IMMUNOCYTOCHEMICAL INVESTIGATION OF INSULIN-SECRETION BY PANCREATIC BETA-CELLS IN CONTROL AND DIABETIC PSAMMOMYS-OBESUS

Hyperproinsulinemia is a characteristic feature of non-insulin depende nt diabetes mellitus (NIDDM) caused by pancreatic beta-cell dysfunctio n through a secretion-related alteration or impaired proinsulin proces sing, We have investigated the insulin processing and secretion in Psa mmomys obesus fed with low- and high-energy diets, which represent a m odel for diet-induced NIDDM, With a high-energy diet the animals devel op hyperglycemia and hyperinsulinemia, whereas those maintained on a l ow-energy diet remain normoglycemic, Although a large amount of insuli n immunoreactivity was detected in beta-cells of the normoglycemic com pared to hyperglycemic animals, in situ hybridization for insulin mRNA demonstrated a particularly high signal in the beta-cells of the hype rglycemic animals, By electron microscopy, the beta-cells of normoglyc emic animals displayed large accumulations of secretory granules, wher eas those of the hyperglycemic animals contained very few granules and large deposits of glycogen, These results reflect a secretory resting condition for the cells of the normoglycemic animals in contrast to s timulated synthetic and secretory activities in the cells of the hyper glycemic ones. Using colloidal gold immunocytochemistry at the electro n microscopic level, we have examined subcellular proinsulin processin g in relation to the convertases PC1 and PC2. Immunolabeling of proins ulin, insulin, C-peptide, PC1, and PC2 in different cell compartments involved in beta-cell secretion were evaluated, Both PC1 and PC2 antig enic sites were detected in beta-cells of hyperglycemic Psammomys, but their labeling intensity was weak compared to the cells of normoglyce mic animals, Zn both groups of animals, higher levels of PC2 were foun d in the Golgi apparatus than in the immature granules, Major decrease s in proinsulin, insulin, PC1, and PC2 immunoreactivity were recorded in beta-cells of the hyperglycemic Psammomys, In addition, all these a ntigenic sites were detected in lysosome-like structures, revealing a major degradation process, These results suggest that the insulin-secr eting cells in hyperglycemic Psammomys obesus ate in a chronic secreto ry state during which impaired processing of proinsulin appears to tak e place.