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DIABETES MELLITUS What is diabetes mellitus? The majority of intake of food is converted into glucose. The pancreas produces the insulin hormone, which help the organism to take advantage of glucose. In persons with diabetes, the insulin does not work. Therefore, the sugar and the fat increase in the blood. The World Wide Epidemic: Prevalence of Diabetes 5% 8% 3% 14% 4% The Worldwide Epidemic: Diabetes Trends Millions with Diabetes 400 370 350 300 300 250 221 177 200 135 150 100 50 30 0 1985 1995 2000 Sources: www.who.int www.idf Zimmet P. et al Nature: 414, 13 Dec 2001 2010 2025 2030 PHYSIOLOGICAL IMPACT th 6 leading cause of death by disease Decreases life expectancy of middle-aged people by 5-10 years 2-4 x greater risk of death d/t heart disease – Compounding factors include: duration of disease, glycemic control, HTN, smoking, dyslipidemia, decreased activity, and obesity Leading cause of blindness in 25-74 year olds Leading cause of non-traumatic amputations Responsible for 25-30% of all new dialysis patients DIABETES MELLITUS Definition: a metabolic disorder in which there is deficiency of insulin production or resistance of organs to the effect of insulin DIABETES MELLITUS Diabetes is a disorder of metabolism--the way our bodies use digested food for growth and energy. Most of the food we eat is broken down into glucose, the form of sugar in the blood. Glucose is the main source of fuel for the body. <http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what> DIABETES MELLITUS After digestion, glucose passes into the bloodstream, where it is used by cells for growth and energy. For glucose to get into cells, insulin must be present. Insulin is a hormone produced by the pancreas, a large gland behind the stomach. <http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what> Regulation of Blood Sugar Cori & Cori (1947) Signal Transduction Decreased Tyrosine-kinase-linked receptor High blood sugar Insulin Liver Blood Pancreas Hormone Glycogen Low blood sugar Glucagon Glycogen synthase Glucose Glycogen phosphorylase GTP-protein-linked receptor Increased Juang RH (2004) BCbasics Normal glucose homeostasis is tightly regulated by three interrelated processes: (1) glucose production in the liver, (2) glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle, (3) actions of insulin and counterregulatory hormones (e.g., glucagon). DIABETES MELLITUS NORMAL: When non-diabetic people eat, the pancreas automatically produces the right amount of insulin to move glucose from blood into our cells. <http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what> DIABETES MELLITUS DIABETES: In people with diabetes, when they eat, the pancreas either produces little or no insulin, or the cells do not respond appropriately to the insulin that is produced (or both) => glucose builds up in the blood, overflows into the urine, and passes out of the body in urine => body loses its main source of fuel even though blood contains large amounts of glucose. <http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what> Diabetes mellitus is not a single disease entity but rather a group of metabolic disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia in diabetes results from defects in insulin secretion, defects in insulin action, most commonly, both. The principal metabolic function of insulin is to increase the rate of glucose transport into certain cells in the body These are the striated muscle cells (including myocardial cells) and, to a lesser extent, adipocytes, representing collectively about two-thirds of the entire body weight. Glucose uptake in other peripheral tissues, most notably the brain, is insulin independent. metabolic effects of insulin - anabolic, with increased synthesis and reduced degradation of glycogen, lipid, and protein. In addition - several mitogenic functions, including initiation of DNA synthesis in certain cells and stimulation of their growth and differentiation. Etiologic Classification of Diabetes Type 1 Diabetes - Mellitus β-cell destruction, leads to absolute insulin deficiency Type 2 Diabetes -Insulin resistance with relative insulin deficiency Genetic Defects of β-Cell Function Genetic Defects in Insulin Processing or