Diabetes Mellitus: Present and Future Preventive Strategies—Part I This is the first in a continuing series of articles
- Thu, 1/17/08 - 5:16am
- 0 Comments
Pages 30 - 37
Diabetes mellitus is a growing concern for the older person. All too often undiagnosed and inappropriately treated, diabetes affects approximately 8% of persons over the age of 65 years and more than 20% of those over age 80. We have come a long way in our understanding of the pathogenesis of this life-threatening and potentially debilitating illness, and new methods of treatment continually become available. Preventing complications of diabetes depends largely on controlling the level of blood sugar, although even with good control certain end-organ effects may be inevitable. Clearly, the best way to impact on this problem is to prevent its development in the first place. This article reviews ways in which diabetes mellitus may be prevented, both in terms of reducing its impact on one’s health, as well as methods that might prevent the development of this disease entirely.
Diabetes mellitus was first described in ancient Egypt. Aretaeus named it in the 1st century ad. Galenus spoke of diabetes in the 2nd century and blamed it on “kidney weakness.” Over the next few centuries, numerous theories attempted to explain its origin and sequellae. Paracelsus in the 16th century noted the presence of a “salt” in the evaporated urine of persons with diabetes, and Thomas Willis advocated tasting urine as part of an examination, claiming that the urine of persons with diabetes tasted “wonderfully sweet, as if imbued with honey or sugar.” In 1775, Mathew Dobson identified the “salt-like” material in diabetic urine as sugar, and in 1815 this was further identified as glucose. Over the years, a variety of treatments for persons with diabetes were used, including starvation. Alkalis were added to the treatment regimen and soon antimony, cathartics, and even opium were tried. In 1848, Claude Bernard found sugar in the hepatic veins of dogs who were fed either sugar or protein. After finding glycogen in the liver, he reported that the body could synthesize its own chemicals, and postulated that diabetes resulted from an overproduction of sugar by the liver. He also reported a renal threshold for glucose above which glycosuria resulted. In the latter part of the 19th century, Bouchardat introduced exercise as an adjunct to carbohydrate restriction.
Dr. Frederick Allen advocated the use of “undernutrition” and demonstrated that weight loss due to “caloric restriction and without glycosuria” was beneficial to the adult person with diabetes who is overweight; he claimed that those who complied with his treatment strategy would have longer lives. Patients who lost a similar amount of weight but who still had glycosuria, however, reportedly did worse and continued to have progressive systemic changes.
In 1893, the French histologist Gustave Languesse suggested that the pancreatic islets of Langerhans had an endocrine function. Oscar Minkowski noted that animals that had their pancreas removed became diabetic. In the summer of 1921, Frederick Banting and Charles Best discovered insulin. On January 11, 1922, Leonard Thompson, a 14-year-old boy with diabetes, received the first extract of insulin, opening a new era for treatment. In 1936, H. C. Hagedorn discovered that when protamine was added to the insulin mixture, there was a dramatic increase in the duration of action to about 24 hours, prolonged even further to 36 hours when zinc was added.
Diabetes soon became a model of study for those interested in the field of aging. It was noted that persons with diabetes had more atherosclerosis, claudication, thickening of their basement membranes, renal changes, and neuropathies; these same findings were also noted to occur at higher rates in older individuals. It was theorized that persons with diabetes exhibited an acceleration of the aging process, something that would affect everyone eventually. It was not for several decades, however, that diabetes was fully accepted as a disease state and not a part of the normal aging process.
In the 1950s, first-generation sulfonylureas were introduced for the treatment of type 2 diabetes. In 1984, second-generation oral agents, glipizide and glyburide, became available for use in the United States. Newer medications have continued to become available and focus on different mechanisms to improve glucose metabolism. Although treatment options continue to expand, many still suffer from the consequences of poorly controlled diabetes. Prevention is the key, and good glucose control appears to be the best way to manage a patient with diabetes, whatever method is used. Studies have demonstrated fewer complications with more stringent control of blood sugar, although this tight-control regimen must be balanced with increased risk of hypoglycemia and its own set of consequences.
This is the first article in a series that will discuss aspects of diabetes mellitus. Although treatment is essential for those who already have been diagnosed, not all treatment involves pharmacologic therapy. In addition, medical science should have as its eventual goal the prevention of diabetes mellitus. This two-part article discusses several methods that might help prevent the development of diabetes mellitus, as well as some theoretical solutions that may become reality in the future.
