Diabetes: The Botanical Option

By Casey Adams, Ph.D.

This July David Graham, M.D., a drug safety officer at the FDA called for the withdrawal of Avandia®, a leading type-2 diabetes drug marketed by Glaxo SmithKline, PLC. Dr. Graham suggested research could indicate the drug possibly caused 205,000 heart attacks and strokes from 1999 to 2006. Dr. Graham also calculated 1600-2200 more patients might suffer these side effects for every month the drug remains on the market. For the over four million type-2 diabetics who’ve taken the drug since 1999, the announcement was a serious one.

According to the Physician’s Desk Reference, rosiglitazone maleate—Avandia’s chemical name—increases glycemic control through increased insulin sensitivity. It is considered a PPAR-gamma (peroxisome proliferators-activated receptor-gamma) agonist, modulating genetic expression of insulin sensitivity at the cell membrane.

The multi-billion dollar (Avandia’s global sales were $3.4 billion last year) question is what help can nature provide for the estimated 18 million people in the U.S. alone with type-2 non-insulin-dependent diabetes mellitus (NIDDM)—including some 14 million not diagnosed?

In a 2003 study review done by Harvard Medical School researchers, 108 clinical trials examined no less than 36 different botanicals with potential anti-diabetic properties. Together with another 9 trials done using supplements, these studies tested 4,565 diabetic patients. The review concluded that 76% of 58 controlled studies showed improved glucose control.(1). Many more studies have been added since 2003 as botanical research has intensified.

New Mechanisms Found

The mechanisms for NIDDM have also undergone vigorous research over the past few years. Primary mechanisms of the past focused on insulin and glucose sensitivity at the cell membrane and the health of pancreatic beta-cells. Recent research has revealed several new complexities.

Originally linked to obesity, leptin is now thought to be involved in hypothalamic energy regulation, stimulation of glucose transport, and the inhibition of insulin secretion by pancreatic beta-cells. Two more recently-discovered hormones are resistin and adiponectin. Resistin has been linked to glucose tolerance and hepatic insulin resistance. Adiponectin is linked to glucose regulation and lipid metabolism. Produced in fat cells, both resistin and adiponectin also apparently mediate PPAR-gamma: Resistin upgrades and adiponectin downgrades insulin resistance through PPAR modulation(2,3,4).

Enzymes are now thought to be a critical part of the mechanism. One enzyme seemingly instrumental to leptin regulation tangential to PPAR-gamma repression is SIRT1. Sirtuins have been implicated in the diabetic mechanism because of their ability to affect genetic expression related to issues of degenerative glucose and insulin metabolism. SIRT1 appears to balance glucose levels by modulating the PGC-1alpha molecule. PGC-1alpha is a transcriptional co-activator. When SIRT1 was inhibited in vivo this increased hypoglycemia, increased glucose and insulin sensitivity as well as increased free fatty acids and cholesterol. On the other hand increased SIRT1 expression reversed these effects, but only in the presence of PGC-1alpha during fasting(5,6).

Yet another recently-discovered hormone implicated in both forms of diabetes is amylin. Amylin is co-secreted with insulin and complements insulin’s actions together with providing a feedback-response mechanism(7).

Other components complicating these mechanisms include glucocorticoids and circulating lipids. These various mechanisms compound to make NIDDM associated with stress, hypertension, visceral adiposity, elevated triglycerides, small dense low-density lipoproteins, decreased HDL, and of course diets high in refined sugars and low in fiber.

Full-Spectrum Strategy

A full spectrum strategy for these complex mechanisms is suggested by Virender Sodhi, M.D., N.D. Dr. Sodhi is also the CEO and co-founder of Ayush Herbs, Inc.—a leading U.S. supplier of Ayurvedic botanical extracts. “I usually suggest to my patients a combination of exercise, multi-herbal therapy and diet modification with plenty of whole food fiber,” says Dr. Sodhi.

Whole foods contain various soluble fibers such as pectin and beta-glucans are known to slow glucose absorption rates and bind LDL cholesterol. A 2002 four-week trial of 13 NIDDM men resulted in increased glycemic control, lower plasma glucose and decreased leptin mRNA in high-fiber subjects (8).

