What is diabetes? Normal blood glucose levels Insulin

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1 DIABETES MELLITUS

2 Introduction to diabetes mellitus What is diabetes? - Heterogenous clinical syndrome in which the central feature is a chronic elevation of the blood glucose concentration - this results in a range of pathologies. - Due to a deficiency of insulin (absolute) or a resistance to insulin (relative). - The chronic hyperglycaemia is associated with long term tissue damage, especially the blood vessels, nerves, heart, kidneys and eyes. Normal blood glucose levels - Normal homeostatic mechanisms maintain blood glucose levels within a narrow range of mmol/l [ca mg/dl (mg%)]. Insulin - consists of two amino acid chains linked by two disulfide bridges - proinsulin in pancreatic beta cell is cleaved to insulin and a connecting peptide (c-peptide levels can be used to measure amount of endogenous insulin production) - main stimulus for release is glucose, but release can also be triggered by amino acids, fatty acids and ketone bodies. Activation of beta2-adrenergic receptors in pancreas also stimulate release of insulin whereas stimulation of the alpha-adrenergic receptors in pancreas inhibit insulin release - effects of insulin are anabolic - conservation of energy, promotes cell growth, suppresses gluconeogenesis and promotes glycogenolysis, promotes peripheral uptake of glucose especially in skeletal muscle cells, encourages storage (as muscle glycogen).

3 Diabetes Definition (continued) Diabetes is a life-long disease marked by high levels of sugar in the blood. It can be caused by too little insulin (a hormone produced by the pancreas to regulate blood sugar), resistance to insulin, or both.

4 Pancreas makes insulin. The role of insulin is to move glucose from the bloodstream into muscle, fat, and liver cells, where it can be used as fuel. People with diabetes have high blood glucose. This is because their pancreas does not make enough insulin or their muscle, fat, and liver cells do not respond to insulin normally, or both. Normal islets of Langerhans, on the right with immunoperoxidase staining for insulin to identify beta cells and on the left with immunoperoxidase staining for glucagon to identify alpha cells, are shown here.

5 Insulin receptors - The receptors for insulin are found on most mammalian cells action of insulin is mediated through these receptors. - Impaired action of insulin can result from defects in the receptors or defects in post-receptor events. Deficiency of insulin - catabolic effects (breakdown of complex molecules) - these contribute to signs and symptoms of diabetes. - glycogen is broken down to glucose; proteins to amino acids; fats to glycerin and free fatty acid. - hyperglycaemia is promoted by increasing glycogenolysis and glycogenesis and a reduction in glucose utilisation.

6 Classification of diabetes mellitus Previous classification: 1. Juvenile onset diabetes/insulin dependent diabetes mellitus 2. Adult onset diabetes/non-insulin dependent diabetes mellitus Now classified as: 1. Type 1: Immune mediated (could be in children with a more rapid onset (classic) or adults with a slower onset LADA, late autoimmune diabetes of adults ) 2. Type 2: Insulin resistant 3. Other specific types (eg certain genetic defects; drug induced; etc) 4. Gestational diabetes mellitus Evolution and changes in the classification and diagnostic criteria have implications for the interpretation of epidemiological studies a lot of important epidemiological work predated the most recent diagnostic criteria.

7 Classification scheme of diabetes mellitus Type 1 diabetes mellitus Type 2 diabetes mellitus Other specific types of diabetes mellitus Gestational diabetes The World Health Organisation (WHO) has prepared a number of classification schemes of diabetes mellitus; nowadays the following is mostly accepted.

8 The epidemiology - Affects generally around 7% of the population in developed countries with large geographic and ethnic variations in incidence. - Type 2 accounts for up to 85%-95% of cases of diabetes mellitus. - For example, in Australia, the prevalence of diabetes was 8% in men, 6.8% in women and is rising. The prevalence of impaired glucose tolerance was 17.4% in men and 15.4% in women.

