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Diabetes mellitus DEFINITION Diabetes mellitus (DM) comprises a group of common metabolic disorders that share the phenotype of hyperglycemia. Factors contributing to hyperglycemia may include: • Reduced insulin secretion, • Decreased glucose utilization • Increased glucose production PHYSIOLOGY - digestion of carbohydrates • This metabolism of carbohydrates is achieved through the secretion of a number of digestive enzymes into the gastrointestinal tract where they attack carbohydrates and gradually convert them into simple sugars like glucose so they can be absorbed into the blood. • The process of digesting carbohydrates begins in the mouth. Our saliva contains an enzyme called amylase that starts breaking down the more complex carbs into simpler types. PHYSIOLOGY - digestion of carbohydrates • Another version of amylase is secreted by the pancreas into the duodenum. This cuts down carbohydrates into simple sugars - maltose, lactose and sucrose. • As the carbohydrate passes further into the intestine, the enzymes maltase, lactase and sucrase chop maltose, lactose and sucrose into smaller bits, which are eventually converted to glucose and absorbed through the intestinal walls into the bloodstream. PHYSIOLOGY - glucose metabolism The Liver • The glucose is taken to the liver through portal vein. There it is stored or distributed to cells throughout the body for energy. In this way, the liver regulates blood glucose levels to provide sufficient energy for the body. • Excess glucose is converted in the liver to glycogen (glycogenogenesis). • If blood sugar levels fall, the glycogen is re-converted to glucose (glycogenolysis) by the hormone glucagon, to prevent hypoglycemia. • If glycogen levels are exhausted, glucagon can trigger the formation of glucose from some amino acids or glycerol (gluconeogenesis). PHYSIOLOGY - glucose metabolism • Glucose from blood to cells is carried across the cell membrane by a family of specialised transporter proteins called glucose transporters (GLUTs) • GLUT 1 – is involved in basal and non-insulin-mediated glucose uptake in many cells • GLUT 2 – in the islet B cell • GLUT 3 – non-insulin-mediated glucose uptake in the brain • GLUT 4 – responsible for insulin-stimulated glucose uptake in muscle and adipose tissue PHYSIOLOGY - glucose metabolism • Glucose is the main stimulator of insulin release from the B cell, through GLUT 2 • Insulin works by binding to a receptor on the target cell surface. • Insulin has many functions such as glucose transport, protein synthesis, lipid synthesis, glycogen synthesis, growth and gene expression • Insulin recruits the cytoplasmatic vesicles with GLUT 4 and causes them to be translocated to the cell surface where GLUT 4 functions as s pore for glucose entry. PHYSIOLOGY • In normal subjects, blood glucose levels are maintained within relatively narrow limits at around 5 mmol/l (90 mg/dl) by the balance between glucose entry into the bloodstream from the liver and from intestinal absorption after meals, and glucose uptake into the peripheral tissues such as muscle. EPIDEMIOLOGY DM have 23.6 million children and adults in the United States (7.8% of the population). While an estimated 17.9 million have been diagnosed with diabetes, unfortunately, 5.7 million people (or nearly one quarter) are unaware that they have the disease. In USA, DM is the leading cause of: – – – end-stage renal disease, nontraumatic lower extremity amputations, adult blindness. CLASSIFICATION Diabetes mellitus is classified on the basis of the pathogenic process that leads to hyperglycemia. We can distinguish: • Type 1 DM • Type 2 DM • Other specific types of diabetes • Gestational diabetes mellitus (GDM) TYPE 1 DIABETES MELLITUS TYPE 1 DIABETES MELLITUS Type 1A DM results from autoimmune beta cell destruction, which leads to insulin deficiency Type 1B DM lack immunologic markers indicative of an autoimmune destructive process of the beta cells. Patients with this type of diabetes develope insulin deficiency by unknown mechanisms Few patients with type 1 DM are in the type 1B idiopathic category; many of these individuals are either African-American or Asian in heritage Type 1 DM most commonly develops before the age of 30, an autoimmune cell destructive process can develop at any age (Latent Autoimmune Diabetes in Adults – LADA). SIGNS AND SYMPTOMS The early detection of diabetes symptoms and treatment can decrease the chance of developing the complications of diabetes. Some typical symptoms for diabetes type 1 include: • Frequent urination (polyuria) • Excessive thirst (polydypsia) • Extreme hunger (polyphagia) • Unusual weight loss Others symptoms • Increased fatigue • Irritability • Blurry vision LAB STUDIES • Blood sugar