Avena sativa L.

Oats are one of the best fiber sources and potent sources of beta-1,3-d-glucan and beta-1,4-d-glucan, as well as avenanthramides—polyphenols shown in studies by Tufts University and USDA Human Nutrition Center as antioxidant and LDL-oxidation protective. In a Finnish randomized controlled study of twelve NIDDM patients, eating higher beta-glucan oat snacks showed lower glucose fasting and load tolerance levels than controls(9). The mechanism includes a slowing of digestive enzyme activity and lipid modulation. Other studies have illustrated oat bran’s ability to decrease total cholesterol and LDL levels on top of lowered post-meal glucose and insulin(10,11).

Several North American suppliers specialize in ingredient oat fibers. Cathy Peterson, Assistant V.P. Applications at SunOpta, Inc. —a leading supplier of stabilized oat bran and oat fiber—explains that most of the beta-glucan content of the oat is in the bran. “However the bran also contains a number of enzymes that can create rancidity,” she says. For this reason SunOpta stabilizes their bran for use in dry mix applications.

Oat Vantage® bran concentrate from GTC Nutrition offers up to 54% beta-glucan. ViscoFiber® from Cevena Bioproducts offers a 45% minimum beta-glucan with a retention of the bran’s natural viscosity and thus many of its health benefits, according to Kristina Williams, Cevena’s Director of Marketing.

Nature can step up the beta-glucan as well. A new variety of high beta-glucan/high avenanthramide oats called HiFi® was bred by the North Dakota State University over the past few years. “HiFi® is about 50% higher in beta-glucan than the oats you’d buy in the grocery store,” says Doug Doehlert, a cereal chemist with the NDSU team. The seed variety has recently entered commercial production under a license agreement between NDSU Research Foundation and North Dakota’s Organic Grain & Milling, Inc. “Hi-Fi® is exciting because we've got optimum beta-glucan levels together with an oat giving our organic growers great yields and disease resistance. It’s smart science—a real win-win whole grain for farmers and consumers.” says Kathryn Begeal, Organic Grain & Milling’s Director of Product Development.

Mushrooms

Medicinal mushrooms contain beta-1,3-d-glucans with beta-1,6-d-glucan and alpha-1,4-glucans—contributing to their glycemic and immune function benefits. Mitchell May, PhD and CEO of Utah mushroom cultivator Synergy Production Laboratories points out that in addition to the prized beta-d-glucan, mushrooms contain various enzymes, sterols and triterpenes. “SPL has developed a proprietary and unique cold-drying process that protects these heat-sensitive enzymes,” says Dr. May.

Improved insulin sensitivity, increased glucose uptake and binding, insulin-like activity and enhanced immune effects have been seen in among the multitude of mushroom studies. “Some of the more researched mushrooms for anti-diabetic action include oyster mushroom, maitake, cordyceps, Tremella fuciformis, Agaricus blazei Murrill, and Jelly Ear fungus Auricularia,” says Brien Quirk, Herbalist and R&D Development manager with California’s Draco Natural Products, Inc. “Of these Maitake seems to have the most research,” he says. David Law, CEO of Gourmet Mushrooms—a 30-year old mushroom cultivating company out of Sebastopol, CA—says their best sellers include C. versicolor, C. sinensis, L. edodes and G. frondosa (Maitake). Gourmet Mushroom currently cultivates thirty different varieties with another 100 in the spawn bank. “Hundreds of mushrooms have these glycemic benefits. Combination use should include at least one variety of each fungus type—polypores, gilled and jelly varieties,” suggests Mr. Law.

Mushroom constituents with insulin-like behavior have captured the interest of Merck Research Laboratories, who after screening upwards of 50,000 compounds discovered demethylasterriquinone B1 (DAQ) from an African mushroom genus Pseudomassaria. Duke University research team leader Michael Pirrung said DAQ “has this fascinating property of being able to activate insulin receptors in cells in basically the same way as insulin, and yet it’s not a protein, as is insulin”(13).