9 The epidemiology (continued) Type 1: - Registries widely used to record incidence - Considerable geographic variability in incidence rates are highest in Norway, Finland, Sweden, Canada; lowest in Japan, Chile, Mexico, China, South America. Incidence is increasing. Type 2: - True prevalence not known. - Type 2 accounts for up to 85%-95% of cases of diabetes mellitus. - Up to 20% over age 80 have diabetes. - Prevalence in Massachusetts, USA has increased from 0.9% in 1958 to 3% in Increasing incidence of diabetes parallels increase in incidence of obesity. - Epidemic in some countries. - Lowest prevalence is in less developed countries and rural areas (up to 2% in China and Africa; >50% in Pima Indians in Arizona). - Increasing incidence of obesity in children may be responsible for increased incidence of type 2 diabetes in children.

10 The aetiology of diabetes mellitus Aetiology of Type 1 Due to selective destruction of pancreatic beta cells by an autoimmune process - assumed to occur following an environmental trigger in genetically susceptible individuals absolute insulin deficiency. Aetiology - Type 1 Genetics Genetic susceptibility - HLA-DR3, -DR4, B8 and B15 predispose to diabetes (account for 40% of the genetic susceptibility). However, the majority of those who are genetically predisposed do not develop diabetes. Risk of developing diabetes when close relative has diabetes are 30% for identical twins, 5% for siblings and 6% for offspring. Aetiology - Type 1 Environment Environmental - could be viral (several have been implicated - Coxsackie B4, retroviruses, rubella, cytomegalovirus, Epstein-Barr); diet (cow's milk has been implicated); stress Viruses may initiate immune mediated damage to beta cells by direct destruction, by the generation of cytokines that can damage the beta cells or by molecular mimicry Immune destruction Markers of immune mediated damage include: islet cell autoantibodies (ICA), insulin autoantibodies (IAA), glutamic decarboxylase autoantibodies (GAD), tyrosinephosphatases autoantibodies (IA-2) Individuals are insulin deficient (absolute insulin deficiency) - hyperglycaemia occurs when about 75% of beta cells are destroyed. Clinical onset is generally acute, but destruction of beta cells had been progressive for many years prior to diagnosis preclinical stage may be up to 5 7 years

11 Diabetes type I An islet of Langerhans demonstrates insulitis with lymphocytic infiltrates in a patient developing type I diabetes mellitus. This lesion precedes clinical onset of diabetes mellitus and is rarely observed.

12 The aetiology of diabetes mellitus (continued) Hypothetical Stages of Type 1 1. Genetic susceptibility 2. Triggering of immune response by environmental agent 3. Autoimmunity develops - antibodies detectable include ICA (islet cell antibodies), IAA (insulin autoantibodies) and anti-gad (glutamic decarboxylase autoantibodies). 4. Clinical diabetes 5. Remission (honeymoon phase) 6. Relapse - need insulin for survival

13 Empirical risk for type 1 diabetes % Monozygotic twins HLA-identical siblings Average risk in siblings General population

14 The aetiology of diabetes mellitus (continued) Aetiology - Type 2 - Insulin resistance creates a relative insulin deficiency. Insulin resistance can be due to a number of reasons - tends to occur in those that are obese. - Consensus is that the aetiology is a multifactorial interaction of environmental and genetic factors Aetiology - Type 2 Genetics - genetic predisposition for Type 2 diabetes is stronger than for Type 1 - concordance rates in monozygotic twins is almost 100% - magnitude of genetic contribution is unknown - probably involves several genes

15 The aetiology of diabetes mellitus (continued) Aetiology - Type 2 Environment i) Lifestyle: - overeating, obesity and inactivity are a high risk for type 2 - most of type 2 patients are obese, but only a few obese people develop diabetes ii) Malnutrition in utero - retrospective analysis has shown an inverse relationship between weight at birth and type 2 diabetes in late adulthood - suggested that malnutrition in utero may damage beta cell development iii) Age iv) Ethnicity

16 Diabetes type II The islets of Langerhans are normal in number or somewhat reduced with type II diabetes mellitus. Fibrosis and deposition of amylin polypeptide within islets are most characteristic of the chronic states of type II diabetes.

