its influence on weight management, but has multiple functions in the body that position it as a player in the metabolic syndrome area. One of the most recent studies in weight management reported CLA supplementation (3.2 g/d as Tonalin® CL A, from Cognis Nutrition & Health) in a group of 40 healthy, overweight subjects for six months over the holiday season actually improved body composition, reducing body fat.⁴⁷ While insulin resistance was not affected, there was a decrease in biomarkers of endothelial dysfunction. However, a study out of the University of Alberta, Edmonton, found a combination of CLA and chromium picolinate could reduce food intake, body weight and fasting insulin levels in an animal model, while simultaneously improving vascular function suggesting their usefulness as adjuncts in treatment of met abolic syndrome.⁴⁸ Japanese researchers found dietary CLA given to obese, diabetic Zucker rats could alter expression of several genes related to lipid metabolism and insulin sensitivity, alleviating insulin resistance and increasing expression of lipolytic genes.⁴⁹

In addition, CLA may work to synergistically enhance the effect of other treatments for metabolic syndrome. Researchers from the University of Manitoba, Winnipeg, examined the effect of the antihypertensive drug, telmisartan, with CLA in a 20- week rat study.⁵⁰ Co-administration of the drug and nutraceutical resulted in significant reductions in body weight, visceral fat, total cholesterol, triglycerides, plasma insulin concentrations and systolic blood pressure, compared to the control group.

Botanicals with Benefits

Around the globe and throughout history, traditional healers have turned to the power of botanicals and plants used naturally in the diet to help treat the conflux of issues seen in metabolic syndrome. Consider the role of soy in Asian cultures, serving as the primary source of protein and delivering its host of phytonutrients. Studies have shown greater intake of soy may reduce the risk of diabetes; data from the Shanghai Women’s Health Study found a 50-percent reduction in the risk of developing type 2 diabetes when comparing the highest versus lowest quintiles of soybean intake.⁵¹ Research from the same cohort also found a clear dose-response relationship between soyfood intake and risk of coronary heart disease,⁵² and an inverse relationship between soyfood intake and both systolic and diastolic blood pressure.⁵³ Interestingly, the study also showed a significant association between abdominal adiposity and mortality risk from CVD and diabetes.⁵⁴

Intervention studies have also shown benefits of including soy in the diet. Researchers at Isfahan University of Medical Sciences, Iran, randomized 42 postmenopausal women with metabolic syndrome to consume a control diet (Dietary Approaches to Stop Hypertension [DASH]), a soy diet (replacing one serving of red meat per day in the DASH diet with soy protein) and soy nut diet (replacing one serving of red meat per day in the DASH diet with soy nuts).⁵⁵ Soy nut consumption reduced inflammatory markers and increased nitric oxide levels, improving endothelial function. Further analysis of the data revealed soy nut consumption also improved glycemic control and lipid profiles more than the control or soy protein diet.⁵⁶

Chinese researchers conducted an intervention with 30 obese adults and found those who consumed a hypocaloric diet with only soy protein (compared to 1/3 soy and 2/3 animal protein) had greater reductions in total cholesterol and LDL cholesterol, as well as greater effects on body fat percentages.⁵⁷ Researchers from the Functional Medicine Research Center, Gig Harbor, Wash., randomly assigned 59 postmenopausal overweight/obese women to the AHA Step 1 diet or a low-glycemic diet delivering 30 g/d of soy protein.⁵⁸ Women on the low-glycemic/soy diet had significantly significant decreases in total cholesterol, LDL cholesterol and triacylglycerol.

An important part of the Asian diet is green tea, which has antioxidant and anti-inflammatory effects, while also positively impacting atherosclerosis, hypertension and obesity.⁵⁹ Boston University researchers note green tea’s flavonoids appear to positively impact endothelial function, reducing cardiovascular risk.⁶⁰ In addition, green tea polyphenols are able to decrease lipid peroxidation and prevent the overproduction of pro-inflammatory cytokines.⁶¹

Of particular interest to researchers has been green tea’s most bioactive flavonoid, epigallocatechin gallate (EGCG). Italian researchers conducted an experiment in spontaneously hypertensive rats (SHR) to examine the effects of EGCG on cardiovascular and metabolic function.⁶² EGCG stimulated production of nitric oxide from the endothelium, improving vasodilation and lowering systolic blood pressure while also benefiting insulin sensitivity. In vitro work from the University of Dundee, Scotland, reported EGCG exerted insulin-mimetic effects, in part by phosphorylation of transcription factors.⁶³ And researchers from the Hamner Institutes for Health Sciences, Research Triangle Park, N.C., report in isolated hepatocytes that EGCG can inhibit glucose production via gluconeogenesis.⁶⁴

Researchers have also cited EGCG for its ability to reduce adipocyte proliferation, while increasing beta-oxidation and thermogenesis.⁶⁵ In a pilot study conducted at Universitary Medicine Berlin, six overweight men given 300 mg/d EGCG had increased fat oxidation in adipose tissue mass.⁶⁶ Thai researchers reported similar findings in their trial involving 60 obese men, in which green tea increased energy expenditure and fat oxidation.⁶⁷ A trial in 76 over weight women, conducted at Maastricht University, Netherlands, also found providing 270 mg/d EGCG plus 150 mg/d caffeine increased weight loss through thermogenesis and fat oxidation and with suppressed leptin.⁶⁸

