Normal Glucose HomeostasisREGULATED BY:1. Glucose production in the liver2. Glucose uptake and utilization by peripheral tissues (skeletal muscle)3. Actions of hormones Normal glucose levels: 70-120mg/dl• FXN of Insulin: to increase the rate of glucose transport into certain cells of the body
Glucose Metabolism: Words you need to know! • Gluconeogenesis: formation of glucose from excess amino acids, fat, and other noncarbohydrate sources. • Glycogenesis: formation of glycogen. • Lipogenesis: formation of fats • Glycogenolysis: process that coverts glycogen to glucose. • Glycolysis: hydrolysis of glucose to pyruvate. • Lipolysis: catabolic degradation of triacylglycerol.
Glucose Metabolism Synthesis of glycogen Breaking down stored glycogenProduction of glucosefrom a.a. & othersubstances Cellular Respiration
Regulation of Glucose Metabolism• HORMONAL REGULATION• Glucose–dependent insulinotropic polypeptide (GIP)• Glucagon-like peptide 1 (GLP-1) – from cells in the gut – stimulate the production of insulin and inhibit glucagon
Metabolic Action of Insulin Liver Adipose MuscleInhibits Glycogenolysis Lipolysis Protein break down Gluconeogenesis Amino acid release KetogeneisSimulates Glycogen fatty acid Glycerol and fatty acid Glucose uptake and synthesis synthesis metabolism Amino acid uptake Synthesis of protein Glycogenesis
Fed State Fasting StateGlucose provides primary energy source Glucose is produced byAmylin acts on area postrema (AP) glycogenolysis and gluconeogenesisINSULIN dominated GLUCAGON dominates
Regulation of Glucose Metabolism• EXERCISE – Initially insulin levels drop and glucagon and catecholamine levels rise• STRESS – Production of stress hormones (corticosteroids and catecholamines) increase production of glucose – Increase production of FFAs – Lead to hyperglycemia
Who has Diabetes Mellitus• 16 Million in the USA• 1 Million/yr• 50K people die of it per year in the USA
What is diabetes mellitus?• GLUCOSE INTOLERANCE• How do you diagnose DM?• More than one fasting plasma glucose level (>126)• Elevated plasma glucose in response to an oral glucose tolerance test (>200)• Polydipsia, polyphagia, polyuria
* MODY might be regarded as the third type TWO* Types of DMType 1 Type 2• Genetic • Genetic, but diff. from Type• Autoimmune 1• Childhood (juvenile) • NOT autoimmune onset • Adult, or maturity onset,• Antibodies to beta cells, e.g., 40’s, 50’s insulitis • Insulin may be low, BUT, peripheral resistance to• Beta cell depletion insulin is the main factor• NON-OBESE patients • OBESE patients
Classification of Diabetes Mellitus
Classification of Diabetes Mellitus
Pathogenesis of Diabetes Mellitus • HLAs: expression of certain HLAs is associated with increased susceptibility to type I diabetes. • Viruses: are considered initiating factors in autoimmune cause of type I diabetes. • Insulin receptor defects: Insulin resistant: can be due to malfunction in insulin receptor, but the cause is not known. In type II diabetes. Antibodies to insulin receptor: in type II diabetes. • Glucose transport: low levels of glucose transporters in type I and II diabetes.
Pathogenesis of Diabetes Mellitus • Type I diabetes mellitus: caused by destruction of islet cells as a result of autoimmune reaction to - cells. • Type II diabetes mellitus: caused by a defect in glucose transport after insulin binds to its receptor.
Type 1 DMGenetic susceptibilityEnvironmental factorsImmunologically mediated destruction of beta cellsPeak about 10-14 years of age
• A 12-year-old female is newly diagnosed with type 1 diabetes mellitus (DM). Which of the following is the most likely cause of her disease?A. A familial, autosomal dominant gene defectB. Obesity and lack of exerciseC. Immune destruction of the pancreasD. Hyperglycemia from eating too many sweets
Pathogenesis of Type I Diabetes
Type 2 DM
Type 2 DM• RESISTANT TO THE ACTION OF INSULIN• Very common: many undiagnosed cases• Interactions of metabolic, genetic, & environment• RISK FACTORS: high BMI (intra-abdominal obesity), family history of DM2, ethnic minority, female gender
• Insulin is less able to facilitate entry of glucose into live, skeletal muscles, adipose tissue• Pancreas eventually “burns out”
Pathogenesis of Type II Diabetes
MODY (Maturity Onset Diabetes of the Young)• Multiple types• 2-5% of diabetics• Primary beta cell defects• Multiple genetic mechanisms, especially GLUCOKINASE mutations
Hyperglycemia in type 2 diabetes mellitus is aresult of:A. insulin deficiency.B. hyperinsulinemia and insulin resistance.C. glucagon deficiency.D. liver dysfunction.
