Oophorectomy promotes islet amyloid formation in human islet amyloid polypeptide transgenic mice.

Abstract

Islet amyloid polypeptide (IAPP) (amylin) is the unique peptide component of the amyloid deposits found at autopsy in >90% of subjects with type 2 diabetes (1). These amyloid deposits are thought to replace islet mass and to thereby contribute to the � -cell dysfunction of the disease. The mechanism(s) underlying islet amyloid deposition is unclear, but an amyloidogenic sequence in IAPP is required. Islet amyloid can develop in humans, nonhuman primates, and cats, but it never develops in rodents because their IAPP lacks the critical amino acid sequence and is thus nonamyloidogenic. Several groups have generated transgenic mice expressing human IAPP (hIAPP) (2). We successfully induced amyloid formation in our hIAPP transgenic mice by feeding a diet containing an increased quantity of fat (9% wt/wt) (3). Interestingly, we noted a gender-dependent difference, as islet amyloid deposits were found in 81% of male transgenic mice but in only 11% of female transgenic mice. This observation suggested that either testicular products promote or ovarian products protect against islet amyloid deposition. Recently, another group has observed a similar gender-dependent difference in islet amyloid deposition in double-transgenic hIAPP ob/ob mice, with 83% of male mice compared with 20% of female mice developing islet amyloid deposits (4). To test the hypothesis that ovarian products protect against the development of islet amyloid in hIAPP transgenic mice, we performed a bilateral oophorectomy (n = 11) or a sham procedure (n = 6) in female hIAPP transgenic mice at 6‐8 weeks of age. The animals were followed for 1 year on a 9% fat (wt/wt) diet. Body weight was measured every 2 weeks throughout the study. At 57 weeks, an intraperitoneal glucose tolerance test was performed after an overnight fast to determine whether glucose tolerance or � -cell function were altered and contributed to amyloidogenesis. When the animals were killed, 4-h fasting plasma glucose, immunoreactive insulin (IRI), and hIAPP levels were measured. The pancreas was harvested and used to quantify IRI and hIAPP content and to determine the prevalence and severity of islet amyloid by thioflavin S staining. The severity of amyloid deposition was determined using an arbitrary scale of 0‐3, where 0 denoted no amyloid and 3 denoted extensive amyloid deposits. A minimum of six islets in each section were examined, and the mean score was calculated. No amyloid was detected in the six sham-operated mice. In sharp contrast, 7 of 11 (64%) oophorectomized mice developed islet amyloid (P < 0.05), with the mean (± SE) severity of amyloid in this group being 0.40 ± 0.18 arbitrary units (range 0‐2.00). Incremental body weight