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

Abstract

One form of maturity-onset diabetes of the young (MODY3) results from mutations in the hepatocyte nuclear factor (HNF)-1alpha gene, located on chromosome 12q24.2. The primary objective of the present study was to search for genetic variation in the HNF-1alpha gene in nine nonrelated Danish Caucasian subjects with MODY. Direct sequencing of the coding region and intron-exon boundaries of the HNF-1alpha 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 beta-cell abnormality. He had a low insulin secretion rate during an OGTT, but a twofold increase in pancreatic beta-cell response after intravenous glucose and a 2.5- to 4-fold increase in beta-cell response after either intravenous tolbutamide or intravenous glucagon loads. In conclusion, 1) mutations in the HNF-1alpha 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 beta-cells to intravenous secretagogues.

beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1alpha and glucokinase mutations.

“…This was rapidly confirmed as a common cause of MODY in U.K. (3,3a), German (17), French (18), Danish (19), Italian (20), Finnish (21), North American (21), and Japanese (22) pedigrees. Subjects with a mutation in the HNF-1␣ gene usually develop diabetes in adolescence or early adulthood.…”

Contrasting Diabetes Phenotypes Associated With Hepatocyte Nuclear Factor-1α and -1β Mutations

“…The acute pancreatic insulin secretory response to tolbutamide was determined by comparing the insulin secretory response to an intravenous glucose bolus (0.3 g/kg) with the insulin secretory response to a tolbutamide bolus (3 mg/kg) in a tolbutamide-modified frequently sampled IVGTT performed as previously described (20,21). The acute insulin response to glucose (PEAKglu) was assessed by the peak increment from baseline.…”

The Private Hepatocyte Nuclear Factor-1α G319S Variant Is Associated With Plasma Lipoprotein Variation in Canadian Oji-Cree

“…[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] MODY3 is clinically distinct from typical type 2 diabetes and probably results from defective pancreatic insulin secretion. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, the underlying mechanistic relationship with the dysfunctional HNF1A gene product is not fully understood for either MODY3 or type 2 diabetes in the Oji-Cree. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]…”