17 Diabetes type II - formerly known as non-insulin-dependent diabetes mellitus (NIDDM), type II, or adult-onset diabetes. - The patients are usually older at the onset of disease, mostly present only minimal symptoms. - Insulin concentrations are mostly increased but they can be normal or decreased. - Obesity is quite common and weight reduction ameliorates the hyperglycaemia. - The disease usually develops after 40 years of age. - Oral hypoglycaemic drugs and dietary manipulation represent the biggest role in therapy; insulin is sometimes required to correct hyperglycaemia.

18 Diabetes type II THE GROUPS OF DISORDERS, OF WHICH TWO ARE MOST COMMON, REPRESENT THE NEW KNOWLEDGE TYPE 2 DIABETES MELLITUS The first one is a decreased ability of insulin to act on peripheral tissues. ("insulin resistance ). Insulin resistance is defined as a decreased biological response to normal concentrations of circulating insulin and represents the primary underlying pathological process. The second is the dysfunction of pancreatic ß-cells, represented by the inability to produce sufficient amount of insulin to overcome insulin resistance in the peripheral tissues. Later on the insulin production can be insufficient to compensate the insulin resistance due to ß-cells dysfunction. The relative deficiency of insulin occur. Long discussion was held about the primary reason - insulin resistance or derangement of insulin production. Data support the concept that insulin resistance is the primary defect, preceding the derangement of insulin secretion. Insulin resistance usually precedes the clinical signs by as much as 20 years. The basis of insulin resistance and insulin secretion defect results from a combination of environmental and genetic factors.

19 Diabets - Thrifty genotype hypothesis: A genetic trait that was important to survival (ability to go without food for extended period) is now detrimental due to abundant food supplies and reductions in physical activity. First proposed by Neel in Certain populations (largely indigenous populations) have developed what is considered a thrifty gene that allows them to survive period of famine when food is in short supply this thrifty gene is associated with a metabolic efficiency that allows storage of calories as fat with minimal energy expenditure. However, when food is plentiful, as occurs in many of these cultures today (the westernisation of diet), the thrifty gene predisposes to obesity (especially central obesity) - this may account for the increased risk for development of diabetes.

20 Gestational diabetes mellitus - usually asymptomatic and not life threatening to the mother. - associated with an increased incidence of neonatal morbidity, neonatal hypoglycaemia, macrosomia and jaundice. Even normal pregnancies are associated with increasing insulin resistance, mostly in the second and third trimesters. Euglycaemia is maintained by increasing insulin secretion. In those women who are not able to increase the secretion of insulin, gestational diabetes develops. The pathophysiology of gestational diabetes mellitus is not well known and includes family history of diabetes mellitus, obesity, complications in previous pregnancy(ies) and advanced maternal age. It is essential to detect pre-existing diabetes mellitus which has a much worse prognosis for the fetus.

21 Other specific types of diabetes mellitus Other specific types of diabetes mellitus are heterogeneous. The following are the biggest groups: genetic defects of ß-cell function genetic defects in insulin action diseases of the exocrine pancreas other endocrinopathies drug- or chemical-induced diabetes mellitus infection-induced diabetes mellitus rare forms of immune-mediated diabetes other genetic syndromes sometimes associated with diabetes The aetiology and pathophysiology are very different, mostly complicated or connected to insulin secretion and action derangement, as well as signal transduction inside the cells disarrangement.

