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

Abstract

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.

Prdm16 is crucial for progression of the multipolar phase during neural differentiation of the developing neocortex

“…A recent study suggested that Sirt1 deacetylates PPARγ during energy deprivation and deacetylated PPARγ then interacts with Prdm16 to alter the balance from energy storage to energy expenditure (Qiang et al, 2012). Moreover, overexpression of PGC1α suppresses NeuroD1 mRNA expression in isolated rat and human islets (Kim et al, 2016). Similarly, we found that deletion of IRE abolished the regulation of PGC1α by Prdm16, suggesting that Prdm16 directly binds the PGC1α promoter region.…”

Prior Exercise Training Prevent Hyperglycemia in STZ Mice by Increasing Hepatic Glycogen and Mitochondrial Function on Skeletal Muscle

“…Moreover, previous exercise training was already showed to prevent the renal and cardiac damage in a model of DM [Silva et al, ]. Our exercise protocol increased the O 2 consumption induced by succinate and ADP by the skeletal muscle of Ex STZ relative to Sed STZ mice probably associated with increase on mitochondrial biogenesis as showed by increased on PGC‐1 α levels [Kim et al, ]. Moreover, the H 2 O 2 production induced by succinate was higher in Ex STZ mice.…”

Antidiabetic Potential of Monoterpenes: A Case of Small Molecules Punching above Their Weight

“…Interestingly, the activation of AMPK in adipocytes has been shown to suppress lipogenesis while promoting energy dissipation suggesting potential antiobesity effect [ 118 ]. Even though some studies still show the paradoxical nature of the AMPK activation in glucose and lipid metabolism, mostly related to the level of stimulation (chronic verses acute) (e.g., [ 119 , 120 ]), the role of AMPK activators in various disease condition have been well documented [ 121 ]. In a recent review [ 122 ], the antidiabetic potential of natural products such as anthocyanins through effect on the AMPK and insulin-signaling pathways have been highlighted.…”