Pinus pinaster

An extract from the bark of the French marine pine tree—a tree indigenous to France—called Pycnogenol® has been the subject of more than 200 studies, 50 of which were human. “Typical dosage ranged from 20 to up to 150 mg in the research,” says Frank Schonlau, PhD, National Health Science’s Director of Scientific Communications. In a study reported by the American Diabetes Association’s Diabetes Care, 30 NIDDM patients took Pycnogenol® daily for three weeks. A dosage of 50mg was enough to significantly lower fasting and post-prandial glucose levels. 100mg and 200mg were even more effective(14).

The mechanism for Pycnogenol® appears to be related to slower glucose uptake, improvement in blood lipids, and increased micro-circulation. The large procyanidin molecules in Pycnogenol® inhibit alpha-glucosidase—the enzyme necessary for glucose absorption. Pycnogenol’s® ‘side-effect’ of increasing micro-circulation was reported helpful for diabetic microangiopathy(14).

Fenugreek

Trigonella foenum-graecum is indigenous to west Asia, southeast Europe and north Africa. It is also cultivated in many other areas. A traditional herb used for glucose control, fenugreek has a long history of success. The crushed plant’s seeds contain alkaloids, coumarins and saponins. Its principle active constituent is 4-hydroxyisoleucine. In one study 17 of 21 NIDDM patients had blood glucose reductions averaging 30 mg/dl after being administered 15 grams of ground seed of fenugreek(15). In another, 60 NIDDM volunteers reduced fasting blood glucose levels from an average of 151 mg/dl to 112 mg/dl after 24 weeks using a 12.5 mg dosage twice a day(16). Other studies have confirmed fenugreek’s action of reducing fasting blood sugar levels together with total cholesterol and triglycerides(17).

Naturex produces a Fenugreek extract standardized to 2% 4-hydroxysoleucine under the name Hydroxylean®.

Caiapo

Ipomoea batas is a white sweet potato indigenous to South America and cultivated particularly Japan. The highly glycoprotein skin of I. batas has been shown to have anti-diabetic action in both animals and humans. In 2002 18 male NIDDM subjects were treated either with placebo, low (2 grams/day) or high (4 grams/day) doses of caiapo powdered tablets for six weeks. The high-dose group showed 13% reduction in fasting glucose, a 42% increase in insulin sensitivity and a 72% increase in glucose tolerance(18,19).

In another study, 61 NIDDM subjects were given either 4 grams of caiapo or placebo daily for 12 weeks. Fasting glucose levels decreased from 143 mg/dl to 128 mg/dl averages in the caiapo group while remaining unchanged in the placebo group. Two-hour glucose levels were also significantly reduced in the caiapo group(20).

Gurmar

Gymnema sylvestre has been in use for thousands of years in Ayurvedic medicine. Its leaves contain gurmarin, gynmenic acids, stigmasterol, quercitol, and various glycosides, resins and saponins. Both the whole plant and its GS4 water-soluble extract fraction have been noted for increased glucose sensitivity and uptake, higher beta-cell count and increased insulin levels. G. sylvestre has been used traditionally for both NIDDM and IDDM (type-1). Interestingly, G. sylvestre has an apparent ability to suppress sweet taste stimuli by blocking taste receptors(21). This apparently comes from its saponins. Its anti-sweetness effect was shown to decrease sweet snack consumption(22).

G. Sylvestre’s diabetic research appears solid. In a 1990 study 27 insulin-dependent IDDM patients were given 400 grams per day of GS4 over a 10-12 month period. Insulin requirements and glycosylated hemoglobin levels both decreased significantly as compared with control subjects(23). Other smaller studies have shown G. sylvestre’s ability to lower fasting glucose and glycosylated hemoglobin(24). In vitro G. sylvestre appears to stimulate insulin release by increasing pancreatic beta-cells’ membrane permeability(25).

