Over 16 million people in the United States have diabetes and this number is growing by the hour. Diabetes is now the fifth leading cause of death in this country.1 By understanding the pathophysiology of diabetes and the environmental factors which contribute to this disease, we can have a better focus on the scope and nature of the threat to our patient population with diabetes.
With this in mind, it’s important to have a thorough knowledge of the potential impact of insulin resistance syndrome, a condition in which the tissues of the body become desensitized to insulin. It is a chronic state that will result in hyperglycemia and its associated complications.
The metabolic manifestation of insulin resistance syndrome include reduced amount of insulin-stimulated glucose uptake; reduced insulin suppression of endogenous glucose production; and reduced antilipolysis.2 With type 2 diabetic patients, there is a loss of early phase insulin secretion, which is also known as beta cell dysfunction.3 The relationship of early insulin secretion to insulin sensitivity in normal individuals is represented by a hyperbolic curve in keeping with the existence of a feedback loop. Deviation from the standard curve demonstrates defects in both insulin secretion and sensitivity in people who are at risk of developing diabetes.4
The reduction of early phase insulin response results in impaired suppression of hepatic glucose production. Therefore, the amount of glucose produced by the liver is not inversely proportional to the amount of glucose influx, and this results in postprandial hyperglycemia.
The target tissues which respond to insulin are chiefly the liver, adipose and indirectly skeletal muscle. Insulin resistance syndrome in the hepatic tissues results in fasting hyperglycemia from the rapid release of glucose from its store of glycogen (glycogenolysis).
In addition, gluconeogenesis converts amino acids, lactate and glycerol released from other tissues into glucose. In the face of insulin resistance, there is no regulation of hepatic glucose uptake and the body is producing glucose to feed the hunger state. Adipose tissue is the most sensitive tissue in the body to insulin. Insulin resistance syndrome results in the accumulation of free fatty acids, promotes lipogenesis and inhibits lipolysis.
In their study, Basu et. al., attempted to determine whether type 2 diabetes mellitus alters systemic and regional free fatty acid metabolism.4 They concluded that type 2 diabetes is associated with a generalized impairment in insulin suppression of lipolysis compared with equally obese non-diabetic individuals. An additional concern is that these circulating free fatty acids can also undergo biosynthesis into cholesterol and phospholipids.4
Skeletal muscle is the other major organ responsible for glucose uptake under the direction of insulin. Ryder et. al., focused their research on the molecular mechanism regulating insulin action and the factors contributing to insulin resistance in skeletal muscle.5 The concluded that type 2 diabetic patients have a defect in insulin signal transduction through the insulin receptor substrate. Secondary to the lack of insulin stimulation, there is decreased uptake of glucose transport. This is a key rate-limiting step in glucose metabolism.5
Exploring The Link Between Obesity And Insulin Resistance
Heredity alone accounts for a small percentage of type 2 diabetes in our population. The majority of patients have a combination of environmental factors. Several of these factors (obesity, lack of exercise, poor diet and age) have been directly associated with insulin resistance syndrome.
Obesity is one of the fastest growing problems in this country today. According to a 2000 article in Diabetes Care, a comparison of average population weights between 1990 and 1998 revealed that the average man and woman had gained 4.3 lbs. and 3.9 lbs. respectively. Obesity-associated insulin resistance is thought to be mediated by circulating free fatty acids whose clearance is reduced in people with type 2 diabetes.
There is plenty of literature supporting the link between obesity and insulin resistance. Steinberger et. al., concluded that adiposity in childhood was a predictive factor of obesity and insulin resistance in young adulthood. Their study also demonstrated that cardiovascular risk in young adulthood is highly correlated to the degree of adiposity.6
A fat rich-diet has been linked to insulin resistance syndrome. Park et. al., studied the relation between a chronic high fat diet and the incidence of insulin resistance syndrome — independent of obesity.7 They put 40 lab rats on a chronic high fat diet. They determined that visceral obesity is associated with insulin resistance. On the other hand, increased intake of complex carbohydrates, such as dietary fiber, appear to improve insulin action.8
The clinically apparent affects of insulin resistance syndrome include obesity, hypertension, dyslipidemia, hyperinsulinemia and hyperglycemia.9
Numerous studies have shown that insulin resistance syndrome correlates to an increased risk for developing cardiovascular complications.10-11 Stoney et. al., showed that insulin resistance is associated with dyslipidemia, which indeed increased the risk for coronary artery disease in women with type 2 diabetes.12 In addition, there is strong support in the literature that insulin resistance syndrome is a risk factor for heart disease in elderly men who have type 2 diabetes.13
What Are The Best Treatment Options?
Medical management of diabetes, especially type 2 diabetes, chiefly consists of insulin and sulfonylureas. However, when insulin resistance syndrome is correlated with diabetes, the pharmacological management should target a different mechanism of action.
