The pathogenesis of NIDDM: the role of the pancreatic beta cell

Abstract

Considerable uncertainty continues to exist regarding the nature of the earliest biochemical changes which culminate in the development of non-insulin-dependent diabetes mellitus (NIDDM) associated with obesity. While a consensus appears to have been achieved concerning the concept that both insulin resistance and defective (or deficient) insulin secretion play important roles in manifest NIDDM [1,2], less clear is the nature of the initial event which, if uncorrected, leads inexorably to diabetes in so many individuals. Many studies have focused on insulin resistance as the primary defect [3,4]. In this model of NIDDM genesis, changes at the level of the insulin receptor (altered affinity for insulin, a decrease in their numbers, or a reduction in signalling molecule generation, for example) or postreceptor events (changes in target enzymes and/or their activation) result in impaired sensitivity to insulin's "glucose-regulatory" effects. Insulin resistance at the level of several targets, most notably skeletal muscle, liver, and adipose tissues, results in the inability of insulin to properly direct the disposition of glucose (and other metabolic fuels as well), a more persistent hyperglycaemia and a continued or at least more prolonged stimulation of the pancreatic beta cell. In this model of the development of NIDDM, insulin resistance precedes and results in hyperinsulinaemia. In addition, while the more persistent hyperglycaemia resulting from insulin resistance provides a stronger signal for beta-cell stimulation, the increase in blood glucose may also, over long periods, exert "toxic" effects on the beta-cell response. Thus, insulin resistance in peripheral tissues requires that the beta cell works harder and for longer periods and if uncorrected may indirectly, via hyperglycaemia, lead to the development of beta-cell decompensation. This adverse effect of hyperglycaemia on beta-cell responsiveness is often referred to as "glucose toxicity" [5].Consistent with the concept that insulin resistance is the primal manifestation of developing diabetes, or the prediabetic state, are several recently published reports [6][7][8]. In them, alterations in muscle glycogen synthase (GS) activity have been reported to occur in non-diabetic relatives of NIDDM patients, a population at increased risk for the development of NIDDM, and in obese patients with or without NIDDM. Of particular note for the present perspective is the observation that in the subjects at risk for diabetes, hyperinsulinaemia is already established. Thus, even in studies supporting some type of insulin resistance at the level of target enzymes as the initial alteration, beta-cell hyper-responsiveness is already evident. Is it possible that the hyperinsulinaemia in these patients precipitates insulin resistance at the level of vulnerable insulin-dependent enzymes?For the last 20 years we have been studying the processes which regulate insulin secretion from pancreatic beta cells. We have been impressed by the ability of cholinergic stimulation to dr...

Acute and chronic effects of glucose and carbachol on insulin secretion and phospholipase C activation: studies with diazoxide and atropine

“…This suggests that, regardless of the compounds used to induce desensitization, their ability to impair secretion might be dependent upon their ability to inactivate PLC. Our working hypothesis, and one supported by a number of observations (28,40,46,47), is that although short-term exposure to compounds that activate PLC positively affect secretion, playing an important role in both biphasic secretion and the induction of time-dependent sensitization or memory, prolonged activation of the enzyme sets into motion a series of events that inhibit its activation.…”

The genetics of type 2 diabetes

“…insulin resistance) plays a key role in disease pathogenesis [4]. However, since many individuals with marked insulin resistance still manage to maintain normal glucose homeostasis, variation in the compensatory capacity of the pancreatic beta‐cell must be an equal partner in disease progression [5]. Efforts to characterize further the crucial intermediate metabolic steps in the development of full‐blown type 2 diabetes have largely foundered on the rocks of individual heterogeneity and the complicating effects of hyperglycaemia (and its treatment) on the very intermediate traits that investigators might wish to measure.…”

Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion.

“…The convergence of these signaling pathways on the translocation of granules, granule docking, and exocytosis results in a complex but characteristic biphasic pattern of insulin release (1)(2)(3). Much effort has been expended and many theories have been developed in trying to understand the mechanisms of biphasicity, in part because of the relationship between the onset of diabetes and the loss of the first phase of glucose-stimulated release (4,5).…”