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OBJECTIVE Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis may result in a change in clinical treatment and impacts prediction of complications and familial risk. In this study, we aimed to assess the prevalence of MODY in multiethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines. RESULTS Of 3,333 participants, 93 (2.8%) carried an LP/P variant in HNF4A (16 participants), GCK (23), HNF1A (44), PDX1 (5), INS (4), and CEL (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 vs. 13.6 ± 2.3 years, P = 0.002) and lower fasting C-peptide levels (3.0 ± 1.7 vs. 4.7 ± 3.5 ng/mL, P < 0.0001). Youth with MODY were less likely to have hypertension (6.9% vs. 19.5%, P = 0.007) and had higher HDL cholesterol (43.8 vs. 39.7 mg/dL, P = 0.006). CONCLUSIONS By comprehensively sequencing the coding regions of all MODY genes, we identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes; importantly, in 89% (n = 83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria for selection of individuals for genetic testing.

OBJECTIVE The rs7903146 T allele in transcription factor 7 like 2 (TCF7L2) is strongly associated with type 2 diabetes (T2D), but the mechanisms for increased risk remain unclear. We evaluated the physiologic and hormonal effects of TCF7L2 genotype before and after interventions that influence glucose physiology. RESEARCH DESIGN AND METHODS We genotyped rs7903146 in 608 individuals without diabetes and recorded biochemical data before and after 1) one dose of glipizide (5 mg) on visit 1 and 2) a 75-g oral glucose tolerance test (OGTT) performed after administration of metformin 500 mg twice daily over 2 days. Incretin levels were measured in 150 of the 608 participants. RESULTS TT risk-allele homozygotes had 1.6 mg/dL higher baseline fasting glucose levels and 2.5 pg/mL lower glucagon levels per T allele than carriers of other genotypes at baseline. In a subset of participants, the T allele was associated with higher basal glucagon-like peptide 1 (GLP-1) levels at visit 1 (β = 1.52, P = 0.02 and β = 0.96, P = 0.002 for total and active GLP-1, respectively), and across all points of the OGTT after metformin administration. Regarding drug response, the T allele was associated with a shorter time (β = −7.00, P = 0.03) and a steeper slope (β = 0.23, P = 0.04) to trough glucose levels after glipizide administration, and lower visit 2 fasting glucose level adjusted for visit 1 fasting glucose level (β = −1.02, P = 0.04) and a greater decline in glucose level between visits (β = −1.61, P = 0.047) after metformin administration. CONCLUSIONS Our findings demonstrate that common variation at TCF7L2 influences acute responses to both glipizide and metformin in people without diabetes and highlight altered incretin signaling as a potential mechanism by which TCF7L2 variation increases T2D risk.