Also out of Asia comes the “king of mushrooms”, maitake (Grifola frondosa). Maitake Products received a patent (U.S. Patent No. 7,214,778) for its SX-Fraction®, covering its anti-diabetic, anti-hypertensive, anti-hyperlipidemic and anti-obesity effects. SX-Fraction is a glycoprotein, an oligosaccharide-bound protein, from which the immune-enhancing portion has been removed during extraction. Researchers at Georgetown University Medical Center, Washington, conducted a study in insulinresistant KK mice to determine the benefits of a water-soluble extract of maitake (as SX-Fraction, from Maitake Products) on glucose/insulin metabolism.⁶⁹ A dose of 140 mg/mouse induced a statistically significant lowering of circulating glucose concentrations; in a chronic test, it lowered both circulating concentrations of glucose and insulin. The findings suggest maitake works by enhancing peripheral insulin sensitivity. And a study in genetically diabetic rats with insulin resistance found providing SX-Fraction to the animals lowered systolic blood pressure after only five days by 15 to 20 mmHg.⁷⁰

There maybe synergistic effects between maitake, niacin-bound chromium and Garcinia cambogia extract, according to another Georgetown trial.⁷¹ In a study of aged, diabetic Zucker fatty rats, the combination of SX-Fraction, niacin-bound chromium (as ChromeMate®, from InterHealth Nutraceuticals) and hydroxycitric acid (HCA) from G. cambogia (as CitriMax®, from InterHealth Nutraceuticals) lowered systolic blood pressure and helped maintain body weight, compared to controls. There was also a general trend for improved renal and liver function. Additional investigation from the research team on a combination of SX-Fraction and niacin-bound chromium reported the extract could lower systolic blood pressure and circulating glucose, as well as decreasing triglycerides in rats.⁷²

On its own, garcinia, a fruit grown in southeast Asia, and west and central Africa, may impact both adipocity and glucose metabolism. In vitro work out of Korea suggests garcinia extract inhibits cytoplasmiclipidaccumulation and adipogenic differentiation of preadipocytes.⁷³ Animal trials have found garcinia improves glucose metabolism and displays leptinlike activity,⁷⁴ as well as aiding in weight loss, although there are concerns about its impact on cholesterol ratios.⁷⁵ Additionally, researchers at the University of Houston examined the impact of HCA (as Super CitriMax, from InterHealth Nutraceuticals) on inflammation, oxidative stress and insulin resistance in obese Zucker rats.⁷⁶ Supplementation reduced food intake and weight gain, while attenuating increases in inflammatory markers, oxidative stress and insulin resistance.

India is the source of several botanicals historically used for controlling diabetes and regulating blood sugar. Gymnema sylvestre ex tract has anti-hyperglycemic activit y and may inhibit glucose uptake, impacting blood glucose management.⁷⁷ Researchers from Tottori University, Yonago, Japan, investigated the effects of gymnema extract in a rat model of metabolic syndrome; they found treatment promoted reduced food intake, decreased body weight and reduced hyperlipidemia, without a rebound after withdrawal.⁷⁸

Gymnema also appears to work in concert with chromium and other botanical agents. Researchers from Georgetown University conducted an eight-week, double blind, placebo-controlled study in which 60 moderately obese subjects received a combination of gymnema extract, niacinbound chromium (as ChromeMate) and HCA (as Super CitriMax) or placebo three times daily, before meals.⁷⁹ Subjects on the active intervention had greater reductions in food intake, weight loss, total cholesterol, triglycerides and serum leptin levels. These findings correlated with earlier animal work by the research team, in which a combination of niacin-bound chromium (as ChromeMate), gymnema and vanadium helped reduce elevated blood pressure and blood cholesterol levels while modulating insulin release.⁸⁰

Coccinia indica

(syn. Cordifolia), also known as ivy gourd, is a creeper that grows widely in India and Bangladesh. It has been used since ancient times as an antidiabetic drug by Ayurvedic healers. A 45-day study in diabetic rats showed C. indica may have hypoglycemic and hypolipidemic effects, decreasing concentrations of blood glucose, lipids and fatty acids and increasing plasma insulin.⁸¹ Research from the same team also found supplementation with C. indica extract had significant antioxidant activity in the liver and kidney of diabetic rats.⁸²

Clinical trials have shown similarly positive results. In a study out of Bangladesh, type 2 diabetics received C. indica tablets or placebo and then were tested for glucose tolerance.⁸³ Intervention significantly improved blood glucose tolerance, with a high level of safety. And in a study out of the Institute of Population Health and Clinical Research, Bangalore, India, 60 type 2 diabetics were randomized to receive 1 g/d of an alcoholic extract of C. indica (as Gencinia™, from Gencor Pacific) or a placebo for 90 days.⁸⁴ There was a significant decrease in fasting and postprandial blood glucose, and glycosylated hemoglobin of the intervention group.

