One form of maturity-onset diabetes of the young (MODY3) results from mutations in the hepatocyte nuclear factor (HNF)-1α gene, located on chromosome 12q24.2. The primary objective of the present study was to search for genetic variation in the HNF-1α gene in nine nonrelated Danish Caucasian subjects with MODY. Direct sequencing of the coding region and intron-exon boundaries of the HNF-1α 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 β-cell abnormality. He had a low insulin secretion rate during an OGTT, but a twofold increase in pancreatic β-cell response after intravenous glucose and a 2.5- to 4-fold increase in β-cell response after either intravenous tolbutamide or intravenous glucagon loads. In conclusion, 1) mutations in the HNF-1α gene are common in Danish Caucasian MODY patients, and 2) early stages in the pathogenesis of MODY3 caused by the P447L mutation may be characterized by a hyperexcitability of β-cells to intravenous secretagogues.
Novel MODY3 Mutations in the Hepatocyte Nuclear Factor-1α Gene: Evidence for a Hyperexcitability of Pancreatic β-cells to Intravenous Secretagogues in a Glucose-Tolerant Carrier of a P447L Mutation
HNF, hepatocyte nuclear factor; IGT, impaired glucose tolerance; IVGTT, intravenous glucose tolerance test; MODY, maturity-onset diabetes of the young; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; PCR, polymerase chain reaction.
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Torben Hansen, Hans Eiberg, Mathias Rouard, Martine Vaxillaire, Ann M Møller, Søren K Rasmussen, Marianne Fridberg, Søren A Urhammer, Jens J Holst, Katrine Almind, Søren M Echwald, Lars Hansen, Graeme I Bell, Oluf Pedersen; Novel MODY3 Mutations in the Hepatocyte Nuclear Factor-1α Gene: Evidence for a Hyperexcitability of Pancreatic β-cells to Intravenous Secretagogues in a Glucose-Tolerant Carrier of a P447L Mutation. Diabetes 1 April 1997; 46 (4): 726–730. https://doi.org/10.2337/diab.46.4.726
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