Extended life span is associated with insulin resistance in a transgenic mouse model of insulinoma secreting human islet amyloid polypeptide.

Pancreatic amyloid is found in patients with insulinomas and type 2 diabetes. To study mechanisms of islet amyloidogenesis, we produced transgenic mice expressing the unique component of human islet amyloid, human islet amyloid polypeptide (hIAPP). These mice develop islet amyloid after 12 mo of high-fat feeding. To determine whether we could accelerate the rate of islet amyloid formation, we crossbred our hIAPP transgenic animals with RIP-Tag mice that develop islet tumors and die at 12 wk of age from hypoglycemia. At 12 wk of age, this new line of hIAPPxRIP-Tag mice was heavier (29.7 +/- 1.0 vs. 25.0 +/- 1.3 g, P < 0.05) and had increased plasma glucose levels (4.6 +/- 0.4 vs. 2.9 +/- 0.6 mmol/l, P < 0.05) compared with littermate RIP-Tag mice. However, the hIAPPxRIP-Tag mice did not display islet amyloid or amyloid fibrils despite high circulating hIAPP levels (24.6 +/- 7.0 pmol/l). Interestingly, hIAPPxRIP-Tag mice had a longer life span than RIP-Tag mice (121 +/- 8 vs. 102 +/- 5 days, P < 0.05). This increase in life span in hIAPPxRIP-Tag was positively correlated with body weight (r = 0.48, P < 0.05) and was associated with decreased insulin sensitivity compared with RIP-Tag mice. hIAPPxRIP-Tag mice did not develop amyloid during their 4-mo life span, suggesting that increased hIAPP secretion is insufficient for islet amyloid formation within such a short time. However, hIAPPxRIP-Tag mice did have an increase in life span that was associated with insulin resistance, suggesting that hIAPP has extrapancreatic effects, possibly on peripheral glucose metabolism.