Fenugreek

is a food and a spice commonly eaten in many parts of the world, and has been used for centuries by Ayurvedic and Traditional Chinese Medicine (TCM) practitioners for treating blood sugar dysfunction. Research suggests fenugreek seeds may help balance blood sugar and have beneficial effects on triglycerides. Studies in diabetic rats, for example, reveal fenugreek inhibits carbohydrate digestion and absorption and enhances peripheral insulin action;⁸⁵ reduces oxidative stress and lipid peroxidation;⁸⁶ and beneficially influences dyslipidemia, coupled with a tendency to inhibit platelet aggregation.⁸⁷ It also appears to inhibit weight gain in rats fed a high-fat diet,⁸⁸ possibly increasing the use of fatty acids during exercise, burning more calories than without supplementation.⁸⁹

Again, human studies have also shown beneficial effects. Researchers at the Jaipur Diabetes and Research Centre evaluated the effects of fenugreek seeds (1 g/d) on glycemic control and insulin resistance in newly diagnosed type 2 diabetics (n=25).⁹⁰ After two months on the intervention, the fenugreek group had improved glycemic control and reduced insulin resistance; there were also decreases in serum triglycerides and increases in HDL cholesterol. Similarly, a clinical trial out of Huazhong University of Science and Technology, Wuhan, China, investigated whether adding fenugreek saponins to sulfonylurea treatment in type 2 diabetics would enhance blood glucose control.⁹¹ The combined treatment significantly improved fasting blood glucose, TCM symptoms and clinical symptomatic scores, compared to the drug alone.

The loquat (Eriobotrya japonica) is a fruit tree in the subfamily Maloideae of the family Rosaceae, indigenous to southeastern China. When standardized to corosolic acid, it may have blood glucose modulating properties. In vitro work in China has shown corosolic acid in a loquat extract suppresses differentiation of pre-adipocytes and promotes glucose uptake.⁹² Further, Korean researchers found loquat extract had strong antioxidant activity, inhibiting free radical generation.⁹³ And loquat extract exerts an anti-hyperglycemic effect in both normal and diabetic mice.⁹⁴

Corosolic acid is also one of the active compounds in Lagerstroemia speciosa, a Southeast Asian botanical known as banaba. A review out of Ohio University, Athens, noted banaba extract contains not only corosolic acid but also gallotannins which, in combination, have an insulin-like glucose transport-inducing activity and exert anti-adipogenesis activity.⁹⁵ In vitro, tannic acid from banaba appears to work by inhibiting the expression of key genes for adipogenesis, and inducing phosphorylation of the insulin receptors.⁹⁶

A study out of Mukogawa Women’s University, Nishinomiya, Japan, examined the effect of banaba’s corosolic acid on metabolic risk factors including obesity, hyper tension, hyperinsulinemia, hyperglycemia and hyperlipidemia in a rat model of metabolic syndrome.⁹⁷ Intervention with corosolic acid lowered blood pressure by 10 percent in eight weeks and dropped serum free fatty acids by 21 percent after only two weeks. Corosolic acid also decreased levels of several oxidative stress and inflammatory markers. And an unpublished clinical trial using a 1 percent corosolic acid extract from banaba (as GlucoTrim™, from OptiPure) involved type 2 diabetics receiving 16, 32 or 48 mg/d of the extract for 15 days at a time, with a 10-day washout period between doses. Compared to the control, GlucoTrim showed a drop in blood glucose levels across the dose range. A statistically significant reduction in blood glucose was observed at the 48 mg/d dose.

Cinnamon

is one of the oldest remedies used in traditional Chinese herbalism. A research review from USDA’s Beltsville Human Nutrition Center noted cinnamon may support healthy blood sugar levels by improving insulin sensitivity, and reducing blood pressure, total cholesterol and body fat levels.⁹⁸ German researchers reported on a trial in 79 type 2 diabetics who received cinnamon extract or placebo daily for four months; intervention significantly reduced fasting plasma glucose levels, particularly among patients with higher levels at baseline.⁹⁹ However, Thai researchers found while cinnamon did have effects on lowering fasting plasma glucose in type 2 diabetics, it was not statistically significantly greater than the effect of placebo.¹⁰⁰ Further, there were no changes in the lipid profiles of either the cinnamon or placebo subjects.

Specialty Compounds

Several specialty compounds and combination formulas have the ability to act on various portions of metabolic syndrome. Standardized French maritime pine bark extract (as Pycnogenol®, from Natural Health Sciences), has a broad range of effects, often attributed to its antioxidant procyanidins and phenolic acids; it has anti-inflammatory, anti-hypertensive and anti-hyperglycemic activity, while protecting against lipid oxidation.¹⁰¹ Polish researchers recently reported Pycnogenol had anti-thrombotic effects in diabetic rats,¹⁰² while Italian researchers found administering Pycnogenol orally to type 2 diabetics improved symptoms of microangiopathy and capillary function.¹⁰³

Pycnogenol also works on blood glucose metabolism. A daily dosage of 50 mg of Pycnogenol lowered both fasting and postprandial blood glucose significantly in type 2 diabetics not on medication, compared to baseline; higher dosages (100 mg/d and 200 mg/d) were even more effective.¹⁰⁴ Further, Pycnogenol appeared to facilitate blood sugar uptake by previously insulinnon- receptive cells. The extract also has beneficial effects for type 2 diabetes who are on medication, according to a study in 77 such patients who took 100 mg/d of Pycnogenol for 12 weeks while on standard treatment. Supplementation significantly lowered plasma glucose levels as compared to placebo and improved endothelial function.¹⁰⁵

