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Early-Onset Type 2 Diabetes: Metabolic and Genetic Characterization in the Mexican Population¹

Departmento de Medicina y Unidad de Genética de la Nutrición del Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (M.L.O.-S., S.R.-J., A.D.-L., J.R.M.-F., M.T.T.-L.); Departamento de Endocrinología y Metabolismo de Lípidos del Instituto Nacional de Ciencias Médicas y Nutrición (C.A.A.-S., E.R.-R., M.A.T., M.L.V.-P., E.G.-G., F.G.-P., J.R.); and Instituto Mexicano del Seguro Social (M.A.), Mexico City 14000, Mexico

Address all correspondence and requests for reprints to: Carlos Alberto Aguilar-Salinas, M.D., or Ma. Teresa Tusié-Luna, M.D., Ph.D., Vasco de Quiroga 15, Mexico City 14000, Mexico. E-mail: caas{at}aztlan.innsz.mx

The objective of this study was to investigate possible defects in the insulin sensitivity and/or the acute insulin response in a group of Mexican patients displaying early-onset type 2 diabetes and to evaluate the contribution 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 secretory response were measured using the minimal model approach. A partial screening for possible mutations in 3 of the 5 genes linked to maturity-onset diabetes of the young was carried out by PCR-single strand conformation polymorphism analysis. A low insulin secretory capacity (AIRg = 68.5 ± 5 µU/mL·min) and a near-normal insulin sensitivity (3.43 ± 0.2 min/µU·mL x 10⁴) were found in these patients. Among this group we found two individuals carrying missense mutations in exon 4 of the hepatocyte nuclear factor-1 (HNF-4) gene (Asp¹²⁶His/Tyr and Arg¹⁵⁴Gln, respectively) and one carrying a nonsense mutation in exon 7 of the HNF-1 gene (Gln⁴⁸⁶stop codon); 7.5% had positive titers for glutamic acid decarboxylase antibodies. Thirty-five percent of cases had insulin resistance; these subjects had the lipid abnormalities seen in the metabolic syndrome. A defect in insulin secretion is the hallmark in Mexican diabetic patients diagnosed between 20 and 40 yr of age. Mutations in either the HNF-1 or the HNF-4 genes are present among the individuals who develop early-onset diabetes in our population. These particular sequence changes have not 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.

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