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The Beta Cell and First-Phase Insulin Secretion: Causative Factors in Beta-Cell Dysfunction

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Causative Factors in Beta-Cell Dysfunction

The ability of the beta cell to increase insulin secretion in response to obesity-related insulin resistance is well described in both humans and rodents. First-phase insulin secretion rises, insulin responses at every glucose concentration rise, and basal insulin secretion increases, all in proportion to prevailing insulin resistance and without producing hypoglycemia.[13,14] In pregnancy-related insulin resistance, insulin secretion similarly rises substantially and then rapidly falls again postpartum. The mechanisms by which compensatory hypersecretion of insulin occurs are not well understood. Moreover, the failure of this compensatory adaptation to insulin resistance in diabetes is less well understood and a subject of intense investigation.

Data in diabetic animal models support reduced beta-cell mass as a significant contributing factor to the diminished insulin secretion in type 2 diabetes. Many of the signals that regulate the balance of beta-cell replication/neogenesis and apoptosis and thus determine net beta-cell mass have been identified, but it is less clear which of these factors contribute to the failure of beta-cell mass augmentation. Obviously, diminished proliferation or increased apoptosis or both will result in lower beta-cell mass. There is evidence that increased beta-cell apoptosis in the ZDF rat, an animal model of type 2 diabetes, underlies the decreased beta-cell mass seen in these animals.[15] Autopsy data examining beta-cell mass in obese and diabetic humans have been sparse and sometimes contradictory. Recently, however, a series of 124 subjects was reported, which included lean and obese IGT and type 2 diabetic cases compared with age- and weight-matched controls. In this study, relative beta-cell volume increased by 50% in obesity and was attributed to increased formation of new islets from exocrine ductal tissue. Relative beta-cell volume was decreased by 40% in obese IGT subjects and by 63% in obese type 2 diabetic subjects compared with nondiabetic controls. Rates of beta-cell replication and formation of new islets in diabetic subjects were equal to those in the nondiabetic subjects; the mechanism of decreased beta-cell mass was attributable to accelerated beta-cell death.[16]

The variety of signals controlling the balance of beta-cell mass include growth factors, cytokines, and hormones, including parathyroid hormone-related protein and the incretin family of hormones. Whether abnormal concentrations or function of these factors contribute to beta-cell decline is unclear. It is tempting to consider, however, that those identified as having pro-proliferative or anti-apoptic effects for beta cells may have therapeutic promise in reversing a major component of abnormal beta-cell function in diabetes.

Beta-cell dysfunction in diabetes is not accounted for solely by reduced beta-cell mass, however. The remaining beta-cells function abnormally. While insulin secretory responses to glucose stimuli are reduced, insulin secretion may be stimulated by non-glucose nutrients such as amino acids and even free fatty acids. Administration of the incretin hormone glucagon-like peptide-1 and the incretin mimetic exenatide partially restore the diminished first-phase insulin response to glucose in diabetic human subjects.[17,18] These findings demonstrate that the loss of first-phase insulin secretion is not a permanent feature of the diabetic beta cell and that defective beta-cell function cannot be attributed to reduced beta-cell mass alone.

Other pathogenetic mechanisms include toxicity to the beta cell from prolonged hyperglycemia ("glucotoxicity") and the elevated free fatty acid levels that frequently coexist in individuals with increased adiposity and insulin resistance ("lipotoxicity").[19] Because normal glucose signaling of insulin secretion requires that glucose entry and metabolism through the glycolytic pathway in the beta cell be completely intact, alterations in intracellular glucose and lipid balance within the cell can interfere with transmission of the glucose stimulus. Beta-cell exhaustion from continuous hyperinsulinemia and islet amyloid deposition may also play a role.