Insulin Action Exocrine Pancreatic Defects Endocrinopathies Infections Drugs Genetic Syndromes Associated with Diabetes Gestational Diabetes Mellitus DM TYPE I Auto-immune disease Constitutes 5-10% of DM diagnosed in the USA Mostly appears in children and young adults Develops as a result of auto-immune destruction of beta-cells in the pancreas Presents with polyuria, thirst, weight loss, marked fatigue Can be complicated by coma with ketoacidosis • <http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what> DM TYPE II Most common form of diabetes Involves about 90-95% of people with DM Associated with: – – – – – – older age obesity family history of DM prior history of gestational diabetes physical inactivity ethnicity • <http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what> DM TYPE II Patient with type II DM usually makes enough insulin but the body cannot use it effectively => insulin resistance Gradually insulin production decreases over the following years Symptoms are similar to type I but develop more gradually • <http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what> Genetic defects of β-cell function Maturity-onset diabetes of the young (MODY), caused by mutations in: Hepatocyte nuclear factor 4α (HNF4A), MODY1 Glucokinase (GCK), MODY2 Hepatocyte nuclear factor 1α (HNF1A), MODY3 Pancreatic and duodenal homeobox 1 (PDX1), MODY4 Hepatocyte nuclear factor 1β (HNF1B), MODY5 Neurogenic differentiation factor 1 (NEUROD1), MODY6 Neonatal diabetes (activating mutations in KCNJ11 and ABCC8, encoding Kir6.2 and SUR1, respectively) Maternally inherited diabetes and deafness (MIDD) due to mitochondrial DNA mutations (m.3243A➙G) Defects in proinsulin conversion Insulin gene mutations Maturity onset Diabetes of Young {MODY } Insulin secretory defect without beta cell loss Autosomal dominant inheritance with high penetrance Early onset before 25 Impaired β - cell function , normal weight , lack of GAD antibodies , lack of INSULIN resistance syndrome Genetic defects in insulin action Type A insulin resistance Lipoatrophic diabetes, including mutations in PPARG Exocrine pancreatic defects Chronic pancreatitis Pancreatectomy/trauma Neoplasia Cystic fibrosis Hemachromatosis Fibrocalculous pancreatopathy Endocrinopathies Acromegaly Cushing syndrome Hyperthyroidism Pheochromocytoma Glucagonoma Infections Cytomegalovirus Coxsackie B virus Congenital rubella Drugs Glucocorticoids Thyroid hormone Interferon-α Protease inhibitors β-adrenergic agonists Thiazides Nicotinic acid Phenytoin (Dilantin) Vacor Genetic syndromes associated with diabetes Down syndrome Kleinfelter syndrome Turner syndrome Prader-Willi syndrome GESTATIONAL DIABETES Develops only during pregnancy More common in: – African Americans – American Indians – Hispanic Americans – women with a family history of diabetes Women with a history of gestational diabetes have a 20-50% chance of getting type II DM within 510 years <http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what> Gestational Diabetes Mellitus Hyperglycemia diagnosed during pregnancy Occurs in 2-5% of pregnancies Occurs due to placental hormone changes that effect insulin function (greater resistance) Screening usually occurs during the 24th-28th week in high risk patients Criteria for diagnosis is different than for Type 1 and Type 2 Dietary changes are initial treatment and insulin is the only BG lowering agent used Concern is both for maternal and fetal well-being Postpartum BG levels usually return to normal Increased risk for Type 2 diabetes (30-50%) Pathogenesis of Type 1 Diabetes Mellitus autoimmune disease in which islet destruction is caused primarily by T lymphocytes reacting against as yet poorly defined β-cell antigens, resulting in a reduction in β-cell mass genetic susceptibility and environmental influences play important roles in the pathogenesis. most commonly develops in childhood, becomes manifest at puberty, and is progressive with age. Most individuals with type 1 diabetes depend on exogenous insulin supplementation for survival, and without insulin, they develop serious metabolic complications such as acute ketoacidosis and coma. The classic manifestations of the disease (hyperglycemia and ketosis) occur late in its course, after more than 