Fat, Obesity, Diabetes and Supplements Part II
by Dr. Emmanuel Opara


As pointed out in the part 1 of this review article, most individuals with non-insulin-dependent diabetes mellitus (NIDDM) or type 2 diabetes suffer from obesity. The development of obesity usually precedes the onset of diabetes in these cases. It is also clear that high dietary fat consumption is a primary factor in the development of obesity-associated type 2 diabetes. It is therefore imperative that individuals at risk, such as those with a family history of diabetes, make very serious efforts to reduce the fat contents of their diets. However, as previously pointed out, consumers have an ambivalent attitude towards fat in their foods. A sensible strategy is to reduce the fat content of foods to a level that maintains foods' palatability. Unfortunately, that level of dietary fat may still be considered high and the use of supplements that will prevent the metabolic consequences of fat consumption becomes very necessary.

 

Fat Alternatives
All kinds of approaches are being explored, with the hope of finding an acceptable strategy for reducing the fat content of foods without compromising the pleasure of eating. One approach has been to manipulate the fatty acid composition of fat in the food. Experiments involving long-chain fatty acids of different degrees of desaturation have yielded conflicting results. In contrast, it has been consistently shown that foods with high contents of medium-chain fatty acids reduce body weight gain when compared to those with high contents of long-chain fatty acids. For instance, in one study, adult rats were fed one of two isocaloric diets comprising fat as 45% of total calories. After six weeks, it was observed that rats fed medium-chain triglycerides had 20% to 5% reductions in body weight and carcass fat content, respectively, compared to those fed long-chain triglycerides.1 It needs to be pointed out that medium-chain fatty acid oxidation occurs predominantly in the peroxisomes whose reaction generates heat and hydrogen peroxide, in contrast to mitochondrial fatty acid oxidation that leads to the production of ATP and water. Excessive hydrogen peroxide production with medium-chain fatty acid feeding may represent yet another health challenge that requires antioxidant supplementation.
 

Another approach that is being actively examined by the food industry is to replace fat in food with alternatives that are safe but have lower caloric values without compromising taste and texture. The replacement agents can be based on natural ingredients, including carbohydrates, soluble fibers and proteins as well as synthetic products such as the hexa-, hepta- and octa-fatty acyl esters of sucrose.(1) This approach appears to be associated with some problems. For instance, it has been reported that the use of sucrosepolyester can have an adverse effect on the body's antioxidant defense systems, the consequences of which are deleterious to health.

A recent trend is to restructure the intramolecular distribution of fatty acids in triglycerides to obtain a reduced caloric load from fat.(1) The principle involves the incorporation of long-chain saturated fatty acids either randomly or specifically on the sn-1 and sn-3 positions of the glycerol moiety. When liberated by the hydrolytic action of pancreatic lipase, long-chain fatty acids may precipitate and become partially indigestible resulting in a reduced caloric content of fat. Since short-chain and medium-chain fatty acids have reduced caloric values, incorporation of these molecules into triglycerides have also been proposed. At present, there is scanty information on the effects of these so-called 'structured lipids' in metabolic regulation.

 

Supplementation
While the search for acceptable food products that will effectively reduce fat consumption without sacrificing the pleasure of eating continues, it is advisable that consumers, particularly those at risk for development of obesity and diabetes, take appropriate steps for disease prevention. There are various supplements available to help achieve this objective and some of these will now be discussed.

Chromium
As apparent from the preceding sections of this review, obesity is a major risk factor for the development of type 2 diabetes. Therefore, supplements that induce weight loss are useful for the prevention and/or treatment of diabetes. One such supplement is chromium which is available as chromium picolinate. The exact mechanism of action of chromium is not completely understood, but it has been shown that this trace element inhibits insulin secretion in isolated pancreatic islets. The implication of such an observation is that chromium intake would reduce insulin levels in the blood. It should be recalled that hyperinsulinemia is a characteristic feature of obesity and it has been hypothesized that high plasma insulin levels may be responsible for excessive body weight gain. It has also been proposed that chromium may act as an insulin sensitizer in type 2 diabetes. It is interesting to note that the chromium concentration in the body appears to decline with age. Along with the age-associated deficiency in antioxidant defense systems, the age-dependent reduction in chromium levels may play a role in the high incidence of type 2 diabetes in elderly individuals. For non-diabetic individuals who are overweight, a daily supplement of 200 micrograms of chromium appear to be appropriate for weight loss. Those people suffering from type 2 diabetes may need higher doses but should seek the advice of their doctors because this mineral may alter insulin requirements.

