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

Abstract

To assess whether an ethnic-specific variant (p.E508K) in the maturity-onset diabetes of the young (MODY) gene hepatocyte nuclear factor-1α (<i>HNF1A</i>) found in Mexicans is associated with higher sensitivity to sulfonylureas, as documented in patients with MODY3. 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. Carriers of the p.E508K variant had a lower maximum insulin peak during the glipizide challenge as compared with noncarriers with diabetes (<i>P</i> < 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 (<i>P</i> < 0.05). A similar but nonsignificant trend was seen in participants without type 2 diabetes. Carriers of variant p.E508K in <i>HNF1A</i> have a reduced insulin response rather than the increased sensitivity to sulfonylureas seen in patients with MODY3.