Hormonal regulation of glycaemia Alice Skoumalová

Glycolysis

Gluconeogenesis

Pentose Phosphate Pathway

Formation and degradation of glycogen

Overview of the major pathways of glucose metabolism

Glucose homeostasis: maintenance of blood glucose levels near 80 to 100 mg/dL (4,4-5,6 mmol/l) insulin and glucagon (regulate fuel mobilization and storage) Hypoglycemia prevention: release of glucose from the large glycogen stores in the liver (glycogenolysis) synthesis of glucose from lactate, glycerol, and amino acids in liver (gluconeogenesis) release of fatty acids from adipose tissue (lipolysis) Hyperglycemia prevention: conversion of glucose to glycogen (glycogen synthesis) conversion of glucose to triacylglycerols in liver and adipose tissue (lipogenesis)

Changes in blood glucose levels after a meal Fasting: ~ 5 mmol/l After a meal: ~ 8 mmol/l (returning to the fasting range by 2 hours) Hyperglycemia: the osmotic effect of glucose, dehydratation, hyperosmolar coma Hypoglycemia: a lack of energy (brain), hemolysis of erythrocytes

Pathways regulated by the release of: glucagon (in response to a lowering of blood glucose levels) insulin (in response to an elevation of blood glucose levels)

Synthesis and secretion of insulin and glucagon: the islets of Langerhans (β- and α-cells) preprohormone (modification - in ER, GC, SV)

Cleavage of proinsulin to insulin: Proinsulin is converted to insulin by proteolytic cleavage, which removes the C-peptide

Major sites of insulin action on fuel metabolism: The storage of nutriens glucose transport into muscle and adipose tissue glucose storage as glycogen (liver, muscle) conversion of glucose to TG (liver) and their storage (adipose tissue) protein synthesis (liver, muscle) inhibition of fuel mobilization

Insulin receptor signaling: the tyrosine kinase activity a dimer (α and ß subunits) Signal transduction: - the ß-subunits autophosphorylate each other when insulin binds (activating the receptor) - the activated receptor binds and phosphorylates IRS (insulin receptor substrate) - multiple binding sites for different proteins

Major sites of glucagone action on fuel metabolism: Mobilization of energy stores release of glucose from liver glycogen stimulating gluconeogenesis from lactate, glycerol, and amino acids (liver) mobilizing fatty acids (adipose tissue)

+ - Regulators of insulin and glucagon release: Glucose Insulin Amino acids + Glucagon -

Insulin Glucagon Epinephrine Cortisol Hormone Function Major metabolic pathways affected Insulin Promotes fuel storage after a meal Promote growth Stimulates glucose storage as glycogen (muscle,liver) Stimulates FA synthesis and storage after a high-carbohydrate meal Stimulates amino acids uptake and protein synthesis Glucagon Mobilizes fuels Maintains blood glucose levels during fasting Activates gluconeogenesis and glycogenolysis (liver) during fasting Activates FA release from adipose tissue Epinephrine Mobilizes fuels during acute stress Stimulates glucose production from glycogen (muscle, liver) Stimulates FA release from adipose tissue Cortisol Provides for changing requirements over the long-term Stimulates amino acid mobilization from muscle protein Stimulates gluconeogenesis

Production of blood glucose Glycogenolysis 2 hours after a meal the primary source of blood glucose during the first few hours of fasting Gluconeogenesis after consumption of the liver glycogen lactate (muscle, erythrocytes), amino acids (muscle), glycerol (adipose tissue)

Liver glycogen Glycogen serves as a carbohydrate reserve, from which glucose can be released The human body can store up to 450 g of glycogen (a third in the liver) Liver glycogen serves in the maintenance of the blood glucose level, it declines to zero in periods of starvation that last more than one day Glykogen ve svalech, pouze pro energii, svaly nemají glukosa-6-fosfatasu

Liver gluconeogenesis Gluconeogenesis occurs predominantly in the liver (90%) Precursors: 1. Amino acids derived from the muscles (prolonged fasting results in a massive degradation of muscle protein) 2. Lactate formed in erythrocytes and in muscles 3. Glycerol produced from the degradation of fats Cortisol, glucagon, epinephrine: promote gluconeogenesis Insulin: inhibits gluconeogenesis

Blood glucose levels at various stages of fasting: Stage of fasting Glucose (mg/dL) Glucose (mM/L) Normal level 80-100 4,4-5,6 Fasting (12 h) 80 4,4 Starvation (3 d) 70 3,9 Starvation (5-6 wk) 65 3,6

Regulation of glycogenolysis in the liver by glucagon: cAMP → protein kinase A: 1. inactivates glycogen synthase 2. activates glycogen phosphorylase

