The SLC16A11 risk haplotype is associated with decreased insulin action, higher transaminases and large-size adipocytes

in European Journal of Endocrinology
Correspondence should be addressed to C A Aguilar-Salinas; Email: caguilarsalinas@yahoo.com
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Objective

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.

Design

Cross-sectional study.

Methods

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.

Results

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< 0.001).

Conclusions

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.

 

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    Comparison of median weight and fat-free mass adjusted M values obtained by the euglycemic–hyperinsulinemic clamp between carriers (n = 75) and non-carriers (n = 72) of the risk SCL16A11 haplotype. Mann–Whitney U test was run and a significantly lower M value was observed in carriers of the risk haplotype for both weight and fat-free mass adjusted M values (P < 0.05).

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    Adipose tissue histology between carriers and non-carriers of the SLC16A11 risk haplotype. A and D. Median adipocyte size and dispersion are represented in the scatter plots ((A) Female, (D) male)). (B and E) Relative frequency histograms for non-carriers (grey) and carriers (black) ((B) Female, (E) male)). (C and F) Microphotography of subcutaneous adipose tissue H&E stained at 20x magnification ((C) Female, (F) male)) *P < 0.01 carriers vs non-carriers.

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