90% of the β cells have been destroyed. Several mechanisms contribute to β-cell destruction, and it is likely that many of these immune mechanisms work together to produce progressive loss of β cells, resulting in clinical diabetes: Type 1 diabetes complex pattern of genetic association the principal susceptibility locus for type 1 diabetes resides in the region that encodes the class II MHC molecules on chromosome 6p21 (HLA-D). Between 90% and 95% - HLA-DR3, or DR4, or both, also evidence to suggest that environmental factors, especially infections, - viruses may be an initiating trigger, -molecular minicry Pathogenesis of Type 2 Diabetes Mellitus pathogenesis of type 2 diabetes remains enigmatic. Environmental influences, such as a sedentary life style and dietary habits, clearly have a role, Nevertheless, genetic factors are even more important than in type 1 diabetes, Among identical twins, the concordance rate is 50% to 90%, while among first-degree relatives with type 2 diabetes (including fraternal twins) the risk of developing the disease is 20% to 40% Insulin Resistance Insulin resistance is defined as the failure of target tissues to respond normally to insulin. leads to decreased uptake of glucose in muscle, reduced glycolysis and fatty acid oxidation in the liver, and an inability to suppress hepatic gluconeogenesis. Few factors play as important a role in the development of insulin resistance as obesity. Obesity and Insulin Resistance. epidemiologic association of obesity with type 2 diabetes - observed in greater than 80% of patients. Insulin resistance is present even in simple obesity unaccompanied by hyperglycemia, indicating a fundamental abnormality of insulin signaling in states of fatty excess (see metabolic syndrome, below). The risk for diabetes increases as the body mass index (a measure of body fat content) increases. It is not only the absolute amount but also the distribution of body fat that has an effect on insulin sensitivity: central obesity (abdominal fat) is more likely to be linked with insulin resistance than are peripheral (gluteal/subcutaneous) fat depots. Obesity can adversely impact insulin sensitivity in numerous ways Nonesterified fatty acids (NEFAs): Adipokines:Leptin and adiponectin improve insulin sensitivity by directly enhancing the activity of the AMP-activated protein kinase (AMPK), an enzyme that promotes fatty acid oxidation, in liver and skeletal muscle. Adiponectin levels are reduced in obesity, thus contributing to insulin resistance. Inflammation: Adipose tissue also secretes a variety of proinflammatory cytokines like tumor necrosis factor, interleukin-6, and macrophage chemoattractant protein-1, the last attracting macrophages to fat deposits. These cytokines induce insulin resistance by increasing cellular “stress,” which in turn, activates multiple signaling cascades that antagonize insulin action on peripheral tissues. Peroxisome proliferator-activated receptor γ (PPAR γ): PPARγ is a nuclear receptor and transcription factor expressed in adipose tissue, and plays a seminal role in adipocyte differentiation. Activation of PPARγ promotes secretion of anti-hyperglycemic adipokines like adiponectin, and shifts the deposition of NEFAs toward adipose tissue and away from liver and skeletal muscle. AS DISCUSSED BELOW, RARE MUTATIONS OF PPARG THAT CAUSE PROFOUND LOSS OF PROTEIN FUNCTION CAN RESULT IN MONOGENIC DIABETES. β-Cell Dysfunction In type 2 diabetes, β cells seemingly exhaust their capacity to adapt to the long-term demands of peripheral insulin resistance. In states of insulin resistance like obesity, insulin secretion is initially higher for each level of glucose than in controls. This hyperinsulinemic state is a compensation for peripheral resistance and can often maintain normal plasma glucose for years. Eventually, however, β-cell compensation becomes inadequate, and there is progression to hyperglycemia. The two metabolic defects that characterize type 2 diabetes are (1) a decreased ability of peripheral tissues to respond to insulin (insulin resistance) and (2) β-cell dysfunction that is manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia. In most cases, INSULIN RESISTANCE IS T2DM is a disorder characterized by a Combination of