Recent data indicate that 65% of adults in the United States are overweight, with a body mass index (BMI) greater than 25 kg/m2. What is more alarming is that close to half of these individuals meet criteria for a diagnosis of obesity, with a BMI greater than 30 kg/m2.1 As the population continues to age and become more obese, diabetes mellitus will most certainly become a greater problem. Advancing age, obesity, and weight gain are major risk factors for the development of type 2 diabetes. On average, every 1 kg increase in weight is associated with a 9% relative increase in the prevalence of diabetes,2 and more than three-quarters of persons with type 2 diabetes are overweight.
It has been well established that a reduction in weight improves insulin sensitivity, glycemic control, and even mortality.3,4 Weight loss also leads to an improvement in lipids, blood pressure, mental outlook, and quality of life. Most studies have demonstrated moderate success in weight loss through a combination of diet, exercise, and behavior modification, with an approximate 8% initial loss over the first year. Long-term weight management is more difficult to sustain, with the majority of patients with diabetes gaining back most, if not all, of the weight they initially lost over time. Nevertheless, this nonpharmacologic approach should be considered in all overweight persons with diabetes.
We continue to see an increase in the number of persons surgically treated for obesity. One study compared results for persons treated with either gastric bypass or biliopancreatic diversion. Eighteen patients without diabetes with severe obesity (BMI, 54 kg/m2) were compared to 20 sex- and age-matched lean subjects (BMI, 24 kg/m2). All individuals underwent metabolic studies including measurement of insulin sensitivity by insulin clamp technique. Following surgery in the obese group, all patients were re-studied at 5-6 months and again at 16-24 months. At baseline, patients who were obese were noted to be hyperinsulinemic, hypertriglyceridemic, and insulin resistant as compared to control subjects who had normal values in all areas. Weight loss was similar following the two methods of bariatric surgery. Of note, those who had gastric bypass surgery had an improvement in insulin sensitivity noted only at 16 months, whereas those who had biliopancreatic diversion surgery normalized as early as 6 months, with continued improvement for the duration of study. These latter changes were noted despite these patients still being obese, with a mean BMI of 33 kg/m2. Insulin sensitivity improved in proportion to weight loss following gastric bypass surgery; biliopancreatic diversion, predominantly a malabsorption-promoting procedure, led to normal insulin sensitivity long before body weight changes were significantly improved. The authors concluded that selective nutrient absorption and gut hormones might be associated with the insulin insensitivity associated with obesity.5
Exercise increases the amount of glucose taken up by muscles, and thus plays an important role in blood sugar regulation. It also helps to increase caloric expenditure and help one lose weight. Even prior to the discovery of insulin by Banting and Best, exercise was recommended as a way to control blood glucose.6 The following are arguments that have been used to support a relationship between exercise and improved insulin sensitivity:
• Older athletes have a lower insulin response to glucose challenge than nonathlete controls;
• Aerobic conditioning of previously inactive obese subjects improves fitness as it lowers the plasma insulin response to glucose, despite no change in glucose tolerance;
• Several days of forced physical inactivity in previously active men led to a loss of glucose tolerance and an increase in the plasma insulin response to an oral glucose challenge;
• Highly trained athletes have been shown to have an increased rate of glucose disposal using glucose clamp techniques; and
• Glucose disposal is highly correlated with maximal exercise capacity (VO2max)
Although data suggest that physical activity promotes glucose uptake by enhancing insulin sensitivity, loss of this sensitivity occurs within a few days of physical inactivity, despite maintaining maximal aerobic capacity. Insulin sensitivity may also be closely related to the depletion of muscle glycogen. It has been reported that even a single session of exercise in men with type 2 diabetes mellitus who are unfit is associated with increased insulin sensitivity and reduced overnight endogenous glucose production.
There is a wealth of epidemiologic evidence to support a relationship between physical inactivity and diminished glucose tolerance; it remains unclear whether exercise is responsible for this difference or some other factor associated with the exercise, such as a change in weight or body composition. In a study of more than 5000 former college athletes and nonathlete, age-matched controls, former college athletes were noted to be leaner than nonathletes up to the age of 70. They were also more physically active, with 74% currently exercising compared to 56% of controls, and had a lower prevalence of diabetes mellitus.7 Another study reported that those individuals in the highest tertile of physical activity had half the prevalence of impaired glucose tolerance (IGT) as those in the lowest tertile.
In the Second National Health and Nutrition Examination Survey, a cross-sectional study that examined the relationship between IGT and a variety of other variables, 15,000 individuals were evaluated; 6.6% were diagnosed with diabetes mellitus, 97% of whom had type 2 disease. An additional 11.2% were identified as having IGT. Physical inactivity was considered to be a risk factor for IGT, independent of other contributing variables including age, past obesity, and family history. Those with IGT were 1.5 times more likely to report little or no exercise, and were twice as likely to have a resting heart rate over 100 beats/min.