An extract of Phaseolus vulgaris, white kidney bean, appears to impact blood glucose and carbohydrate metabolism. Indian researchers reported administering the extract to diabetic rats significantly reduced elevated blood glucose, serum triglycerides and total cholesterol.¹⁰⁶ And a Spanish study found the alpha amylase inhibitor from P. vulgaris extract could reduce glycemia and food intake in normal and diabetic rats, normalize elevated blood glucose in diabetic rats.¹⁰⁷ In addition, a clinical trial using a patented P. vulgaris extract, Phase 2® (from Pharmachem Laboratories), in 60 overweight adults found providing 445 mg/d of Phase 2 for 30 days resulted in significantly greater reduction of body weight, BMI and fat mass.¹⁰⁸

Olive leaf extract

may also play a role in reducing the effects of metabolic syndrome. Studies sponsored by Frutraom on its branded Benolea® EFLA®943 ingredient have found it supports optimal blood pressure, blood sugar levels and cholesterol levels, while providing antioxidant protection, primarily through its oleuropein content. A German trial involving 20 monozygotic twin pairs with borderline hyper tension found eight weeks of treatment with 500 mg/d or 1,000 mg/d of Benolea had a significant antihypertensive effect, while also lowering LDL cholesterol values.¹⁰⁹ Similar findings were reported in a rat study, in which Benolea was shown to dose-dependently prevent induced increases in blood pressure and reduce established hypertension.¹¹⁰ Company research has further shown 100 mg/kg of Benolea given to healthy rats increases glucose tolerance and lowers blood sugar levels in response to a glucose challenge.

Several other proprietar y ingredients may help manage metabolic syndrome. Citricoma™, from HP Ingredients, is a proprietary blend of polymethoxylated flavones (PMFs) and Eurycoma longifolia. Company research suggests the compound inhibits the 11(beta)-HSD1 enzymes, reducing systemic and local cortisol concentrations (liver and adipose tissue), promoting healthy blood sugar control and healthy weight loss. In a six-week placebo-controlled study in 50 moderately overweight men and women, those taking Citricoma while following a holistic program of nutritional diet, exercise and stress management lost 2.7 kg (compared to 0.78 kg for the placebo), and 2.4 kg of body fat loss (0.55 kg for the placebo).¹¹¹ Total cholesterol and LDL cholesterol were also lower in the Citricoma group.

PMFs, this time in combination with Phello dendron amurense, also appear in the patented ingredient Flavoxine from Next Pharmaceuticals. In a company-sponsored study conducted at the University of Yaounde I, Cameroon, 45 overweight subjects received 1,480 mg/d of Flavoxine for eight weeks in a double blind, placebo-controlled intervention. Treatment improved lipid levels, decreased blood pressure and significantly decreased fasting glucose levels. In addition, intervention aided in weight loss.

Another specialty compound is decaffeinated green coffee bean extract (available as Svetol®, from Berkem), which may work to help support weight management and glucose balance. A double blind, placebo-controlled clinical trial, published at the end of 2006 in Phytothérapie, showed 60 days of treatment with Svetol resulted in a mean reduction in weight of 4.97 +/-0.32 kg (5.7 percent), compared to a mean reduction of 2.45 +/-0.37 kg (2.9 percent) in the control group.¹¹² Intervention also significantly reduced BMI and significantly increased the muscle mass/fat mass ratio. Svetol also works to inhibit glucose absorption from the digestive tract, according to a new clinical trial.¹¹³ Svetol (400 mg/d) for 40 days significantly reduced the post-load glycemia after an oral glucose tolerance test without any change in the preload glycemia.

While metabolic syndrome incidence is on the rise, formulators and marketers of functional foods and dietary supplements have an ideal opportunity to provide multi-action products that can get to the core of the problem and enhance long-term health.

Editor's Note: References follow on next page.

References

1. Lutsey PL, Steffen LM, Stevens J. “Dietary Intake and the Development of the Metabolic Syndrome. The Atherosclerosis Risk in Communities Study.” Circulation. 2008 Jan 22 [Epub ahead of print].

2. Cook S et al. “Metabolic syndrome rates in United States adolescents, from the National Health and Nutrition Examination Survey, 1999-2002.” J Pediatr. 2008 Feb;152(2):165-70. Epub 2007 Oct 22.

3. Biddinger SB et al. “Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis.” Cell Metab. 2008 Feb;7(2):125-34.

4. Giugliano D, Ceriello A, Esposito K. “Are there specific treatments for the metabolic syndrome?” Am J Clin Nutr. 2008 Jan;87(1):8-11.

5. Bulló M et al. “Inflammation, obesity and comorbidities: the role of diet.” Public Health Nutr. 2007 Oct;10(10A):1164-72.

6. Bo S et al. “Effectiveness of a lifestyle intervention on metabolic syndrome. A randomized controlled trial.” J Gen Intern Med. 2007 Dec;22(12):1695-703. Epub 2007 Oct 6.

7. Millen BE et al. “Nutritional risk and the metabolic syndrome in women: opportunities for preventive intervention from the Framingham Nutrition Study.” Am J Clin Nutr. 2006 Aug;84(2):434-41.

8. Galisteo M, Duarte J, Zarzuelo A. “Effects of dietary fibers on disturbances clustered in the metabolic syndrome.” J Nutr Biochem. 2008 Feb;19(2):71-84. Epub 2007 Jul 6.

9. Bo S et al. “Dietary magnesium and fiber intakes and inflammatory and metabolic indicators in middle-aged subjects from a population-based cohort.” Am J Clin Nutr. 2006 Nov;84(5):1062-9.

