Early-onset type 2 diabetes: Metabolic and genetic characterization in theMexican population

The objective of this study was to investigate possible defects in the insu lin sensitivity and/or the acute insulin response in a group of Mexican pat ients displaying early-onset type 2 diabetes and to evaluate the contributi on of mutations in three of the genes linked to maturity-onset diabetes of the young. We studied 40 Mexican patients with an age of diagnosis between 20 and 40 yr in which the insulin sensitivity as well as the insulin secret ory response were measured using the minimal model approach. A partial scre ening for possible mutations in 3 of the 5 genes linked to maturity-onset d iabetes of the young was carried out by PCR-single strand conformation poly morphism analysis. A low insulin secretory capacity (AIRg = 68.5 +/- 5 muU/ mL.min) and a near-normal insulin sensitivity (3.43 +/- 0.2 min/ muU.mL x 1 0(4)) were found in these patients. Among this group we found two individua ls carrying missense mutations in exon 4 of the hepatocyte nuclear factor-1 alpha (HNF-4 alpha) gene (Asp(126)-->His/Tyr and Arg(154)-->Gln, respectiv ely) and one carrying a nonsense mutation in exon 7 of the HNF-1 alpha gene (Gln(486)-->stop codon); 7.5% had positive titers for glutamic acid decarb oxylase antibodies. Thirty-five percent of cases had insulin resistance; th ese subjects had the lipid abnormalities seen in the metabolic syndrome. A defect in insulin secretion is the hallmark in Mexican diabetic patients di agnosed between 20 and 40 yr of age. Mutations in either the HNF-1 alpha or the HNF-4 alpha genes are present among the individuals who develop early- onset diabetes in our population. These particular sequence changes have no t: been previously reported and therefore represent putative new mutations. Even in the absence of endogenous hyperinsulinemia, insulin resistance is associated with an adverse lipid profile.