Introduction: The role of insulin resistance in the pathogenesis and treatment of noninsulin-dependent diabetes mellitus

Abstract

T” e complex nature of diabetes mellitus has become increasingly apparent during recent years and it is now known that this disorder can no longer be considered to be one disease. It has been suggested that at least two major subdivisions should be recognized, namely insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) [ 11. These two variants of the diabetic syndrome differ in many respects, not the least of which is their differences in metabolic characteristics. Over 40 years ago, it was suggested by Himsworth and Kerr [2] that patients with diabetes could be subdivided into two categories on the basis of their ability to respond to a combined challenge of oral glucose and intravenous insulin. Patients who would be classified by today’s criteria as those with NIDDM [I] were found to be insulin-insensitive: that is, their plasma glucose levels were markedly elevated after the combined glucoseinsulin challenge. In contrast, patients who would satisfy the criteria for a diagnosis of IDDM, were found to be insulin-sensitive, and had a blunted or no rise in plasma glucose levels, after the glucose-insulin challenge. On the basis of these and other observations, Himsworth [3] suggested: “We should accustom ourselves to the idea that a primary deficiency of insulin is only one, and then not the commonest form of the diabetic syndrome. ” For reasons which are unclear in retrospect, the admonition of Himsworth about the complex nature of diabetes has been largely unheeded. Certainly, it was not because published data challenged his division of patients into those with insulin-insensitive and those with insulin-sensitive diabetes mellitus. However, considerable support for the point of view presented by Himsworth came with the development of radioimmunoassay for insulin. Yalow and Berson [4] clearly indicated, in their epochal paper, that circulating insulin levels in patients with NIDDM were often equal to or greater than those of control subjects with normal glucose tolerance. On the basis of their data, these investigators concluded “that the tissues of the maturity-onset diabetic patient do not respond to his insulin as well as the tissues of the nondiabetic respond to his insulin” [4]. Nothing reported on subsequently has seriously challenged this statement. However, the countless papers published since the original observation by Yalow and Berson [4] have served to provide a sharper definition of the plasma level of circulating insulin in patients with diabetes [s]. Thus, there is general agreement that patients with IDDM are absolutely insulin deficient, a finding consistent with the definition of this syndrome as one consisting of patients who are prone to develop diabetic ketoacidosis [ 11. In contrast, patients with NIDDM are ketosis resistant, and do not require exogenous insulin for short-term survival [ 11. This clinical difference could have been predicted from the knowledge of the plasma insulin response of these patients as reported on by Yalow and Berson [4]. Thus, there is considerable support for the view that patients with NIDDM have insulin levels which are often equal to or greater than those of persons with normal glucose tolerance. Based on these considerations, it is possible to draw two conclusions about the metabolic defect in patients with NIDDM. On the one hand, it can be argued that these patients are relatively insulin deficient: that is to say, if they had an absolutely intact endocrine-secreting pancreas, they would manufacture sufficient insulin to maintain normal glucose tolerance. On the other hand, it seems impossible to escape the inference that the efficiency of insulin-stimulated glucose uptake is reduced in patients with NIDDM. There is now considerable direct experimental support for this assumption [5], and the methods that have been used to confirm the presence of insulin resistance in NIDDM will be discussed in detail in this symposium. Although it is now apparent that insulin resistance is a characteristic of NIDDM, the significance of this metabolic defect in the pathogenesis of NIDDM remains