INSULIN AND GLUCAGON METABOLISMMetabolism is the flow of energy throughout the body.
When we eat food energy is delivered in the form of amino acids, fatty acids and glucose.Glucose is the main and crucial source of energy for our body. Energy is required by our body for normal functioning and maintaining the state of homeostasis in our body. Many tissues and cells can use fats or protein as an energy source but others, such as brain and RBCs can only use glucose as an energy source. Excess glucose in blood is stored in the form of glycogen in liver cells (10% of its mass) and muscle cells (1% of its mass).In case of high glucose diet or under starvation conditions the blood glucose level is maintained to its normal value by the functioning of two endocrine pancreatic enzymes called insulin and glucagon.
Insulin (glucose storage): Insulin is released by ? cells of islets of Langerhans (located in pancreas) usually in response to increase in blood glucose level which then increases the uptake of glucose and glycogen storage in liver and muscles.Glucagon (glucose release):Glucagon is released by ? cells of islets of Langerhans usually in response to low inulin level (indirectly decrease in blood glucose level) which then converts glycogen into glucose by sending signals to liver and muscles.Insulin MetabolismCARBOHYDRATE METABOLISM:Increase in glucose uptake:• Insulin increases glucose uptake from extra cellular fluid into the tissues e.g adipose, mammary glands etc.• In adipose and extrahepatic i.e other than liver tissues insulin causes the rearrangement of glucose transporter from golgi apparatus to plasma membrane where they act as carriers in transfer of D-galactose and glucose across the membrane.
• Also the liver uptake of glucose is increased by insulin as it causes the synthesis of enzymes called glucokinase that phosphorylates glucose resulting in decrease of its intracellular blood concentration. Glucokinase also amplifies more insulin release as blood glucose level rises.Increase in glycolysis:Glycolysis is an irreversible process that converts glucose into ATP which is the most basic form of energy that can be utilized by our body. It occurs in liver, muscles and other tissues.
Insulin enhances glycolysis process by acting as a positive regulator and inducing the synthesis of key enzymes involved in glycolysis process i.e phosphofructokinase (PFK) and pyruvate kinase (PK).Stimulating glycogenesis process:The conversion of glucose into glycogen (glycogenesis) is stimulated by insulin as it directly stimulates protein phosphatase-1 which causes dephosphorylation of key and rate limiting glycogen synthase enzyme, converting it to its active form.Decreasing gluconeogenesis:Insulin decreases gluconeogenesis by:• Repressing the formation of a key enzyme phosphoenolpyruvate carboxykinase (PEPCK) by reducing the rate of the gene transcribing this enzyme.• Allosterically inhibiting another key enzyme of gluconeogenesis i.
e fructose 1,6 bi-phosphate (insulin dephosphorylates fructose 2,6 bi-phosphate converting it ito its inactive form and thus increasing its concentration in the cell wwhich allosterrically inhibits fructose 1,6 bi-phosphate)Decreasing glycogenolysis:Insulin decreases glycogenolysis by:• Dephosphorylating key and rate limiting enzyme glycogen phosphorylase with help of protein phosphatase enzyme hence converting it into its inactive form.• Insulin also represses the expression of glucose 6-phosphatase enzyme.LIPID METABOLISM:Insulin affects lipid metabolism by decreasing free fatty acid (FFA) level and increasing triacylglycerol (TAG) storage by following mechanisms:Decrease in lipolysis:The breakdown of lipids or fatty acids i.e lipolysis in adipose tissue occurs due to insulin and lowers the plasma free fatty acid (FFA) conc. This is done by inactivating a key enzyme of lipolysis i.e triacylglycerol lipase by following mechanism:• Insulin activates phosphoprotein phosphatase which then dephosphorylates and inactivates triacylglycerol.• At the same time, insulin activates phosphodiesterase enzyme which then degrades cyclic AMP, a positive signal for lipolysis, which will result preventing phosphorylation and reactivation of triacylglycerol (TAG) lipase.
