Inherited β-Cell Dysfunction in Lean Individuals With Type 2 Diabetes

  1. Clayton E. Mathews2
  1. 1Department of Food Science and Human Nutrition, University of Florida, Gainesville, Florida
  2. 2Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida
  1. Corresponding author: Clayton E. Mathews, clayton.mathews{at}pathology.ufl.edu.

The syndromes comprising diabetes mellitus share the common feature of β-cell failure. Inheritance of β-cell failure is clear in patients diagnosed with the MODY (maturity-onset diabetes of the young, also referred to as monogenic diabetes in youth) syndromes (1), as well as in permanent neonatal diabetes mellitus (2) where mutations in genes essential for insulin secretion associate with elevated blood glucose. Causative alleles for β-cell dysfunction have been identified for the monogenic forms of diabetes. Likewise, a role for genes impacting glucose-stimulated insulin secretion has been proposed for some polygenic forms of diabetes mellitus. Genome-wide association studies have not associated single nucleotide polymorphisms (SNPs) in genes required for optimal insulin secretion with autoimmune type 1A diabetes. In contrast, latent autoimmune diabetes of adults has been associated with TCF7L2 (3), a gene associated with reduced insulin secretion (4). TCF7L2 is one of the most significant loci for type 2 diabetes (5) and, along with HNF1B/HNF4A (6) and KCNJ11 (7), tie genes involved in β-cell dysfunction to risk for developing type 2 diabetes in overweight individuals. In this issue of Diabetes, a new report (8) proposes that a recently identified type 2 diabetes risk gene is linked to dysfunctional glucose-stimulated insulin secretion (GSIS) in lean Japanese patients with type 2 diabetes.

Lean type 2 diabetes is highly prevalent in Japan …

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