level (hyperglycemia) • Urine analysis – Acetonuria – Glucosuria • Gasometry (acidosis) • Specific autoantibodies (present) • C-peptide (low) – part of pro-insulin which is co-secreted with insulin TYPE 2 DIABETES MELLITUS TYPE 2 DIABETES MELLITUS Is a heterogeneous group of disorders characterized by variable degrees of insulin resistance, impaired insulin secretion and increased glucose production Distinct genetic and metabolic defects in insulin action and/or secretion give rise to the common phenotype of hyperglycemia in type 2 DM Type 2 DM more typically with increasing age, but it also occurs in children, particularly in obese adolescents Type 2 DM is more often than type 1 DM TYPE 2 DIABETES MELLITUS RISK FACTORS Family history of diabetes Obesity (BMI ≥25 kg/m2) Habitual phisical inactivity Race/ethnicity (African American, Native American, Asian American, Pacyfic Islander) Previously identified impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) History of gestational diabetes mellitus or delivery of baby >4kg Hypertension HDL cholesterol level ≤ 35 mg/dl (0.90 mmol/l) and/or triglyceride level ≥250 mg/dl (2.82 mmol/l) Polycystic ovary syndrome Acantosis nigricans History of vascular disease SIGNS AND SYMPTOMS Diabetes often goes undiagnosed because many of its symptoms seem so harmless. It can be diagnosed accidently. Recent studies indicate that the early detection of diabetes symptoms and treatment can decrease the chance of developing the complications of diabetes. Some diabetes symptoms include: • Frequent urination (polyuria) • Excessive thirst (polydypsia) • Extreme hunger (polyphagia) • Unusual weight loss • Increased fatigue • Irritability • Blurry vision • Skin infections • Genital and urine infections LAB STUDIES • Blood sugar level (hyperglycemia) • Urine analysis – Glucosuria – Leucocyturia – Bacteriuria • Gasometry (normal) • C-peptide (normal or high) ACCESSORY INVESTIGATIONS • When you diagnose DM type 2 you have to look for chronic complications. – Eye examination – fundoscopy for retinopathy – Creatinin level, microalbuminuria for nephropathy – Testing of vibration, temperature and touch sense for neuropathy • When you diagnose DM type 1 you have to look for chronic complications after around 5 years. OTHER SPECIFIC TYPES OF DIABETES Other ethiologies for DM include specific genetic defects in insulin secretion or action, metabolic abnormalities that impair insulin secretion, mitochondrial abnormalities, and a host of conditions that impair glucose tolerance. Genetic defects of beta cell function Genetic defects in insulin action Disease of the exocrine pancreas – pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis Endocrinopathies – acromegaly, Cushing’s syndrome, pheochromocytoma, glucagonoma Drugs or chemical-induced – glucocorticoids, thyroid hormone Infections – congenital rubella, cytomegalovirus, coxackie Uncommon forms of immune-mediated diabetes Other genetic syndroms sometimes associated with diabetes – Down’s syndrom, Klineferter’s syndrom, Turner’s syndrom GESTATIONAL DIABETES MELLITUS (GDM) Diabetes mellitus developed during pregnency. Insulin resistance related to the metabolic changes of late pregnency increases insulin requirements. Most women revert to normal glucose tolerance post-partum but have a substantial risk (30 to 60%) of developing DM later in life. DIAGNOSIS Glucose tolerance is classified into three categories based on the fasting plasma glucose (FPG) FPG <5.6 mmol/l (100 mg/dl) is considered normal FPG ≥5.6 mmol/l (100 mg/dl) but <7,0 mmol/l (126 mg/dl) is defined as impaired fasting glucose (IFG) FPG ≥7,0 mmol/l (126 mg/dl) warrants the diagnosis of DM When patient have impaired fasting glucose (IFG) we make 75g oral glucose load and assey glucose level after 2 hours Glucose level 2 h after a 75g oral glucose load: <7.8 mmol/l (140 mg/dl) is normal ≥7.8 mmol/l (140 mg/dl) but <11,1 mmol/l (200 mg/dl) is defined as impaired glucose tolerance (IGT) ≥ 11,1 mmol/l (200 mg/dl) is DM DIAGNOSIS Criteria for the diagnosis of DM: • fasting plasma glucose (FPG) ≥7,0 mmol/l (126 mg/dl) • 2 h plasma glucose ≥ 11,1 mmol/l (200 mg/dl) during an oral glucose tolerance test • Symptoms of diabetes plus random blood glucose concentration ≥ 11,1 mmol/l (200 mg/dl) In absence of unequivocal hyperglycemia and acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day. Patient with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) are at substantial risk for developing type 2 DM (40% risk over the next 5 years) and cardiovascular disease. SCREENING The American Diabetes Association (ADA) recomends screening all individuals >45 years every 3 years and screening individuals with additional risk factors for type 2 DM at an earlier age. LONG-TERM TREATMENT OF DM The goals of