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The Paradoxical Effects of AMPK on Insulin Gene Expression and Glucose-Induced Insulin Secretion

Ji-Won Kim1, Young-Hye You1, Dong-Sik Ham1

  • 1Department of Endocrinology & Metabolism, The Catholic University of Korea, Seoul, 137-040, Korea.

Journal of Cellular Biochemistry
|June 25, 2015
PubMed

Insights

AMP-activated protein kinase (AMPK) activation protects against glucolipotoxicity-induced pancreatic beta-cell dysfunction. This study shows that AMPK activation preserves insulin gene expression and glucose-stimulated insulin secretion (GSIS) under harmful conditions.

Area of Science:

  • Metabolic regulation
  • Cellular dysfunction
  • Diabetes research

Background:

  • AMP-activated protein kinase (AMPK) activation is known to inhibit insulin gene expression and glucose-stimulated insulin secretion (GSIS).
  • Mechanisms underlying AMPK's effects on beta-cell function and its role in glucolipotoxicity remain unclear.
  • Glucolipotoxicity contributes to beta-cell dysfunction, a hallmark of type 2 diabetes mellitus.

Purpose of the Study:

  • To investigate the impact of 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR), an AMPK activator, and peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) on beta-cell-specific genes under glucolipotoxic conditions.
  • To evaluate the protective effects of AICAR against glucolipotoxicity-induced beta-cell dysfunction in vitro and in vivo.
  • To explore the role of PGC-1α in mediating these effects.

Main Methods:

  • Real-time PCR was used to measure mRNA expression of insulin and NEUROD1 in isolated rat and human islets.
  • Insulin secretion was assessed in response to glucose stimulation.
  • AICAR was administered to hyperglycemic mice with 90% pancreatectomy to assess in vivo effects on glucose tolerance and insulin secretion.

Main Results:

  • Glucolipotoxicity and PGC-1α overexpression suppressed insulin and NEUROD1 mRNA expression in isolated islets.
  • AICAR treatment and PGC-1α inhibition preserved insulin and NEUROD1 mRNA expression under glucolipotoxic conditions.
  • AICAR treatment and PGC-1α inhibition maintained GSIS in islets exposed to glucolipotoxicity.
  • In vivo, AICAR administration improved glucose tolerance and insulin secretion in hyperglycemic mice.

Conclusions:

  • AMPK activation, via AICAR treatment, protects pancreatic beta-cells against glucolipotoxicity-induced dysfunction.
  • AMPK activation preserves key beta-cell genes and insulin secretion under detrimental metabolic conditions.
  • Targeting AMPK and PGC-1α may offer novel therapeutic strategies for type 2 diabetes by mitigating glucolipotoxicity.
Keywords:
AICARAMPKGLUCOLIPOTOXICITYPGC-1αTYPE 2 DIABETES MELLITUS

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