Amylin influences insulin-stimulated glucose metabolism by two independent mechanisms

Castle, Arthur L.; Kuo, Chia‐Hua; Ivy, John L.

doi:10.1152/ajpendo.1998.274.1.e6

Cited by 12 publications

(12 citation statements)

References 32 publications

(81 reference statements)

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“…AMY is co‐localised and co‐released with insulin in the β pancreatic cells (Pittner et al ., 1994) and is generally considered to be a glyco‐regulatory peptide that inhibits the actions of insulin (Deems et al ., 1991; Castle et al ., 1998). But we have previously shown that AMY also induced a weak vasorelaxant effect probably via the CGRP 1 receptor in both the human and the porcine coronary circulation (Hasbak et al ., 2001, 2003).…”

Section: Introductionmentioning

confidence: 99%

Increased αCGRP potency and CGRP‐receptor antagonist affinity in isolated hypoxic porcine intramyocardial arteries

Hasbak

Eskesen

Schifter

et al. 2005

British J Pharmacology

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1 This study describes the effects of hypoxia on relaxing responses and cAMP production induced by the known vasodilator peptides: aCGRP, amylin (AMY) and adrenomedullin (AM) on isolated pig coronary arteries in vitro. 2 Hypoxic incubation increased the vasorelaxant effect of aCGRP (four-fold; Po0.05), AMY (3.2-fold; Po0.05), but not significantly for AM (two-fold; NS). 3 Whereas hypoxia had no effect on arterial cAMP levels, it significantly potentiated the production of cAMP stimulated of aCGRP and AMY, but not of AM. 4 The antagonist aCGRP 8-37 also exerted an increased effect in hypoxia. The Schild plot-derived pK B values revealed an increase in the apparent affinity of the antagonist for the CGRP 1 receptor from 7.0 to 7.2 under control conditions versus 8.0 in hypoxia. 5 Removal of endothelium, peptidase inhibitors, preincubation with the adenosine A 2A receptor antagonist CSC (10 À3 M), the ATP-sensitive K-channel inhibitor glibenclamide (10 À5 M), the cyclooxygenase inhibitor indomethacin (10 À3 M) or NG-monomethyl-L-arginine (10 À4 M) had no effect on the aCGRP-induced vasorelaxation in hypoxia; neither did hypoxia influence the levels of CGRP and AM receptor mRNA. 6 We conclude that hypoxic incubation increases the relaxation and cAMP production induced by aCGRP and AMY in rings of porcine coronary arteries in vitro. A concomitant release of adenosine, a cyclooxygenase product, an endothelium-derived substance, activation of vascular ATP-sensitive Kchannels, peptidase inhibitors or changes in CGRP and AM receptor mRNA cannot account for the changes observed in hypoxia. Moreover, aCGRP showed increased affinity at the CGRP 1 receptor during hypoxia, possibly due to a conformational change at the CGRP 1 receptor site.

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Section: Introductionmentioning

confidence: 99%

Increased αCGRP potency and CGRP‐receptor antagonist affinity in isolated hypoxic porcine intramyocardial arteries

Hasbak

Eskesen

Schifter

et al. 2005

British J Pharmacology

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“…Thus far, any involvement of amylin in insulin resistance has been attributed to its effects on glucose metabolism (5,21,25,28). However, recent experiments in our laboratory demonstrated that amylin-(8-37), a truncated form of rat amylin, lowered plasma nonesterified fatty acid (NEFA) and glycerol in normal rats.…”

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confidence: 99%

Evidence that amylin stimulates lipolysis in vivo: a possible mediator of induced insulin resistance

Lim-Fraser

Cooney

et al. 2001

American Journal of Physiology-Endocrinology and Metabolism

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The present study investigated the role of amylin in lipid metabolism and its possible implications for insulin resistance. In 5- to 7-h-fasted conscious rats, infusion of rat amylin (5 nmol/h for 4 h) elevated plasma glucose, lactate, and insulin (P <0.05 vs. control, repeated-measures ANOVA) with peak values occurring within 60 min. Despite the insulin rise, plasma nonesterified fatty acids (NEFA) and glycerol were also elevated (P < 0.001 vs. control), and these elevations (80% above basal) were sustained over the 4-h infusion period. Although unaltered in plasma, triglyceride content in liver was increased by 28% (P < 0.001) with a similar tendency in muscle (18%, P = 0.1). Infusion of the rat amylin antagonist amylin-(8-37) (125 nmol/h) induced opposite basal plasma changes to amylin, i.e., lowered plasma NEFA, glycerol, glucose, and insulin levels (all P < 0.05 vs. control); additionally, amylin-(8-37) blocked amylin-induced elevations of these parameters (P < 0.01). Treatment with acipimox (10 mg/kg), an anti-lipolytic agent, before or after amylin infusion blocked amylin's effects on plasma NEFA, glycerol, and insulin but not on glucose and lactate. We conclude that amylin could exert a lipolytic-like action in vivo that is blocked by and is opposite to effects of its antagonist amylin-(8-37). Further studies are warranted to examine the physiological implications of lipid mobilization for amylin-induced insulin resistance.

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“…For example, amylin, a hormone co-secreted with insulin from pancreatic islet ␤-cells, has been shown to antagonize insulin's metabolic actions both in vivo and in vitro (12)(13)(14)(15)(16). It can inhibit insulin-stimulated glucose uptake and glycogen synthesis.…”

Section: 3mentioning

confidence: 99%

Alteration in Phosphorylation of P20 Is Associated With Insulin Resistance

Wang

et al. 2001

Diabetes

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We have recently identified a small phosphoprotein, P20, as a common intracellular target for insulin and several of its antagonists, including amylin, epinephrine, and calcitonin gene-related peptide. These hormones elicit phosphorylation of P20 at its different sites, producing three phosphorylated isoforms: S1 with an isoelectric point (pI) value of 6.0, S2 with a pI value of 5.9, and S3 with a pI value of 5.6 (FEBS Letters 457:149 -152 and 462:25-30, 1999). In the current study, we showed that P20 is one of the most abundant phosphoproteins in rat extensor digitorum longus (EDL) muscle. Insulin and amylin antagonize each other's actions in the phosphorylation of this protein in rat EDL muscle. Insulin inhibits amylinevoked phosphorylation of S2 and S3, whereas amylin decreases insulin-induced phosphorylation of S1. In rats made insulin resistant by dexamethasone treatment, levels of the phosphoisoforms S2 and S3, which were barely detectable in healthy rats in the absence of hormone stimulation, were significantly increased. Moreover, the ability of insulin to inhibit amylin-evoked phosphorylation of these two isoforms was greatly attenuated. These results suggested that alterations in the phosphorylation of P20 might be associated with insulin resistance and that P20 could serve as a useful marker to dissect the cellular mechanisms of this disease.

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Amylin influences insulin-stimulated glucose metabolism by two independent mechanisms

Cited by 12 publications

References 32 publications

Increased αCGRP potency and CGRP‐receptor antagonist affinity in isolated hypoxic porcine intramyocardial arteries

Increased αCGRP potency and CGRP‐receptor antagonist affinity in isolated hypoxic porcine intramyocardial arteries

Evidence that amylin stimulates lipolysis in vivo: a possible mediator of induced insulin resistance

Alteration in Phosphorylation of P20 Is Associated With Insulin Resistance

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