Pathogenesis of NIDDM: A Balanced Overview

Abstract

Non-insulin-dependent diabetes mellitus (NIDDM) results from an imbalance between insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional studies have demonstrated that the earliest detectable abnormality in NIDDM is an impairment in the body's ability to respond to insulin. Because the pancreas is able to appropriately augment its secretion of insulin to offset the insulin resistance, glucose tolerance remains normal. With time, however, the beta-cell fails to maintain its high rate of insulin secretion and the relative insulinopenia (i.e., relative to the degree of insulin resistance) leads to the development of impaired glucose tolerance and eventually overt diabetes mellitus. The cause of pancreatic "exhaustion" remains unknown but may be related to the effect of glucose toxicity in a genetically predisposed beta-cell. Information concerning the loss of first-phase insulin secretion, altered pulsatility of insulin release, and enhanced proinsulin-insulin secretory ratio is discussed as it pertains to altered beta-cell function in NIDDM. Insulin resistance in NIDDM involves both hepatic and peripheral, muscle, tissues. In the postabsorptive state hepatic glucose output is normal or increased, despite the presence of fasting hyperinsulinemia, whereas the efficiency of tissue glucose uptake is reduced. In response to both endogenously secreted or exogenously administered insulin, hepatic glucose production fails to suppress normally and muscle glucose uptake is diminished. The accelerated rate of hepatic glucose output is due entirely to augmented gluconeogenesis. In muscle many cellular defects in insulin action have been described including impaired insulin-receptor tyrosine kinase activity, diminished glucose transport, and reduced glycogen synthase and pyruvate dehydrogenase. The abnormalities account for disturbances in the two major intracellular pathways of glucose disposal, glycogen synthesis, and glucose oxidation. In the earliest stages of NIDDM, the major defect involves the inability of insulin to promote glucose uptake and storage as glycogen. Other potential mechanisms that have been put forward to explain the insulin resistance, include increased lipid oxidation, altered skeletal muscle capillary density/fiber type/blood flow, impaired insulin transport across the vascular endothelium, increased amylin, calcitonin gene-related peptide levels, and glucose toxicity.

High intakes of milk, but not meat, increase s-insulin and insulin resistance in 8-year-old boys

“…The conventional understanding is that hyperinsulinemia, which is seen at insulin resistance and not at least at NIDDM, is a secondary phenomenon to insulin resistance (DeFronzo, 1988;DeFronzo et al, 1992;Swinburn et al, 1995). However, results from some studies indicate the opposite allegation, that is, that increased insulin secretion and/or hyperinsulinemia in some conditions may precede and actually be the cause of insulin resistance (Rizza et al, 1985;Del Prato et al, 1994;Le Stunff & Bougneres, 1994).…”

Role of insulin resistance in the pathogenesis of NIDDM

“…In any type of diabetes, NIDDM [103], IDDM [104,105] or pancreatogenic [106], insulin sensitivity is impaired compared to matched non-diabetic individuals. In patients with IDDM, insulin sensitivity is normal if glycaemic control is normal, as in patients who are in clinical remission [107], or in whom glycaemic control has been normalized by intensive insulin therapy [108][109][110].…”

Long-term effect of maternal obesity on pancreatic beta cells of offspring: reduced beta cell adaptation to high glucose and high-fat diet challenges in adult female mouse offspring

“…However, diabetes will not occur unless there is also a reduction in pancreatic beta cell function [13,14]. Until now, the impact of maternal diabetes or obesity on long-term beta cell function in the offspring has not been tested.…”