We also found that the SREBP-1c processing in -cells was irresponsive to acute stimulation of glucose and insulin, which was distinct from that in lipogenic tissues. However, 2-day exposure to these agents promoted SREBP-1c processing. Therefore, the SREBP-1c maturation could be implicated in the pathogenesis of -cell glucolipotoxicity.
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...
A higher intake of whole grain is associated with decreased risk of deteriorating glucose tolerance including progression from normal glucose tolerance to prediabetes by mechanisms likely tied to effects on insulin sensitivity. Effect modifications by TCF7L2 genetic polymorphisms are supported.
The success of pancreatic β-cells transplantation to treat type 1 diabetes has been hindered by massive β-cell dysfunction and loss of β-cells that follows the procedure. Hypoxia-mediated cell death has been considered one of the main difficulties that must be overcome for transplantation to be regarded as a reliable therapy. Here we have investigated the mechanisms underlying β-cell death in response to hypoxia (1% O2). Our studies show that mouse insulinoma cell line 6 (Min6) cells undergo apoptosis with caspase-3 activation occurring as early as 2 h following exposure to hypoxia. Hypoxia induces endoplasmic reticulum stress in Min6 cells leading to activation of the three branches of the unfolded protein response pathway. In response to hypoxia the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) is upregulated. The important role of CHOP in the apoptotic process was highlighted by the rescue of Min6 cells from hypoxia-mediated apoptosis observed in CHOP-knockdown cells. Culturing isolated pancreatic mouse islets at normoxia showed intracellular hypoxia with accumulation of hypoxia-inducible factor-1α and upregulation of CHOP, the latter one occurring as early as 4 h after isolation. Finally, we observed that pancreatic islets of type 2 db/db diabetic mice were more hypoxic than their counterpart in normoglycemic animals. This finding indicates that hypoxia-mediated apoptosis may occur in type 2 diabetes.
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