Diabetes Mellitus Type II - Research Paper Example

Diabetes Mellitus Type II Diabetes mellitus is a chronic polygenic (caused by more than one genes) syndrome characterized by impaired carbohydrate metabolism that presents as chronic hyperglycemia (high blood glucose) and glycosuria (glucose excretion in urine). The patients are not able metabolize carbohydrates due to deficiency of insulin or ineffectiveness of insulin. Diabetes could also be seen due to decreased ratio of insulin/anti-insulin hormones. More often than not, diabetes is accompanied with secondary changes in metabolism of protein, lipids, water and electrolytes with grave consequences, if not treated. History The Indian physician Sushruta in 400 B.C. described the sweet taste of urine from individuals affected with a disease called ‘sugar’. Around 250 B.C., the name “diabetes” was first used, meaning in Greek “to siphon”, reflecting the marked polyuria and loss of water in diabetes. The complete term “diabetes mellitus” was coined in 1674 by Thomas Willis, personal physician to King Charles II. Gradually the latin word for honey, “mellitus” was added due to its link with sweet urine (Settley, 1996). Causes and Types of diabetes mellitus Diabetes mellitus is a heterogeneous clinical disorder with two major classifications: primary and secondary. Secondary diabetes is a condition when hyperglycemia (diabetes) is due to the complications of another disease. As per the latest recommendations of American Diabetes Association (2010) diabetes should be classified into four classes viz. I. Type 1 diabetes: Previously known as insulin dependent diabetes mellitus (IDDM), since the patients require exogenous insulin for survival. Type I diabetes involves β-cell destruction leading to absolute deficiency of insulin. According to ADA (2010), Type 1 diabetes could be described under two sub-headings – a) Immune-mediated - where the autoantibodies against β-cells of pancreas destroy the islets of langerhans, b) Idiopathic diabetes – with no known cause of diabetes mostly seen in people of African or Asian ancestry. II. Type 2 diabetes: It represents 90-95% of all diabetes cases and presents with peripheral resistance to the effects of insulin or a defect in insulin processing/secretion. The disorder is also known as non-insulin dependent diabetes mellitus (NIDDM), because insulin is not required for treatment in most of cases. It manifests at a later age (>40 years) that acquires it the third name -- late or ‘adult-onset diabetes’ and has a slow and silent onset. NIDDM is more commonly found in obese (particularly trunkal obesity) individuals and is more prevalent in females than in males. III. Other Specific Types of Diabetes: Under this category ADA (2010) classifies the diabetic patients with other known causes of diabetes. Some of these are, briefly, presented here. Genetic (single gene) defects of the β-cell. A number of mutations in genes responsible for insulin receptor (e.g. laprechaunism) or its signal transduction (e.g. hepatocyte nuclear factor-1α), enzymes responsible for insulin activation or other carbohydrate metabolic hormones (e.g. glucagon) can be the etiological factor behind diabetes. These forms of diabetes, manifest at the age < 25 years and are known as Maturity Onset Diabetes of Young (MODY). Diseases of the exocrine pancreas. Injury or loss of pancreatic tissue acquired by pancreatitis, trauma, infection, pancreatectomy, and pancreatic carcinoma can be cause of impaired insulin secretion and diabetes. Endocrinopathies. Several hormones (e.g., growth hormone, cortisol, glucagon, epinephrine), known as ‘anti-insulin hormones’, antagonize insulin action. Excess amounts of these hormones (e.g., acromegaly, Cushing’s syndrome, glucagonoma and pheochromocytoma, respectively) can cause diabetes. Drug- or chemical-induced diabetes. Many chemicals, drugs or hormones can impair insulin secretion from the pancreatic β-cells. The examples include - toxins such as Vacor (a rat poison) and intravenous pentamidine, drugs, e.g. nicotinic acid and hormones, e.g. glucocorticoids, can impair insulin action. Patients receiving interferon therapy have also been reported to develop diabetes due to stimulated autoimmune reaction against the β-cells. Infections. Certain viruses have been associated with β-cell destruction. The examples include - coxsackie virus B, cytomegalovirus, adenovirus, and mumps have been implicated in inducing certain cases of the disease. Uncommon forms of immune-mediated diabetes. This category includes diabetic patients in whom an autoimmune syndrome is the primary disorder but diabetes develops due to antibodies developed against insulin