Mechanisms of β-Cell Death in Type 2 Diabetes

Abstract

A decrease in the number of functional insulin-producing ␤-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in ␤-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of ␤-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K ؉ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-B, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of ␤-cell secretory function and cell turnover. Thus, the mechanisms regulating ␤-cell proliferation, apoptosis, and function are inseparable processes. Diabetes 54 (Suppl. 2):S108 -S113, 2005 F or many years, the contribution of a reduction in ␤-cell mass to the development of type 2 diabetes was heavily debated. Recently, several publications have convincingly confirmed this hypothesis (1-3), leading to a rapid overemphasis of this etiological factor. Indeed, other mechanisms contributing to the failure of the ␤-cell to produce enough insulin appear more and more neglected. While we strongly believe that ␤-cell destruction is an important etiological factor in the development and progression of type 2 diabetes, in this review, we will highlight evidence that this is not dissociable from an intrinsic secretory defect. We will show that pathways regulating ␤-cell turnover are also implicated in ␤-cell insulin secretory function. It follows that adaptive mechanisms of function and mass share common regulatory pathways and will therefore act in concert. Depending on the prevailing concentration and the intracellular pathways activated, some factors may be deleterious to ␤-cell mass while enhancing insulin secretion, protective to the ␤-cell while inhibiting function, or even protective to the ␤-cell while enhancing function. It will become apparent that the failure of the ␤-cell in type 2 diabetes is akin to a multifactorial equation, with an overall negative result.Thus, although we will review the factors and mechanisms regulating ␤-cell mass individually, only in a minority of diabetic patients does one single etiological factor underlie the failure of the ␤-cell. In addition to maturityonset diabetes of the young, another example of this is autoimmune-mediated destruction of ␤-cells in young lean individuals. However, given that the incidence of type 1 diabetes increases with obesity (4), that insulin resistance is a risk factor for the progression of this condition (5), and that ϳ50% of the general population carry the same genetic predisposition (6), this example already implicates multiple etiological factors. Recognition of ␤-cell destruction not only in type 1 but also in type 2 diabetes led us to recently propose a unif...

Beta cell death in hyperglycaemic Psammomys obesus is not cytokine-mediated

“…Using both methods, IL-1β and iNOS were immunohistochemically undetectable. Thus, and in contrast to Donath and collaborators [6,8,9], we were unable to find any evidence for hyperglycaemia-induced IL-1β or iNOS immunostaining at the protein level, either in pancreatic beta cells or in immune cells in the Psammomys pancreas [12]. As we analysed islets from gerbils that had been on a high-energy diet both for 1 and for 3 weeks, we can also exclude a transient increase in expression of IL-1β.…”

“…In these infiltrated type 1 diabetes islets the immune cells showed a dense immunostaining for IL-1β and iNOS [12,16]. To exclude the possibility that low contents of IL-1β and iNOS could have been masked by fixation in the immunohistochemical staining procedure, we used both 4% paraformaldehyde fixed pancreatic tissue [12,16], as used by Donath and collaborators [6], and cryostat sections of unfixed pancreas tissue of Psammomys obesus. Using both methods, IL-1β and iNOS were immunohistochemically undetectable.…”

“…More recently the authors endorsed this observation and in addition demonstrated IL-1β gene and protein expression in isolated islets from human type 2 diabetic donors, as well as in islets from healthy human donors incubated for 3 days at 30 mmol/l glucose [6,9]. On the basis of these observations, the authors proposed that the proinflammatory cytokine IL-1β also plays a prominent role in pancreatic beta cell loss in type 2 diabetes mellitus [4,6,9].…”

“…On the basis of these observations, the authors proposed that the proinflammatory cytokine IL-1β also plays a prominent role in pancreatic beta cell loss in type 2 diabetes mellitus [4,6,9]. However, other authors were not able to confirm these observations.…”

“…Recently it has been proposed that cytokines may also be involved in the aetiopathology of beta cell death in type 2 diabetes mellitus [4][5][6][7]. Major support for this hypothesis was derived from experiments on the gerbil Psammomys obesus (sand rat) [8,9], an established type 2 diabetes animal model [10,11].…”