Overstimulation and beta-cell function.

Abstract

Previous and present evidence ascribes an important role to overstimulation of ␤-cells for the secretory abnormalities associated with type 2 diabetes. The abnormality most clearly linked to overstimulation is the elevated ratio of circulating proinsulin to insulin. Evidence obtained in human pancreatic islets suggests that aberrations in insulin oscillations that occur in type 2 diabetes could at least in part be linked to abnormalities in cytoplasmic Ca 2+ oscillations induced by overstimulation. Furthermore, in a transplantation model, we have obtained evidence for long-lasting, perhaps irreversible, effects of overstimulation, implying that this is a causative factor for the well-recognized deterioration of insulin secretion with increasing duration of type 2 diabetes. The mechanisms behind the effects of overstimulation are only partly clarified, but it is clear that reduced insulin secretion after overstimulation is only partly explained by decreased insulin stores. In cultured human pancreatic islets, overstimulation by high glucose leads to a rise in cytoplasmic Ca 2+ levels, which persists after normalization of the glucose levels. Persistent elevation of cytoplasmic Ca 2+ may trigger apoptosis, thus participating in long-term irreversible deterioration of ␤-cell function. These data provide sufficient rationale for clinical studies to test the beneficial effects of relative ␤-cell rest in type 2 diabetic patients. Diabetes 50 (Suppl. 1): S122-S124, 2001I n 1986, Leahy et al. (1) reported that 48 h of marked hyperglycemia in normal rats, achieved by massive glucose infusions, produced almost total insensitivity to glucose when insulin release was subsequently measured from the perfused pancreas. This desensitizing effect was specific for glucose and other secretagogues, such as arginine, eliciting normal or even exaggerated responses. Desensitization was reversible within 24 h. One of us (V.G.) later showed that if glucose-induced insulin secretion during glucose infusion was blocked by the simultaneous infusion of diazoxide, no later desensitization occurred; if anything, insulin responses to glucose were enhanced (2) (Fig. 1). Because the levels of hyperglycemia were kept similar with or without diazoxide, it was concluded that the desensitizing effect was due to overstimulation of the ␤-cells rather than to effects of hyperglycemia per se.We studied the desensitizing effect of overstimulation further in vitro (3). It was found to be induced in perifused islets by only a few hours of glucose stimulation. The decline of insulin secretion during prolonged in vitro stimulation mimicked that first described by Bolaffi et al. (4) as the third phase of insulin secretion, was proportionate to the degree of stimulation, and could be totally prevented by blocking glucose-induced insulin secretion with diazoxide.Which mechanisms explain desensitization by overstimulation and its prevention by diazoxide? Diazoxide blocks glucose-induced insulin secretion by opening K + -ATP channels (5). An effect of overstimula...

Can we slow the rising incidence of childhood-onset autoimmune diabetes? The overload hypothesis

“…There is good evidence that overloading the beta cell is associated with insulin secretory abnormalities in type 2 diabetes, and that deterioration of beta cell function may in part be caused by accelerated apoptosis [36]. Apoptosis is also an important feature of beta cell death in type 1 diabetes, and a recent review of experimental data concluded that immunological, inflammatory and metabolic signals combine to cause it [37].…”

Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

“…The causes of disturbed beta cell function in type 2 diabetes are not known in detail, but increased insulin secretion by the individual beta cells in response to insulin resistance and/or hyperglycaemia could be an important factor in the deterioration of beta cell function [1,2]. Normalisation of glycaemia with insulin in type 2 diabetic patients can enhance beta cell function [3,4,5], and strategies to reduce insulin secretion have been shown to improve beta cell function in these patients [6,7] and in rodent models of diabetes [8,9].…”

Anti-CD38 autoantibodies: Characterisation in new-onset Type I diabetes and latent autoimmune diabetes of the adult (LADA) and comparison with other islet autoantibodies

“…Regarding this second possibility, the repeated observation that the vast preponderance of anti-CD38 aAbs are endowed with agonistic properties is appealing. Prolonged Ca 2+ influx in the beta cell is known to trigger several deleterious effects such as desensitisation [4] and apoptosis [47]. The large preponderance of agonistic features for anti-CD38 aAbs is also in line with the clinical and metabolic correlations observed.…”

“…Whether this damage occurs by autoimmune mechanisms, as in Type I (insulin-dependent) diabetes mellitus [1], or by other less defined phenomena (e.g., glucose toxicity [2], lipotoxicity [3], prolonged excessive insulin secretion [4]), as in Type II (non-insulin-dependent) diabetes mellitus [5], the final result is impaired insulin secretion [6]. A number of autoantibodies (aAbs) marking the immune-mediated destruction of the beta cell typical of Type I diabetes have been described since the identification of islet cell antibodies (ICA) [7].…”