Untangling the interplay of genetic and metabolic influences on beta-cell function: Examples of potential therapeutic implications involving TCF7L2 and FFAR1

Robert Wagner; Harald Staiger; Susanne Ullrich; Norbert Stefan; Andreas Fritsche; Hans-Ulrich Häring

doi:10.1016/j.molmet.2014.01.001

Untangling the interplay of genetic and metabolic influences on beta-cell function: Examples of potential therapeutic implications involving TCF7L2 and FFAR1

Mol Metab. 2014 Jan 22;3(3):261-7. doi: 10.1016/j.molmet.2014.01.001. eCollection 2014 Jun.

Authors

Robert Wagner¹, Harald Staiger², Susanne Ullrich², Norbert Stefan², Andreas Fritsche², Hans-Ulrich Häring²

Affiliations

¹ Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of the Eberhard Karls University, Tübingen, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.
² Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of the Eberhard Karls University, Tübingen, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.

Abstract

Deteriorating beta-cell function is a common feature of type 2 diabetes. In this review, we briefly address the regulation of beta-cell function, and discuss some of the main determinants of beta-cell failure. We will focus on the role of interactions between the genetic background and metabolic environment (insulin resistance, fuel supply and flux as well as metabolic signaling). We present data on the function of the strongest common diabetes risk variant, the single nucleotide polymorphism (SNP) rs7903146 in TCF7L2. As also mirrored by its interaction with glycemia on insulin secretion, this SNP in large part confers resistance against the incretin effect. Genetic influence on insulin secretion also interacts with free fatty acids, as evidenced by data on rs1573611 in FFAR1. Several medications marketed by now or currently under development for diabetes treatment engage these pathways, and therapeutic implications from these findings are soon to be expected.

Keywords: Beta-cell failure; Beta-cell function; FFAR1; Gene×environment interaction; Incretin resistance; Pharmacogenetics; TCF7L2.

Publication types

Review