Regulation of Glucose metabolism Mahmoud A. Alfaqih BDS PhD Jordan University of Science and Technology Lippincott’s illustrated reviews: Biochemistry (latest edition)

Regulation of glucose metabolism is primarily mediated by the action of insulin and glucagon. Catecholeamines (Epinephrine and Nor-epinephrine play a supporting role) Herein we will discuss; structure, function, regulation and mechanism of action of Insulin and Glucagon

Insulin A polypeptide hormone Produced by β cells of islets of langerhans Islets of langerhans make only (1 to 2%) of the total cells of the pancreas Anabolic hormone that favors synthesis of Glycogen, triglycerides and protein

Structure of Insulin 51 amino acids arranged in two polypeptide chains (A and B) Two disulfide bridges between A and B, and intra-molecular disulfide bridge in chain A

Structure of Insulin

Synthesis and Secretion of Insulin Insulin is first made as a precursor chain called preproinsulin (in the cytoplasm) (inactive). N-terminal signal sequence (AKA leader sequence) is cleaved from preproinsulin during transport to endoplasmic reticulum The resulting chain (called proinsulin) is transported to Golgi complex Inside Golgi complex proinsulin is cleaved into mature insulin and C-peptide

Both insulin and C peptide are stored in secretory granules and are released together by exocytosis

Synthesis and secretion on insulin

Regulation of insulin secretion Tightly coordinated with the release of Glucagon Secretion is stimulated by:  Glucose (most important stimulus)  Amino acids (particularly Arginine)  Gastrointestinal hormones (Example: Secretin)

Regulation of insulin secretion Inhibition of insulin secretion  Scarce dietary fuel  Stress (fever or infection) These effects are mediated by epinephrine (from adrenal medulla) stimulated by nervous system Epinephrine causes rapid mobilization of glucose (from liver) and fatty acids (from adipose tissue) Nervous system overrides plasma glucose as primary regulator of insulin secretion

Regulation of insulin secretion

Metabolic effects of insulin 1.Effect on carbohydrate metabolism: Liver  Inhibits breakdown of glycogen (Glycogenolysis) and synthesis of glucose (Gluconeogenesis)  Stimulates synthesis of glycogen Adipose tissue  Increases glucose uptake

Metabolic effects of insulin 1.Effect on carbohydrate metabolism: Muscle  Activates glycogen synthesis  Enhance glucose uptake

Metabolic effects of insulin 2. Effect on lipid metabolism: Affects adipose tissue and causes a reduction in plasma fatty acids  A decrease in triglyceride degradation (inhibits hormone sensitive lipase)  An increase in triglyceride synthesis by:  Increased glucose uptake which is converted into glycerol 3 phosphate  Activation of lipoprotein lipase which provides fatty acids for esterification

Metabolic effects of insulin 3. Effect on protein metabolism:  Increases protein synthesis by increasing entry of amino acids

Mechanism of insulin action Insulin binds to specific high affinity cell membrane receptors Receptors are located on the cell membranes of liver, muscle and adipose

Structure of Insulin receptor Synthesized as a single polypeptide that is glycosylated and cleaved into two subunits The two subunits termed (α and β) are assembled as a tetramer. There is a disulfide bridge that connects α subunits together. A disulfide bridge connects α with β subunit β subunit spans plasma membrane. α subunit is extra-cellular, contains insulin binding site.

Signal transduction of insulin receptor signaling Binding of insulin to α subunits induces a conformational change Conformational change is transduced to β subunit This allows for auto-phosphorylation of specific tyrosine residues on β subunit Auto-phosphorylation induces phosphorylation of a group of proteins called Insulin Receptor Substartes (IRS) Phosphorylated IRS activate multiple biological pathways

Tissue specific requirement of insulin for glucose transport Insulin promotes the recruitment of insulin sensitive glucose transporters GLUT-4

Time course of insulin action Immediate Increase in glucose uptake by adipose tissue and skeletal muscles Minutes to hours Hours to days Changes in enzymatic activity Changes in phosphorylation state An increase in the amount of many enzymes (Glucokinase, pyruvate kinase, Phosphofructokinase)

Glucagon Glucagon is a polypeptide hormone secreted by α cells of pancreatic islets of Langerhans Glucagon maintains blood glucose levels by:  Activation of hepatic glycogenolysis.  Activation of gluconeogenesis. Glucagon is made of 29 amino acids arranged in a single polypeptide chain

Counter-regulatory hormones Glucagon, epinephrine, cortisol, and growth hormone oppose the actions of insulin

Regulation of Glucagon secretion Stimulation of glucagon secretion:  Low blood glucose (Primary stimulus to prevent hypoglycemia)  Amino acids  Epinephrine from adrenal medulla  Norepinephrine from sympathetic innervation N.B: During periods of stress and trauma, glucagon levels increase regardless of blood glucose levels

Regulation of glucagon secretion Inhibition of glucagon secretion:  Elevated blood glucose  Insulin

Metabolic effects of Glucagon Effects on carbohydrate metabolism:  Increase in breakdown of liver glycogen  Increase in gluconeogenesis Effects on lipid metabolim:  Hepatic oxidation of fatty acids and subsequent formation of ketone bodies from acetyl CoA  Effect on adipose tissue is minimal in humans

Metabolic effects of Glucagon Effects on protein metabolism:  Increase in uptake of amino acids by liver.  Increase in availability of carbon skeletons for gluconeogenesis.

Mechanism of action of Glucagon Glucagon binds to high affinity hepatic glucagon receptors. Binding of glucagon leads to activation of Adenylate cyclase Adenylate cyclase converts ATP to cAMP (second messenger) cAMP activates cAMP dependent protein kinase This results in phosphorylation dependent activation or inhibition of key enzymes

Metabolic changes during fasting Mahmoud A. Alfaqih BDS PhD Jordan University of Science and Technology

Fasting Overview Result from an inability to obtain food, the desire to lose weight, or in clinical situations (trauma, surgery, neoplasms, or burns) Plasma levels of glucose, amino acids, and TAG fall A decline in insulin secretion and an increase in glucagon release Catabolic period characterized by degradation of TAG, glycogen, and protein

Fasting Overview Metabolic changes that take place are guided by: 1.The need to maintain plasma levels of glucose to sustain the brain, RBCs. 2.The need to mobilize fatty acids from adipose tissue, and the synthesis and release of ketone bodies from the liver.

Liver during fasting

Adipose tissue during fasting

Resting skeletal muscle during fasting

Brain during fasting

Kidney in prolonged fasting  In early starvation and beyond, the kidneys play an important role.  Kidney expresses the enzymes of gluconeogenesis, including glucose 6-phosphatase.  In late fasting about 50% of gluconeogenesis occurs in the kidney.

Role of ammonia produced by the kidneys in acid base balance  The glutamine released from muscle's metabolism of branched- chain amino acids is taken up by the kidney  Glutamine is converted into α-ketoglutarate and ammonia by the action of renal glutaminase and glutamate dehydrogenase.  α-ketoglutarate can enter the TCA cycle.  The ammonia picks up H + from ketone body dissociation, and is excreted in the urine as NH 4 +, decreasing acidity.  In long-term fasting, there is a switch from nitrogen disposal in the form of urea to disposal in the form of ammonia.