The biosynthesis and processing of proinsulin was investigated in the diabetic Goto-Kakizaki (GK) rat. Immunofluorescence microscopy comparing GK and Wistar control rat pancreata revealed marked changes in the distribution of -cells and pronounced -cell heterogeneity in the expression patterns of insulin, prohormone convertases PC1, PC2, carboxypeptidase E (CPE) and the PC-binding proteins 7B2 and ProSAAS. Western blot analyses of isolated islets revealed little difference in PC1 and CPE expression but PC2 immunoreactivity was markedly lower in the GK islets. The processing of the PC2-dependent substrate chromogranin A was reduced as evidenced by the appearance of intermediates. No differences were seen in the biosynthesis and post-translational modification of PC1, PC2 or CPE following incubation of islets in 16·7 mM glucose, but incubation in 3·3 mM glucose resulted in decreased PC2 biosynthesis in the GK islets. The rates of biosynthesis, processing and secretion of newly synthesized (pro)insulin were comparable. Circulating insulin immunoreactivity in both Wistar and GK rats was predominantly insulin 1 and 2 in the expected ratios with no (pro)insulin evident. Thus, the marked changes in islet morphology and PC2 expression did not impact the rate or extent of proinsulin processing either in vitro or in vivo in this experimental model.

The impact of genetic factors and maternal diabetes on glucose tolerance and pancreatic beta-cell function was studied in first generation (F1) offspring generated in crosses between the spontaneously diabetic Goto-Kakizaki (GK)-Wistar rat and normoglycemic control Wistar rats (W). The (GK x W) F1 hybrids were offspring of either male GK (mGK) and female Wistar (fW) (mGK x fW) or male Wistar (mW) and female GK (fGK) (mW x fGK) rats. Already at 8 days of age, blood glucose levels were elevated in GK (7.6 +/- 0.5 vs. 4.8 +/- 0.3 mM in W; P < 0.001) and in F1 rats (6.0 +/- 0.3 in mGK x fW and 6.6 +/- 0.4 mM in mW x fGK; both P < 0.01 vs. W). In 2-month-old male rats, glucose (2 g/kg, intraperitoneally) markedly increased blood glucose levels after 60 min in GK rats (18.1 +/- 0.6 vs. 5.5 +/- 0.3 mM in W; P < 0.001) and moderately increased levels in F1 rats (9.9 +/- 0.9 in mGK x fW and 11.6 +/- 1.0 mM in mW x fGK, both P < 0.01 vs. W). Similar patterns were obtained in female rats. Repeated backcrossing of F1 with W rats successively improved glucose tolerance. In perfused pancreases of male rats, the 20-min insulin response to 16.7 mM glucose was -7.44 +/- 5.18 pmol in GK rats, 71.57 +/- 12.25 pmol in W rats, 9.00 +/- 0.89 pmol in mGK x fW rats, and 18.20 +/- 3.97 pmol in mW x fGK rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancreastatin is a peptide isolated from the porcine pancreas and shown to inhibit insulin release. We have studied the immunocytochemical distribution of pancreastatin in three porcine endocrine tissues: pancreas, gut, and adenohypophysis. Pancreastatin-specific immunoreactivity was found in all three locations and distributed to numerous cells. In the pancreas, we performed the alternate labeling of consecutive thick (immunofluorescence) or thin (protein A-gold) sections and we observed that pancreastatin colocalizes to secretory granules of insulin and somatostatin-containing cells. The relationship of pancreastatin to chromogranin A is discussed.

Elevated proinsulin and proinsulin/insulin ratios are features of abnormal beta-cell function in type 2 diabetes. The participation of genetic factors is disputed. The authors wished to investigate relations between family history of diabetes on one hand and proinsulin as well as proinsulin/immunoreactive insulin ratios on the other. A large, population-based sample of Swedish men aged 35-54 years in 1992 was studied. Subjects without known diabetes were selected either to have a strong family history of diabetes (n = 1,619) or no history of the disease (n = 1,495). An oral glucose tolerance test detected 172 subjects with impaired glucose tolerance and 55 subjects with previously unknown diabetes according to World Health Organization 1985 criteria. In multiple regression analysis, fasting levels of proinsulin and proinsulin/insulin ratios were positively associated both with the 2-hour glucose level (as a continuous variable) and with obesity, whereas a negative association was found with birth weight. No association was found with family history of diabetes or with chronologic age. These findings indicate that elevated proinsulin and proinsulin/insulin ratios are secondary to increased demands on beta-cell secretion induced by hyperglycemia and insulin resistance with no discernible influence of family history of diabetes.

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