Compensatory recovery of blood glucose levels in KKA(y) mice fed a high-fat diet: insulin-sparing effects of PACAP overexpression in β cells.

Inadequate compensatory insulin secretion is observed during the development of type 2 diabetes and deteriorates over time in a manner that is difficult to reverse. Here, we found that plasma glucose levels in genetically diabetic KKA(y) mice fed a high-fat diet were markedly increased in young mice. However, the levels started to decrease at 22 weeks of age and returned to normal levels at around 40 weeks of age. These changes were accompanied by a marked increase in insulin levels from week 25 onwards. Decreased energy intake and suppressed fat pad accumulation were observed at 44-45 weeks of age compared with those at 19-22 weeks of age. β cell-specific overexpression of pituitary adenylate cyclase-activating polypeptide (PACAP), an insulinotropic neuropeptide, decreased the insulin levels required to compensate for hyperglycemia. Glucose disposal was significantly enhanced despite impaired insulin sensitivity in 41-44-week-old A(y) mice without or with PACAP overexpression. In conclusion, the present results provide further evidence that PACAP is involved in the regulation of hyperinsulinemia and islet hyperplasia in type 2 diabetes. Our results also indicate that A(y) mice fed a high-fat diet constitute an animal model suitable to study compensatory islet hyperplasia.