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Am J Physiol Endocrinol Metab (November 12, 2003). doi:10.1152/ajpendo.00137.2003
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00137.2003v1
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Submitted on March 31, 2003
Accepted on November 4, 2003

EXTENDED LIFE SPAN IS ASSOCIATED WITH INSULIN RESISTANCE IN A TRANSGENIC MOUSE MODEL OF INSULINOMA SECRETING HUMAN ISLET AMYLOID POLYPEPTIDE

Sofianos Andrikopoulos1, Rebecca L. Hull1, C. Bruce Verchere1, Feng Wang1, Shani M. Wilbur1, Thomas N. Wight2, Lucy Marzban3, and Steven E. Kahn1*

1 Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA
2 Hope Heart Institute and Department of Pathology, University of Washington, Seattle, WA, USA
3 B.C. Research Institute for Children's and Women's Health, Vancouver, BC, Canada

* To whom correspondence should be addressed. E-mail: skahn{at}u.washington.edu.

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 months 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 weeks of age from hypoglycemia. At 12 weeks of age this new line of hIAPPxRIP-Tag mice were heavier (29.7±1.0 vs 25.0±1.3 grams, P<0.05) and had increased plasma glucose levels (4.6±0.4 vs 2.9±0.6 mmol/L, P<0.05) compared to 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 lifespan in hIAPPxRIP-Tag was positively correlated with body weight (r=0.48, P<0.05) and was associated with decreased insulin sensitivity compared to RIP-Tag mice. hIAPPxRIP-Tag mice did not develop amyloid during their 4 month 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 which was associated with insulin resistance suggesting that hIAPP has extra-pancreatic effects, possibly on peripheral glucose metabolism.






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