Diabetes, Anatomy and Physiology of Insulin - Essay Example

? Diabetes Introduction Diabetes is a metabolic disorder characterized by hyperglycaemia, glycosuria, hyperlipaemia, negative nitrogen balance and sometimes ketonaemia. A widespread pathological changes is thickening of capillary basement membrane, increase in vessel wall matrix and cellular proliferation resulting in vascular complications like lumen narrowing, early atherosclerosis, sclerosis of glomerular capillaries, retinopathy, neuropathy and peripheral vascular insufficiency (An RCN guide to the National Service Framework for Diabetes). Enhanced nonenzymatic glycosylation of tissue proteins due to persistent exposure to high glucose concentrations and the accumulation of larger quantities of sorbitol (a reduced product of glucose) in tissues are believed to be causative in the pathological changes of diabetes. The concentration of glycosylated haemoglobin (HbA1c) is taken as an index of protein glycosylation: it reflects the state of glycaemia over the preceding 2-3 months (Davidson, 2010; Tripathi, 2008). Two major types of diabetes are- Type I or insulin dependent diabetes mellitus (IDDM), juvenile onset diabetes mellitus, which is caused due to the destruction of ?- cells of pancreatic islets, majority of the cases are autoimmune (type 1A) antibodies that destroy ?-cells and are detectable in blood. In all type I cases circulating insulin levels are low or very low and patients are more prone to ketosis. However this is less prevalent and has low degree of genetic predisposition (Davidson, 2010; Tripathi, 2008). Type II diabetes or noninsulin-dependent diabetes (NIDDM), maturity onset diabetes mellitus. There is no loss or moderate reduction in ?-cells mass; insulin in circulation is low, normal or even high, no anti-?-cell antibody is demonstrable; has a high degree of genetic predisposition; generally has a late onset (past middle age). Over 90% cases are type 2 DM. Causes may be- abnormality in gluco-receptor of ? cells so that they respond at higher glucose concentration or relative ?-cell deficiency. Another cause that is related with DM comprise reduced sensitivity of peripheral tissues to insulin: reduction in number of insulin receptors. Many hypertensives are hyperinsulinaemic but normoglycaemic and exhibit insulin resistance associated with dyslipidaemia (metabolic syndrome). Hyperinsulinaemia per se has been implicated in causing angiopathy. Other contributing characteristics involves, excessive secretion of hyperglycaemic hormones (glucagon) or due to obesity that is responsible for relative insulin deficiency- the ?-cells lag behind (Davidson, 2010; Tripathi, 2008). Anatomy and Physiology of Insulin Blood glucose is highly regulated within a thin range. An equilibrium is conserved between the entry of glucose into the circulation from the liver, supplemented by intestinal absorption after meals as well as up[take of glucose by the peripheral tissues especially the skeletal muscle. Brain requires a constant supply of glucose and is not able to oxidize free fatty acids but is solely dependent on the glucose as the chief metabolic fuel. When there is decline in the intestinal glucose absorption between meals, hepatic glucose output is enhanced, this is in response to reduced insulin levels and elevated levels of the counter-regulatory hormones, glucagon and epinephrine (adrenaline). The liver produces glucose by the process of gluconeogenesis and glycogen breakdown. The chief components for gluconeogenesis are glycerol and amino acids (Davidson, 2010; Tripathi, 2008). After meals, blood insulin levels rise. insulin is an anabolic hormone with profound effects on the metabolism of carbohydrate, fat as well as protein. Insulin is secreted from pancreatic ? cells into the portal circulation. Various factors also influence and enhance insulin release encompassing amino acids and hormones like glucagon-like peptide 1 (GLP-1), released from the gut, incited by the food ingestion. Insulin on the other hand diminishes blood glucose by restraining hepatic glucose production and stimulating glucose uptake in skeletal muscle and fat, mediated by glucose transporter, GLUT 4 (Davidson, 2010; Tripathi, 2008). Adipocytes and the liver synthesize triglyceride from non-esterified or free fatty acids (FFAs) and glycerol. insulin stimulates lipogenesis and inhibits lipolysis, promoting triglyceride gathering. Lipolysis is stimulated by catecholamines and liberates FFAs which in turn could be oxidized by many tissues. Partial oxidation in the liver provides energy to drive the process of gluconeogenesis that results in the formation of ketone bodies (acetoacetate, which can be reduced to 3-hydroxybutyrate or decarboxylated to acetone) produced in the mitochondria of hepatocytes. The ketone bodies that are generated in the process are organic acids, which when formed in small amounts are oxidized and utilized as metabolic fuel. However, the rate of utilization of ketone bodies by peripheral tissues is limited and when the rate