Objective: To describe the progression of beta-cell dysfunction, now presumed to be the primary progenitor of type 2 diabetes, which appears early in the clinical course (perhaps antedating and even contributing to the development of insulin resistance) and progressively worsens even under treatment.
Data sources: Medline search of all relevant clinical and review articles.
Study selection: By the author.
Data extraction: By the author.
Data synthesis: The physiology of glucose homeostasis requires the close cooperation of a number of organ systems, humoral secretions, and neural signaling complexes; disruption of any of these processes may lead to the development of type 2 diabetes. Predisposing risk factors for type 2 diabetes include overweight and obesity, poor diet, and lack of exercise. Genetic factors, many of which as yet require elucidation, may also elevate the risk of developing type 2 diabetes. Insulin resistance (IR) has long been recognized as a primary, if not the primary, cause of type 2 diabetes. Recent research in disease pathogenesis suggests that IR is neither a necessary nor sufficient condition for development and progression of type 2 diabetes. Although IR is highly correlated with type 2 diabetes, many individuals with IR will not go on to develop the disease; and the disease may be present in individuals not markedly insulin resistant. The primary progenitor of type 2 diabetes is now presumed to be progressive beta-cell dysfunction, which appears early in the clinical course (perhaps antedating and even contributing to the development of IR) and progressively worsens even under treatment. Among the mechanisms of beta-cell dysfunction in type 2 diabetes is the reduction or abrogation of the "incretin effect."
Conclusion: The incretins are gut hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which in healthy individuals potentiate glucose-dependent insulin secretion. In addition, these hormones, and particularly GLP-1, have a number of protective effects on the beta-cell, including reduction in apoptosis and promotion of beta-cell proliferation and neogenesis. As these benefits are lost in diabetes, "repairing" the incretin effect has become an important treatment target. Treatments that maintain the beta-cell could offer durable glycemic control and potentially reduce the micro- and macrovascular complications associated with type 2 diabetes.