Novel MODY3 Mutations in the Hepatocyte Nuclear Factor-la Gene Evidence for a Hyperexcitability of Pancreatic p-cells to Intravenous Secretagogues in a Glucose-Tolerant Carrier of a P447L Mutation
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چکیده
One form of maturity-onset diabetes of the young (M0DY3) results from mutations in the hepatocyte nuclear factor (HNF)-la gene, located on chromosome 12q24.2. The primary objective of the present study was to search for genetic variation in the HNF-la gene in nine nonrelated Danish Caucasian subjects with MODY. Direct sequencing of the coding region and intron-exon boundaries of the HNF-la gene revealed 2 novel and 1 previously reported missense mutations and 2 novel frameshift mutations in five of nine MODY subjects. These five mutations were found in neither 84 NIDDM patients nor 84 control subjects. One glucose-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 tolerance test, and a glucagon test to examine for a possible early 0-cell abnormality. He had a low insulin secretion rate during an OGTT, but a twofold increase in pancreatic p-cell response after intravenous glucose and a 2.5to 4-fold increase in p-cell response after either intravenous tolbutamide or intravenous glucagon loads. In conclusion, 2) mutations in the HNF-la gene are common in Danish Caucasian MODY patients, and 2) early stages in the pathogenesis of M0DY3 caused by the P447L mutation may be characterized by a hyperexcitability of p-cells to intravenous secretagogues. Diabetes 46:726-730, 1997
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