Ayush, Inc. standardizes their G. sylvestre extracts to gymnemic acid content. Shalinder Sodhi, N.D., President of Ayush, Inc., suggests a range from 25% to 75% gymnemic acid for efficacy. “We control gurmar production from field through extraction, so we can customize the extraction to specification,” says Dr. Sodhi.

“Cinnamon”

Cinnamomum cassia shouldn’t be confused with “true” Ceylon cinnamon Cinnamomum verum—the variety used for cinnamon sticks. C. cassia is by far more active and also the most used on retail shelves. C. cassia contains cinnamaldehyde, coumarin, cinnamyl acetate and 2-hydroxycinnamaldehyde(26). In vitro analyses reveal the extract and a water-soluble flavanoid polyphenolic polymer contains insulin-like activity, showing glucose uptake, glycogen synthesis and increased phosphorylation of the insulin receptor(27,28,29). Other bioactives have stimulated autophosphorylation of truncated insulin receptors, apparently inhibiting PTP-1—known to shut down the insulin receptor(30).

In a 2003 double-blind study of 60 NIDDM volunteers C. cassia reduced mean fasting serum glucose by 18-29% with significant lipid reductions after forty days at different dosages(31). In a 2006 random double-blind study of 79 NIDDM, patients took either water-extracted cinnamon equivalent to 3 grams every day for four months or a placebo. Fasting glucose levels reduced 10.3% for the cinnamon group as opposed to 3.4% for the placebo group(32). Though a 2006 study of postmenopausal NIDDM women curiously showed little effect(33), a 2007 study of 14 healthy subjects taking 6 grams of cinnamon in pudding after meals significantly delayed food stomach emptying and reduced post-prandial glucose levels.(34).

Cinnamon is Draco’s biggest anti-diabetes seller. “Draco uses a proprietary pressurized hot-water extraction process which breaks down the plant cell walls to yield an 8% flavanoid standardization,” says Mr. Quirk.

Garcinia Cambogia

The rind of this small fruit grown in Asia contains hydroxycitric acid (HCA), which has undergone several human and in vivo studies showing appetite reduction, increased fat oxidation, lower triglycerides, reductions in body weight(35), substantially decreased leptin levels(36) and more recently, lower fasting glucose levels(37).

A patented HCA extract from InterHealth Nutraceuticals, Inc. was the subject of the later two studies. “Our Super CitriMax^® has been shown to provide numerous benefits that can help those who are risk for or suffer from type 2 diabetes, including benefits related to weight-management and cardiovascular health," said Paul Dijkstra, InterHealth Nutraceuticals’ CEO.

Bitter Melon

Mormordica charantia is another traditional botanical medicine. Constituents charantin, vincin and polypeptide-p from the juice of the unripe fruit have been reported to have anti-diabetic activity. Though still under debate, mechanisms for bitter melon appear to be related to polypeptide-p’s insulin-like behavior along with glucose absorption inhibition, regulation/stimulation of insulin and improved glycogen-synthesis. Though human studies have been scant, a number of in vivo studies have shown bitter melon to have a 30% to 48% lowering effect on blood glucose levels(38,39,40,41,42).

Ayush’s Dr. V. Sodhi says M. charantia’s long history of clinical use in India is due to its dual-mechanism: “While synthetic drugs typically have one mechanism, botanical genetics more closely match the complicated nature of human genetics. Botanicals thus have a dual effect of upgrading or downgrading activity as needed to balance a particular weakness,” he said.

Prickly pear cactus

Opuntia streptacantha and Opuntia ficus indicaenus—also referred to as nopal—grows primarily in the arid climates of Mexico and the Southwestern U.S. In reviewing the literature on both human and animal studies, it appears that nopal’s action glucose tolerance effects appears to stem from its ability to modulate LDL cholesterol(43). Various clinical trials done in Spain with NIDDM patients concluded that nopal reduced serum glucose levels following dextrose challenges(44,45,46,47,48).

