Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice

Cell Metab. 2014 Oct 7;20(4):593-602. doi: 10.1016/j.cmet.2014.08.012. Epub 2014 Sep 25.

Abstract

Pancreatic β cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of β cell mass. It's unclear how one begets the other. We have shown that loss of β cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature β cells results in early-onset, maturity-onset diabetes of the young (MODY)-like diabetes, with abnormalities of the MODY networks Hnf4α, Hnf1α, and Pdx1. FoxO-deficient β cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as an energy source. This results in impaired ATP generation and reduced Ca(2+)-dependent insulin secretion. The present findings demonstrate a secretory defect caused by impaired FoxO activity that antedates dedifferentiation. We propose that defects in both pancreatic β cell function and mass arise through FoxO-dependent mechanisms during diabetes progression.

Publication types

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

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Calcium / metabolism
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism
  • Cell Cycle Proteins
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology*
  • Disease Models, Animal
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / deficiency
  • Forkhead Transcription Factors / genetics*
  • Gene Expression Profiling
  • Glucose Tolerance Test
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Homeodomain Proteins / metabolism
  • Insulin / metabolism*
  • Insulin-Secreting Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Trans-Activators / metabolism

Substances

  • Blood Glucose
  • Calcium Channels, L-Type
  • Cell Cycle Proteins
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • FoxO4 protein, mouse
  • Foxo1 protein, mouse
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 4
  • Hnf1a protein, mouse
  • Hnf4a protein, mouse
  • Homeodomain Proteins
  • Insulin
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Calcium

Supplementary concepts

  • Mason-Type Diabetes

Associated data

  • GEO/GSE60505