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The Paradoxical Effects of AMPK on Insulin Gene Expression and Glucose‐Induced Insulin Secretion
Author(s) -
Kim JiWon,
You YoungHye,
Ham DongSik,
Yang Hae Kyung,
Yoon KunHo
Publication year - 2016
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25271
Subject(s) - endocrinology , medicine , ampk , insulin , glucokinase , islet , protein kinase a , chemistry , biology , kinase , microbiology and biotechnology
The activation of AMP‐activated protein kinase (AMPK) is known to repress the expression of the insulin gene and glucose‐stimulated insulin secretion (GSIS). However, the mechanisms by which this occurs, as well as the effects of AMPK activation on glucolipotoxicity‐induced β‐cell dysfunction, have not been elucidated. To investigate the effects of 5‐amino‐4‐imidazolecarboxamide ribonucleotide (AICAR) and peroxisome proliferator‐activated receptorγ‐coactivator‐1α (PGC‐1α) on β‐cell‐specific genes under glucolipotoxic conditions, we performed real‐time PCR and measured insulin secretion by primary islets. To study these effects in vivo, we administered AICAR for 10 days (1 mg/g body weight) to 90% pancreatectomized hyperglycemic mice. The exposure of isolated rat and human islets to glucolipotoxic conditions and the overexpression of PGC‐1α suppressed insulin and NEUROD1 mRNA expression. However, the expression of these genes was preserved by AICAR treatment and by PGC‐1α inhibition. Exposure of isolated islets to glucolipotoxic conditions for 3 days decreased GSIS, which was also well maintained by AICAR treatment and by PGC‐1α inhibition. The administration of AICAR to 90% pancreatectomized hyperglycemic mice improved glucose tolerance and insulin secretion. These results indicate that treatment of islets with an AMPK agonist under glucolipotoxic conditions protects against glucolipotoxicity‐induced β‐cell dysfunction. A better understanding of the functions of molecules such as PGC‐1α and AMPK, which play key roles in intracellular fuel regulation, could herald a new era for the treatment of patients with type 2 diabetes mellitus by providing protection against glucolipotoxicity. J. Cell. Biochem. 117: 239–246, 2016. © 2015 Wiley Periodicals, Inc.