β-Cell Failure in Diabetes and Preservation by Clinical Treatment

Abstract

There is a progressive deterioration in β-cell function and mass in type 2 diabetics. It was found that islet function was about 50% of normal at the time of diagnosis, and a reduction in β-cell mass of about 60% was shown at necropsy. The reduction of β-cell mass is attributable to accelerated apoptosis. The major factors for progressive loss of β-cell function and mass are glucotoxicity, lipotoxicity, proinflammatory cytokines, leptin, and islet cell amyloid. Impaired β-cell function and possibly β-cell mass appear to be reversible, particularly at early stages of the disease where the limiting threshold for reversibility of decreased β-cell mass has probably not been passed. Among the interventions to preserve or “rejuvenate” β-cells, short-term intensive insulin therapy of newly diagnosed type 2 diabetes will improve β-cell function, usually leading to a temporary remission time. Another intervention is the induction of β-cell “rest” by selective activation of ATP-sensitive K+ (KATP) channels, using drugs such as diazoxide. A third type of intervention is the use of antiapoptotic drugs, such as the thiazolidinediones (TZDs), and incretin mimetics and enhancers, which have demonstrated significant clinical evidence of effects on human β-cell function. The TZDs improve insulin secretory capacity, decrease β-cell apoptosis, and reduce islet cell amyloid with maintenance of neogenesis. The TZDs have indirect effects on β-cells by being insulin sensitizers. The direct effects are via peroxisome proliferator-activated receptor γ activation in pancreatic islets, with TZDs consistently improving basal β-cell function. These beneficial effects are sustained in some individuals with time. There are several trials on prevention of diabetes with TZDs. Incretin hormones, which are released from the gastrointestinal tract in response to nutrient ingestion to enhance glucose-dependent insulin secretion from the pancreas, aid the overall maintenance of glucose homeostasis through slowing of gastric emptying, inhibition of glucagon secretion, and control of body weight. From the two major incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), only the first one or its mimetics or enhancers can be used for treatment because the diabetic β-cell is resistant to GIP action. Because of the rapid inactivation of GLP-1 by dipeptidyl peptidase (DPP)-IV, several incretin analogs were developed: GLP-1 receptor agonists (incretin mimetics) exenatide (synthetic exendin-4) and liraglutide, by conjugation of GLP-1 to circulating albumin. The acute effect of GLP-1 and GLP-1 receptor agonists on β-cells is stimulation of glucose-dependent insulin release, followed by enhancement of insulin biosynthesis and stimulation of insulin gene transcription. The chronic action is stimulating β-cell proliferation, induction of islet neogenesis, and inhibition of β-cell apoptosis, thus promoting expansion of β-cell mass, as observed in rodent diabetes and in cultured β-cells. Exenatide and liraglutide enhanced postprandial β-cell function. The inhibition of the activity of the DPP-IV enzyme enhances endogenous GLP-1 action in vivo, mediated not only by GLP-1 but also by other mediators. In preclinical studies, oral active DPP-IV inhibitors (sitagliptin and vildagliptin) also promoted β-cell proliferation, neogenesis, and inhibition of apoptosis in rodents. Meal tolerance tests showed improvement in postprandial β-cell function. Obviously, it is difficult to estimate the protective effects of incretin mimetics and enhancers on β-cells in humans, and there is no clinical evidence that these drugs really have protective effects on β-cells.