of production of liver exceeds their removal, it results in hyperketonaemia. This condition is known to be physiological and occurs during starvation, when low insulin levels and high catecholamine levels increase lipolysis as well as delivery of FFAs to the liver (Davidson, 2010; Tripathi, 2008). Etiology and Pathology of DM In both of the common types of diabetes, environmental factors interact with genetic propensity to establish which individual develop the clinical syndrome, and the timing of its commencement. However, the fundamental genes, environmental factors and pathophysiology vary considerably between type 1 and type 2 diabetes. Type 1 diabetes was formerly termed 'insulin-dependent diabetes mellitus' (IDDM) and is generally related with profound insulin deficiency necessitating replacement therapy. Type 2 diabetes was earlier termed 'non-insulin-dependent diabetes mellitus' (NIDDM) because patients preserve the ability to produce some insulin but display impaired sensitivity to insulin i.e. insulin resistance, and primarily can be treated without insulin replacement therapy. However, on long term basis many patients with type II DM may require insulin therapy for controlling blood sugar level, because of poor compliance of dietary management and/ or associated with adverse drug reaction to oral hypoglycemic drugs (Davidson, 2010; Tripathi, 2008). Pathology of Type I diabetes is T cell mediated autoimmune disease that involves destruction of insulin secreting ?-cells in the pancreatic islets. Profound hyperglycaemia occur when 75- 90% of the ?-cells are destroyed by antibodies directed against them (Davidson, 2010; Tripathi, 2008). Risk factors- Genetic factors are associated with the first-degree relatives. Studies reveal that identical twins has 35% of risk while if both the parents have diabetes, up to 30% of the risk is accounted. Environmental factors associated with the DM involves viral infection of pancreas which alters immunogenicity of ?-cells. It is observed that less exposure to microbes during the early childhood limits maturation of the immune system and enhances the individual's susceptibility to autoimmune diseases. One of the prevailing factors in the present scenario is the stress, which is known to precipitate type 1 diabetes as it incites the secretion of counter-regulatory hormones and modulate immune activity. Dietary factors rich in nitrosamines found in smoked and cured meats as well as coffee are found to possess diabetogenic toxins, bovine serum albumin is also known to induce diabetes (Davidson, 2010; Tripathi, 2008). In type 1 DM there is a progressive ?-cell destruction as a result as a result insulin secretion and normal glucose level can no longer be maintained. High glucose level damage he remaining ?- cells and a severe insulin deficiency occurs. Hyperglycaemia leads to following clinical features- Glycosuria, polyuria, increased thirst, polyphagia, secondary hyperaldosteronism because of excessive water loss from body, hyperaldosteronism leads to increased K+ loss in urine. Due to defective energy metabolism there is breakdown of fat to ketone bodies from fat depots, resulting in increased ketone level in blood, this leads to the development of ketoacidosis and weight loss (Davidson, 2010; Tripathi, 2008). Pathology of type II diabetes- Insulin resistance is the hallmark of type II DM, it is a complex condition where initially insulin secretion is normal, gradually, there occurs resistance to the actions of insulin in liver and muscles combined with impaired pancreatic ?-cell function leading to relative insulin deficiency (Davidson, 2010; Tripathi, 2008). Risk factors- Type II diabetes is chiefly contributed by central (visceral) obesity, and dyslipidaemia comprising high level of LDL and low level of HDL are the vital factors responsible for insulin resistance syndrome or metabolic syndrome. In this case insulin resistance is the primary defect and obesity serves as an amplifier of the insulin resistance. The characteristics of insulin resistance involves- hyperinsulinaemia, type 2 diabetes or impaired glucose tolerance, hypertension, microalbuminuria, enhanced fibrinogen, enhanced plasminogen activator inhibitor-1 as well as increased plasma uric acid. In the early stages of the loss of ? cell mass is moderate, increased plasma glucose and FFAs exert toxic effects on pancreatic ?