L-Glutamine
induce weight loss, is L-glutamine. L-glutamine is a fatty acid oxidation inhibitor. Since fatty acid oxidation is linked to increased insulin output by the pancreas, glutamine supplementation prevents hyperinsulinemia, and enhances glucose utilization resulting in the reduction of hyperglycemia. In this manner, L-glutamine supplementation abolishes the characteristic insulin resistance associated with high -fat diet. In a study using an obesity- and diabetes-prone strain of mice, C57BL/6J, on a high fat diet, within one week of supplementing L-glutamine results indicated a minimum of a 5% reduction in body weight accompanied by a normalization of plasma insulin levels.(2) After two months of glutamine supplementation, blood glucose levels in the previously obese and diabetic animals became normal. In the study, L-glutamine was supplemented as approximately 3% of total calories a significant quantity of glutamine. Further studies are required to determine the lowest effective dose and duration of L-glutamine supplementation to induce weight loss in humans. Anecdotal reports indicate that L-glutamine supplementation as low as 1 gram per day (at bedtime) for 2 months has been found to be effective in lowering blood sugar levels in human subjects with type 2 diabetes.

L-glutamine is a preferred fuel source for a variety of cells and is also a precursor for the biosynthesis of the antioxidant glutathione and other important biological compounds such as glycogen, nucleotides and proteins. In normal individuals, supplemental glutamine would, therefore, be utilized for different biological processes. The dose requirement for this amino acid would be greater in disease. Until controlled experiments are performed with diabetic patients, supplemental glutamine should be limited to less than 5 grams-per-day. It is, however, not advisable for individuals who have advanced diabetes with complications of kidney or liver disease to take glutamine supplements.

Other Important Supplements
There are some lesser known supplements which have shown laudable promise for protection from diabetes. One such supplement is taurine. Studies in rats have shown that taurine supplementation is associated with a lowering effect on blood sugar levels. Indeed, these studies indicate that taurine supplementation has a protective effect on the development of diabetes associated with the administration of a diabetogenic substance called streptozotocin. This implies that taurine supplementation may offer protection to non-diabetic individuals who are at risk for the development of the disease. Taurine has also been shown to have a suppressive effect on insulin secretion and may therefore help to prevent hyperinsulinemia which appears to be a plausible factor in the development of obesity and non-insulin -dependent diabetes.

Gymnema Sylvestre
Another promising supplement is an extract of gymnema sylvestre, a woody climber that grows in tropical forests of the central and southern parts of India. Although this product has been used for the treatment of diabetes in India over many centuries, the first scientific demonstration of its antidiabetic properties in humans was made about 70 years ago when it was observed that leaves of Gymnema sylvestre reduced glycosuria (glucose in urine) in individuals with diabetes.(3) Although in vitro studies to examine the effect of this extract on insulin secretion remain to be performed, Gymnema sylvestre use appears to enhance insulin secretion and the functional viability of the endocrine pancreas in vivo. This supplement represents a unique and interesting product because it is one of those few agents that may have beneficial effects on both type 1 and type 2 diabetes.(4) Gymnema sylvestre extract appears to be particularly effective when administered as an adjunct to oral antidiabetic agents. For instance, in a study in India, Gymnema sylvestre extract (called GS4) was administered as an adjunct to conventional oral agents at a dose of 400 mg. per day in 22 type 2 diabetic patients for 18-20 months. During the GS4 supplementation, the patients had the dosage of their conventional drugs reduced and still showed a reduction in blood glucose, glycosylated hemoglobin and other proteins. Five of the 22 patients were able to discontinue their conventional drugs and maintain adequate blood glucose control on the GS4 supplement action alone.(5)

Oxidative stress
A growing area of research is the relationship between oxidative stress and diabetes. It had been recognized earlier that increased free radical damage was associated with the development of diabetic complications of micro- and macro-angiopathies. The development of these diabetic complications has usually been attributed to the nonenzymatic glycation of tissue proteins. However, it is only recently that researchers examined the possible role for free radicals in the pathogenesis of diabetes. In this article, the relationship between free radical production and fat metabolism has been outlined. Also, the mechanism by which an increased free radical load shuts off glucose metabolism through the inhibition of glycolytic and electron transport enzymes, thereby causing hyperglycemia, was discussed in the first part of this review. In addition, it has been suggested that altering plasma membrane fluidity increases free radical concentrations which causes an impairment of insulin action, resulting in insulin resistance.(6) It should be recalled that tissue antioxidant levels decline with increasing age, thereby putting elderly individuals at risk for the development of diabetes and other diseases.