Clinical Manifestations of Type I Diabetes
Symptomatic manifestations of insulin deficit in Diabetes
Classification of DiabetesDM: Type 1Absolute insulindeficiencyDM: Type 2Insulin resistancePre-diabetes:IGT & IFGGestationaldiabetes mellitus
Complications ofDiabetes Mellitus
Complications of Diabetes Mellitus • Retinopathy • Neuropathy • Angiopathy • Nephropathy • Infection RETINOPATHY • Hyperlipidemia and atherosclerosis • Hypoglycemia (insulin shock/ insulin reaction, too much Insulin) • Diabetic ketoacidosis (Too little insulin) • Protein glycation NEPHROSCLEROSIS
Chronic Complications of DM• Microvascular disease: capillary basement membrane thickening—ischemia – Retinopathy – Diabetic nephropathy• Macrovascular disease: unrelated to the severity of disease—causes much morbidity & mortality; glycosylated end products & high serum lipids cause atherosclerosis--ischemia – Coronary artery disease – Stroke – Peripheral arterial disease• Diabetic neuropathies: most common complication in Western countries, nerve cell damage—more sensory than motor• Infection: sensory impairment, hypoxia (glycosylated RBCs), increased pathogens like glucose, decreased blood supply, abnormal WBCs)
Acute Complications: Hypoglycemia
Acute Complications: Diabetic ketoacidosis Insulinopenia (in type I diabetes) Use of fatty acids from triglycerides as a major source of energy Fatty acid degradation Production of acetyl CoA Production of keto acids (ketone bodies) (acetoacetate, -hydroxybutyrate)
A 19-year-old female with type 1 diabetes mellitus wasadmitted to the hospital with the following lab values: serumglucose 500 mg/dl (high); urine glucose and ketones 4+(high); arterial pH 7.20 (low). Her parents state that she hasbeen sick with the “flu” for a week. Which of the followingstatements best explains her acidotic state?A. Increased insulin levels promote protein breakdown and ketone formation.B. Her uncontrolled diabetes has led to renal failure.C. Low serum insulin promotes lipid storage and a corresponding release of ketones.D. Insulin deficiency promotes lipid metabolism and ketone formation.
Acute Complications Protein glycation• Nonenzymatic binding of free amino groups of proteins to glucose and other sugars.• Protein glycation commonly occurs in RBCs, glumeruli, nerve cells, and other tissues.• Extent of protein glycation is proportional to extracellular glucose concentration.• Excessive glycation causes alterations in protein’s physical and biochemical properties.• New research suggest that many diabetes complications are caused by glycation of specific proteins.
Diagnostic Tests for Diabetes Mellitus Function tests in diabetes • Postprandial plasma glucose • Oral glucose tolerance test Other tests in diabetes • Glucose • Glycated hemoglobin • Albumin (protein) • Insulin • Keto acids • Hydrogen ion • Electrolytes • Osmolality • Body fluid volume • Anion gap • BUN • Lipids
Function tests in diabetes Both tests measure clearance rate of glucose load from the blood. Postprandial plasma glucose: • A high in carbohydrate meal is used (75 g glucose drink is preferred) as carbohydrate load. • Plasma glucose is measured 2 hours after carbohydrate ingestion. • Two postprandial tests with glucose levels 200 mg/dl are suggestive of diabetes. Oral glucose tolerance test (OGTT): under controlled conditions. • Carbohydrate intake is controlled 3 days before the test. • Glucose load is 40 g glucose/m2 body area. • Blood glucose is measured 2 hours after glucose load. • Glucose level 200 mg/dl is suggestive of diabetes.
Glucose Fasting plasma glucose: • Repeated levels 126 mg/dl…strongly suggest diabetes. • Levels 100 – 126 mg/dl …impaired fasting glucose. • Increase in fasting plasma glucose is directly proportional to severity of diabetes mellitus. Urinary glucose: • Renal threshold for glucose is 180 g/dl, and in diabetics it is increased to 300 mg/dl. Urinary glucose is a poor marker for diabetes mellitus.
Insulin • Type I diabetics: fasting plasma insulin is low. • Type II diabetics: fasting plasma insulin is normal, it is high if plasma glucose 250 mg/dl
Keto acids • Measured in both blood and urine. • Plasma keto acids may be normal even though urinary keto acids are high, this is due to increase urinary excretion of keto acids from renal compensation to low pH. • Controlled diabetics should have both normal plasma and urinary keto acid levels.
Albumin • Urinary protein (microalbuminuria) is one of the earliest signs of glomerular nephropathy. • Albumin / creatinine 20-30 mg/day suggests microalbuminuria. • Without intervention macroalbuminuria (>300mg/day) – Leading cause of end stage renal disease in US