10. Katcher HI et al. “The effects of a whole grain enriched hypocaloric diet on cardiovascular disease risk factors in men and women with metabolic syndrome.” Am J Clin Nutr. 2008 Jan;87(1):79-90.

11. Panahi S et al. “Beta-glucan from two sources of oat concentrate affect postprandial glycemia in relation to the level of viscosity.” J Am Coll Nutr. 2007 Dec;26(6):639-44.

12. Greenway F et al. “Fourteen Weeks of Treatment with Viscofiber® Increased Fasting Levels of Glucagon-Like Peptide-1 and Peptide-YY.” J Med Food. 2007 Dec;10(4):720-4.

13. Queenan KM et al. “Concentrated oat beta-glucan, a fermentable fiber, lowers serum cholesterol in hypercholesterolemic adults in a randomized controlled trial.” Nutr J. 2007 Mar 26;6:6.

14. Maki KC et al. “Effects of consuming foods containing oat beta-glucan on blood pressure, carbohydrate metabolism and biomarkers of oxidative stress in men and women with elevated blood pressure.” Eur J Clin Nutr. 2007 Jun;61(6):786-95. Epub 2006 Dec 6.

15. Butt MS et al. “Guar gum: a miracle therapy for hypercholesterolemia, hyperglycemia and obesity.” Crit Rev Food Sci Nutr. 2007;47(4):389-96.

16. Prieto PG et al. “Short-term and long-term effects of guar on postprandial plasma glucose, insulin and glucagon-like peptide 1 concentration in healthy rats.” Horm Metab Res. 2006 Jun;38(6):397-404.

17. Barre DE. “The role of consumption of alpha-linolenic, eicosapentaenoic and docosahexaenoic acids in human metabolic syndrome and type 2 diabetes--a mini-review.” J Oleo Sci. 2007;56(7):319-25.

18. Ebbesson SO et al. “Fatty Acid Consumption and Metabolic Syndrome Components: The GOCADAN Study.” J Cardiometab Syndr. 2007 Fall;2(4):244-249.

19. Lombardo YB, Hein G, Chicco A. “Metabolic syndrome: effects of n-3 PUFAs on a model of dyslipidemia, insulin resistance and adiposity.” Lipids. 2007 May;42(5):427-37. Epub 2007 Mar 17.

20. Ford ES et al. “Intake of dietary magnesium and the prevalence of the metabolic syndrome among U.S. adults.” Obesity (Silver Spring). 2007 May;15(5):1139-46.

21. He K et al. “Magnesium intake and the metabolic syndrome: epidemiologic evidence to date.” J Cardiometab Syndr. 2006 Fall;1(5):351-5.

22. He K et al. “Magnesium intake and incidence of metabolic syndrome among young adults.” Circulation. 2006 Apr 4;113(13):1675-82. Epub 2006 Mar 27.

23. Hummel M, Standl E, Schnell O. “Chromium in metabolic and cardiovascular disease.” Horm Metab Res. 2007 Oct;39(10):743-51.

24. Jain SK, Rains JL, Croad JL. “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. Epub 2007 May 18.

25. Cefalu WT et al. “Oral chromium picolinate improves carbohydrate and lipid metabolism and enhances skeletal muscle Glut-4 translocation in obese, hyperinsulinemic (JCR-LA corpulent) rats.” J Nutr. 2002 Jun;132(6):1107-14.

26. Martin J et al. “Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes.” Diabetes Care. 2006 Aug;29(8):1826-32.

27. Albarracin C et al. “Combination of chromium and biotin improves coronary risk factors in hypercholesterolemic type 2 diabetes mellitus: a placebo-controlled, double-blind randomized clinical trial.” J Cardiometab Syndr. 2007 Spring;2(2):91-7.

28. Albarracin CA et al. “Chromium picolinate and biotin combination improves glucose metabolism in treated, uncontrolled overweight to obese patients with type 2 diabetes.” Diabetes Metab Res Rev. 2008 Jan;24(1):41-51.

29. Kim MH et al. “Risk Factors Associated with Metabolic Syndrome in Korean Elderly.” Ann Nutr Metab. 2008 Jan 10;51(6):533-540 [Epub ahead of print].

30. Montonen J et al. “Dietary antioxidant intake and risk of type 2 diabetes.” Diabetes Care. 2004 Feb;27(2):362-6.

31. Wan Nazaimoon WM, Khalid BA. “Tocotrienols-rich diet decreases advanced glycosylation end-products in non-diabetic rats and improves glycemic control in streptozotocin-induced diabetic rats.” Malays J Pathol. 2002;24:77-82.

32. Chen CW, Cheng HH. “A rice bran oil diet increases LDL-receptor and HMG-CoA reductase mRNA expressions and insulin sensitivity in rats with streptozotocin/nicotinamide-induced type 2 diabetes.” J Nutr. 2006;136(6):1472-6.

33. Qureshi AA, Sami SA, Khan FA. “Effects of stabilized rice bran, its soluble and fiber fractions on blood glucose levels and serum lipid parameters in humans with diabetes mellitus Types I and II.” J Nutr Biochem. 2002;13:175-187.

34. Baliarsingh S, Beg ZH, Ahmad J. “The therapeutic impacts of tocotrienols in type 2 diabetic patients with hyperlipidemia.” Atherosclerosis. 2005;182:367-74.

35. Pershadsingh HA. “Alpha-lipoic acid: physiologic mechanisms and indications for the treatment of metabolic syndrome.” Expert Opin Investig Drugs. 2007 Mar;16(3):291-302.

