Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus
El Habib Hani, … , Joel F. Habener, Philippe Froguel
El Habib Hani, … , Joel F. Habener, Philippe Froguel
Published November 1, 1999
Citation Information: J Clin Invest. 1999;104(9):R41-R48. https://doi.org/10.1172/JCI7469.
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Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus is a common disabling disease with onset in middle-aged individuals, caused by an imbalance between insulin production and action. Genetic studies point to major genetic components, but, with the exception of maturity-onset diabetes of the young (MODY), specific diabetes susceptibility genes remain to be identified. Recent studies showed that a dominant negative mutation in the insulin promoter factor-1 (IPF-1), a pancreatic β-cell specific transcription factor, causes pancreatic agenesis and MODY. Thus, we investigated 192 French, non-MODY type 2 diabetic families for mutations in IPF-1. We identified 3 novel IPF-1 mutations, including 2 substitutions (Q59L and D76N) and an in-frame proline insertion (InsCCG243). Functional transactivation assays of these IPF-1 mutant isoforms in a β-pancreatic tumor cell line transfected with a transcriptional reporter and IPF-1 expression plasmids demonstrate a significant inhibition of basal insulin promoter activity (stronger with the InsCCG243 mutant). We find that the InsCCG243 mutation is linked, in 2 families, to an autosomal dominant-like late-onset form of type 2 diabetes, in which insulin secretion becomes progressively impaired. The lower penetrance D76N and Q59L mutations were more prevalent and were associated with a relative risk of 12.6 for diabetes and with decreased glucose-stimulated insulin-secretion in nondiabetic subjects. We propose that IPF-1 mutations can cause MODY or apparently monogenic late-onset diabetes and that they represent a significant risk factor for type 2 diabetes in humans.

Authors

El Habib Hani, Doris A. Stoffers, Jean-Claude Chèvre, Emmanuelle Durand, Violeta Stanojevic, Christian Dina, Joel F. Habener, Philippe Froguel

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Segregation of the IPF-1 D76N variation in the 9 type 2 diabetic familie...
Segregation of the IPF-1 D76N variation in the 9 type 2 diabetic families in which it was detected. These families belong to a large collection, ascertained in France for the presence of at least 2 sibs presenting with overt type 2 diabetes, and additional family members were recruited, when available (ref. 16). Filled, half-filled, and open symbols represent subjects with overt type 2 diabetes mellitus, impaired glucose tolerance, and normal glucose tolerance, respectively. Under each symbol, the first line corresponds the actual age; the second line shows the age at diagnosis of overt type 2 diabetes (when appropriate). The third line shows individual BMI values (kg/m2), and the fourth line shows the genotype at IPF-1 codon 76 (italicized): N, Normal allele; M, mutant allele.