Sweet Killing in Obesity and Diabetes: The Metabolic Role of the BH3-only Protein BIM

J Mol Biol. 2018 Sep 14;430(18 Pt B):3041-3050. doi: 10.1016/j.jmb.2018.07.022. Epub 2018 Jul 21.

Abstract

Diabetes is a metabolic disorder affecting more than 400 million individuals and their families worldwide. The major forms of diabetes (types 1 and 2) are characterized by pancreatic β-cell dysfunction and, in some cases, loss of β-cell mass causing hyperglycemia due to absolute or relative insulin deficiency. The BCL-2 homology 3 (BH3)-only protein BIM has a wide role in apoptosis induction in cells. In this review, we describe the apoptotic mechanisms mediated by BIM activation in β cells in obesity and both forms of diabetes. We focus on molecular pathways triggered by inflammation, saturated fats, and high levels of glucose. Besides its role in cell death, BIM has been implicated in the regulation of mitochondrial oxidative phosphorylation and cellular metabolism in hepatocytes. BIM is both a key mediator of pancreatic β-cell death and hepatic insulin resistance and is thus a potential therapeutic target for novel anti-diabetogenic drugs. We consider the implications and challenges of targeting BIM in the treatment of the disease.

Keywords: BH3-only proteins; BIM; apoptosis; type 1 diabetes; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Apoptosis
  • Autoimmunity
  • Bcl-2-Like Protein 11 / antagonists & inhibitors
  • Bcl-2-Like Protein 11 / chemistry
  • Bcl-2-Like Protein 11 / metabolism*
  • Diabetes Mellitus / diagnosis
  • Diabetes Mellitus / drug therapy
  • Diabetes Mellitus / etiology*
  • Diabetes Mellitus / metabolism*
  • Hepatocytes / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance
  • Insulin-Secreting Cells / immunology
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Mitochondria / metabolism
  • Molecular Targeted Therapy
  • Obesity / drug therapy
  • Obesity / etiology*
  • Obesity / metabolism*
  • Peptide Fragments* / chemistry
  • Protein Interaction Domains and Motifs*
  • Proto-Oncogene Proteins* / chemistry
  • Signal Transduction

Substances

  • Bax protein (53-86)
  • Bcl-2-Like Protein 11
  • Insulin
  • Peptide Fragments
  • Proto-Oncogene Proteins