A study of more than 1200 physician marathon runners and 683 nonrunning physician controls reported that runners were leaner and had a 40% lower prevalence of diabetes mellitus than non-running controls. They were also one-fifth as likely to have hypertension and less likely to be smokers and have hypercholesterolemia.
Type 2 diabetes is characterized by insulin resistance and is influenced by obesity and physical inactivity. Exercise should be considered an important way to maximize glucose tolerance and reduce the risk of developing frank diabetes. It should be noted that fitness is not a prerequisite for improvement in glycemic control. Improved glucose tolerance may not result from a program of physical training if the time since the last exercise session was sufficiently distant to result in a “detraining effect.” Exercise should be encouraged, but it is not without risk, especially in older individuals or those who may have pre-existing coronary disease, hypertension, or other medical conditions. Cardiac arrhythmia or myocardial infarction may result from the increase in oxygen demand, and a medical evaluation should be done prior to embarking on any change in exercise to determine risk and whether the exercise should initially be done under closely supervised conditions. Diabetic retinopathy may worsen in those who already have diabetes, especially if blood pressure increases above 170 mm Hg during exercise. There is also the risk of damage to joints and soft tissues.
An exercise program should be tailored to avoid an excessive rise in systolic blood pressure during exercise. Autonomic neuropathy may be present in persons with diabetes, and post-exercise hypotension and syncope may occur more commonly. An exercise tolerance test or stress test should be performed prior to starting an exercise program, and yearly in those over 45-50 years of age with known coronary artery disease or diabetes with co-existing hypertension and/or hyperlipidemia.
In planning an individualized exercise program, it is important to keep in mind the type of exercise and its intensity, duration, and frequency. In general, aerobic activities such as biking, walking, or swimming improve cardiovascular fitness, blood pressure, weight management, and metabolic control of blood glucose and lipids. These exercises are also less likely to cause injury and have a higher degree of acceptance. The intensity of the exercise program will help determine its safety and the ability of the individual to comply for long periods. In general, those with a normal exercise tolerance test can embark on a program that corresponds to about 50-65% of maximal functional capacity. If the individual can “walk and talk” at the same time during the exercise, the intensity level is usually not excessive. Those with an abnormal exercise tolerance test should be prescribed exercise at levels below those at which these abnormalities were noted with medical supervision, such as provided through a cardiac rehabilitation program. Intensity and duration go hand in hand, with the recommended duration between 30 and 60 minutes of sustained exercise per day.
ROLE OF DIETARY FACTORS IN MANAGEMENT/PREVENTION
Many claims have been made about the benefit of various nutritional supplements and foods and their ability to improve insulin sensitivity. Epidemiologic studies suggest that green tea, for example, may improve insulin sensitivity in both humans and obese mice,8 an effect believed to be due to green tea’s antioxidant effects from a polyphenol present or epigallocatechin-3-gallate (EGCG). Claims have also been made for the ability of green tea to improve hypertension, lower levels of low-density lipoprotein, and play a role in cancer prevention.
Alpha-lipoic acid has been used to improve insulin-stimulated glucose disposal9,10 and glucose uptake by skeletal muscles. This form of dietary treatment has been most commonly studied in relation to treating diabetic-related neuropathy, although future studies may shed some light on a possible preventive effect as well. In one study, 80 patients with diabetes were randomly assigned to one of four groups to receive alpha-lipoic acid, selenium, vitamin E, or placebo. After 3 months, those who received 600 mg of alpha-lipoic acid daily had significant improvement in levels of thiobarbituric acid reactive substance, urinary albumin excretion, and signs of neuropathy.11 In another study, 328 non–insulin-dependent patients with diabetes who had known neuropathy were treated with either alpha-lipoic acid or placebo. Those who were treated with alpha-lipoic acid had significantly reduced pain scores. Clearly, much more data are needed prior to making any definitive conclusion regarding the role of alpha-lipoic acid in preventing and/or treating any aspect of diabetes mellitus.
