NOVEL MODY3 MUTATIONS IN THE HEPATOCYTE NUCLEAR FACTOR-1-ALPHA GENE -EVIDENCE FOR A HYPEREXCITABILITY OF PANCREATIC BETA-CELLS TO INTRAVENOUS SECRETAGOGUES IN A GLUCOSE-TOLERANT CARRIER OF A P447L MUTATION

One form of maturity-onset diabetes of the young (MODY3) results from mutations in the hepatocyte nuclear factor (HNF)-1 alpha gene, located on chromosome 12q24.2. The primary objective of the present study was to search for genetic variation in the HNF-1 alpha gene in nine nonre lated Danish Caucasian subjects with MODY. Direct sequencing of the co ding region and intron-exon boundaries of the HNF-1 alpha gene reveale d 2 novel and 1 previously reported missense mutations and 2 novel fra meshift mutations in five of nine MODY subjects, These five mutations mere found in neither 84 NIDDM patients nor 84 control subjects, One g lucose-tolerant lean male with a P447L missense mutation, which in his relatives caused MODY, underwent an oral glucose tolerance test (OGTT ), a tolbutamide modified frequently sampled intravenous glucose toler ance test, and a glucagon test to examine for a possible early beta-ce ll abnormality, He had a low insulin secretion rate during an OGTT, bu t a twofold increase in pancreatic beta-cell response after intravenou s glucose and a 2.5- to 4-fold increase in beta-cell response after ei ther intravenous tolbutamide or intravenous glucagon loads, In conclus ion, 1) mutations in the HNF-1 alpha gene are common in Danish Caucasi an MODY patients, and 2) early stages in the pathogenesis of MODY3 cau sed by the P447L mutation may be characterized by a hyperexcitability of beta-cells to intravenous secretagogues.