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Amylin activates glycogen phosphorylase and inactivates glycogen synthase via a cAMP-independent mechanism
R O Deems1, R W Deacon, D A Young
1Sandoz Research Institute, East Hanover, NJ 07936.
Abstract:
Although the novel pancreatic peptide amylin has been shown to induce insulin resistance and decrease glucose uptake, the mechanism of amylin's actions is unknown. The following study evaluated the effect of amylin on glycogen metabolism in isolated soleus muscles in the presence and absence of insulin (200 microU/ml). Total glycogen, glycogen phosphorylase and glycogen synthases activities, and cAMP levels were measured. Total glycogen levels were significantly decreased by amylin (100 nM) in fed or fasted muscles under conditions of insulin stimulation. Amylin (100 nM) activated glycogen phosphorylase by as much as 100% and decreased glycogen synthase activity by over 60%, depending on the metabolic state of the muscles. These effects where comparable to those of the beta adrenergic agonist isoproterenol. A lower concentration of amylin (1 nM) did not significantly affect glycogen levels, glycogen phosphorylase, or glycogen synthase activity. Cyclic AMP levels were increased two-fold by isoproterenol but were unaffected by amylin. In conclusion, amylin induces glycogenolysis by decreasing glycogen synthesis and increasing breakdown. The effect of amylin on enzyme activity is consistent with a phosphorylation-dependent mechanism. It is likely that these events are mediated via a cAMP independent protein kinase.
Insights
Amylin, a pancreatic peptide, disrupts glucose metabolism by activating glycogen breakdown and inhibiting glycogen synthesis in muscles. This mechanism, independent of cyclic AMP, contributes to insulin resistance.
Area of Science:
- Endocrinology
- Molecular Metabolism
- Muscle Physiology
Background:
- Amylin is a novel pancreatic peptide linked to insulin resistance and reduced glucose uptake.
- The precise molecular mechanisms underlying amylin's metabolic effects remain largely unknown.
Purpose of the Study:
- To investigate the impact of amylin on glycogen metabolism in isolated soleus muscles.
- To elucidate the role of amylin in regulating glycogen synthesis and breakdown pathways.
Main Methods:
- Isolated soleus muscles were incubated with varying concentrations of amylin (1 nM and 100 nM) with or without insulin (200 microU/ml).
- Measurements included total glycogen content, glycogen phosphorylase and glycogen synthase activities, and cyclic AMP (cAMP) levels.
- Enzyme activities and metabolite levels were compared to those affected by the beta-adrenergic agonist isoproterenol.
Main Results:
- Amylin (100 nM) significantly decreased total glycogen levels in muscles, irrespective of feeding status, particularly under insulin stimulation.
- High-dose amylin activated glycogen phosphorylase (up to 100%) and inhibited glycogen synthase (over 60%), mimicking isoproterenol's effects.
- Low-dose amylin (1 nM) showed no significant impact on glycogen metabolism or enzyme activities.
- Isoproterenol increased cAMP levels twofold, while amylin did not affect cAMP concentrations.
Conclusions:
- Amylin promotes glycogenolysis (glycogen breakdown) by simultaneously inhibiting glycogen synthesis and enhancing glycogen breakdown.
- The observed enzyme activity changes suggest a phosphorylation-dependent mechanism.
- Amylin's metabolic effects appear to be mediated through a cyclic AMP-independent protein kinase pathway.