Physiology: Carbohydrate Metabolism

The pancreas the gland responsible. Insulin production and secretion. Insulin receptors. Glucose transporters. Insulin action. Abnormal carbohydrate metabolism.

Pancreas: Only 2% of the pancreas weight is beta cell. Those cell produce insulin in the rate of one unit per each kilogram of body weight. Over 80% of beta cells should be lost before diabetes develops. GLUCAGONINSULIN

Proinsulin Centr- omere CATCALPTH c-Ha-ras INSIGF-2  -globin Short arm of chromosome 11 C peptide Insulin A chain Insulin B chain Proinsulin Insulin A chain Insulin B chain C peptide Insulin Production

Insulin Structure Alpha chain Beta chain Disulfide bridges The hormone is protein with high molecular weight. Unstable if taken orally. Metabolized by the kidney.

 Glucokinase ( GK ) is the rate limiting step for glucose metabolism by the islets. Generation of ATP from the electron transport chain closes an ATP-dependent potassium channel. Opens a voltage-dependent calcium channel. Increase intracellular calcium leads to the stimulation of insulin secretion. Diabetes 1996; 45: x Insulin Secretion

 Free Fatty Acids: Fatty acid acyl-CoA can augment insulin secretion. Increase intracellular calcium stimulate exocytosis. Protein kinase C ( PKC ) enhance exocytosis.

K+K+ Sulphonylureas Dépolarisation K ATP Channel close x Ca 2+ Ca 2+ Influx Ashcroft, Gribble, Diabetologia (1999) 42: Sulphonylureas Pancreatic mode of action Insuline secretion through exocytosis Insulin

Loss of the first phase in insulin secretion is the initial biological abnormality type 2 patient will manifest. This will result in an elevation of the postprandial glucose. In type 2 diabetes the second phase will be more and longer which can result in post-meal hypoglycemia. Insulin Secretion

Fasting Plasma Insulin (  U/ml ) Fasting Plasma Glucose ( mg/dl ) Glucose toxicity Increase of fasting blood glucose, fasting plasma insulin will increase. At the level of 140 mg/dl there will be a decline in fasting insulin level. Glucose concentration more than 200 mg/dl will paralize the pancrease. Metabolism 1989; 38:

The insulin receptor gene: 1370 amino acids. Two parts alpha and beta subunits. Three mutation have been described. Clinical presentation: 1- Sever insulin resistance. 2- Acanthosis nigrican. 3- Hirsutism and virilization. 4- Mental retardation. 5- Mental retardation. 6- Dental dysplasia. Chromosome 19 Alpha-subunit COOH NH2    Cell membrane Rabson-Mendenhall syndrome The Insulin Receptor

Insulin receptor The first step in insulin action is the activation of tyrosine kinase of the  sub-unit. Initiate a series of events involving a cascade of phosphorylation-dephosphorylation. Stimulation of intracellular glucose metabolism. Initial step is the activation of the glucose transport system.

Glucose uptake GLUT-4 transporter on cell membrane Insulin insulin-stimulated translocation of glucose transporters

OrganGlucose transporterHK couplerClassification Brain GLUT1HK-IGlucose dependent Erythrocyte GLUT1HK-IGlucose dependent Adipocyte GLUT4HK-IIInsulin dependent Muscle GLUT4HK-IIInsulin dependent Liver GLUT2HK-IVLGlucose sensor GK  - cell GLUT2HK-IVB ( glucokinase ) Glucose sensor Gut GLUT3-symporter----Sodium dependent Kidney GLUT3-symporter----Sodium dependent Glucose transporters

B cell High blood glucose Insulin Impaired insulin release Glucoseuptake Excessive glucose output Impaired glucose transport FFA FFA Glucose Metabolism

Skeletal muscle Brain Splanchnic bed Adipose tissue Control NIDDM Glucose uptake ( mg/kg/min ) Insulin resistance is the major contributor for the pathogenesis of type 2 diabetes. Resistance could be at the level of insulin receptors or post receptor defect. Skeletal muscle is the major contributor to insulin resistance in patients with type 2 diabetes. Hepatic glucose production

Indogenous glucose production should balance with total body glucose uptake. Major production come from glycogenolysis. Major uptake is through glucose oxidation. Glycogenolysis Glycerol (2%) Pyruvate (1%) Lactate (16%) Amino Acids (6%) Other Glycolysis Glucose Oxidation Splanchnic Glucose Uptake Hepatic glucose production

Glucose Fatty acid Citrate  Acetyl CoA  Fatty acid Glucose  Glucose 6- Phosphate  Phospho-fructokinase  Frucose 6- Phosphate  Frucose 1,6- bisphosphate  Pyruvate  Acetyl CoA   Randle cycle Glucose metabolism during fast state Non-diabetic subject: During an over night fast liver will supply energy from glycogen store. Muscle will utilize energy from free fatty acids (FFA) by Randle cycle. This will decrease glucose transport through cellular membrane.

Fasted state Fructose 6- Phosphate  Fructose 2,6- bisphosphate Fructose 1,6- bishosphate Phosphoenol pyruvate Oxaloacetate pyruvate Fed state Fructose 6- Phosphate  Fructose 2,6- bisphosphate Fructose 1,6- bishosphate Phosphoenol pyruvate Oxaloacetate pyruvate Glucose metabolism during fast and fed state

Insulin deficiency Blood glucose Insulin resistance Diabetes Mellitus is a group of metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with log-term damage, dysfunction, and failure of various organs, especially the eyes, Kidneys, nerves, heart, and blood vessels. Pathogenesis of type 2 Diabetes Mellitus

Natural History of Type 2 Diabetes Mellitus Age Microvascular Complication IGT Postprandial Fasting Hyperglycemia Hyperglycemia Macrovascular Complication Disability Insulin resistance Hyperinsulinemia  HDL cholesterol  Triglyceride Hypertension Atherosclerosis Normo-insulinemia Retinopathy Nephropathy Neuropathy Hypoinsulinemia Blindness Renal Failure Amputation IHD Stroke Genetic background for: Insulin secretion Insulin sensitivity complications Environmental factors: Nutrition Obesity Physical inactivity Disability Death

Natural History of Type 2 Diabetes Mellitus Decrease Glucose-induced insulin secretion Insulin deficiency Insulin resistance Decrease Tissue response to insulin Genetic Acquired Glucotoxicity Lipotoxicity Genetic Acquired Obesity Vo2max Age Smoking Increase Hepatic glucose production Increase Cellular glucose uptake Hyperglycemia Impaired beta cell function Post- receptor defect Decrease Glucose transport Decrease Insulin binding Basal Hyperinsulinemia Hyperglycemia Hypoinsulinemia

Beta Cell function (%) IGT PPHyper T2 Phase I T2 Phase II Phase III Years from diagnosis UKPDS data

Prevalence Age groups Age : Prevalence of type 2 diabetes increase with age. Females are significantly higher than males. The prevalence is almost double after the age of 55 years.