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


METHODS
Medline search of all relevant clinical and review articles.


METHODS
By the author.


METHODS
By the author.


RESULTS
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."


CONCLUSIONS
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.
Campbell
R Keith
RK
Dept. of Pharmacotherapy, College of Pharmacy, Washington State University, Pullman, WA 99164-6510, USA. rkcamp@wsu.edu
D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D018450:Disease Progression; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D054795:Incretins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D011236:Prediabetic State / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D012307:Risk Factors
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1