Foods high in complex carbohydrates and fiber, such as whole grains, legumes, and vegetables, reportedly slow the release of glucose into the bloodstream, with numerous studies claiming the benefits of a diet rich in guar and pectin. The American Dietetic Association has reported that vegetarian diets are associated with a reduced incidence of diabetes and heart disease. For years, nutritionists have used the glycemic index to indicate which foods are more prone to cause the greatest insulin response. Foods with a higher rating, or those causing a higher insulin response, include white bread, bagels, English muffins, instant hot cereals, low-fat frozen desserts, raisins or other dried fruits, whole milk and cheeses, peanuts and peanut butter, and hot dogs and luncheon meats. Foods with a low rating, or those that are not associated with a high insulin response, include most vegetables and leafy greens, pitted fruits and melons, whole-grain breads, whole-grain cereals, sweet potatoes and yams, skim milk, buttermilk, poultry, lean cuts of beef, pork, veal, shellfish, most legumes, and most nuts. Foods that are cooked rank higher than raw foods. Fruits and vegetables that have been juiced or puréed are higher than when the same fruit or vegetables are eaten whole.
Supplements of vitamin B6, biotin, chromium, magnesium, vanadium, essential fatty acids, and flaxseed oil have all been suggested as a way of improving insulin sensitivity. Although not conclusive by any means, several studies support a role of B6 in regulation of blood sugar in persons with diabetes mellitus, as well as a reduction of symptoms of diabetic neuropathy.12 Biotin reportedly synergizes the action of insulin and may also have an effect on improving symptoms of neuropathy in patients with diabetes.13 Although not scientifically proven, topical application of capsicum, a cayenne pepper extract, when used in association with vitamin B12 has also been reported to help relieve the pain of diabetic-induced neuropathy.
Vitamin C has been reported in one study to reduce insulin requirements as well as prevent the development of diabetic-induced cataracts.14 An association between vitamin C deficiency and insulin-producing cells in the pancreas has also been suggested. Vitamin E has been reported to improve glucose control in patients with diabetes, but little scientific data are available to support its use for this purpose.
Chromium has received a great deal of attention for its possible role in preventing or treating diabetes mellitus.15 It is known that chromium is affected by glucose and insulin in the blood, and deficiency of chromium, a rare condition, may impair glucose tolerance. Chromium supplements have been used as a treatment adjunct in persons with both type 1 and type 2 diabetes mellitus. In one study, glucose tolerance was significantly improved with daily doses of 150 mcg of trivalent chromium.16
Potassium supplementation has also been reported to help improve insulin sensitivity and secretion,17 and vanadium in doses of 5-20 mg daily has been reported as a possible way to help regulate blood sugar. There are still too few data, however, to make any particular conclusions regarding these agents.
Co-enzyme Q10, also known as ubiquinone, has been reported to stimulate the production of insulin and improve glucose tolerance when taken in doses of 80 mg per day for at least 3 months. Claims have also been made that amino acid supplementation may improve insulin production; these claims need to be substantiated with additional controlled studies.
The Multiple Risk Factor Intervention Trial (MRFIT)18 evaluated 12,866 middle-aged men at high risk for coronary heart disease to study the effects of a change in diet that reduced saturated fat, cholesterol, and calorie intake, counseling to stop smoking, antihypertensive therapy as appropriate, and increased physical activity.18 Those who were able to comply with the recommendations and who reduced their BMI had a reduced risk for developing diabetes. Smoking was associated with an increased risk for developing diabetes.18
Over the years, many plants have been reported to have hypoglycemic properties. These include bilberry, goat’s rue (Tephrosia virginiana), fenugreek seed, bitter melon, garlic, mulberry leaves, olive leaves, psyllium seed, and ginseng.19 Unfortunately, most studies to date report results from only a few subjects, and there are few placebo-controlled, blinded studies on which to base conclusions. Nevertheless, gymnesyl, an ayurvedic herb used to treat both type 1 and type 2 diabetes, reportedly improved blood sugar in 21 of 22 subjects with type 2 diabetes and resulted in a lower usual dose of oral hypoglycemic agent. Gymnesyl was given in a dose of 400 mg daily, along with the person’s usual oral hypoglycemic agent. Five subjects were reportedly able to maintain normal blood sugars with diet and gymnesyl alone.20
Fenugreek seeds given as a powder twice daily at a dose of 25-50 g to persons with type 1 diabetes mellitus reportedly lowered fasting blood sugar, 24-hour urinary excretion of glucose, and insulin requirements. Patients with type 2 diabetes were noted to have a significantly reduced postprandial glucose following the use of powdered fenugreek seeds soaked in water for 21 days.20
Huereque, derived from the root of the huereque cactus, has been reported to improve glucose tolerance in persons with diabetes, although this effect reportedly is self-limited and requires additional study.
