Fate of the beta-cell in the pathophysiology of type 2 diabetes

J Am Pharm Assoc (2003). Sep-Oct 2009;49 Suppl 1:S10-5. doi: 10.1331/JAPhA.2009.09076.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Disease Progression
  • Gastric Inhibitory Polypeptide / metabolism
  • Glucagon-Like Peptide 1 / metabolism
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Incretins / metabolism
  • Insulin / metabolism
  • Insulin Resistance*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Prediabetic State / drug therapy
  • Prediabetic State / etiology
  • Prediabetic State / metabolism
  • Prediabetic State / physiopathology*
  • Risk Factors

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • Incretins
  • Insulin
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1