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

Abstract

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.

• Authors: Alexandro J Martagón, Omar Yaxmehen Bello-Chavolla, Olimpia Arellano-Campos, Paloma Almeda-Valdés, Geoffrey A Walford, Ivette Cruz-Bautista, Donají V Gómez-Velasco, Roopa Mehta, Liliana Muñoz-Hernández, Magdalena Sevilla-González, Tannia L Viveros-Ruiz, María Luisa Ordoñez-Sánchez, Rosario Rodríguez-Guillen, Jose C Florez, María Teresa Tusié-Luna, Carlos A Aguilar-Salinas, Slim Initiative in Genomic Medicine for the Americas (SIGMA) Type 2 Diabetes Consortium
• Journal: Diabetes care (Diabetes Care) Vol. 41 Issue 8 Pg. 1726-1731 (08 2018) ISSN: 1935-5548 [Electronic] United States
• PMID: 29844095 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by the American Diabetes Association.

Chemical References

• HNF1A protein, human
• Hepatocyte Nuclear Factor 1-alpha
• Insulin
• Sulfonylurea Compounds

Topics

• Adolescent
• Adult
• Aged
• Amino Acid Substitution
• Case-Control Studies
• Diabetes Mellitus, Type 2 (blood, drug therapy, ethnology, genetics)
• Drug Resistance (genetics)
• Female
• Glucose Tolerance Test
• Hepatocyte Nuclear Factor 1-alpha (genetics)
• Heterozygote
• Humans
• Insulin (therapeutic use)
• Insulin Resistance (genetics)
• Male
• Mexico (ethnology)
• Middle Aged
• Mutation, Missense
• Polymorphism, Single Nucleotide
• Sulfonylurea Compounds (therapeutic use)
• Young Adult