therapy for type 1 or type 2 DM are to: • Eliminate symptoms related to hyperglicemia • Reduce or eliminate the long-therm microvascular and macrovascular complications of DM • Allow the patient to achive as normal a life style as possible The • • • • • • • • • patient with type 1 or type 2 DM should receive education about: nutrition, exercise, self-monitoring of blood glucose, Urine ketone monitoring (type 1 DM), Insuline administration, Management of hypoglycemia, Foot and skin care, care of diabetes during illness, medications to lower the plasma glucose. LONG-TERM TREATMENT OF DM Optimal monitoring of glycemic control involves plasma glucose measurements by the patient and an assessment of longterm control by the physician (measurement of hemoglobin A1c and review of the patient’s self-measurements of plasma glucose). These measurements provide a picture of short-term glycemic control, whereas the A1c reflects average glycemic control over the previous 2 to 3 months Ideal goals for glicemic control Preprandial plasma glucose – 5.0-7.2 mmol/l (90-130 mg/dl) Peak postprandial plasma glucose – <10 mmol/l (180 mg/dl) Hemoglobin A1c – <7.0% TREATMENT OF TYPE 1 DM • Insulin therapy TREATMENT OF TYPE 2 DM Menagement of type 2 diabetes: • Glycemic control – Diet/lifestyle – Exercise – Medication • Treat associated conditions – Dyslipidemia – Hypertension – Obesity – Coronary heart disease • Screen for/manage complications of diabetes – Retinopathy – Cardiovascular disease – Nephropathy – Neuropathy – Other complications TREATMENT OF TYPE 2 DM Advances in therapy of type 2 DM have generated considerable enthusiasm for oral glucose-lowering agents that target different pathophysiologic processes in type 2 DM. Based on their mechanisms of action, oral glucose-lowering agents are subdivided into agents that: • increase insulin secretion, • reduce glucose production, or increase insulin secretion, • reduce glucose production or increase insulin sensitivity Insulin therapy in type 2 DM Insulin therapy is ultimately required by a substantial number of the disorder and the relative insulin deficiency that develops in patients with long standing diabetes. COMPLICATIONS OF DM • ACUTE – • Diabetic ketoacidosis CHRONIC – Microangiopathy • • • – Macroangiopaty • • • – Retinopathy Nuropathy Nephropathy Coronary artery disease Peripheral vascular disease Cerebrovascular disease Other • • • Infectious Cataracts Glaucoma Diabetic ketoacidosis • Is a state of severe, uncontrolled diabetes due to insulin deficiency, and characterised by high blood glucose, volume depletion, ketone body concentrations and acidosis. • Is a serious condition with a mortality of 510% Diabetic ketoacidosis – causes The common precipitating causes of ketoacidosis are: 1. Infection (pneumonia, urine tract infection, gastroenteritis, sepsis) 2. Management errors (giving the wrong dose of insulin or failing to increase dosage during intercurrent illness) 3. Newly presenting type 1 diabetes 4. Myocardial infarction 5. Drugs (cocaine) 6. Pregnancy 7. In about 40% there is no obvious cause Diabetic ketoacidosis – mechanism • Relative or absolute insulin deficiency in the presence of catabolic counter-regulatory ‘stress’ hormones (catecholamines, cortisol, glucagon and growth hormone) leads to hepatic overproduction of glucose and ketones. • Lipolysis is promoted with the relase of nonestrified fatty acids from adipose tissue, which in the liver are oxidised to the ketone bodies: acetoacetic acid, 3-hydroxybutyric acid and acetone. • Ketone bodies contribute to the acidosis and fluid depletion Diabetic ketoacidosis – clinical features • • • • • • Polyuria and nocturia Thirst Weight loss Weakness Blurred vision Abdominal pain (can resemble acute pancreatitis or surgical abdomen) • Leg cramps • Nausea and vomiting • Confusion and drowsiness Diabetic ketoacidosis – physical findings • • • • • • • • Tachycardia Dry mucous membranes/reduced skin turgor Dehydration/hypotension Tachypnea Acidotic (Kussmaul) respiration (hyperventilation) Abdominal tenderness Coma (10% of cases) Acetone which is volatile can often be smelled on the breath of ketoacidotic patients (fruity odor) Diabetic ketoacidosis – laboratory abnormalities • • • • • • • Hyperglycaemia Ketosis Metabolic acidosis (increased anion gap) Creatinine – elevated due to volume depletion Leukocytosis Hypertriglyceridemia, hyperlipoproteinemia Serum osmolality is mildly to moderately elevated Diabetic ketoacidosis – treatment 1. Fluids (isotonic saline 1l/h; usually 4-6 l in first 24h) 2. Potassium; if serum potassium is: <3.5 mmol/l add 40 mmol K+ 3.5-5.5 mmol/l add 20 mmol K+ >5.5 mmol/l add no K+ 3. Insulin Bolus IV 0.1 units/kg and than 0.1 units/kg per hour by continous IV infusion Thank you for your attention!!!