-Cell Glucokinase Deficiency and Hyperglycemia Are Associated With Reduced Islet Amyloid Deposition in a Mouse Model of Type 2 Diabetes

Type 2 diabetes is characterized by impaired -cell function, hyperglycemia, and islet amyloid deposition. The primary constituent of islet amyloid is the 37–amino acid -cell product called islet amyloid polypeptide (IAPP) or amylin. To study mechanisms of islet amyloid formation, we developed a transgenic mouse model that produces and secretes the amyloidogenic human IAPP (hIAPP) molecule and have shown that 81% of male transgenic mice develop islet amyloid after 14 months on a high-fat diet. To test whether impaired -cell function and hyperglycemia could enhance islet amyloid formation, we cross-bred our hIAPP transgenic mice with -cell glucokinase-knockout mice (GKKO) that have impaired glucose-mediated insulin secretion and fasting hyperglycemia. The resulting new (hIAPP GKKO) line of mice had higher basal plasma glucose concentrations than the hIAPP transgenic mice at 3, 6, and 12 months of age (P < 0.05), as did GKKO mice compared with hIAPP transgenic mice at 6 and 12 months of age (P < 0.05). Basal plasma immunoreactive insulin (IRI) levels were lower in hIAPP GKKO mice than in hIAPP transgenic mice at 6 months of age (P < 0.05). The area under the glucose curve in response to an intraperitoneal glucose challenge (1 g/kg body weight) was larger in hIAPP GKKO mice than in hIAPP transgenic mice at 3, 6, and 12 months of age (P < 0.005) and in GKKO mice compared with hIAPP transgenic mice at 6 and 12 months of age (P < 0.005). The area under the IRI curve was lower in hIAPP GKKO mice at 6 and 12 months of age (P < 0.05) than in hIAPP transgenic mice and in GKKO mice compared with hIAPP transgenic mice at 12 months of age (P < 0.05). Despite the presence of hyperglycemia, hIAPP GKKO mice had a lower incidence (4 of 17 vs. 12 of 19, P < 0.05) and amount (0.40 ± 0.24 vs. 1.2 ± 0.3 arbitrary units, P < 0.05) of islet amyloid than hIAPP transgenic mice had. As expected, no islet amyloid was observed in GKKO mice lacking the hIAPP transgene (0 of 13). There was no difference in pancreatic content of IRI and hIAPP among the three groups of mice. Thus, despite the presence of impaired islet function and hyperglycemia, hIAPP GKKO mice had a decreased incidence and quantity of islet amyloid. Therefore, our data suggest that impaired -cell glucose metabolism or hyperglycemia are not likely to contribute to islet amyloid formation in diabetes. Furthermore, this finding may explain the lack of progression of glycemia in patients with maturity-onset diabetes of the young. Diabetes 49:2056–2062, 2000