-cells and thereby impair insulin secretion (Davidson, 2010; Tripathi, 2008). Genetic predisposition indicate that if the age of onset of the DM type II is between 25-44 then 53% risk is present with the sibling contracting DM while if the age of onset is 65-80 years then 31% risk is present with the siblings (Davidson, 2010; Tripathi, 2008). Environmental risk factors encompass dietary habits together with obesity and sedentary life style. The risk of developing type 2 diabetes enhances tenfold in individuals with BMI > 30kg/m2, the kind of food intake also becomes a determinant for type II DM, sweet foods rich in refined carbohydrate consumed frequently may enhance the demand for insulin secretion while high-fat foods may enhance FFAs and exacerbate insulin resistance (Davidson, 2010; Tripathi, 2008). In type II DM hyperglycaemia develops slowly over months or years and there is a rise in renal threshold for glucose, as a result glycosuria is limited and osmotic symptoms are mild, as a result DM is detected as a coincidence and in majority of the cases it remains undetected for a longer period. The condition is asymptomatic and prolonged interval of fatigue may be observed (Diabetes Insight Centre). Diagnosis of Diabetes Test urine for ketones and glucose; measure random or fasting blood glucose; diagnosis confirmed by fasting plasma glucose >7.0 mmol/l, random plasma glucose >11.1mmol/l. Blood testing- Blood sugar level (BSL), glycated haemoglobin, blood lipids, Diabetic ketoacidosis is one of the major complications in type I DM. Symptoms of diabetic ketoacidosis- 1.Polyuria, thirst- hyperosmotic blood because of excess sugar leads to osmotic diuresis. It can cause dehydration. It can be managed by prompt i.v insulin infusion and fluid replacement i.v 0.9% saline infusion 2. Weight loss, weakness- due to defective carbohydrate metabolism as blood glucose cannot enter muscle and peripheral tissues due to lack of insulin. It can be managed by prompt insulin administration. 3. Leg cramps- because of K+ loss as it is pumped out of the cells. Managed by K+ replacement. Signs of Diabetic ketoacidosis- dehydration, hypotension, tachycardia, air hunger, smell of acetone in breath, confusion, drowsiness, coma (Davidson, 2010; Tripathi, 2008). Management of ketoacidosis- administration of short acting insulin, fluid replacement, K+ replacement and antibiotics if infection is present (Morris, 1997; Davidson, 2010; Tripathi, 2008). Complications of Diabetes Microvascular/ Neuropathic 1. Retinopathy, cataract- impaired vision. Diagnosed by visual acuity, distance vision using Snell's chart at 6m. Lens opacification- ophthalmoscope; fundal examination for retinopathy. Management can be done by maximize control of blood glucose, lipid and blood pressure. Advised to stop smoking and alcohol intake. Fundoscopy every 6-12 months. 2. Nephropathy- renal failure has the following risk factors- Poor control of BSL, long duration of diabetes, hypertension and a positive family history of diabetic nephropathy (DN). Diagnosed by screening for microalbuminuria. Urinary albumin: creatinine ratio (3-30mg/mmol). Microalbuminuria can be managed with ACE inhibitors, calcium channel blockers like verapamil. 3. Diabetic neuropathy- diagnosed with- blood pressure response to standing, blood pressure response to sustained hand grip, heart rate response to standing. Management of pain and paraesthesiae- intensive insulin therapy, drugs like imipramine, carbamazepine. Management of postural hypotension is done by support stockings, fludrocortisone. Management of gastroparesis by dopamine antagonist. Management of diarrhoea- loperamide. 4. Diabetic foot- diagnosed with ulcer. Management is done by treating infection, avoiding weight bearing, controlling edema and appropriate antibiotics for infection. 5. Hypertension- diagnosed by blood pressure recording >140/80 mm of Hg. Managed by ACE inhibitors like enalapril, licinopril or AT1 receptor antagonist like losartan as diabetes causes atherosclerosis which causes increase in peripheral resistance and increase in aldosterone synthesis which is responsible for salt and water retention. 6. Lipodystrophy- caused by older insulin due to repeated subcutaneous injections of insulin over same site. Management- can be avoided by frequent change of injection site over skin and use of newer insulin- genetic recombinant form. 7. Erectile dysfunction in males- can lead to impotency. Cause- atherosclerosis of blood vessel. Managed by PDEI- sildenafil. 8. Thyroid enlargement 9. Acanthosis nigricans- blackening of axilla and neck skin may be a sign of insulin resistance. Managed by appropriate blood sugar level by insulin. 10. Non-ketotic hyperosmolar diabetic coma- BSL >50mmol/l- Managed by insulin. 11. Myocardial infarction- long term complication of uncontrolled diabetes (Davidson, 2010; Tripathi, 2008). Adequate aerobic exercise helps in controlling weight and aids in the management of diabetes. References An RCN guide to the National Service Framework for Diabetes. (n.d.) Retrieved from http://www.rcn.org.uk/__data/assets/pdf_file/0011/78572/002011.pdf. Davidson's Principles & Practice of Medicine. (2010). 21st Edition, Publisher Churchill Livingstone. Diabetes Insight Centre. (n.d.) Retrieved from http://www.actos.com/diabetesinsightcenter/compliance.aspx. Morris, A. D., Boyle, DIR., McMahon, A. D., Greene, S,A., MacDonald, T. M., Newton, R, W. (1997). for the DARTS/MEMO Collaboration. Adherence to insulin treatment, glycemic control, and ketoacidosis in insulin-dependent diabetes mellitus. Lancet, 350,1505 -1510. Tripathi, K. D. (2008). Essentials of Medical Pharmacology. 6th Edition. Publisher Jaypee Brothers Medical Publishers. Read More