36. Koh EH et al. “Intracellular Fatty Acid metabolism in skeletal muscle and insulin resistance.” Curr Diabetes Rev. 2005 Aug;1(3):331-6.

37. Targonsky ED et al. “alpha-lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells.” Diabetologia. 2006 Jul;49(7):1587-98. Epub 2006 May 13.

38. Sola S et al. “Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study.” Circulation. 2005 Jan 25;111(3):343-8. Epub 2005 Jan 17.

39. Kamenova P. “Improvement of insulin sensitivity in patients with type 2 diabetes mellitus after oral administration of alpha-lipoic acid.” Hormones (Athens). 2006 Oct-Dec;5(4):251-8.

40. Liu J. “The Effects and Mechanisms of Mitochondrial Nutrient alpha-Lipoic Acid on Improving Age-Associated Mitochondrial and Cognitive Dysfunction: An Overview.” Neurochem Res. 2008 Jan;33(1):194-203. Epub 2007 Jun 29.

41. Hagen TM et al. “Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetyl-L-carnitine and/or lipoic acid.” Ann N Y Acad Sci. 2002 Apr;959:491-507.

42. Shen W et al. “R-alpha-Lipoic acid and acetyl-L: -carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes.” Diabetologia. 2008 Jan;51(1):165-74. Epub 2007 Nov 17.

43. Cave MC et al. “Obesity, inflammation, and the potential application of pharmaconutrition.” Nutr Clin Pract. 2008 Feb;23(1):16-34.

44. Rajasekar P, Anuradha CV. “Effect of L-carnitine on skeletal muscle lipids and oxidative stress in rats fed high-fructose diet.” Exp Diabetes Res. 2007;2007:72741.

45. Rajasekar P, Palanisamy N, Anuradha CV. “Increase in nitric oxide and reductions in blood pressure, protein kinase C beta II and oxidative stress by L-carnitine: a study in the fructose-fed hypertensive rat.” Clin Exp Hypertens. 2007 Nov;29(8):517-30.

46. Rajasekar P, Viswanathan P, Anuradha CV. “Renoprotective action of L-carnitine in fructose-induced metabolic syndrome.” Diabetes Obes Metab. 2008 Feb;10(2):171-80. Epub 2007 Dec 17.

47. Watras AC et al. “The role of conjugated linoleic acid in reduce body fat and preventing holiday weight gain.” Int J Obes. DOI: 10.1038/sj.ijo.0803437

48. Proctor SD et al. “Synergistic effects of conjugated linoleic acid and chromium picolinate improve vascular function and renal pathophysiology in the insulin-resistant JCR:LA-cp rat.” Diabetes Obes Metab. 2007 Jan;9(1):87-95.

49. Inoue N et al. “Dietary conjugated linoleic acid lowered tumor necrosis factor-alpha content and altered expression of genes related to lipid metabolism and insulin sensitivity in the skeletal muscle of Zucker rats.” J Agric Food Chem. 2006 Oct 4;54(20):7935-9.

50. Abdullah MM et al. “The effects of simultaneous administration of dietary conjugated linoleic acid and telmisartan on cardiovascular risks in rats.” Lipids. 2007 Sep;42(9):855-64. Epub 2007 Aug 7.

51. Villegas R et al. “Legume and soy food intake and the incidence of type 2 diabetes in the Shanghai Women's Health Study.” Am J Clin Nutr. 2008 Jan;87(1):162-7.

52. Zhang X et al. “Soy food consumption is associated with lower risk of coronary heart disease in Chinese women.” J Nutr. 2003 Sep;133(9):2874-8.

53. Yang G et al. “Longitudinal study of soy food intake and blood pressure among middle-aged and elderly Chinese women.” Am J Clin Nutr. 2005 May;81(5):1012-7.

54. Zhang X et al. “Abdominal adiposity and mortality in Chinese women.” Arch Intern Med. 2007 May 14;167(9):886-92.

55. Azadbakht L et al. “Soy consumption, markers of inflammation, and endothelial function: a cross-over study in postmenopausal women with the metabolic syndrome.” Diabetes Care. 2007 Apr;30(4):967-73.

56. Azadbakht L et al. “Soy inclusion in the diet improves features of the metabolic syndrome: a randomized crossover study in postmenopausal women.” Am J Clin Nutr. 2007 Mar;85(3):735-41.

57. Liao FH et al. “Effectiveness of a soy-based compared with a traditional low-calorie diet on weight loss and lipid levels in overweight adults.” Nutrition. 2007 Jul-Aug;23(7-8):551-6. Epub 2007 Jun 15.

58. Lukaczer D et al. “Effect of a low glycemic index diet with soy protein and phytosterols on CVD risk factors in postmenopausal women.” Nutrition. 2006 Feb;22(2):104-13.

59. Cheng TO. “All teas are not created equal: the Chinese green tea and cardiovascular health.” Int J Cardiol. 2006 Apr 14;108(3):301-8. Epub 2005 Jun 22.

60. Shenouda SM, Vita JA. “Effects of flavonoid-containing beverages and EGCG on endothelial function.” J Am Coll Nutr. 2007 Aug;26(4):366S-372S.

61. Tipoe GL et al. “Green tea polyphenols as an anti-oxidant and anti-inflammatory agent for cardiovascular protection.” Cardiovasc Hematol Disord Drug Targets. 2007 Jun;7(2):135-44.