22 Diagnosis of diabetes mellitus Classical symptoms of hyperglycaemia: - polyuria (excessive urination) - polydipsia (thirst) - nocturia (nocturnal urination) - lethargy - weight loss

23 Diabetes - characteristics TYPE I Patients with type 1 diabetes usually develop symptoms over a short period of time, and the condition is often diagnosed in an emergency setting. In addition to having high glucose levels, acutely ill type 1 diabetics have high levels of ketones. Ketones (acetone, acetoacetate, β-hydroxybutyrate) are produced by the breakdown of fat and muscle, and they are toxic at high levels. Ketones in the blood cause a condition called "acidosis" (low blood ph). Urine testing detects both glucose and ketones in the urine. Blood glucose levels are also high. TYPE II Because type 2 diabetes develops slowly, some people with high blood sugar experience no symptoms at all.

24 Diabetes type II risk factors There are many risk factors for diabetes, including: A parent, brother, or sister with diabetes Obesity Age greater than 45 years Some ethnic groups (particularly African-Americans and Hispanic Americans) Gestational diabetes or delivering a baby weighing more than 9 pounds (ca. 4,5kg) High blood pressure High blood levels of triglycerides High blood cholesterol level

25 Criteria for diagnosis - signs and tests A urine analysis may be used to look for glucose and ketones from the breakdown of fat. However, a urine test alone does not diagnose diabetes. The following blood glucose tests are used to diagnose diabetes: Fasting blood glucose level -- diabetes is diagnosed if higher than 126 mg/dl (7mmol/l) on two occasions (fasting is no food for > 8 hours). Random (non-fasting) blood glucose level -- diabetes is suspected if higher than 200 mg/dl (11.1mmol/l) and accompanied by the classic symptoms of increased thirst, urination, and fatigue. (This test must be confirmed with a fasting blood glucose test.) Oral glucose tolerance test -- diabetes is diagnosed if glucose level is higher than 200 mg/dl (11.1mmol/l) after 2 hours (This test is used more for type 2 diabetes.)

26 Impaired glucose tolerance (IGT): - represents an intermediate category between normal and diabetes an area of uncertainty - at higher risk of developing type 2 diabetes and macrovascular disease (sometimes called dysglycaemic macroangiopathy ) - usually clinically asymptomatic - not at increased risk for microvascular complications - a small percent with IGT revert to normal glucose tolerance on subsequent tests - the diagnostic levels for fasting blood glucose are considered to be at a level that there is an increased risk for microvascular disease and not at the assumed lower levels when there may be an increased risk for macrovascular disease

27 Diabetes - treatment There is no cure for diabetes. The immediate goals are to stabilize your blood sugar and eliminate the symptoms of high blood sugar. The long-term goals of treatment are to prolong life, relieve symptoms, and prevent long-term complications such as heart disease and kidney failure.

28 LONG-TERM COMPLICATIONS OF DIABETES MELLITUS

29 Cardiovascular complications Heart disease and stroke Heart disease is the leading cause of diabetes-related deaths. Adults with diabetes have heart disease death rates about two to four times higher than adults without diabetes. The risk for stroke is two to four times higher among people with diabetes. About 65 percent of deaths among people with diabetes are due to heart disease and stroke. High blood pressure About 73 percent of adults with diabetes have blood pressure greater than or equal to 130/80 mm Hg or use prescription medications for hypertension.

30 Atherosclerosis - Persons with diabetes mellitus, either type I or type II, have early and accelerated atherosclerosis. The most serious complications of this are atherosclerotic heart disease, cerebrovascular disease, and renal disease. - The most common cause of death with diabetes mellitus is myocardial infarction. - Peripheral vascular disease is a particular problem with diabetes mellitus and is made worse through the development of diabetic neuropathy, leading to propensity for injury.

31 The left anterior descending coronary artery that courses over the anterior surface of the heart shown here is opened to demonstrate a recent red-black thrombus filling the lumen in a patient with diabetes mellitus. The interventricular septum has been sectioned to reveal a large recent myocardial infarction (about 4 to 7 days old) with a tan-yellow necrotic center surrounded by a zone of hyperemia, gross. About half of persons with diabetes mellitus will die from a myocardial infarction as a consequence of coronary atherosclerosis.

