Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

Abstract

Aims/hypothesis: Glucose and the peptide growth factors insulin, IGF-I and IGF-II strongly regulate beta cell mass. Furthermore, beta cell expression of IGF-I receptor (Igf1r) and insulin receptor (Insr) is mandatory for several steps of insulin secretion. Materials and methods: We hypothesised that glucose concentration might regulate expression of Igf1r, Insr and insulin receptor-related receptor (Insrr) in islets and beta cells. Moreover, since the ratio of ATP:ADP is the most important intracellular mechanism involved in insulin secretion, and since depletion of ATP leads to AMP accumulation, we evaluated the role of AMP-activated protein kinase (AMPK) in glucose-dependent receptor regulation. Results: In rat islets, high glucose exposure (25 mmol/l) increased gene expression of Igf1r, Insr and Insrr but also of the metabolic glycolysis gene liver-type pyruvate kinase (Pklr) compared with intermediate (6.2 mmol/l) or low glucose concentration (1.6 mmol/l) after 24 h. In rat INS-1E beta cells, only Pklr expression was suppressed by low glucose as in islets, while Insr and Insrr were suppressed by high and increased by low glucose levels. Igf1r expression was suppressed by both high-and low-glucose concentration. Activation of AMPK by 5-amino-imidazolecarboxamide riboside (AICAR, 0.5 mmol/l) suppressed Pklr expression, but strongly stimulated gene expression of Igf1r, Insr and Insrr. Protein expression of IR and IGF-IR reflected glucose and AICARregulated mRNA expression of both receptors in INS-1E cells. Conclusions/interpretation: We conclude that glucose directly interacts with islet and beta cell expression of growth factor receptors that are mandatory for both beta cell growth and insulin secretion. Stimulation of Igf1r and Insr gene expression by the AMPK-activator AICAR might indicate involvement of AMPK in the regulation of Igf1r, Insr and Insrr expression in beta cells.

Glycerolipid Metabolism and Signaling in Health and Disease

“…We suggest that glucose and other nutrient stimuli reduce ␤-cell AMPK activity (176), leading to a change in the phosphorylation state of ATGL and/or HSL, or regulatory proteins with subsequent enhanced lipolysis and the activation of the lipid amplification arm of glucose signaling for insulin secretion (12). In accordance with this hypothesis are the following observations: 1) both HSL and ATGL contain AMPK regulatory sites; 2) glucose rapidly reduces islet AMPK activity (177,178); 3) the AMPK activator 5-aminoimidazole carboxamide riboside (AICAR) and a constitutively active AMPK mutant curtail glucose-stimulated insulin secretion in MIN6 ␤-cells (178).…”

Chronic Hexosamine Flux Stimulates Fatty Acid Oxidation by Activating AMP-activated Protein Kinase in Adipocytes

“…Raile et al (39), for example, found inhibition of AMPK activity in INS-1E cells after short term high glucose treatment (10 min), as would be expected from an acute effect mediated by an increase in cellular energy state. However, the same investigators found that this inhibition was lost with prolonged treatment (24 h) with high glucose (39). We have also observed that short term glucose treatment (30 min) inhibits AMPK activity in 3T3L1 adipocytes (data not shown).…”

Mutated ATP synthase induces oxidative stress and impaired insulin secretion in β‐cells of female BHE/cdb rats

“…AMPK-regulated phosphorylation of ACC reduces cytoplasmic malonyl CoA concentrations, disinhibiting carnitine palmitoyl transferase-1 and increasing fatty acid oxidation [37]. AMPK activation has been associated with inhibition of preproinsulin mRNA transcription [38] and induction of β-cell apoptosis [39] and PPAR-α [40], all of which occurred in BHE/cdb β-cells. Therefore, phosphorylation of AMPK may be an important adaptation in the BHE/cdb islets.…”