62. Potenza MA et al. “EGCG, a green tea polyphenol, improves endothelial function and insulin sensitivity, reduces blood pressure, and protects against myocardial I/R injury in SHR.” Am J Physiol Endocrinol Metab. 2007 May;292(5):E1378-87. Epub 2007 Jan 16.

63. Anton S, Melville L, Rena G. “Epigallocatechin gallate (EGCG) mimics insulin action on the transcription factor FOXO1a and elicits cellular responses in the presence and absence of insulin.” Cell Signal. 2007 Feb;19(2):378-83. Epub 2006 Jul 25.

64. Collins QF et al. “Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5’-AMP-activated protein kinase.” J Biol Chem. 2007 Oct 12;282(41):30143-9. Epub 2007 Aug 27.

65. Wolfram S, Wang Y, Thielecke F. “Anti-obesity effects of green tea: from bedside to bench.” Mol Nutr Food Res. 2006 Feb;50(2):176-87.

66. Boschmann M, Thielecke F. “The effects of epigallocatechin-3-gallate on thermogenesis and fat oxidation in obese men: a pilot study.” J Am Coll Nutr. 2007 Aug;26(4):389S-395S.

67. Auvichayapat P et al. “Effectiveness of green tea on weight reduction in obese Thais: A randomized, controlled trial.” Physiol Behav. 2007 Oct 18 [Epub ahead of print].

68. Westerterp-Plantenga MS, Lejeune MP, Kovacs EM. “Body weight loss and weight maintenance in relation to habitual caffeine intake and green tea supplementation.” Obes Res. 2005 Jul;13(7):1195-204.

69. Manohar V et al. “Effects of a water-soluble extract of maitake mushroom on circulating glucose/insulin concentrations in KK mice.” Diabetes Obes Metab. 2002;4:43-8.

70. Preuss H et al. “Antihypertensive and metabolic effects of whole Maitake mushroom powder and its fractions in two rat strains.” Mol Cell Biochem. 200;237:129-36.

71. Talpur N et al. “Effects of niacin-bound chromium, Maitake mushroom fraction SX and (-)-hydroxycitric acid on the metabolic syndrome in aged diabetic Zucker fatty rats.” Mol Cell Biochem. 2003 Oct;252(1-2):369-77.

72. 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.

73. Kim MS et al. “Anti-adipogenic effects of Garcinia extract on the lipid droplet accumulation and the expression of transcription factor.” Biofactors. 2004;22(1-4):193-6.

74. Hayamizu K et al. “Effect of Garcinia cambogia extract on serum leptin and insulin in mice.” Fitoterapia. 2003 Apr;74(3):267-73.

75. Oluyemi KA et al. “Erythropoietic and anti-obesity effects of Garcinia cambogia (bitter kola) in Wistar rats.” Biotechnol Appl Biochem. 2007 Jan;46(Pt 1):69-72.

76. Asghar M et al. “Super CitriMax (HCA-SX) attenuates increases in oxidative stress, inflammation, insulin resistance, and body weight in developing obese Zucker rats.” Mol Cell Biochem. 2007 Oct;304(1-2):93-9. Epub 2007 May 15.

77. Kimura I. “Medical benefits of using natural compounds and their derivatives having multiple pharmacological actions.” Yakugaku Zasshi. 2006 Mar;126(3):133-43.

78. Luo H et al. “Decreased bodyweight without rebound and regulated lipoprotein metabolism by gymnemate in genetic multifactor syndrome animal.” Mol Cell Biochem. 2007 May;299(1-2):93-8.

79. Preuss HG et al. “Effects of a natural extract of (-)-hydroxycitric acid (HCA-SX) and a combination of HCA-SX plus niacin-bound chromium and Gymnema sylvestre extract on weight loss.” Diabetes Obes Metab. 2004 May;6(3):171-80.

80. Preuss HG et al. “Comparative effects of chromium, vanadium and gymnema sylvestre on sugar-induced blood pressure elevations in SHR.” J Am Coll Nutr. 1998 Apr;17(2):116-23.

81. Pari L, Venkateswaran S. “Protective effect of Coccinia indica on changes in the fatty acid composition in streptozotocin induced diabetic rats.” Pharmazie. 2003 Jun;58(6):409-12.

82. Venkateswaran S, Pari L. “Effect of Coccinia indica leaves on antioxidant status in streptozotocin-induced diabetic rats.” J Ethnopharmacol. 2003 Feb;84(2-3):163-8.

83. Khan AK, Akhtar S, Mahtab H. “Treatment of diabetes mellitus with Coccinia indica.” Br Med J. 1980 April 12;280(6220):1044.

84. Kuriyan R et al. “Effect of supplementation of Coccinia Cordifolia extract on newly detected diabetic patients.” Diabetes Care. 2008 Feb;31(2):216-20.

85. Hannan JM et al. “Soluble dietary fibre fraction of Trigonella foenum-graecum (fenugreek) seed improves glucose homeostasis in animal models of type 1 and type 2 diabetes by delaying carbohydrate digestion and absorption, and enhancing insulin action.” Br J Nutr. 2007 Mar;97(3):514-21.

86. Annida B, Stanely Mainzen Prince P. “Supplementation of fenugreek leaves reduces oxidative stress in streptozotocin-induced diabetic rats.” J Med Food. 2005 Fall;8(3):382-5.

