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Impaired glucose stimulated insulin secretion is coupled with exocrine pancreatic lesions in the Cohen diabetic rat

¹The Diabetes Unit, Department of Internal Medicine and The Hadassah Diabetes Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
²Institute of Clinical Biochemistry and
³Centre of Anatomy, Hannover Medical School, Hannover, Germany
⁴Department of Pathology,
⁵Endocrinology and Metabolism Service, Department of Internal Medicine, and
⁷Division of Pediatric Endocrinology, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
⁶Laboratory for Molecular Medicine and Israeli Rat Genome Center, Faculty of Health Sciences, Barzilai Medical Center, Campus of the Ben-Gurion University, Ashkelon, Israel

Objective: The Cohen diabetes-sensitive (CDs) rat develops postprandial hyperglycemia when fed a high-sucrose, copper-poor diet (HSD) while the Cohen diabetes-resistant (CDr) rat maintains normoglycemia. The pathophysiological basis of diabetes was studied in the Cohen diabetic rat centering on the interplay between the exocrine and endocrine compartments of the pancreas.

Research Design and Methods: Studies utilized male CDs and CDr rats fed 1-month HSD. Serum insulin and glucose levels were measured during glucose and insulin tolerance tests. The pancreas was evaluated for weight, insulin content, macrophage and fat infiltration. Glucose-stimulated insulin secretion was determined in isolated perfused pancreas and in islets.

Results: Hyperglycemic CDs rats exhibited reduced pancreatic weight with lipid deposits and IL1-ß-positive macrophage infiltration in the exocrine pancreas. Islet morphology was preserved and total pancreatic insulin content did not differ from that of CDr rats. Lipids did not accumulate in skeletal muscle, nor was insulin resistance observed in hyperglycemic CDs rats. Intravenous glucose-tolerance test revealed markedly elevated glucose levels associated with diminished insulin output. Insulin release was induced in-vivo by the non-nutrient secretagogues arginine and tolbutamide, suggesting a selective unresponsiveness to glucose. Decreased glucose-stimulated insulin secretion was observed in the isolated perfused pancreas of the hyperglycemic CDs rat while islets isolated from these rats exhibited glucose-dependent insulin secretion and proinsulin biosynthesis.

Conclusions: The association of the in-vivo insulin secretory defect with lipid accumulation and activated macrophage infiltration in the exocrine pancreas suggests that changes in the islet microenvironment are the culprit in the insulin secretory malfunction observed in-vivo.

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