Hormones and metabolism an overview Saffron Whitehead

Metabolic paths of glucose Glycogen glycogenolysis + GLUTs + + Glucose -6 phosphate Glucose Circulation - glycolysis gluconeogenesis - lipolysis - Pyruvate PROTEIN FAT lipogenesis + + TCA cycle Stimulatory and inhibitory effects of insulin on the fate of glucose + -

Hepatic portal vein The liver sits at the head of the portal vein. It has a high capacity to take up glucose and can buffer increases in blood sugar concentration

The major pathways of glucose metabolism in the liver Glycogenolysis Glycogen Gluconeogenesis Glycolysis Glucose Glucose-6-phosophate Phosphoenol pyruvate Lipolysis Amino acids Fatty acids (triglycerides) Pyruvate Keto acids Keto acids Acetyl CoA Oxaloacetate TCA

+ + + + + + Major metabolic pathways in skeletal muscle Glycogen Glucose G 6-P + Stimulated by insulin GLUT 4 Pyruvate + Stimulated by adrenaline Lactate TCA Amino acids Fatty acids Fatty acids + LPL TAG TAG in lipoprotein particles

Exogenous pathway of lipoprotein metabolism Chylomicrons Dietary fat HDL Hydrolysis by lipoprotein lipase in capillary beds of fat and muscle Chylomicrons LPL action FA FA Muscle Fat Chylomicron remnants taken up by liver

Action of lipoprotein lipase in white adipose tissue Lipoprotein lipase is attached to the glycocalyx and acts on lipoprotein particles in the capillary From Metabolic Regulation by KN Fryan

LDL particles taken up by tissues Direct reuptake of some VLDL particles Endogenous pathway of lipoprotein metabolism Liver TAG HDL Hydrolysis by lipoprotein lipase in capillary beds of fat and muscle VLDL particles LPL action FA FA Muscle Fat LDL particles taken up by tissues Tissues

Cholesterol ester is hydrolysed in the lysosomes The LDL receptor and regulation of cellular cholesterol content Cholesterol ester is hydrolysed in the lysosomes Raised cholesterol reduces synthesis of LDL receptors and inhibits cholesterol synthesis

Fatty acid and glucose metabolism in white fat Chylomicron TAG VLDL TAG capillary Lipoprotein lipase + esterification Fatty acids TAG Nor-adrenline + lipogenesis + + Glucose Glycerol-3-phosphate GLUT 4 Fatty acids/ glycerol + Stimulated by insulin

Hormones of the endocrine pancreas Arrangement of cells in a single islet -  cells constitute approximately 60% of each islet Single islet surrounded by exocrine acini Islets 1-1.5% of pancreatic mass ~ 1 million islets

Control of insulin and glucagon secretion Arterial blood Arteriole GLUT 2 o Insulin Glucagon Som, PP o o o o o o o o Insulin secreting granules o o o o o o o o Venule Venous blood Fenestrated capillaries to aid entry of hormones into circulation

Insulin secretion is stimulated by Dose reponse curve of insulin secretion in relation to blood glucose concentrations Insulin secretion is stimulated by raised blood glucose concentrations most amino acids (to somewhat differing extents) NEFAs? Secretion regulated by autonomic nervous system ~ 50% insulin reaching the liver is removed in its ‘first passage’ Insulin release Threshold for insulin release ~ 5 mmol/l glucose 0 5 10 15 20 Glucose concentration (mmol/l)

Family of glucose transporters

Metabolic paths of glucose Glycogen glycogenolysis + GLUTs + + Glucose -6 phosphate Glucose Circulation - glycolysis gluconeogenesis - lipolysis - Pyruvate PROTEIN FAT lipogenesis + + TCA cycle Stimulatory and inhibitory effects of insulin on the fate of glucose + -

Glucagon secretion is suppressed by a rise in blood glucose concentration stimulated by amino acids Raised blood glucose concentrations lower insulin:glucagon ratio. The reverse occurs when blood glucose concentrations fall Only significant effects of glucagon are on the liver stimulating the production of glucose - gluconeogenesis, glycogenolysis 10-15% is removed in its ‘first passage’ effect

Growth hormone stimulates the production of IGFs --> stimulatory effect on growth stimulates fat mobilization: delayed effect compared with rapid effects of adrenaline stimulates hepatic glucose production - gluconeogenesis and glycogenolysis

Stimulates fat mobilization (increases hormone sensitive lipase) Cortisol Stimulates fat mobilization (increases hormone sensitive lipase) stimulates gluconeogenesis inhibits uptake of glucose by muscle (mechanism?) stimulates breakdown of muscle protein Diabetogenic hormone Symptoms of Cushing’s

Adrenergic receptors, second messenger and effects of catecholamines Net effect of adrenaline and nor adrenaline will depend on relative abundance of different receptors in different tissues and on concentration of hormones. High’ish concentrations - increased heart rate, rise in circulating concentrations of glucose and NEFAs e.g. mobilization of stores of glycogen and TAG Very high concentrations - increased TPR and some inhibition of metabolic processes

Stimulates proteolysis Graves’ disease Thyroid hormone (T3) Stimulates metabolic rate by increasing size and number of mitochondria, stimulating Na+- K+-ATPase activity. This accounts for 15-40% of a cells resting energy expenditure Stimulates proteolysis Graves’ disease

Hormonal regulation of proteins synthesis and breakdown in muscle + - Protein synthesis Protein catabolism From Metabolic Regulation by KN Fryan

Amino acid metabolism in the liver Pyruvate/TCA intermediate Transamination Glutamate + NH3 Keto acid TCA cycle Acetyl CoA Pyruvate/TCA intermediate Urea cycle Ketogenesis Lipogenesis Gluconeogenesis

Fatty acid and glucose metabolism in white fat Insulin stimulates the esterification of fatty acids to triaglycerol, the main store of chemical energy in white adipose tissue Fatty acid and glucose metabolism in white fat Insulin stimulates lipoprotein lipase (LPL) and the insertion of GLUT 4 channels into the membrane Adrenaline stimulates hormone sensitive lipase (HSL) and insulin inhibits HSL From Metabolic Regulation by KN Fryan

Non-esterified fatty acid (NEFA) metabolism after an overnight fast Non-esterified fatty acid (NEFA) metabolism after an overnight fast. Triacylglycerol (TAG) is converted back to fatty acids and released into the circulation for use by muscle and formation of ketone bodies in the liver and formation of TAG for recirculation as VLDL Other energy sources in the post absorptive state are through hepatic gluconeogenesis and glycogenolysis From Metabolic Regulation by KN Fryan

Glucose metabolism after breakfast From Metabolic Regulation by KN Fryan

- + Metabolic pattern in untreated diabetes mellitus type 1 Pathways stimulated by lack of insulin Pathways inhibited by lack of insulin + -

Formation of ketone bodies Insulin inhibits -oxidation and lipolysis In diabetes oxaloacetate is consumed by the gluconeogenic pathway Excess acetyl CoA is shunted into formation of ketone bodies

Integration of the utilization of fatty acids and glucose Oxidation of fatty acids in muscle reduces uptake and oxidation of glucose This leads to impairment of glucose uptake and loss of the action of insulin (resistance) From Metabolic Regulation by KN Fryan