87. Hannan JM et al. “Effect of soluble dietary fibre fraction of Trigonella foenum graecum on glycemic, insulinemic, lipidemic and platelet aggregation status of Type 2 diabetic model rats.” J Ethnopharmacol. 2003 Sep;88(1):73-7.

88. Handa T et al. “Effects of fenugreek seed extract in obese mice fed a high-fat diet.” Biosci Biotechnol Biochem. 2005 Jun;69(6):1186-8.

89. Ikeuchi M et al. “Effects of fenugreek seeds (Trigonella foenum greaecum) extract on endurance capacity in mice.” J Nutr Sci Vitaminol (Tokyo). 2006 Aug;52(4):287-92.

90. Gupta A, Gupta R, Lal B. “Effect of Trigonella foenum-graecum (fenugreek) seeds on glycaemic control and insulin resistance in type 2 diabetes mellitus: a double blind placebo controlled study.” J Assoc Physicians India. 2001 Nov;49:1057-61.

91. Lu FR et al. “Clinical Observation on Trigonella Foenum-graecum L. total saponins in combination with sulfonylureas in the treatment of type 2 diabetes mellitus.” Chin J Integr Med. 2008 Jan 25 [Epub ahead of print].

92. Zong W, Zhao G. “Corosolic acid isolation from the leaves of Eriobotrta japonica showing the effects on carbohydrate metabolism and differentiation of 3T3-L1 adipocytes.” Asia Pac J Clin Nutr. 2007;16 Suppl 1:346-52.

93. Jung HA et al. “Antioxidant flavonoids and chlorogenic acid from the leaves of Eriobotrya japonica.” Arch Pharm Res. 1999 Apr;22(2):213-8.

94. Chen J et al. “Hypoglycemic effects of a sesquiterpene glycoside isolated from leaves of loquat (Eriobotrya japonica (Thunb.) Lindl.).” Phytomedicine. 2008 Jan;15(1-2):98-102. Epub 2007 Feb 8.

95. Klein G et al. “Antidiabetes and Anti-obesity Activity of Lagerstroemia speciosa.” Evid Based Complement Alternat Med. 2007 Dec;4(4):401-7.

96. Liu X et al. “Tannic acid stimulates glucose transport and inhibits adipocyte differentiation in 3T3-L1 cells.” J Nutr. 2005 Feb;135(2):165-71.

97. Yamaguchi Y et al. “Corosolic acid prevents oxidative stress, inflammation and hypertension in SHR/NDmcr-cp rats, a model of metabolic syndrome.” Life Sci. 2006 Nov 25;79(26):2474-9. Epub 2006 Aug 17.

98. Anderson RA. “Chromium and polyphenols from cinnamon improve insulin sensitivity.” Proc Nutr Soc. 2008 Feb;67(1):48-53.

99. Mang B et al. “Effects of a cinnamon extract on plasma glucose, HbA, and serum lipids in diabetes mellitus type 2.” Eur J Clin Invest. 2006 May;36(5):340-4.

100. Suppapitiporn S, Kanpaksi N, Suppapitiporn S. “The effect of cinnamon cassia powder in type 2 diabetes mellitus.” J Med Assoc Thai. 2006 Sep;89 Suppl 3:S200-5.

101. Rohdewald P. “A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology.” Int J Clin Pharmacol Ther. 2002 Apr;40(4):158-68.

102. Nocun M et al. “French maritime pine bark extract (Pycnogenol®) reduces thromboxane generation in blood from diabetic male rats.” Biomed Pharmacother. 2007 Jul 30 [Epub ahead of print].

103. Cesarone MR et al. “Improvement of diabetic microangiopathy with pycnogenol: A prospective, controlled study.” Angiology. 2006 Aug-Sep;57(4):431-6.

104. Liu X, Zhou HJ, Rohdewald P. “French maritime pine bark extract Pycnogenol dose-dependently lowers glucose in type 2 diabetic patients.” Diabetes Care. 2004 Mar;27(3):839.

105. Liu X et al. “Antidiabetic effect of Pycnogenol French maritime pine bark extract in patients with diabetes type II.” Life Sci. 2004;75:2505-13.

106. Venkateswaran S, Pari L, Saravanan G. “Effect of Phaseolus vulgaris on circulatory antioxidants and lipids in rats with streptozotocin-induced diabetes.” J Med Food. 2002 Summer;5(2):97-103.

107. Tormo MA et al. “White bean amylase inhibitor administered orally reduces glycaemia in type 2 diabetic rats.” Br J Nutr. 2006 Sep;96(3):539-44.

108. Celleno L et al. “A Dietary Supplement Containing Standardized Phaseolus vulgaris Extract Influences Body Composition of Overweight Men and Women.” Int J Med Sci. 2007; 4:45-52.

109. Moccetti T et al. “Effect of EFLA®943 in adult twins with mild hypertension.” Kongressband Phytopharmaka Phytotherapie. 2005;S30.

110. Khayyal MT et al. “Blood pressure lowering effect on an olive leaf extract (Olea europaea) in L-NAME induced hypertension in rats.” Arzneim-Forsch/Drug Res. 2002;52(11):797-802.

111. Presented at American College of Nutrition Conference, Orlando, Fla., September 2007

112. Dellalibera SO et al. Phytothérapie. 2006;4:1-4.

113. Blum J et al. NUTRAfoods. 2007;6(3):13-17.