Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression

Abstract

AMP-activated protein kinase (AMPK) has recently been implicated in the control of preproinsulin gene expression in pancreatic islet β-cells [da Silva Xavier, Leclerc, Salt, Doiron, Hardie, Kahn and Rutter (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 4023–4028]. Using pharmacological and molecular strategies to regulate AMPK activity in rat islets and clonal MIN6 β-cells, we show here that the effects of AMPK are exerted largely upstream of insulin release. Thus forced increases in AMPK activity achieved pharmacologically with 5-amino-4-imidazolecarboxamide riboside (AICAR), or by adenoviral overexpression of a truncated, constitutively active form of the enzyme (AMPKα1.T172D), blocked glucose-stimulated insulin secretion. In MIN6 cells, activation of AMPK suppressed glucose metabolism, as assessed by changes in total, cytosolic or mitochondrial [ATP] and NAD(P)H, and reduced increases in intracellular [Ca2+] caused by either glucose or tolbutamide. By contrast, inactivation of AMPK by expression of a dominant-negative form of the enzyme mutated in the catalytic site (AMPKα1.D157A) did not affect glucose-stimulated increases in [ATP], NAD(P)H or intracellular [Ca2+], but led to the unregulated release of insulin. These results indicate that inhibition of AMPK by glucose is essential for the activation of insulin secretion by the sugar, and may contribute to the transcriptional stimulation of the preproinsulin gene. Modulation of AMPK activity in the β-cell may thus represent a novel therapeutic strategy for the treatment of type 2 diabetes mellitus.

Adiponectin induces insulin secretion in vitro and in vivo at a low glucose concentration

“…However, AICAR significantly decreased insulin secretion from mouse pancreatic islets (p=0.024; Fig. 3c) [28]. These results suggest that AMPK is not involved in adiponectinstimulated insulin secretion at low glucose concentrations.…”

“…However, adiponectin did not affect the phosphorylation of AMPK in pancreatic islets at 5.6 mmol/ l glucose. Since AMPK in pancreatic beta cells is activated by low glucose concentrations [28], adiponectin may be unable to further activate AMPK at this low glucose concentration. By contrast, although the AMPK activator AICAR activated AMPK at this low glucose concentration, AICAR also decreased insulin secretion under these conditions.…”

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

“…For example, an attempt should be made to replicate our results using islets from AMPK −/− mice to verify the role of this important molecule in physiological and pharmacological stimulation of insulin secretion. Previous reports have shown different relationships between the activation of AMPK and glucosestimulated insulin secretion [16][17][18][43][44][45]. However, these differences may be explained in large part by the different glucose concentrations and experimental systems employed in the different studies.…”

“…However, these differences may be explained in large part by the different glucose concentrations and experimental systems employed in the different studies. Forced increases in AMPK activity by AICAR treatment or by adenoviral overexpression of a truncated, constitutively active form of the enzyme (AMPKα1.T 172 D) have been shown to block glucose-stimulated insulin secretion in MIN6 cells and isolated rat islets [44] and lead to apoptosis of beta cells [46]. By contrast, inactivation of AMPK by expression of a dominant-negative form of the enzyme (AMPKα1.D 157 A) increases insulin secretion at a low glucose concentration (3 mmol/l) but not at a high glucose concentration [44].…”

Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

“…GLUT2 and glucokinase, and fluctuations in glucose within the normal physiological range alter the rate of glucose metabolism and consequently modulate the AMPK activity. In these cells, the activation of AMPK appears to play important roles in the physiological responses to hypoglycaemia, such as reduced secretion of insulin and increased secretion of glucagon and adrenaline by the pancreas and adrenal medulla (17)(18)(19)(20) . Deprivation of oxygen (hypoxia) is another stress that can limit catabolism, thus causing increases in AMP: ATP and AMPK activation.…”