• Clara Cieza-Borrella, Gonzalo Díaz-Soto, Isabel Martínez-Pino, Manuel Puig-Domingo, and Rogelio González-Sarmiento.
• From the *Unidad de Medicina Molecular, Departamento de Medicina, IBSAL and IBMCC, Universidad de Salamanca-CSIC, Salamanca; †Servicio de Endocrinología, U. Diabetes, Hospital Clínico Universitario de Valladolid, IEN-UVa, Valladolid; ‡Centro Nacional de Epidemiología, ISCIII, CIBERESP, Madrid; and §Servicio de Endocrinología y Nutrición, Hospital Germans Trias i Pujol, Badalona, Spain.
• J. Investig. Med. 2014 Dec 1; 62 (8): 968974968-74.

PurposeType 2 diabetes mellitus (type 2 DM) and maturity-onset diabetes of the young present some similar clinical and biochemical characteristics that make them difficult to differentiate. Currently, the polymorphism T130I (rs1800961) in the HNF4A (hepatocyte nuclear factor 4A) gene has been described as a risk factor to type 2 DM and shows an autosomal dominant inheritance pattern associated to β-cell function decrease. The aim of the present work was to characterize the phenotypic profile of the T130I carrier and noncarrier relatives included in 3 unrelated families.MethodsWe studied GCK, HNF1A, and HNF4A genes by polymerase chain reaction and sequencing in 3 unrelated subjects from Valladolid, Spain, in which maturity-onset diabetes of the young was suspected. We collected genetic, clinical, and biochemical data from these subjects and their relatives in order to check the presence of the T130I polymorphism.ResultsThe heterozygous T130I mutation was the unique functional gene variation that could explain diabetes phenotype. We observed significant differences in glucose metabolism, lipid profile, and Homeostasis Model Assessment index when we compared T130I mutation carriers and noncarriers. Diabetes diagnosed in T130I mutation carriers was related to stressful situations in an earlier age and tightly associated with gestational diabetes. Fasting plasma glucose and HbA(1c) levels increased with age in all carriers (r = 0.69 and r = 0.66, P < 0.01), respectively.ConclusionsOur study supports the T130I variant in HNF4A as a major susceptibility genotype associated with early-onset type 2 DM. Healthy carriers of this mutation require a stricter control in the population of central Spain.

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