Regulation of gluconeogenesis: inactivation of the glycolytic enzymes and activation of the enzymes of gluconeogenesis 1. Pyruvate → PEP Pyruvate kinase - inactivation by cAMP (glucagon) Phosphoenolpyruvate carboxykinase - induced by glucagon, epinephrine, and cortisol 2. Fructose 1,6-P → Fructose 6-P Phosphofructokinase - activated by fructose 2,6-P) Fructose 1,6-bisphosphatase - inhibited by fructose 2,6-P) 3. Glucose 6-P → Glucose Glucokinase - high Km for glucose, induced by insulin Glucose 6-phosphatase - induced during fasting

Sources of blood glucose in fed, fasting, and starved states:

Blood-placentar barier GLUT 2 Liver Kidney Pancreatic β-cells Transporter Tissue distribution Comments GLUT 1 Erythrocytes Blood-brain barier Blood-placentar barier Present in high concentrations GLUT 2 Liver Kidney Pancreatic β-cells Intestinal mucosa cells A high Km for glucose The glucose sensor in the pancreas GLUT 3 Brain Major transporter in the brain GLUT 4 Adipose tissue Sceletal muscle Heart muscle Insulin-sensitive transporter! The number increases on the cell surface. GLUT 5 Intestinal epithelium A fructose transporter

Stimulation by insulin of glucose transport into muscle and adipose cells: Binding of insulin to its cell membrane receptor causes vesicles containing glucose transport proteins to move from inside the cell to the cell membrane

Diabetes mellitus chronic disease characterized by derangements in carbohydrate, fat and protein metabolism caused by either complete absence of insulin or relative insulin deficiency 2 types: Type 1 (insulin-dependent): no insulin defective ß-cells function (an autoimmune disease) Type 2 (non-insulin-dependent): „the insulin resistance“ (unknown cause, often obesity) = impaired function of insulin receptors (TNF, resistin) - the lower number of receptors - signal cascade abnormalities

Pathways affected by insulin 1. Carbohydrate metabolism stimulation of glucose utilization: glycogen synthase ↑ glycolysis ↑ inhibition of gluconeogenesis the transport of glucose into tissues (muscle, adipose tissue) 2. Lipid metabolism stimulation of the glucose conversion into FA: acetyl CoA carboxylase ↑ NADPH (PPP ↑) storage of fat: lipoprotein lipase ↑ inhibition of the degradation of fat: hormone sensitive lipase ↓

Effects of insulin deficiency 1. Glucose uptake and utilization↓ 2. Proteolysis↑ 3. Gluconeogenesis↑ 3. Degradation of fat↑ Hypeglycemia (≥9mmol/l) Glucosuria Hyperlipidemia Metabolic acidosis Ketonuria

Types of diabetes: Type I (insulin-dependent) Type II (non-insulin-dependent) Incidence 10-20% 80-90% Age childhood, the teens Middle-aged, older Cause An autoimmune disease Complete absence of insulin Unknown Relative insulin deficiency Symptoms Hyperglycemia, hypertriglyceridemia, ketoacidosis Hyperglycemia, hypertriglyceridemia Habitus Thinness Obesity Ketoacidosis Yes No Insulin Very low or absent Normal (increased) Therapy Diet, drugs, insulin

The oral glucose tolerance test (oGTT): The blood glucose level returns to the basal level by 2 hours

The oral glucose tolerance test (oGTT): diagnosis of diabetes; administration of glucose (75g) in an aqueous solution glucose level determination before and at 30, 60 and 120 minutes after the glucose load Diagnosis Time Venous blood (glucose mmol/l) Plasm (glukose mmol/l) Capillary blood (glukose mmol/l) Diabetes mellitus fasting 2h (after the glucose load) ≥6,7 ≥10 ≥7,8 ≥11,1 Impaired glucose tolerance <6,7 6,7-10 <7,8 7,8-11,1

The diabetes complications: 1. Acute A. Hyperglycemic coma: the elderly, DM 2 (not recognized diabetes, failure to take insulin, an infection, coincidental medical problem), hyperglycemia ( 50mM), dehydratation B. Hypoglycemic coma: insulin overdose, sweating, tremulousness, palpitations, confusion C. Ketoacidosis: acute insulin deficiency, DM 1, the smell of acetone on the breath, Kussmaul respiration, dehydratation 2. Chronic A. Microvascular (diabetic retinopathy, nefropathy, neuropathy) nonenzymatic glycation of proteins in vascular tissue B. Makrovascular (atherosclerosis) nonenzymatic glycation of proteins in vascular tissue and lipoproteins C. Diabetic cataract: increased osmolarity of the lens (increased acitivity of the polyol pathway → ↑sorbitol) nonenzymatic glycation of proteins of lens

Hyperglycemia - protein glycation: hemoglobin vascular tissue proteins → contribute to the diabetic complications (cataracta, atherosclerosis, retinopathy, nephropathy) Glycated proteins: - impaired structure and fucntion The importance of the maintance of low glucose levels in diabetic patients !

Lens metabolism: Diabetic cataract : ↑glucose concentration in the lens → ↑aldose reductase activity → sorbitol accumulation → ↑osmolarity, structural changes of proteins