We identified an inframe insertion of a proline in the insulin promoter factor 1 (IPF1) gene (InsCCG243), which was relatively common (minor allele frequency approximately 0.08) in African Americans and showed a trend to association with type 2 diabetes in preliminary studies.
Chronic hyperglycemia, independent of plasma lipid levels, is sufficient for the loss of beta-cell differentiation and secretory function in the db/db mouse model of diabetes.
Our aim was to identify whether IPF1 gene mutations play a role in Italian early-onset type 2 diabetic (T2D) patients and what functional impact mutations may have in the beta cell.
We screened 264 unrelated subjects with type 2 diabetes diagnosed before 40 yr of age and a family history of diabetes for mutations in the minimal promoter and coding region of the IPF-1 gene (IPF1).
Coding variants of the pancreas duodenum homeobox gene (PDX1) were proposed to predispose late-onset type 2 diabetes and to decrease transactivation in vitro.
Interestingly, functional variants of the MODY 4 gene (insulin promoter factor-1) have been associated with both MODY and the common form of type 2 diabetes.
We genotyped U.S. Caucasians with (n = 217) and without (n = 176) Type 2 diabetes to determine if three previously identified variants (Cys18Arg, Asp76Asn, Arg197His) in the IPF-1 gene play a role in the development of Type 2 diabetes.
Although mutations in the IPF-1 gene are rare in early- (3.5 %) and late-onset (2.7 % ) Type II diabetes, they are functionally important and occur also in families with other MODY mutations.
Heterozygous mutations in the gene result in impaired glucose tolerance and symptoms of diabetes as seen in MODY4 and late-onset Type II (non-insulin-dependent) diabetes mellitus.
We have observed a combined prevalence of missense variants in the coding region of the IPF-1 gene of around 1%, in unselected patients with the common form of late-onset type 2 diabetes.
Mutations in the genes for hepatocyte nuclear factor (HNF)-1alpha, -4alpha, -1beta, and -3beta; the dimerization cofactor of HNF-1; and insulin promoter factor 1 are not common causes of early-onset type 2 diabetes in Pima Indians.
We conclude that variants in IPF-1 are not a common cause of MODY or late-onset type 2 diabetes in the Caucasian population, and that in terms of insulin transcription both the N76 and the T140 mutations are likely to represent functionally normal IPF-1 variants with no direct role in the pathogenesis of MODY or late-onset type 2 diabetes mellitus.
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.
We conclude that mutations in the IPF-1 gene may predispose to type 2 diabetes and are a rare cause of MODY and pancreatic agenesis, with the phenotype depending upon the severity of the mutation.
We then examined them on genomic DNA in six MODY probands without mutations in the MODY1, MODY3 and MODY4 genes and in 54 patients with late-onset Type II diabetes by combined single strand conformational polymorphism-heteroduplex analysis followed by direct sequencing of identified variants.
In this study 88 patients with non-insulin-dependent diabetes mellitus (NIDDM) who were diagnosed as diabetic at less than 40 years of age, 55 patients with insulin-dependent-diabetes (IDDM), and 67 normal control subjects were analysed for variants in the upstream region of the IPF1 gene by direct sequencing.