pancreatic β-cellscomponents or insulin receptors e.g. Stiff-man syndrome and systemic lupus erythematosus. Bronze diabetes. Bronze diabetes (hemochromatosis) occurs due to excessive absorption and deposition of iron in tissues, such as skin causing bronzed color of skin. The deposition of iron in pancreas may lead to pancreatic β-cell atrophy. IV. Gestational diabetes (GDM). It occurs for the first time due to stresses of pregnancy and mostly disappears after delivery, but the risk of relapse in subsequent pregnancy is high, which may lead to overt permanent type 2 diabetes mellitus. Approximately 7% of all pregnancies (ranging from 1 to 14%) are complicated by GDM, resulting in more than 200,000 cases annually. Hormonal changes of pregnancy are accompanied by an increased insulin resistance. These hormones, e.g., human placental lactogen, have a blocking effect on insulin that usually begins at 20-24 weeks of gestation. Normally, the mothers β-cells compensate by producing additional insulin to overcome such resistance. Failure of such compensation leads to gestational type 2 diabetes mellitus (Metzger and Coustan 1998). Symptoms and Presentation Typically, its symptoms include polydypsia (excessive thirst), polyuria (increased frequency of urination), polyphagia (hunger), glucosuria, lipemia and risk of developing vascular disease, peripheral neuropathy, impaired immunity, ketoacidosis and weight loss (particularly in type 1 diabetes mellitus). Genetic predisposition and other risk factors type II Diabetes Genetic Components - Genetically, type 2 diabetes is a polygenic disease, but most of the gene mutations involved in the disorder remain poorly defined (Lebovitz, 1999). Some of the genes are: Insulin gene, Insulin receptor gene, Lipoprotein lipase gene, Peroxisomal proliferator activated receptor gamma (PPARγ), Phosphoinositide-3-kinase regulatory subunit 1 gene, Sulfonylurea receptor gene, Genes for β-cells K-ATP channel (ATP-sensitive potassium channel), Calpain 10 - a calcium-activated neutral protease gene, Glucagon receptor gene, Glucokinase gene, GLUT2 glucose transporter gene, Hepatocyte nuclear factor 4α gene. Environmental factors such as food intake and exercise play an important role in type 2 diabetes, particularly in the development of peripheral insulin resistance. Hyperglycemia itself may impair insulin secretion, because high glucose levels desensitize β-cells, cause β-cell dysfunction (glucose toxicity), or both. Obesity and weight gain, particularly with trunkal pattern, overeating of fat, processed foods and refined carbohydrates, decreased muscle mass and sedentary lifestyle are major predisposing risk factors. Adipose tissue also appears to function as an endocrine organ, releasing multiple factors (adipocytokines) that favorably (adiponectin) and adversely (tumor necrosis factor-α, Interleukin 6, leptin, resistin) influence glucose metabolism. Intrauterine growth restriction (IUGR) - Babies with intrauterine growth restriction and low birth weight predispose to insulin resistance in later life. Metabolic disturbances in diabetes Insulin deficiency and/or resistance affect all major metabolic pathways. Glucose accumulates in blood (hyperglycemia) that exceeds the renal threshold and, hence, is excreted in urine in large amounts (glucosuria). Glucose is osmotically active and, hence, draws large amount of water into the plasma (hyperosmosis) and urine causing polyuria. Excessive loss of water through urine leads to thirst (polydypsia) and hunger (polyphagia). Weakness, tiredness, muscle wasting and weight loss occur due to inability of muscles to take up glucose and tissue protein catabolism that provides amino acids for gluconeogenesis. The lowered insulin/anti-insulin hormone (glucagon) ratio stimulates lipolysis and mobilization of fats causing weight loss. The glycerol released from lipolysis is utilized for gluconeogenesis, which further aggravates hyperglycemia. The high levels of plasma free fatty acids impair insulin responsiveness by reducing peripheral glucose utilization. Excess blood fatty acids may also lead to fatty liver. Dyslipidemia Enhanced b-oxidation of fatty acids produces excess acetyl-CoA, which is used for cholesterol synthesis, leading to dyslipidemia, vascular abnormalities, atherosclerosis and stroke. The excess acetyl-CoA is also diverted to the synthesis of ketone bodies leading to ketonemia, ketonuria and ketoacidosis. Ketonuria depletes bodys sodium that leads to drowsiness and coma in uncontrolled diabetes. Glycosylation of the proteins Persistent hyperglycemia during diabetes causes spontaneous non-enzymatic glycosylation of protein in blood vessels leading to