Coccina indica

C. indica is a creeper growing primarily in India and Bangladesh. Extracts from the roots and leaves are used. C. indica appears significantly high in pectins, chitooligosaccharide-specific lectin and a number of other components. In a 1998 study, 500 mgm/kg body weight of dried extract was given to 30 NIDDM patients for six weeks. Increased-glucose control was concluded. From the data it appeared that C. indica’s insulin-like activity was related to modulating several glyolytic and lipolytic enzymes,(49) and the repression of the glucose-6-phosphatase enzyme(51). In a six-week trial of 32 NIDDM patients, 10 of the 16 patients taking C. indica showed significant improvement in glucose tolerance while none of the 16 control group showed improvement(50). A number of in vivo studies have shown C. indica’s ability to lower fasting glucose levels, some as low as 24%(51).

Aloe vera

The dried gel from the Aloe vera (family:Aloeaceae) plant has been shown useful in three studies on NIDDM. Five phytosterols lophenol, 24-methyl-lophenol, 24-ethyl-lophenol, cycloartanol, and 24-methylene-cycloartanol together with water-soluble fiber glucomannan, appear to be the active constituents. Blood sugar reduction of up to 55% has been shown in in vivo research(52). The mechanism is thought to be related to its beta-cell protective effects, inhibitory effects on glucose-absorption speed and a modulation of liver enzymes.

A half-teaspoonful of aloe daily for 4-14 weeks decreased fasting glucose levels from a mean of 273 mg/dl to 151 mg/dl for five NIDDM patients(53). Two other human studies have confirmed similar effects with one teaspoon daily(54,55).

Naturex’s aloe extract called Verapure® standardizes to 5% aloe polysaccharides.

Pterocarpus marsupium

One of the most illustrative studies showing botanicals’ NIDDM effects was published in 2005. In a double-blinded randomized study comparing Pterocarpus marsupium with the popular diabetes drug tolbutamide, 365 newly-diagnosed or untreated NIDDM patients were treated either with P. marsupium or tobutamide for 36 weeks. 86% of the Pterocarpus treatment group achieved glycemic control while 94% of the 177 tolbutamide-treated patients achieved control, based on fasting and post-prandial blood glucose (with average reduction ranges of 23-31% and 28%-34% respectively). As other trials of this botanical have confirmed, there were no adverse effects of Pterocarpus(56).

Dr. Shalinder Sodhi discussed Pterocarpus in detail. “It has a very long history of use in India for both types of diabetes,” he said. “The entire bark of the tree can be used as a powder or whole piece. In India it is sometimes administered as a cup carved from the tree wood, and the prescription will be to fill the cup with water, let it soak overnight to absorb the extract and drink the water the next day. The bioactive constituents will no longer be present when the color of the flavanoid disappears from the water.” The mechanism for Pterocarpus—with constituents thought to be epicatechin, marsupin and pterosupin—is not well understood, but Dr. Sodhi says it is believed to restore beta-cell health.

Option Botanical

There are a number of lesser-known botanicals showing blood-sugar metabolism effects. Herbalist Brien Quirk of Draco says “we have a long list of extracts with limited research showing beneficial blood sugar management effects including Solomon seal, Eucommia, Rehmannia; plum extract, miracle fruit (Synsepalum dulcificum), litchi fruit, cornus fruit (cornelian cherry or dogwood fruit), goji berry, black rice extract, stevia and Lo Han Guo (Siraitia grosvenori).” He goes on to say that spice extracts from the Labiatae family—including sage, oregano, rosemary, and lemon balm—work by inhibiting alpha glucosidase. “Astragalus sp. and Rhodiola crenulata also have unappreciated research showing anti-diabetic activity,” Quirk says.

Dr. Sodhi attests to the range of botanical options, adding neem (Azadirachta indica) as one of the more understated botanicals with anti-diabetic action. Last year a study of 10 NIDDM patients showed neem’s significant hypoglycemic effects(57). Dr. Sodhi resigns by saying “there are so many traditional botanicals which support glycemic function in one way or another.”

Thus it appears we are seeing only the tip of the iceberg when it comes to the potential for botanical solutions in blood sugar disorders. Dr. Graham will probably appreciate this as he considers botanical medicine’s long safety history.