title: Beta-cell dysfunction induced by chronic hyperglycemia. Current ideas on mechanism of impaired glucose-induced insulin secretion.
abstract: Non-insulin-dependent diabetes mellitus is characterized by abnormal beta-cell function. The characteristic secretory defect is a selective loss of glucose-induced insulin secretion. Substantial data have been generated in animal models to support the concept that chronic hyperglycemia causes the loss of glucorecognition (the so-called glucose toxicity hypothesis). This review summarizes the data supporting the concept of hyperglycemia-induced beta-cell dysfunction and then focuses on the ideas for the mechanism of the glucose unresponsiveness. The lack of access to islet tissue in humans means that these studies have all been conducted in animal models. Another major stumbling block continues to be the lack of in vitro systems that faithfully reproduce the secretory abnormalities that occur in vivo. Despite these limitations, many hypotheses are being investigated that span most of the major intracellular steps for glucose-induced insulin secretion, including abnormalities in glucose transport, storage, metabolism/oxidation, and the second messengers. No single hypothesis stands out as being able to explain all of the characteristics of the secretory abnormalities. In the last few years major advances have occurred in our knowledge about the events that normally cause glucose-induced insulin secretion. Similarly, biochemical and molecular tools have become available to probe the different steps. As better in vitro models of the selective glucose unresponsiveness become available, rapid progress can be expected in unraveling the biochemical basis for the loss of glucose responsiveness in diabetic rat models. The long-term hope is that this information will lead to innovative new strategies for the therapy of non-insulin-dependent diabetes mellitus.
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA 02215.
authors.forename: J L
authors.initials: JL
authors.lastname: Leahy
authors.forename: S
authors.initials: S
authors.lastname: Bonner-Weir
authors.forename: G C
authors.initials: GC
authors.lastname: Weir
mesh_terms: D002908:Chronic Disease; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000150:complications*; D007515:Islets of Langerhans / Q000503:physiopathology*; D016381:Islets of Langerhans Transplantation