Increase in fatty acid synthesis:Insulin decreases fatty acid synthesis by:• Activating pyruvate dehydrogenase complex (PDH) by dephosphorylating it which causes the conversion of pyruvate into acetyl CoA (used in fatty acid synthesis).• Stimulating ATP citrate lyase synthesis which promotes the cleavage of citrate into acetyl CoA in cytosol hence used up by fatty acid synthesis.• Induces acetyl CoA carboxylase synthesis (a key enzyme of FA synthesis) ,by lowering free fatty acid level, and also of fatty acid synthase, another key enzyme of fatty acid synthesis.Increase in synthesis of triacylglycerol:Increase in triacylglcerol synthesis through insulin is done by:• Increase in FA synthesis provides acyl CoA which is needed for triacylglycerol synthesis.• It also causes the production of lipoprotein lipase which then hydrolyzes triacylglycerol present in chylomicrons (circulating) and very low density lipids VLDL resulting in FFA release.
These FFA are then taken up by adipocytes and used for triacylglycerol synthesis• Also as the FFA in plasma are decreased less are oxidized and utilized for cholesterol or ketone bodies.PROTEIN SYNTHESIS:Insulin increases the protein synthesis by following mechanisms:• Increasing the rate of synthesis of amino acids and its membrane transporters.• Enhancing synthesis of mRNA, gene transcription and affecting ribosomal level translation (by increase in synthesis of polyamines, used in ribosomal RNA synthesis, and phosphorylating 6S ribosome of 40S subunit).MINERAL METABOLISM:Insulin decreases potassium and inorganic phosphate level in blood by increasing gluconeogenesis and glycolysis (phosphorylation of glucose).Glucagon MetabolismCARBOHYDRATE METABOLISM:The net effect is increase in blood glucose level by the action of glucagon by following mechanisms:Increase in glycogenolysis:In liver glucagon stimulates the production of glucose 6 phosphatase that in turn dephosphorylates glucose 6 phosphate to glucose during glycogenolysis. This doesnot occur in muscles as the lack glucose 6 phosphatase enzyme.
Increase in gluconeogenesis:In liver formation of glucose (gluconeogenesis) is stimulated by the synthesis of three key enzymes of this process PEP-carboxylase, pyruvate carboxylase and fructose 1,6 bi-phosphate. This is done by increase in hepatic cAMP due to glucagon which activates protein kinase, which then by phosphorylation of histones causes synthesis of these enzymes. Also glucagon increases amino acid concentration by increasing protein degradation, which are then utilized in gluconeogenesis,LIPID METABOLISM:Increase in lipolysis:In liver and adipose tissue glucagon causes TAG degradation resulting in FFA and glycerol production. Then ? oxidation of FA occurs and ketone bodies might be formed in increased degradation (ketosis).
Decrease in fatty acid synthesis:Increase in FFA conc., by lipolysis, cAMP level and protein kinases, by glucagon, inhibits acetyl CoA carboxylase (key enzyme of fatty acid synthesis) due to the action of long chain acyl CoA and phosphorylation by kinases.PROTEIN METABOLISMNet effect is decrease in protein synthesis by preventing addition of amino acids into peptide chains. This is achieved by inactivation of ribosomal subunits, by protein kinases released due to glucagon. Glucagon also increases protein catabolism as illustrated before for gluconeogenesis.MINERAL METABOLISM:Glucagon causes increase in potassium level due to glycogenolysis, and decrease in calcium concentration by stimulating thyroid gland to release calcitonin.
METABOLIC SUMMARYMETABOLIC PROCESES INSULIN GLUCAGONCARBS METABOLISM Glycolysis Glycogenesis METABOLIC PROCESSES INSULIN GLUCAGONGluconeogenesis Glycogenolysis LIPID METABOLISM Lipolysis Fatty Acid synthesis TAG synthesis PROTEIN METABLISM Protein synthesis Ribosomal translation MINERAL METABOLISM K+ level RECENT DICOVERIESNew approach to Diabetes 2 treatement :A pharmacologist at Hoffman La Roche searched 12000 synthetic chemicals and found the one that can be used to stimulate glucokinase activity i.e named RO-28-165. In lab rats use of this compound increased insulin level and consequently decreased in blood glucose level. This approach can be used to treat diabetes 2 disease.