32 Cardiovascular complications Aortic atherosclerosis is demonstrated in three aortas, from minimal at the bottom to severe at the top. Diabetics tend to have more advanced, extensive atherosclerosis.

33 Ocular complications Diabetic retinopathy is one of the leading causes for irreversible blindness. This retinopathy can occur with either type I or type II diabetes mellitus, usually a decade or so after the onset of diabetes. Most persons with type I diabetes and many of those with type II diabetes develop some background (non-proliferative ) retinopathy. Proliferative retinopathy is more ominous and is more likely to occur when diabetes mellitus is poorly controlled.

34 Ocular complications Glaucoma with marked cupping of the optic disk is seen on funduscopic examination. In severe retinopathy, neovascularization may lead to adhesions (synechiae) between iris and cornea or iris and lens. Neovascularization of the iris leads to secondary glaucoma with blindness.

35 Ocular complications Cataracts of the crystalline lens with opacification are more frequent in persons with diabetes mellitus. Cataracts are more common in diabetics. This predilection for development of cataracts is felt to result from hyperglycemia leading to accumulation of sorbitol that results in osmotic damage to the crystalline lens.

36 Ocular complications Blindness Diabetes is the leading cause of new cases of blindness among adults aged years. Diabetic retinopathy causes 12,000 to 24,000 new cases of blindness each year in USA.

37 Renal Complications There are a variety of complications involving the kidney. Both nodular and diffuse glomerulosclerosis can lead to chronic renal failure. Diabetics are prone to infections, particularly pyelonephritis. Both bacterial and fungal infections can occur.

38 Renal complications A renal glomerulus demonstrate nodular glomerulosclerosis with diabetes mellitus. This lesion is quite characteristic for diabetes mellitus. A diffuse glomerulosclerosis may also be seen. Kidney disease Diabetes is the leading cause of end-stage renal disease, accounting for 44 percent of new cases. In 2001, 42,813 people with diabetes began treatment for endstage renal disease (USA). In 2001, a total of 142,963 people with end-stage renal disease due to diabetes were living on chronic dialysis or with a kidney transplant (USA).

39 Complications of pregnancy Poorly controlled diabetes before conception and during the first trimester of pregnancy can cause major birth defects in 5 percent to 10 percent of pregnancies and spontaneous abortions in 15 percent to 20 percent of pregnancies. Poorly controlled diabetes during the second and third trimesters of pregnancy can result in excessively large babies, posing a risk to the mother and the child.

40 Nervous system disease About 60 percent to 70 percent of people with diabetes have mild to severe forms of nervous system damage. The results of such damage include impaired sensation or pain in the feet or hands, slowed digestion of food in the stomach, carpal tunnel syndrome, and other nerve problems. Severe forms of diabetic nerve disease are a major contributing cause of lower-extremity amputations. Amputations More than 60 percent of nontraumatic lower-limb amputations occur among people with diabetes. In , about 82,000 nontraumatic lower-limb amputations were performed annually among people with diabetes (USA).

41 A diabetic foot with a previous healed transmetatarsal amputation demonstrates an ulcer in the region of the ankle. Gangrenous necrosis and ulceration involving the lower extremity is shown here. Diabetics have accelerated atherosclerosis that can be extensive to involve peripheral vasculature and predispose to this complication.

42 Dental disease Periodontal (gum) disease is more common among people with diabetes. Among young adults, those with diabetes have about twice the risk of those without diabetes. Almost one-third of people with diabetes have severe periodontal diseases with loss of attachment of the gums to the teeth measuring 5 millimeters or more. Other complications Uncontrolled diabetes often leads to biochemical imbalances that can cause acute life-threatening events, such as diabetic ketoacidosis and hyperosmolar (nonketotic) coma. People with diabetes are more susceptible to many other illnesses and, once they acquire these illnesses, often have worse prognoses. For example, they are more likely to die with pneumonia or influenza than people who do not have diabetes.

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