Insulin Biosynthesis in Experimental Hereditary Diabetes

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Abstract
Studies of proinsulin-insulin relationships were performed on serum and isolated pancreatic islets from normal (C57 BL/Ks) and spontaneously diabetic (CSlBL/Ks-dbdb) mice. The diabetic syndrome in these animals is inherited as an autO8omal recessive trait with complete penetrance and is characterized by the early development of obesity and hyperinsulinemia, followed by progressive hyperglycemia. Gel nitration chromatography of diabetic mouse serum revealed that proinsulin comprised a relatively small proportion (9.6 per cent) of the total circulating insulin immunoreactivity. Although diabetic mouse islets were enlarged, insulin content per islet was diminished, while proinsulin content per islet was similar to normal. Islet proinsulin:insulin ratios correlated sgnificantly with both blood glucose and serum insulin levels. This appeared to result from the fact that sustained hyperglycemia caused mainly a depletion of islet insulin, whereas proinsulin content remained unchanged, thereby increasing proinsulin:insulin ratios. In vitro labeling experiments with H-3-leucine demonstrated no significant difference in the rate or pattern of incorporation of radioactivity into proinsulin and insulin fractions of normal and diabetic islets after 90 and 180 minutes of incubation. Therefore, the apparent biological ineffectiveness of the high circulating levels of immunoreactive insulin in this diabetic syndrome did not appear to be the result of a disproportionate release of biologically less potent proinsulin, nor did there appear to be a detectable abnormality in proinsulin-insulin biosynthesis as assessed by these methods.

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