reduced tissue sensitivity to insulin and inadequate secretion of insulin from the pancreas. Hyperglycemia in T2DM is a failure of theβ cells to meet an increased demand for insulin in the body MORPHOLOGY PANCREAS TYPE - 1 - reduction in number & size of islets - leukocytic infilteration of islets TYPE - 2 - subtle reduction in islet cell mass - amyloid replacement of islets Diabetes Mellitus Absence (or ineffectiveness of ) insulin Cellular resistance Cells can’t use glucose for energy – Starvation mode • Compensatory breakdown of body fat/protein • Ketone bodies from faulty fat breakdown • Metabolic acidosis, compensatory breathing (Kussmal’s breathing) DM TYPE II Symptoms of type II DM include: – – – – – – – – – Fatigue Nausea Frequent urination/polyuria Thirst Unusual weight loss Blurred vision Frequent infections Slow healing of wounds or sores Sometimes no specific symptoms • <http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what> Diabetes Mellitus HYPERGLYCEMIA: fluid/electrolyte imbalance. – Polyuria • Sodium, chloride, potassium excreted – Polydipsia from dehydration – Polyphagia: cells are starving, so person feels hungry despite eating huge amounts of food. Starvation state remains until insulin is available. CLINICAL Onset: usually childhood and adolescence Onset: usually adult; increasing incidence in childhood and adolescence Normal weight or weight loss preceding diagnosis Vast majority are obese (80%) Progressive decrease in insulin levels Increased blood insulin (early); normal or moderate decrease in insulin (late) Circulating islet autoantibodies (anti-insulin, antiGAD, anti-ICA512) No islet auto-antibodies Diabetic ketoacidosis in absence of insulin therapy Nonketotic hyperosmolar coma more common GENETICS Major linkage to MHC class I and II genes; also linked to polymorphisms in CTLA4 and PTPN22, and insulin gene VNTRs No HLA linkage; linkage to candidate diabetogenic and obesity-related genes (TCF7L2, PPARG, FTO, etc.) PATHOGENESIS Dysfunction in regulatory T cells (Tregs) leading to breakdown in self-tolerance to islet autoantigens Insulin resistance in peripheral tissues, failure of compensation by β-cells Multiple obesity-associated factors (circulating nonesterified fatty acids, inflammatory mediators, adipocytokines) linked to pathogenesis of insulin resistance PATHOLOGY Insulitis (inflammatory infiltrate of T cells and macrophages) No insulitis; amyloid deposition in islets β-cell depletion, islet atrophy Mild β-cell depletion Type II Diabetes Diagnostic testing - when to do it: People 45 years old => if normal then every 3 years MKSAP13 Endocrinology and Metabolism. American College of Physicians 2004. Type II Diabetes: diagnostic testing Younger than 45 yr or more often than every 3 years if: overweight first degree relative with diabetes member of high risk ethnic group (Afro-American, Hispanic American, Native American, Asian American, Pacific Islander) delivered a baby 9 lbs. gestational diabetes hypertensive (BP 140/90mmHg) High Density Lipoprotein cholesterol 35mg/dl or less TriGlyceride level 250mg/dl or more pre-diabetes MKSAP13 Endocrinology and Metabolism. American College of Physicians 2004. Who’s at risk of Type II? Diabetes Mellitus The good news: – Blood glucose control reduces complications of Diabetes! Diabetes Mellitus Complications of chronic hyperglycemia – Macrovascular complications • Cardiovascular disease (heart attack) • Cerebrovascular disease (strokes) – Microvascular • • • • Blindness (retinal proliferation, macular degeneration) Amputations Diabetic neuropathy (diffuse, generalized, or focal) Erectile dysfunction The Laboratory Examination Laboratory plays an important part in the diagnosis and care of diabetic patients Diagnosis Blood glucose levels - 70 to 120 mg/dL. Diagnosis - By Elevation Of Blood Glucose By Any One Of Three Criteria: A random blood glucose concentration of 200 mg/dL or higher, with classical signs and symptoms A fasting glucose concentration of 126 mg/dL or higher on more than one occasion, An abnormal oral glucose tolerance test (OGTT), in which the glucose concentration is 200 mg/dL or higher 2 hours after a standard carbohydrate load (75 gm of glucose). Method: Glucose Oxidase GLU+2H2O+O2 GOD Gluconic acid +2H2O2 