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Physiopathology of pancreas
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PANCREAS INSULIN GLUCAGON SOMATOSTATIN
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INSULIN – STRUCTURE peptide
low species variability (ie. Porcine and human insulin – 1 AA is different) half life 5-8 minutes degradation in liver and kidneys
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BLOOD GLUCOSE REGULATION
INSULIN AND GLUCAGON
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INSULIN –REGULATION OF SECRETION
STIMULATION Increased glucose Increased AA Increased fatty acids Gastrin Cholecystokinin Glucagon Epinephrine Parasympathetic system INHIBITION Decreased glucose Decreased AA Decreased fatty acids somatostatin
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INSULIN - LIVER Increased glucose uptake
Stimulation of glycogenogenesis Stimulation of glycolysis Inhibition of gluconeogenesis Increased fatty acids and very low density lipopoteins (VLDL) synthesis
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INSULIN - MUSCLES Increased glucose uptake
Stimulation of glycogenogenesis Stimulation of glycolysis Stimulation of aminoacids transport Stimulation of protein synthesis
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INSULIN - ADIPOCYTES Increased glucose uptake
Stimulation of glycolysis Stimulation of α-glycerol phosphate synthesis Inhibition of lipolysis
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GLUCAGON –REGULATION OF SECRETION
STIMULATION Decreased glucose Decreased AA Exercise Stress Sympathetic system INHIBITION Insulin Increased glucose Somatostatin
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GLUCAGON – METABOLIC EFFECTS
LIPIDS Oxidation of fat in hepatocytes => ketones => alternate to glucose fuel Release of FA from adipocytes CARBOHYDRATES Stimulation of glycogenolysis Stimulation of gluconeogenesis Increased FA => inhibition of glucose uptake by muscles and adipocytes PROTEINS AA uptake into liver => gluconeogenesis Activation of liver urea cycle
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Metabolic Effects of Insulin and Glucagon
ORGAN FUNCTION/FINDING INSULIN GLUCAGON Liver Glycogen formation/storage ↑ ↓ Glycogen breakdown Lipid synthesis (TGs, VLDLs) Fatty acid oxidation Amino acid uptake Muscle Glucose uptake — Fat tissue Lipid uptake Fatty acid esterification to TGs Triglyceride lysis Blood Glucose concentration VLDL concentration Ketone bodies concentration TG, triglycerides; VLDL, very low density lipoproteins; ↑, increased activity or concentration; ↓, decreased activity or concentration.
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SOMATOSTATIN 14-aminoacid peptide
produced in delta cells of pancreas (also in GI tract, hypothalamus) Release stimulated by: glucose aminoacids fatty acids secretin cholecystokinin Actions: decreases gut motility inhibits release of gastrin, secretin, cholecystokinin decreases gastric acid secretion decreases gastric emptying decreases gallblader contraction suppresses insulin and glucagon release suppresses growth hormone release
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Control of eating behavior. CCK, cholecystokinin.
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Insulin and glucagon
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Pathogenesis of hyperglycemia.
1, Glycogenolysis. 2, Gluconeogenesis. 3, Reduced uptake of glucose-contributing hyperglycemia. 4, Glucosuria. 5, Lipolysis. 6, Proteolysis. 7, Fatty acid metabolism. Acetyl CoA, acetyl coenzyme A; glucose-6-P, glucose-6-phosphate; TCA, tricarboxylic acid; TG, triglycerides.