thickening of the basement membrane, particularly of the small blood vessels (microangiopathy). The microvascular changes in the eye, kidney and nerves leads to most of diabetes-associated complications, i.e., diabetic retinopathy, diabetic nephropathy and diabetic neuropathy (Peppa, Uribarri and Vlassara 2003). Poor wound healing is seen due to inhibition of protein synthesis and impaired cross linking of collagen fibers. Cataract is also increasingly associated with diabetes. Glycosylation of the lens protein (α-crystallin) and osmotic damage by accumulation of hexosamine and sorbitol through the polyol pathway are the contributing factors for the cataract formation. Peripheral neuropathy is due to a combination of microangiopathy, loss of water-soluble vitamins and activation of the polyol pathway (depletes myoinositol and increases Na+ accumulation in nerve cell). The increased production of superoxides, glycosylation of blood and tissue proteins with advanced glycation end (AGE) products contribute to the development of the complications of diabetes like skin necrobiosis, delayed wound healing, gangrene and macrovascular abnormalities (atherosclerosis). The metabolic changes in diabetes mellitus are summarized in Fig. 1. Screening and diagnosis of Diabetes Symptomatic hyperglycemia shows up for both types of diabetes, but in type 2 its detection is mostly accidental on routine examination and during stress conditions. The American Diabetes Association (2010) recommends routine screening of all adults for type 2 diabetes beginning at age 45, especially if they are overweight or obese, with repeat screening every three years. Type 2 diabetes is becoming a growing problem in children and adolescents in high-risk populations. To address this issue, the ADA recommends screening children every 2 years, beginning at age 10 or the onset of puberty. Diagnosis of diabetes can be made using the fasting plasma glucose, random plasma glucose, or the oral glucose tolerance test. Testing should be performed on two separate days using one or more of these tests. The use of the hemoglobin A1c assay has now (ADA, 2010) been included in the criteria for the diagnosis of diabetes (Table 1). Table 1. ADA criteria for diagnosis of diabetes mellitus 1. Hemoglobin A1C* ≥ 6.5 % 2. Fasting Plasma Glucose ≥ 126 mg/dl (7.0 mmol/l) 3. 2-hr post-loading plasma glucose ≥ 200 mg/dl (11.1 mmol/l) 4. Random plasma glucose ≥ 200 mg/dl (11.1 mmol/l) Impaired glucose tolerance i.e. a plasma glucose level between 100 mg/dl and 125 mg/dl have been found to be associated with increased risk for the development of diabetes. A random plasma glucose level, which is obtained at any time of the day regardless of the time of the last meal, can be used in individuals with symptoms of hyperglycemia. A random plasma glucose level of >200 mg/dL (11.1 mM/L) is diagnostic of diabetes. The diagnosis, of course, should be confirmed by repeating the random plasma glucose or preferably by obtaining a fasting plasma glucose level on at least one additional occasion. B. Glucose tolerance test (or curve). The test is used for detection of symptomless, early diabetes, differentiation of different types and severity of diabetes, and help adjustment and following up of the treatment. It tests the ability of the body to dispose of glucose. The patient is given 100 g of glucose orally after an overnight fast and blood glucose is measured over 2.5 hours as shown in figure 2. .afet C. Post-glucose-loading tests. Formal (five samples) OGTT is usually not necessary to establish the diagnosis of diabetes mellitus. A plasma glucose level two hours after oral ingestion of (75 g or 100 g) glucose may identify individuals with abnormal glucose tolerance, particularly in high risk populations in which postprandial hyperglycemia is evident early in the disease. The criterion for the diagnosis of diabetes is a 2-hr glucose >200 mg/dL (11.1 mM/L) after a 75 g oral glucose load (American Diabetes Association and World Health Organization criteria). Monitoring Glycemic Control in Diabetes Mellitus A. Hemoglobin A1c Spontaneous, non-enzymatic glycosylation of plasma and other proteins is the etiological basis of a number of complications of DM. Along with other proteins, hemoglobin is also glycosylated and, hence, the level of glycosylated hemoglobin, or the hemoglobin A1c (HbA1c) represents the long-standing (6-8 weeks) hyperglycemia. HbA1c assay, thus, is the most widely accepted laboratory test for measuring glycemic control and is recommended for routine use in the management of patients with diabetes mellitus (Jeffcoate S. 2003). The American Diabetes Association goal HbA1c is Read More