2H2O2 +4-aminoantipyrine +1,7-dihy- droxynaphthalene POD red dye Reference Interval Fasting glucose : 3.9 - 6.11mmol/l (fasting is defined as no calorie intake for at least 8 hours) Urine Tests URINE "GLUCOSE" – lacks sensitivity = positivity in disease – poor specificity = negativity in health Problems – renal threshold variable 6 to 15 mmol/L – interferences : Clinitest / Glucose oxidase strips IF URINE TEST POSITIVE A CONFIRMATORY BLOOD TEST IS NEEDED Blood Tests Glucose – whole blood 10-15% lower than plasma – venous 10% lower than capillary – Venous blood - loss of 0.33 mmol/L per hour – There is no decrease within 24 h in the presence of sodium fluoride Oral Glucose Tolerance Test (OGTT) A venous blood sample will be collected for the determination of fasting glucose Load of 75g of glucose is ingested within 5 min Blood samples will be collected at timed intervals (30min, 60min, 120min) for the determination of glucose OGTT Criteria Plasma glucose (mmol/L) 0 min Non diabetic < 6.1 Impaired glucose tolerance 6.1 - 6.9 11.1 Diabetic > 7.0 120 min < 7.8 >7.8 - > 11.1 Glycosylated proteins Caused by non-enzymatic glycosylation – Glycosylated hemoglobin • HbA1c - LGI ref range 4.6-6.5 % • indicates previous 2-3 months glycaemic exposure • n.b. affetced by altered red cell survival – Fructosamine • mirrors glycosylation of all serum proteins • indicates previous 2-3 weeks glycaemic exposure • used pregnancy/children in some sites – Glycosylated albumin • indicates previous several days glycaemic exposure • not commonly used Hemoglobin A1c HbA1c is stable glycosylated hemoglobin Its percentage concentration indicates cumulative glucose exposure Hemoglobin A1c A good indicator of blood glucose control. Gives a % that indicates control over the preceding 2-3 months. Performed 2 times a year. A hemoglobin of 6% indicates good control and level >8% indicates action is needed. Lowering HbA1C Reduces Risk of Complications Secondary Diabetes Mellitus DM occurs as a result of another problem (primary) – Diseases – Conditions – Medications • • • • Thiazides Diuretics Beta blockers Steroids Hyperglycemia is diagnostic for DM Treatment of the primary cause may resolve the DM but lifestyle modifications and medications may be needed as well Pre-Diabetes Pre-diabetes refers to a state between “normal” and “diabetes” = fasting plasma glucose 100-125mg/dL (higher than normal but not high enough for diagnosis of diabetes) Affects about 41 million people in USA (previously referred to as either impaired fasting glucose or impaired glucose tolerance) Impaired Fasting Glucose Defined as a fasting plasma blood glucose of >/= to 110 but < 126 Increased risk for DM Must educate regarding risks and need for lifestyle modifications Impaired Glucose Tolerance Defined as a plasma blood glucose of >/= to 140 but < 200 after a 2 hour 75 gram glucose tolerance test 8-10% of US population have this problem with a 25 % risk of developing DM 2 Compounding risk factors effect risk of developing Type 2 DM – – – – Age Activity Comorbidities Weight Increased risk for macrovascular diseases Must educate regarding risks and need for lifestyle modifications Diabetes is preventable by life style modification Maintain a healthy body weight Half an hour of exercise daily Eat a healthy diet (fruits, vegetables, bread, milk) Triad of Treatment Diet Medication – Oral hypoglycemics – Insulins Exercise Diabetes Mellitus Prevention of effects: combination approach – Increased exercise • Decreases need for insulin – Reduce calorie intake • Improves insulin sensitivity – Weight reduction • Improves insulin action Classification of Diabetes Type I DM Type II DM Aetiology Autoimmune (- cell destruction) Insulin resistance and -cell dysfunction Peak age 12 years 60 years Prevalence 0.3% 6% (>10% above 60 years) Presentation Osmotic symptoms, weight loss (days to weeks), DKA Patient usually slim Osmotic symptoms, diabetic complications (months to years). Patient usually obese Treatment Diet and insulin Diet, exercise (weight loss), oral hypoglycemics, Insulin later In Conclusion : Diabetes is a very complicated disease. It is easy to diagnosis and it is difficult to treat Laboratory plays an important part in the diagnosis and care of diabetic patients