Affiliation:
1. Research Division, Joslin Diabetes Center Boston Departments of Medicine, Brigham and Women's Hospital and New England Deaconess Hospital, Harvard Medical School Boston Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology Cambridge, Massachusetts
Abstract
The NSTZ rat model combines loss of glucose-induced insulin secretion with a reduced amount of the high Km B-cell glucose transporter, GLUT2. The purpose of this study was to determine whether the restoration of glucose-induced insulin secretion was paralleled by an increase of GLUT2. Rats injected at 2 days of age with 90 mg/kg STZ were studied at 8–13 wk of age. Insulin secretion was assessed in the isolated perfused pancreas with 16.7 mM glucose preceded by 40 min of 0 or 5.5 mM glucose. In control rats, 16.7 mM glucose caused the same large biphasic insulin response whether preceded by 0 or 5.5 mM glucose. In NSTZ rats, after 5.5 mM glucose, 16.7 mM glucose elicited virtually no rise in insulin release. In contrast, after 0 mM glucose, a large insulin response to the glucose challenge occurred that was equal to that of the control groups when the differences in B-cell mass were taken into account. However, the dose-response curve for glucose-induced insulin secretion was shifted to the left, and no second phase of insulin secretion was observed. GLUT2 was assessed after the perfusions by indirect immunofluorescence with anti-GLUT2 antisera. Both control groups showed homogenous staining in all B-cells. NSTZ rats perfused with 5.5 mM glucose had a marked diminution in GLUT2 staining. We observed no increase in GLUT2 staining in the NSTZ rats perfused with 0 mM glucose. In summary, our results show: 1) the recovered glucose responsiveness in NSTZ rats after perfusion with 0 mM glucose appears in the presence of a reduced level of GLUT2; 2) the recovered glucose-induced insulin secretion is abnormal in that the glucose dose-response curve is shifted to lower glucose concentrations and a blunted second phase occurs. These results suggest that several steps are altered in the glucose signaling pathway of glucose unresponsive B-cells from NSTZ rats, and that a reduction of GLUT2 level may be only a partial cause of the secretory defects of diabetic B-cells.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
Cited by
10 articles.
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