Reduced pancreatic polypeptide response to hypoglycemia and amylin response to arginine in subjects with a mutation in the HNF-4 alpha/MODY1 gene

Subjects with the Q268X mutation in the hepatocyte nuclear factor (HNF)-4 a lpha gene (RW pedigree/maturity-onset diabetes of the young [MODY]-1) have diminished insulin and glucagon secretory responses to arginine. To determi ne if pancreatic polypeptide (PP) secretion is likewise in involved, we stu died PP responses to insulin-induced hypoglycemia in 17 RW pedigree members : 6 nondiabetic mutation-negative [ND(-)], 4 nondiabetic mutation-positive [ND(+)], and 7 diabetic mutation-positive [D(+)]. Subjects received 0.08 U/ kg body wt human regular insulin as an intravenous bolus to produce moderat e self-limited hypoglycemia. PP areas under the curve (PP-AUCs) were compar ed among groups. With hypoglycemia, the PP-AUC was tower in the D(+) group (14,907 +/- 6,444 pg/ml, P = 0.03) and the ND(+) group (14,622 + 6,015 pg/m l, P = 0.04) compared with the ND(-) group (21,120 +/- 4,158 pg/ml). In add ition, to determine if the beta-cell secretory defect in response to argini ne involves amylin in addition to insulin secretion, we analyzed samples fr om 17 previously studied RW pedigree subjects. We compared the AUCs during arginine infusions for the 3 groups both at euglycemia and hyperglycemia as well as their C-peptide-to-amylin ratios. The D(+) and ND(+) groups had de creased amylin AUCs during both arginine infusions compared with the ND(-) group, but had similar C-peptide-to-amylin ratios. These results suggest th at the HNF-4 alpha mutation in the RW/MODY1 pedigree confers a generalized defect in islet cell function involving PP cells in addition to beta- and a lpha-cells, and beta-cell impairment involving proportional deficits in ins ulin and amylin secretion.