There is agreement among researchers that glutathione, the major cellular antioxidant, plays a prominent role in the functional viability of both the exocrine and endocrine pancreas. It has already been mentioned that aged individuals have a deficiency of glutathione. It is therefore not surprising to find that, in elderly subjects with impaired glucose tolerance, acute intravenous glutathione supplementation enhanced glucose -stimulated insulin secretion.6 In our laboratory, we have also found that the addition of glutathione monoethyl ester to a lipid infusate prevented the development of insulin resistance associated with intravenous lipid administration. These studies thus support the observations that, in type 2 diabetic patients with a relative deficiency of plasma insulin levels caused by insulin resistance, glutathione supplements may prove to be beneficial.(6) Glutathione, a tripeptide comprising glutamate, cysteine and glycine, acts by degrading peroxides in a reaction that involves the enzyme glutathione peroxidase, thereby removing the inhibitory effects of these reactive oxygen species on glucose metabolism. Daily glutathione supplements up to 1 gram per day appear to be appropriate. However, one drawback of glutathione supplementation is that the active molecule, which is reduced glutathion (GSH), is not easily transported across cell membranes. It is known, though, that the oral GSH supplement is broken down by gastrointestinal enzymes and the constituent amino acids absorbed for the resynthesis of GSH within cells. Researchers have continued to explore the development of safe and effective GSH analogues for supplementation.

Other antioxidant supplements that have been found to lower free radical concentrations and improve insulin action are vitamins C and E.(6) These antioxidant vitamins have also been found to be useful in preventing diabetic complications by working in a biochemical chain with glutathione to degrade reactive oxygen species. These vitamins can be used as both preventive and therapeutic agents in either individuals at risk or those with diabetes. For preventive purposes, vitamin C supplementation at doses of 500 - 1000 mg./day and vitamin E supplement at a dose of 400 Units/day are recommended. Lower doses are probably not of any use. As therapeutic agents, higher doses are required; vitamin C doses up to 2 gram/day and a vitamin E dose of about 800 Units/day have been found to be beneficial in regulating blood sugar levels in type 2 diabetic patients. Nutritional supplements, particularly fat-soluble substances like vitamin E, are absorbed better when taken with meals. The action of another antioxidant, coenzyme Q10 or ubiquinone, on blood sugar regulation needs to be studied in detail. There is some indication that this substance which enhances oxidative phosphorylation may be useful in preventing the development of diabetes. Doses of 100-200 mg./day have been recommended.

Conclusion
It is apparent from this review that a variety of nutritional supplements play a prominent role in the prevention of diabetes in individuals at risk for the development of the disease. Chromium and the antioxidant vitamins C and E have been found to be efficacious in controlling blood sugar levels in type 2 diabetes and in the prevention of diabetic complications. Other supplements with promise in both diabetes prevention and treatment include, L-glutamine, taurine, CoQ10 and Gymnema sylvestre. Future research should be directed at the examination of the potentials of these supplements and their appropriate effective doses in diabetes. Nondiabetic, overweight individuals may explore the use of supplements such as chromium and L -glutamine for weight loss and prevention of diabetes. Also, other healthy, high-risk individuals such as the elderly and those with a diabetic family history, would derive benefits from taking effective doses of vitamins C and E (preferably together) for the prevention and adjunctive treatment of diabetes. Those individuals already suffering from the disease should only take supplements under the supervision of their physicians.

Dr. Emmanuel C. Opara is a research professor in the Departments of Surgery and Cell Biology and is a member of the Sara W. Stedman Center for Nutritional Studies at Duke University Medical Center in Durham, North Carolina.

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References
1. Weststrate JA. Fat and Obesity. Int J Obesity 19 (suppl.5): S38-S43, 1995.
2. Opara EC et al. L-glutamine supplementation of a high-fat diet reduces body weight and attenuates hyperglycemia and hyperinsulinemia. J Nutr 126: 273-279, 1996.
3. K.G. Gharpurey, Indian Medical Gazette. 1926;61: 155 (Abstr.).
4. ERB Shanmugasundaram, K.L. Gopinath, K. Rhada Shanmugasundaram, et al, Journal of Ethnopharmacology 1990; 30: 265-279.
5. K Baskaran, B. Kicar Ahamath, K. Radah Shanmugasundaram, et al, Journal of Ethnopharmacology 1990; 30: 295-300
6. Paolisso G, Giugliano D. Oxidative stress and insulin action: is there a relationship? Diabetologia 39: 357-363, 1996.

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