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The discovery that metabolic consequences of type 1 diabetes (insulin deficiency attributable to failure of pancreatic beta cells, generally induced by autoimmune phenomena) could be corrected by administration of pancreatic extracts and ultimately purified insulin gave rise to a powerful belief system in which insulin deficiency is embraced as the cause of diabetes under all circumstances. We now know that more than 90% of individuals with diabetes have type 2 diabetes, a condition in which insulin resistance is among the primary defects. However, the evolution of diabetes is such that at any given level of insulin resistance the pancreatic compensatory mechanism is inadequate to meet demands and insulin deficiency is a relatively late manifestation of the disorder. Surprisingly, this dichotomy was anticipated in the 1930s. Himsworth was interested in the causes of hyperglycemia in patients with diabetes and performed what Gerald Reaven described as ''a series of simple, but elegant experiments aimed at understanding.'' The results led to the proposal that ''the diminished ability of the tissues to utilize glucose is referable either to a deficiency of insulin or to insensitivity to insulin, although it is possible that both factors may operate simultaneously.'' These remarkably prescient observations led to the development of the concept of the syndrome of insulin resistance (sometimes referred to as metabolic syndrome X).

Only recently have these ideas, developed so effectively by Dr. Reaven, become conventional wisdom. In fact, syndromes of insulin resistance are manifest by impaired responses to insulin in skeletal muscle, adipose tissue, and the liver, clusters of abnormality including dyslipidemia with high triglycerides, low HDL cholesterol, decreased LDL particle size, postprandial lipemia, increased susceptibility to oxidation of LDL, obesity, hypertension, impaired fibrinolysis, and perhaps of most importance to the patient at risk, accelerated coronary artery disease manifested by acute coronary syndromes. Some or all of these derangements are seen in patients with syndromes of insulin resistance even in the ab- -o sence of the derangements in intermediary metabolism typical of diabetes, including hyperglycemia. Thus, women with the polycystic ovarian syndrome who are £ insulin resistant have accelerated coronary disease as do normal subjects who are not diabetic but have elevated fasting concentrations of insulin in blood.

Although hyperglycemia per se is a powerful determinant of microvascular M

disease and may contribute to macrovascular disease, the increasing recognition that macroangiopathy and particularly coronary artery disease is strongly associ-

& u ated with insulin resistance in patients with type 2 diabetes has led to a reformulation of its presumed pathogenesis. Insulin resistance and its consequences, including hyperinsulinemia, have been directly and indirectly linked to the acceleration of coronary artery disease. Thus, even though glycemic control remains the primary objective in therapy of patients with type 2 diabetes, amelioration of insulin resistance is imperative if the rate of evolution of at least some complications, including coronary disease, is to be diminished.

One aspect of insulin resistance that has been implicated directly in accelerating coronary disease includes the effects of insulin on synthesis of plasminogen activator inhibitor type-1 (PAI-1) with consequent augmentation of concentrations of PAI-1 in blood in subjects with insulin resistance, including obese nondi-abetic subjects. Impaired fibrinolysis is the result. Another aspect of insulin resistance is endothelial dysfunction that may contribute to hypertension in patients with type 2 diabetes, a strongly associated phenomenon. It occurs in subjects with insulin resistance and hyperinsulinemia without hyperglycemia as well. Thus, it is critical to seek to ameliorate insulin resistance as well as to control hyperglyce-mia and hyperlipidemia in patients with type 2 diabetes.

Such considerations have led to the initiation of national multicenter randomized patient assignment clinical trials such as the BARI 2D investigation. In this recently initiated investigation, patients with type 2 diabetes and overt coronary artery disease are being randomized in a 2 X 2 factorial design. One randomization is to treatment of the coronary artery disease itself with coronary intervention (either percutaneous or surgical) as opposed to medical management of the coronary artery disease. The second randomization is to treatment with insulin-providing as opposed to insulin-sensitizing regimens in patients whose coronary disease is being managed in both fashions. The study seeks to determine whether relatively early coronary intervention is or is not beneficial in patients with type 2 diabetes and overt coronary artery disease. In addition, it is designed to determine whether insulin-sensitizing regimens offer an advantage in comparison with insulin-providing regimens with respect to the rate of evolution of coronary artery disease and, if so, whether the advantage is evident in patients whose coronary disease is managed initially medically, initially with intervention, or both. Results in several smaller studies indicate that reduction of insulin resistance with the use of thiazolidinediones diminishes the rate of progression of atherosclerotic disease as judged from ultrasonic interrogation of carotid arteries and assessment of intimal/medial thickness. |

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