Ultrastructural and secretory heterogeneity of fa/fa (Zucker) rat islets

Many previous studies of obese rodents documented biochemical changes in pancreatic islets that contribute to hyperinsulinemia in vivo. Those studies used heterogenous populations of islets, although the size of islets from obese rats ranges from < 100 to > 500 mu m. Here, functional and morphological changes in size-sorted (< 125 and > 250 mu m diameter) islets from obese Zucker (fa/fa) rats were correlated. Ultrastructural examination revealed that > 250 mu m cultured islets had an increased number of immature secretory granules in the beta cells. The number of degranulated beta cells in > 250 and < 125 mu m cultured islets from fa/fa rats was higher than in lean rat islets (33 vs 25%). The glucose EC50 Values for cultured islets were 4.64 +/- 0.43, 7.9 +/- 0.70 and 7.29 +/- 1.64 mmol.l(-1) for > 250 mu m, < 125 mu m, and lean groups, respectively. Inhibition of insulin secretion by 10 mmol.l(-1) mannoheptulose was reduced by 50% in > 250 mu m islets compared with small islets. Studies of individual beta cells by reverse hemolytic plaque assay revealed 3-fold more cells from > 250 mu m islets were stimulated by 1.4 mmol.l(-1) glucose than cells from < 125 mu m islets. We conclude that functional defects in mixed size populations of islets from fa/fa rats are mainly due to alterations in the large islets, whereas smaller islets have relatively normal function. Exposure to high glucose exacerbates morphological and functional differences of large islets, which could have important implications in the transition to noninsulin-dependent diabetes when beta cell insulin production is unable to compensate for hyperglycemia. (C) 1998 Elsevier Science Ireland Ltd.