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Glycogen phosphorylase, glucose output and vasoconstriction in the perfused rat liver. Concentration-dependence of actions of adrenaline, vasopressin and angiotensin II.

ABSTRACT: 1. Glycogen phosphorylase (a form, in rapidly freeze-clamped samples) and glucose release were measured in the perfused liver, in response to a range of concentrations of adrenaline, [8-arginine]vasopressin (anti-diuretic hormone) and angiotensin II. 2. All three hormones increased phosphorylase a activity by about 10 mumol/min per g of fresh liver, which was more than sufficient to explain concomitant glucose release (1-2mumol/min per g). 3. Minimally effective concentrations which activated phosphorylase were: adrenaline, 10nM (2ng/ml); vasopressin, 40pM (40pg/ml, 15 muunits/ml); angiotensin II, 60pM (60pg/ml). 4. Glycogen synthase activity was inhibited by adrenaline and vasopressin but not significantly by angiotensin II. 5. Vasoconstriction observed with adrenaline and angiotensin II (but not vasopressin) might explain part of the activation of phosphorylase, since equivalent vasoconstriction (in separate perfusions) activated phosphorylase, did not stimulate glucose output or inhibit synthase. 6. The potency of these effects suggests that all three hormones can stimulate hepatic glycogen degradation in vivo (by direct hepatic action). It is proposed that hormones, and ischaemia, stimulate glycogen degradation to provide glucose phosphates for disposal within the liver cell, as well as for release as free gluose.

SUBMITTER: Hems DA

PROVIDER: S-EPMC1164243 | biostudies-other | 1976 Nov

REPOSITORIES: biostudies-other

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Project description:Background and purposeGlycogen phosphorylase (GP) is the key enzyme for glycogen degradation. GP inhibitors (GPi-s) are glucose lowering agents that cause the accumulation of glucose in the liver as glycogen. Glycogen metabolism has implications in beta cell function. Glycogen degradation can maintain cellular glucose levels, which feeds into catabolism to maintain insulin secretion, and elevated glycogen degradation levels contribute to glucotoxicity. The purpose of this study was to assess whether influencing glycogen metabolism in beta cells by GPi-s affects the function of these cells.Experimental approachThe effects of structurally different GPi-s were investigated on MIN6 insulinoma cells and in a mouse model of diabetes.Key resultsGPi treatment increased glycogen content and, consequently, the surface area of glycogen in MIN6 cells. Furthermore, GPi treatment induced insulin receptor β (InsRβ), Akt and p70S6K phosphorylation, as well as pancreatic and duodenal homeobox 1(PDX1) and insulin expression. In line with these findings, GPi-s enhanced non-stimulated and glucose-stimulated insulin secretion in MIN6 cells. The InsRβ was shown to co-localize with glycogen particles as confirmed by in silico screening, where components of InsR signalling were identified as glycogen-bound proteins. GPi-s also activated the pathway of insulin secretion, indicated by enhanced glycolysis, mitochondrial oxidation and calcium signalling. Finally, GPi-s increased the size of islets of Langerhans and improved glucose-induced insulin release in mice.Conclusion and implicationsThese data suggest that GPi-s also target beta cells and can be repurposed as agents to preserve beta cell function or even ameliorate beta cell dysfunction in different forms of diabetes.Linked articlesThis article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.

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Glycogen phosphorylase, glucose output and vasoconstriction in the perfused rat liver. Concentration-dependence of actions of adrenaline, vasopressin and angiotensin II.

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