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Causes of Hyperglycemia
Diabetes mellitus Endocrine hyperfunction syndromes Glucagonoma Cushing’s syndrome Growth hormone hypersecretion Thyrotoxicosis Pheochromocytoma Acute pancreatitis Drugs Thiazide diuretics Phenytoin Hormones (e.g., cortisone, thyroxin)
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Signs and Symptoms of Hyperglycemia
Glucose increased in blood, urine, and body fluids Polyuria—nocturia Dehydration—dry mouth, skin, and mucosae Polydipsia and increased thirst Polyphagia and feeling of hunger Weight loss/gain Fatigue, nausea Blurry vision and headaches Pruritus vulvae or balanitis due to Candida albicans Mood change, irritability, apathy
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Causes of Hypoglycemia
Diabetes therapy related Insulin Sulfonylurea Tumors secreting insulin or IGF Insulinoma Sarcomas Carcinoma of liver, kidneys, adrenal glands Drugs Pentamidine Sulfonamides Salicylates Major organ failure Liver failure Kidney failure Heart failure Systemic diseases Multiple organ failure Sepsis Malnutrition Alcoholism Childhood inborn errors of metabolism
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DIABETES MELLITUS 2000 – 2030 number of cases[miliions]
![DIABETES MELLITUS 2000 – 2030 number of cases[miliions]](http://slideplayer.com/slide/17098582/98/images/22/DIABETES+MELLITUS+2000+%E2%80%93+2030+number+of+cases%5Bmiliions%5D.jpg "DIABETES MELLITUS 2000 – 2030 number of cases[miliions]")
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Classification of Diabetes Mellitus (DM)
Type 1 DM (absolute insulin deficiency due to beta cell destruction) Type 2 DM (insulin resistance and relative insulin deficiency) Other types of DM Genetic defects involving islet cells, insulin receptors, etc. Genetic and chromosomal syndromes (e.g., Down, Turner’s, and Klinefelter’s) Pancreatic diseases and pancreatectomy Systemic diseases (e.g., hemochromatosis, autoimmune endocrine insufficiency) Excess of insulin antagonizing hormones (e.g., glucagons, corticosteroids, growth hormone, thyroid hormones) Drug-induced DM (e.g., thiazide diuretics)
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Comparison of Types 1 and 2 Diabetes Mellitus (DM)
FEATURES TYPE 1 DM TYPE 2 DM Prevalence 0.5%, women = men 4–5%, women > men Concordance in identical twins 30–70% 80–90% Autoimmunity Yes (anti-islet antibodies) No Age at onset >20 yr >30 yr Onset of symptoms Sudden Gradual Body build Lean Obese Insulin in blood Low then absent Increased (early) or decreased (late) Insulin resistance Yes Ketosis Common Uncommon
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Clinical Findings in Diabetic Acidosis
CAUSE Hyperglycemia Increased hepatic gluconeogenesis, glycogenolysis Inhibition of glycolysis Polyuria Osmotic diuresis Dehydration Polyuria and inadequate water intake (dry skin and mucosae) Orthostatic hypotension Loss of minerals (low Na+, K+) Polyuria and urinary loss of minerals Ketonemia Increased lipolysis due to lack of insulin and excess of catecholamines and glucagon Acetone odor Ketonuria Acidosis with anion gap Low bicarbonate Buffering of ketone bodies in blood Kussmaul breathing Acidosis and excess blood CO2 Coma Multifactorial
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Comparison of Coma due to Diabetic Ketoacidosis and
Hyperosmolar Nonketotic Diabetes Mellitus (DM) CAUSE OF COMA FEATURE DIABETIC KETOACIDOSIS HYPEROSMOLAR NONKETOTIC DM Age Young (<30 yr) Older (>60 yr) Onset Sudden (<2 days) Insidious (>1 wk) First sign of DM Yes (25%) Yes (35%) Plasma/serum findings Glucose in plasma <600 mg/dL >600 mg/dL pH <7.30 >7.30 Ketone bodies + – Bicarbonate <15 mEq/L >15 mEq/L Osmolality <320 mOsm/kg >320 mOsm/kg Na+ 130–140 mEq/L 145–155 mEq/L K+ 5–6 mEq/L 4–5 mEq/L Insulin requirement Yes, almost always Yes or no Mortality 5–10% 10–20%
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DIABETES MELLITUS - COMPLICATIONS
ACUTE Ketoacidosis Polyuria Dehydration Hyperosmolar coma CHRONIC Microangiopathy Macroangiopathy Neuropathy Nephropathy Ulcerations Hyperlipidemia Protein wasting
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Diabetic foot
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DIABETIC RETINOPATHY
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DIABETIC NEPHROPATHY
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HYPERFILTRATION => GLOMERULOSCLEROSIS
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