One double-blind, placebo-controlled study investigated the effect of ginseng on newly diagnosed individuals with type 2 diabetes.21 Thirty-six patients were randomized to ingest over an 8-week period one tablet daily containing placebo, ginseng 100 mg, or ginseng 200 mg. The specific type of ginseng given was not mentioned in the report. Ginseng reportedly was associated with improved mood, psychophysical performance, and reduced fasting blood glucose and body weight. The 200-mg dose of ginseng improved glycated hemoglobin as well.21
Other claims have been made for nontraditional preventive and treatment options for diabetes mellitus, including chelation therapy; oxygen therapy; use of acupuncture in combination with various chinese herbs including astragalus, wild yam, and rehmannia; and ayurvedic therapies including herbal massages and herbal steam saunas, fasting, and purges. Additional data are needed, however, prior to any definitive conclusion being made.
In general, individuals with diabetes or who are at risk of developing diabetes should eat a diet that emphasizes foods high in complex carbohydrates and fiber. The use of refined sugars, alcohol, tobacco, and caffeine should be eliminated or greatly reduced. Weight should be maintained at “average weight for age” established and published by the Metropolitan Life Insurance company. Various supplements and nontraditional dietary therapies have been suggested as possibly being beneficial, although data are not conclusive. Caution is advised when using these, as they may have side effects when taken in doses beyond that obtained as part of a normal diet.
Part II of this article will discuss pharmacologic approaches to the prevention of diabetes mellitus as well as genetic and oxidative factors that play a role in diabetes and may hold the key to prevention.
REFERENCES 1. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among U.S. adults, 1999-2000. JAMA 2002;288:1723-1727. 2. Mokdad AH, Ford ES, Bowman BA, et al. Diabetes trends in the U.S.: 1990-1998. Diabetes Care 2000;23:1278-1283. 3. Franz MJ, Bantle JP, Beebe CA, et al. American Diabetes Association. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2003;26(suppl 1):S51-S61. 4. Williamson DF, Thompson TJ, Thun M, et al. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care 2000;23:1499-1504. 5. Muscelli E, Mingrone G, Camastra S, et al. Differential effect of weight loss on insulin resistance in surgically treated obese patients. Am J Med 2005;118:51-57. 6. Allen FM, Stillman E, Fitz R. Exercise (monograph 11). New York: Rockefeller Institute of Medical Research,1919;486-499.7. Frisch RE, Wyshak G, Albright TE, et al. Lower prevalence of diabetes in female former college athletes compared with nonathletes. Diabetes 1986;35:1101-1105. 8. Tsuneki H, Ishizuka M, Terasawa M, et al. Effect of green tea on blood glucose levels and serum proteomic patterns in diabetic (db/db) mice and on glucose metabolism in healthy humans. BMC Pharmacol 2004;4(1):18. 9. Evans JL, Goldfine ID. Alpha-lipoic acid: A multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Diabetes Technol Ther 2000;2(3):401-413. 10. Jacob S, Henriksen EJ, Tritschler HJ, et al. Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes 1996;104(3):284-288. 11. Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995;38(12):1425-1433. 12. Jones CL, Gonzalez V. Pyridoxine deficiency: A new factor in diabetic neuropathy. J Am Podiatry Assoc 1978;68(9):646-653. 13. Koutsikos D, Agroyannis B, Tzanatos-Exarchou H. Biotin for diabetic peripheral neuropathy. Biomed Pharmacother 1990; 44(10):511-514. 14. Devamanoharan PS, Henein M, Morris S, et al. Prevention of selenite cataract by vitamin C. Exp Eye Res 1991;52(5):563-568. 15. Anderson R, Cheng N, Bryden N, et al. Beneficial effect of chromium for people with type II diabetes. Diabetes 1996;45 (suppl 2):124A. 16. Hambidge KM. Chromium nutrition in man. Am J Clin Nutr 1974;27(5):505-514. 17. Norbiato G, Bevilacqua M, Meroni R, et al. Effects of potassium supplementation on insulin binding and insulin action in human obesity: Protein-modified fast and refeeding. Eur J Clin Invest 1984;14(6):414-419. 18. Davey Smith G, Bracha Y, Svendsen KH, et al. Incidence of type 2 diabetes in the randomized Multiple Risk Factor Intervention Trial. Ann Intern Med 2005;142:313-322. 19. Ivorra MD, Paya M, Villar A. A review of natural products and plants as potential antidiabetic drugs. J Ethnopharmacol 1989;27(3):243-275. 20. Murray MT. Are botanical medicines useful in diabetes? The American Journal of Natural Medicine 1994;1(3):5-7. 21. Sotaniemi EA, Haapakoski E, Rautio A. Ginseng therapy in non-insulin-dependent diabetic patients. Diabetes Care 1995; 18(10):1373-1375.