C57BL/KsJ db/db mice develop hyperphagic obesity and nonketotic diabetes similar to non-insulin-dependent diabetes mellitus in humans. Initially the mice demonstrate an abundant β-cell mass and hyperinsulinemia, which is followed by apparent β-cell loss. As an index of insulin synthesis, this study assesses pancreatic proinsulin mRNA, measured by dot hybridization to cloned cDNA, during the development of diabetes in the mice. Changes in proinsulin mRNA from 5 to 13 wk of age are compared with serum insulin, pancreatic insulin content, and blood glucose. In control (+ /db) mice, total proinsulin mRNA and pancreatic insulin content increased with age. Both changes were proportional to an increase in body weight. Obesity, hyperglycemia, and hyperinsulinemia were evident in diabetic (db/db) mice at 5 wk of age. Although pancreatic insulin content was comparable to that in the + /db controls at 5 wk, a fourfold relative elevation of proinsulin mRNA was observed. Despite an increase in body weight, proinsulin mRNA concentration and total proinsulin mRNA fell to levels similar to those of the control mice at 10 and 13 wk, associated with a loss of hyperinsulinemia, a mild decrease in pancreatic insulin content, and a marked increase in fasting blood glucose. A separate group of db/db mice was pair fed with the + /db controls from 4 to 13 wk. These diet-restricted diabetic mice were heavier than control mice and gained weight with age, but they weighed less than the unrestricted mice at all ages. Compared with the unrestricted db/db mice, a more modest fasting hyperglycemia was apparent, and a persistent hyperinsulinemia was observed. This group also preserved a high proinsulin mRNA concentration and showed a less marked fall in total proinsulin mRNA. Pancreatic insulin content was lower than that of controls, but a modest increase occurred with age.

A strong correlation between serum insulin and total proinsulin mRNA is apparent in this study. Hyperinsulinemia in young diabetic mice is associated with abundant proinsulin mRNA, but occurrence of hyperglycemia and reduced pancreatic insulin content suggests that the ability to augment insulin synthesis is limited and insufficient to meet metabolic needs. The deterioration of hyperinsulinemia with age, accompanying more profound fasting hyperglycemia, is associated with a reduction of insulin synthesis reflected by a decreased total proinsulin mRNA. The loss of insulin synthetic capacity in these diabetic mice can be lessened by diet restriction, suggesting that the maintenance of total proinsulin mRNA in diet-restricted db/db mice may be important in ameliorating their diabetic state.