Omar Yaxmehen Bello-Chavolla, Paloma Almeda-Valdes, Donaji Gomez-Velasco, Tannia Viveros-Ruiz, Ivette Cruz-Bautista, Alonso Romo-Romo, Daniel Sánchez-Lázaro, Dushan Meza-Oviedo, Arsenio Vargas-Vázquez, Olimpia Arellano Campos, Magdalena del Rocío Sevilla-González, Alexandro J Martagón, Liliana Muñoz Hernández, Roopa Mehta, César Rodolfo Caballeros-Barragán and Carlos A Aguilar-Salinas
We developed a novel non-insulin-based fasting score to evaluate insulin sensitivity validated against the euglycemic–hyperinsulinemic clamp (EHC). We also evaluated its correlation with ectopic fact accumulation and its capacity to predict incident type 2 diabetes mellitus (T2D).
Design and methods
The discovery sample was composed by 125 subjects (57 without and 68 with T2D) that underwent an EHC. We defined METS-IR as Ln((2*G0)+TG0)*BMI)/(Ln(HDL-c)) (G0: fasting glucose, TG0: fasting triglycerides, BMI: body mass index, HDL-c: high-density lipoprotein cholesterol), and compared its diagnostic performance against the M-value adjusted by fat-free mass (MFFM) obtained by an EHC. METS-IR was validated in a sample with EHC data, a sample with modified frequently sampled intravenous glucose tolerance test (FSIVGTT) data and a large cohort against HOMA-IR. We evaluated the correlation of the score with intrahepatic and intrapancreatic fat measured using magnetic resonance spectroscopy. Subsequently, we evaluated its ability to predict incident T2D cases in a prospective validation cohort of 6144 subjects.
METS-IR demonstrated the better correlation with the MFFM (ρ = −0.622, P < 0.001) and diagnostic performance to detect impaired insulin sensitivity compared to both EHC (AUC: 0.84, 95% CI: 0.78–0.90) and the SI index obtained from the FSIVGTT (AUC: 0.67, 95% CI: 0.53–0.81). METS-IR significantly correlated with intravisceral, intrahepatic and intrapancreatic fat and fasting insulin levels (P < 0.001). After a two-year follow-up, subjects with METS-IR in the highest quartile (>50.39) had the highest adjusted risk to develop T2D (HR: 3.91, 95% CI: 2.25–6.81). Furthermore, subjects with incident T2D had higher baseline METS-IR compared to healthy controls (50.2 ± 10.2 vs 44.7 ± 9.2, P < 0.001).
METS-IR is a novel score to evaluate cardiometabolic risk in healthy and at-risk subjects and a promising tool for screening of insulin sensitivity.
Paloma Almeda-Valdes, Donaji V Gómez Velasco, Olimpia Arellano Campos, Omar Yaxmehen Bello-Chavolla, Magdalena del Rocío Sevilla-González, Tannia Viveros Ruiz, Alexandro J Martagón Rosado, Claudia J Bautista, Liliana Muñoz Hernandez, Ivette Cruz-Bautista, Hortensia Moreno-Macias, Alicia Huerta-Chagoya, Karen Guadalupe Rodríguez-Álvarez, Geoffrey A Walford, Suzanne B R Jacobs, Luz E Guillen Pineda, Ma Luisa Ordoñez-Sánchez, Ernesto Roldan-Valadez, Joaquín Azpiroz, Jannette Furuzawa-Carballeda, Patricia Clark, Miguel F Herrera-Hernández, Elena Zambrano, Jose C Florez, María Teresa Tusié Luna and Carlos A Aguilar-Salinas
A haplotype at chromosome 17p13 that reduces expression and function of the solute carrier transporter SLC16A11 is associated with increased risk for type 2 diabetes in Mexicans. We aim to investigate the detailed metabolic profile of SLC16A11 risk haplotype carriers to identify potential physiological mechanisms explaining the increased type 2 diabetes risk.
We evaluated carriers (n = 72) and non-carriers (n = 75) of the SLC16A11 risk haplotype, with or without type 2 diabetes. An independent sample of 1069 subjects was used to replicate biochemical findings. The evaluation included euglycemic–hyperinsulinemic clamp, frequently sampled intravenous glucose tolerance test (FSIVGTT), dual-energy X-ray absorptiometry (DXA), MRI and spectroscopy and subcutaneous abdominal adipose tissue biopsies.
Fat-free mass (FFM)-adjusted M value was lower in carriers of the SLC16A11 risk haplotype after adjusting for age and type 2 diabetes status (β = −0.164, P
= 0.04). Subjects with type 2 diabetes and the risk haplotype demonstrated an increase of 8.76 U/L in alanine aminotransferase (ALT) (P
= 0.02) and of 7.34 U/L in gamma-glutamyltransferase (GGT) (P
= 0.05) compared with non-carriers and after adjusting for gender, age and ancestry. Among women with the risk haplotype and normal BMI, the adipocyte size was higher (P
Individuals carrying the SLC16A11 risk haplotype exhibited decreased insulin action. Higher serum ALT and GGT levels were found in carriers with type 2 diabetes, and larger adipocytes in subcutaneous fat in the size distribution in carrier women with normal weight.