Metformin is an oral hyperglycemic agent, which improves glucose tolerance in patients with diabetes. Therefore, Metformin lowers both basal and postprandial plasma glucose levels and targets the hepatic system for this effect.14 Unlike sulfonylureas, Metformin does not stimulate insulin production, but it does inhibit gluconeogenesis in the liver. Multiple studies have shown that Metformin has positive benefits, such as reducing HgA1c, preventing heart attack, and improving the survival rate of those who have type 2 diabetes.15
Thiazolidinediones (i.e. Avandia, Actos) are the other key class of drug treatment for insulin resistance syndrome. These drugs primarily act to decrease insulin resistance through improved sensitivity to insulin in muscle and adipose tissue. In higher dosages, thiazolidinediones also inhibit hepatic gluconeogenesis. Their unique mechanism of action depends on the presence of insulin for activity. Thiazolidinedione decreases hepatic glucose transport and increases insulin dependent glucose disposal in skeletal muscle. Its mechanism is also critical for controlling glucose and lipid metabolism.16 Literature supports that using thiazolidinediones significantly lowers circulating free fatty acid levels.17
Clearly, multi-drug therapy is the optimal way to manage diabetic patients with insulin resistance syndrome. This allows physicians to target multiple tissue levels and provides a comprehensive approach. It has been demonstrated that the combination of sulfonurea and Metformin decreased the HgA1c level 11 to 12 percent in just 13 weeks.18
In the United States, only 4 percent of patients with diabetes receive both insulin and oral hyperglycemics for their condition. However, given the facts of insulin resistance syndrome and the mechanism of its action, multi-drug therapy is clearly the optimal treatment option. Certainly, this medical treatment should be combined with the well-documented benefits of an appropriate diet and exercise program.
Insulin resistance itself is an important risk factor for the development of hypercholesterolemia, hypertension, atherosclerotic heart disease, coronary heart disease, and chronic heart failure.19,20 New evidence suggests that young, obese children are at risk of developing insulin resistance syndrome many years before diabetes is even diagnosed. New “healthy living” programs in the home and school environment appear to be a key factor in preventing insulin resistance syndrome and the eventual onset of diabetes in this high-risk population.
Mr. Yen is a first-year resident at the University of Texas Health Science Center at San Antonio.
Dr. Steinberg is an Assistant Professor in the Department of Orthopaedics/Podiatry Service at the University of Texas Health Science Center. He is also the Medical Director of the Texas Diabetes Institute Podiatry Clinic.
1. www.medicine.uiowa.edu/ortho/diabetic_  foot_infections.htm
2. Stumvoll M, Gerich J. Clinical features of insulin resistance and beta cell dysfunction and the relationship to type 2 diabetes. Clinics in Laboratory Medicine 2001; 21(1):31-51.
3. Khan SE. Beta cell failure: causes and consequences. International J of Clinical Practice2001; Supplement (123):13-8.
4. Basu A, Basu R, Shah P, Vella A, Rizza RA, Jensen MD. Systemic and regional free fatty acid metabolism in type 2 diabetes. Am J of Physiology – Endocrinology & Metabolism 2001; 280(6): E1000-6.
5. Ryder JW, Gilbert M, Zierath JR. Skeletal muscle and insulin sensitivity: pathophysiological alterations. Frontiers in Bioscience 2001; 6:D154-63.
6. Steinberger J, Moran A, Hong CP, Jacobs DR Jr, Sinaiko AR. Adiposity in childhood predicts obesity and insulin resistance in young adulthood. J of pediatrics 2001; 138(4):453-4.
7. Park S, Kim YW, Kim JY, Jang EC, Doh KO, Lee SK. Effect of high fat diet on insulin resistance: dietary fat versus visceral fat mass. J of Korean medical science 2001; 16(4):386-90.
8. Bessesen DH. The role of carbohydrates in insulin resistance. J of Nutrition 2001; 131(10); 2782S-2786S.
9. Laaskso M. Insulin resistance and its impact on the approach to therapy of type 2 diabetes. International J of Clinical Practice 2001; supplement (121):8-12.
10. Kareinen A, Viitanen L,Halonen P, Lehto S, Laakso M. Cardiovascular risk factors associated with insulin resistance cluster in families with early onset coronary heart disease. Arteriosclerosis, Thrombosis & Vascular Biology 2001; 21(8): 1346-52.
11. Strutton DR, Stang PE, Erbey JR, Lydick E. Estimated coronary heart disease attributable to insulin resistance in populations with and without type 2 diabetes. Am J of Management care 2001; 7(8):765-73.
12. Stoney RM, O’Dea K, Herbert KE, Dragicevic G, Giles GG, Cumpston GN, Best JD. Insulin resistance as a major determinant of increased coronary heart disease risk in postmenopausal women with type 2 diabetes. Diabetes Medicine 2001; 18(6): 476-82.
13. Kussisto J, Lempiainen P, Mykkanen L, Laakso M. Insulin resistance syndrome predicts coronary heart disease events in elderly type 2 diabetic men. Diabetic care 2001; 24(9):1629-33.
14. Reasner CA. Glucophage: How it works. Diabetes Self-Management 1999; July/August :pp.41-7.
15. UKPDS Group. Lancet 1998; 352: 854-65.
16. Reasner CA, Defronzo RA. Treatment of type 2 diabetes mellitua: A rational approach based on its pathophysiololgy. Am Acad Fam Phs 2001; 63:1687-88, 1691-92.
17. Hevner AL, Peichart D, Janez A, Olefsky J. Thiazolidinedione treatment prevents free fatty acids-induced insulin resisitance in male wistar rat. Diabetes 2001; 50(10): 2316-22.
18. Morris et al. Diabetes 2000; 49(suppl.1):A76.
19. Coats AJ, Anker SD, Anker S. Insulin resisitance in chronic heart failure. J of cardiovascular pharmacology 2000; 35(7 suppl 4)S9-14.
20. Skrha J. Diabetes mellitus- a risk factor for cardiovascular diseases. Vnitrni Lekarstvi 2001; 47(5):281-4.