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Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms.

Publication ,  Journal Article
Rusu, V; Hoch, E; Mercader, JM; Tenen, DE; Gymrek, M; Hartigan, CR; DeRan, M; von Grotthuss, M; Fontanillas, P; Spooner, A; Guzman, G; Ng, MCY ...
Published in: Cell
June 29, 2017

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.

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Published In

Cell

DOI

EISSN

1097-4172

Publication Date

June 29, 2017

Volume

170

Issue

1

Start / End Page

199 / 212.e20

Location

United States

Related Subject Headings

  • Monocarboxylic Acid Transporters
  • Models, Molecular
  • Liver
  • Humans
  • Histone Code
  • Heterozygote
  • Hepatocytes
  • Haplotypes
  • Gene Knockdown Techniques
  • Diabetes Mellitus, Type 2
 

Citation

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Rusu, V., Hoch, E., Mercader, J. M., Tenen, D. E., Gymrek, M., Hartigan, C. R., … Lander, E. S. (2017). Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms. Cell, 170(1), 199-212.e20. https://doi.org/10.1016/j.cell.2017.06.011
Rusu, Victor, Eitan Hoch, Josep M. Mercader, Danielle E. Tenen, Melissa Gymrek, Christina R. Hartigan, Michael DeRan, et al. “Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms.Cell 170, no. 1 (June 29, 2017): 199-212.e20. https://doi.org/10.1016/j.cell.2017.06.011.
Rusu V, Hoch E, Mercader JM, Tenen DE, Gymrek M, Hartigan CR, et al. Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms. Cell. 2017 Jun 29;170(1):199-212.e20.
Rusu, Victor, et al. “Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms.Cell, vol. 170, no. 1, June 2017, pp. 199-212.e20. Pubmed, doi:10.1016/j.cell.2017.06.011.
Rusu V, Hoch E, Mercader JM, Tenen DE, Gymrek M, Hartigan CR, DeRan M, von Grotthuss M, Fontanillas P, Spooner A, Guzman G, Deik AA, Pierce KA, Dennis C, Clish CB, Carr SA, Wagner BK, Schenone M, Ng MCY, Chen BH, MEDIA Consortium, SIGMA T2D Consortium, Centeno-Cruz F, Zerrweck C, Orozco L, Altshuler DM, Schreiber SL, Florez JC, Jacobs SBR, Lander ES. Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms. Cell. 2017 Jun 29;170(1):199-212.e20.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

June 29, 2017

Volume

170

Issue

1

Start / End Page

199 / 212.e20

Location

United States

Related Subject Headings

  • Monocarboxylic Acid Transporters
  • Models, Molecular
  • Liver
  • Humans
  • Histone Code
  • Heterozygote
  • Hepatocytes
  • Haplotypes
  • Gene Knockdown Techniques
  • Diabetes Mellitus, Type 2