A basic requirement for all vertebrates is stability of the level of blood glucose. This is essential for brain function. Regardless of large fluctuations in physical activity and food intake, blood sugar levels are held within very narrow limits. The key to this is insulin, the secretion of which is closely regulated by circulating substrates of energy metabolism. Insulin signals food abundance and initiates uptake and storage of carbohydrates, fats and amino acids. Energy supply and stability of blood sugar levels postprandial is usually accorded to glucagon and the catecholamines, but the reduction in insulin signalling postprandial is almost certainly just as important. How does insulin influence our metabolism? What are the key events in its action?
1. A brief summary of effects on key metabolic pathways and enzymes.
Control of the key enzymes of metabolism can be divided into two classes:
1. Covalent modification of enzymes, usually by phosphorylation or dephosphorylation of serine, threonine or tyrosine residues.
2. Allosteric feedback and feed-forward regulation by metabolic intermediates.
Enzymes involved in metabolism can be either activated or inactivated by phosphorylation. Examples or this are glycogen phosphorylase and hormone-sensitive lipase which are activated when phosphorylated and glycogen synthetase and pyruvate dehydrogenase are inactivated through phosphorylation. The protein kinases that catalyze phosphorylation of these enzymes are subject to control through cyclic nucleotides (PKA and cyclic AMP), Ca++ and diacylglycerol (PKC) and PI(3,4,5P)P3 (PKB).
The extent of enzyme phosphorylation is controlled by the balance between protein kinases and protein phosphatases. The picture becomes extremely complex when one knows that protein kinases can activate protein phosphatases. This is clearly the case for the insulin-activation of pyruvate dehydrogenase and, therefore, crucial in insulin's stimulation of hepatic lipid synthesis.
Hormone-sensitive lipase activity in fat cells is regulated largely through cAMP activation of protein kinase A (PKA). The cyclic nucleotide levels is controlled through the balance between hormone-regulated G-protein control of adenylate cyclase and breakdown of cAMP catalyzed by phosphodiesterase. Insulin regulates cAMP levels through its stimulatory effect on the esterase and reduction of cAMP levels.
Insulin and “Opposing” Hormones control Metabolism
Insulin is an anabolic hormone, causing cells to take up energy substrates at times of excess. Insulin action is countered by the catabolic hormones glucagon, adrenalin and noradrenalin, and growth hormone. These act primarily through cyclic AMP (cAMP) and protein kinase A.
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