Reduced insulin exocytosis in human pancreatic β-cells with gene variants linked to type 2 diabetes

Diabetes. 2012 Jul;61(7):1726-33. doi: 10.2337/db11-1516. Epub 2012 Apr 9.

Abstract

The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features in relation to genetic risk profiles in diabetic and nondiabetic donors. Islets from donors with T2D exhibited impaired insulin secretion, which was more pronounced in lean than obese diabetic donors. We assessed the impact of 14 disease susceptibility variants on measures of glucose sensing, exocytosis, and structure. Variants near TCF7L2 and ADRA2A were associated with reduced glucose-induced insulin secretion, whereas susceptibility variants near ADRA2A, KCNJ11, KCNQ1, and TCF7L2 were associated with reduced depolarization-evoked insulin exocytosis. KCNQ1, ADRA2A, KCNJ11, HHEX/IDE, and SLC2A2 variants affected granule docking. We combined our results to create a novel genetic risk score for β-cell dysfunction that includes aberrant granule docking, decreased Ca(2+) sensitivity of exocytosis, and reduced insulin release. Individuals with a high risk score displayed an impaired response to intravenous glucose and deteriorating insulin secretion over time. Our results underscore the importance of defects in β-cell exocytosis in T2D and demonstrate the potential of cellular phenotypic characterization in the elucidation of complex genetic disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Exocytosis / genetics*
  • Genetic Predisposition to Disease / genetics
  • Genetic Variation*
  • Glucose Transporter Type 2 / genetics
  • Glucose Transporter Type 2 / physiology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / physiology
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / physiology
  • Insulin-Secreting Cells / ultrastructure
  • KCNQ1 Potassium Channel / genetics
  • KCNQ1 Potassium Channel / physiology
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / physiology
  • Receptors, Adrenergic, alpha-2 / genetics
  • Receptors, Adrenergic, alpha-2 / physiology
  • Transcription Factor 7-Like 2 Protein / genetics
  • Transcription Factor 7-Like 2 Protein / physiology
  • Transcription Factors / genetics
  • Transcription Factors / physiology

Substances

  • ADRA2A protein, human
  • Glucose Transporter Type 2
  • HHEX protein, human
  • Homeodomain Proteins
  • Insulin
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Kir6.2 channel
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Adrenergic, alpha-2
  • SLC2A2 protein, human
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors