Mexican Carriers of the HNF1A p.E508K Variant Do Not Experience an Enhanced Response to Sulfonylureas

• DOI: 10.2337/dc18-0384
• Publication Date: 2018-05-29T14:15:17Z
• Authors: Alexandro J. Mart...; Omar Yaxmehen Bel...; Olimpia Arellano-...; Paloma Almeda-Valdés; Geoffrey A. Walford; Ivette Cruz-Bautista; Donají V. Gómez-V...; Roopa Mehta; Liliana Muñoz-Her...; Magdalena Sevilla...; Tannia L. Viveros...; María Luisa Ordoñ...; Rosario Rodríguez...; Jose C. Florez; María Teresa Tusi...; Carlos A. Aguilar...; ; Josep M. Mercader; Alicia Huerta-Cha...; Hortensia Moreno-...; Humberto García-O...; Alisa Manning; Lizz Caulkins; Jason Flannick; Nick Patterson; Angélica Martínez...; Federico Centeno-...; Francisco Martin ...; Carlos Zerrweck; Cecilia Contreras...; Elvia Mendoza-Caamal; Cristina Revilla-...; Sergio Islas Andrade; Emilio Córdova; Xavier Soberón; María Elena Gonzá...; Lynne Wilkens; Loic Le Marchand; Kristine Monroe; Laurence Kolonel; Olimpia Arellano-...; María L. Ordóñez-...; Maribel Rodríguez...; Yayoi Segura-Kato; Rosario Rodríguez...; Ivette Cruz-Bautista; Linda Liliana Muñ...; Alexandro J. Mart...; Magdalena del Roc...; Donají Gómez; Paloma Almeda-Valdés; Maria Eugenia Garay; Juan Manuel Malac...; Noël P. Burtt; Maria L. Cortes; David M. Altshuler; Christopher A. Ha...; Carlos A. Aguilar...; Clicerio González...; Lorena Orozco; Teresa Tusié-Luna; Jose C. Florez
• Keywords: Adult; Male; Heterozygote; 0303 health sciences; Adolescent; Drug Resistance; Mutation, Missense; Glucose Tolerance Test; Middle Aged; Polymorphism, Single Nucleotide; 3. Good health; 03 medical and health sciences; Sulfonylurea Compounds; Amino Acid Substitution; Diabetes Mellitus, Type 2; Case-Control Studies; Humans; Insulin; Female; Hepatocyte Nuclear Factor 1-alpha; Insulin Resistance; Mexico; Aged

OBJECTIVE To assess whether an ethnic-specific variant (p.E508K) in the maturity-onset diabetes of the young (MODY) gene hepatocyte nuclear factor-1α (HNF1A) found in Mexicans is associated with higher sensitivity to sulfonylureas, as documented in patients with MODY3.

RESEARCH DESIGN AND METHODS We recruited 96 participants (46 variant carriers and 50 age- and sex-matched noncarriers). Response to glipizide (one 2.5–5.0-mg dose), metformin (four 500-mg doses), and an oral glucose challenge was evaluated using a previously validated protocol. Glucose and insulin levels and their areas under the curve (AUCs) were compared between groups.

RESULTS Carriers of the p.E508K variant had a lower maximum insulin peak during the glipizide challenge as compared with noncarriers with diabetes (P < 0.05). Also, carriers had a lower insulin response after the oral glucose challenge. Following an oral glucose tolerance test in the presence of metformin, carriers of the p.E508K variant with diabetes had a lower maximum insulin peak and total and incremental insulin AUC value as compared with noncarriers with diabetes (P < 0.05). A similar but nonsignificant trend was seen in participants without type 2 diabetes.

CONCLUSIONS Carriers of variant p.E508K in HNF1A have a reduced insulin response rather than the increased sensitivity to sulfonylureas seen in patients with MODY3.