Metabolic disorders Part 3 07.12.08 Typical mechanisms of

Metabolic disorders Part 3 07.12.08

Typical mechanisms of carbohydrate metabolism disorders Disorders of digestion and absorption Disorders of the gluconeogenesis and glycolysis Altered synthesis and breakdown of glycogen (glycogenoses) Disorders of glucose uptake by the cells Hypoglycemia, hyperglycemia

Normal blood glucose concentration – 3,3-5,5 mmol/l Normoglycemia Peripheral cells Intestine Liver (glycogenolysis, glycogenesis, gluconeogenesis) Insulin Counter hormones — + Glucostat – maintenance of the constant blood glucose level

Regulation of blood glucose level Glucose counter regulatory hormones: elevation of blood glucose Lowering of blood glucose:

The effects of insulin on metabolism

Features of type 1 and 2 diabetes

Insulitis – a mechanism of the type I diabetes mellitus

Role of viruses in the pathogenesis of T1DM

Proposed mechanisms of β-cell death

Pathogenesis of diabetic ketoacidosis Deficiency of insulin; excess of counter regulatory hormons Decreased glucose utilization Increased glucose production Increased mobilization of fatty acids Ketonemia Ketonuria Hyperglycemia Glucosuria Osmotic diuresis Blood hyperosmolarity and dehydration Metabolic acidosis CNS impairment Circulatory disorders (hypotension, tachycardia) Coma

Normal state Diabetic ketoacidosis

Pathogenesis of T2DM

Prereceptor level (anomalous insulin) Receptor level (decreased number of insulin receptors, decreased affinity of the receptors) At the level of glucose transport (decreased number of GLUT) Postreceptor level (disorders of signal transduction and kinase phosphorylation) Mechanisms of insulin resistance

Components of the insulin resistance syndrome

Consequences of hyperglycemia Glucosuria, polyuria, secondary polydipsia … Blood hyperosmolarity, tissue dehydration, hyperosmolar coma Non-enzymatic glycation of proteins (albumins, hemoglobin etc.) – formation of advanced glycation end-products Endothelial dysfunction (micro- and macroangiopathy) Formation of autoantigens (autoimmune reactions)

Role of lipid glycation in the pathogenesis of atherosclerosis (macroangiopathy) in diabetes

Cellular effects of advanced glycation end-products

Advanced glycation end-products mediated vessel injury: pathogenesis of diabetic microangiopathy

Major clinical manifestations of diabetes: - Retinopathy - Cerebrovascular disease - Premature coronary artery disease - Autonomic dysfunction (gastroparesis, diarrhea) - Peripheral vascular disease - Peripheral neuropathy (pain, loss of sensation) - Nephropathy (renal failure)

Diabetic foot ulcers: peripheral arterial disease + diabetic neuropathy

Diabetes is currently one of the leading causes of renal failure Normal gromerulus Diabetic nephropathy

Diabetes is a leading cause of blindness in the USA Diabetic retinopathy

Increased utilization of glucose by the cells – increased insulin production, treatment with insulin – formation of insulin-like growth factors Disorders of glycogenolysis (glycogenoses, liver cirrhosis) Disorders of glucose reabsorption (renal diabtes) Prolonged intensive physical exercise Mechanisms of hypoglycemia

Mechanisms of compensation in hypoglycemia Activation of sympathetic nervous system (glycogenolysis) Increased production of glucose counter regulatory hormones, gluconeogenesis, activation of lipolysis and decreased utilization of glucose

Hypoglycemic coma Blood glucose of less than 2,0-1,5 mmol/l Amount of glucose in the neurons Brain hypoxia Energy deficiency in the neurons Water and electrolyte imbalance Injury of the neuronal membranes Cellular hyperhydratation Disturbed electrogenesis cortex function Excitation of the neurons of the spinal cord Excitation, seizures Coma

Basics of Body Fluids Water is primary body fluid. 40%-60% of weight in adult. Affected by age, sex, & body fat. Distribution: 2 major compartments-ICF & ECF. ICF: in cells. 2/3 of body fluid in adults. ECF: outside cells. 1/3 of body fluid. 4 compartments-intravascular, interstitial, lymph, & transcellular

Schematic representation of body fluid compartments in man (70 kg)

Basics of Body Fluids Intravascular: plasma Interstitial: surrounds the cells;3/4 ECF Transcellular: CSF, pericardial, pleural, etc Lymph: lymphatic system

Water Balance

Edema – pathological accumulation of the fluid within the extravascular space, i. e., interstitium and/or cells Main mechanisms of edema: Increased microvascular permeability (hypersensitivity type I); Decreased lymph drainage (elephant leg); Increased hydrostatic pressure in the capillaries (venous congestion); Decreased oncotic pressure of the blood (hypoproteinemia); Severe retention of water and salts (renal failure)