SBI241 - Week 9.docx

**SBI241 -- Week 9** **Diabetes Mellitus** - a group of disorders with abnormal glucose metabolism in common. characterised by chronic hyperglycaemia and other disturbances of carbohydrate, protein and fat metabolism. While diabetes indicates an increased urine output, mellitus is Latin for honey...

**SBI241 -- Week 9** **Diabetes Mellitus** - a group of disorders with abnormal glucose metabolism in common. characterised by chronic hyperglycaemia and other disturbances of carbohydrate, protein and fat metabolism. While diabetes indicates an increased urine output, mellitus is Latin for honey --- hence the urine is sweet (contains glucose) and copious. [3 main categories of diabetes mellitus] 1. *[Type 1]* -- absolute insulin deficiency 2. *[Type 2]* -- insulin resistance with an insulin secretory deficit 3. *[Gestational diabetes]* **Type 1 Diabetes Mellitus** results from autoimmune destruction of beta (β) cells in the islets of Langerhans. This is thought to be the result of a gene--environment interaction, with the strongest genetic risk markers in the human leucocyte antigen (HLA) region of chromosome 6. Genetic factors may increase susceptibility to environmental causes of diabetes. Before hyperglycaemia occurs, 80--90% of the insulin-secreting beta cells of the islets of Langerhans must be destroyed. This is because the remaining cells can increase their production of insulin to compensate, but with so few beta cells remaining, insulin production is no longer adequate. With a lack of insulin, there is a relative excess of glucagon (produced by alpha cells). **[Hyperglycaemia]** and **[ketonaemia]** can result from insulin deficiency alone, but a relative excess of glucagon clearly facilitates the metabolic alterations seen in diabetes. [Clinical manifestations] 1. Polyphagia 2. Polydipsia 3. Polyuria *[Evaluation and treatment]* [polydipsia, polyuria, polyphagia, weight loss and hyperglycaemia] (usually determined by a glucometer) are present in fasting and postprandial states. [Management] requires individual planning according to type of disease, age and activity level, but all individuals require some combination of: - Insulin - meal planning - exercise. **Type 2 Diabetes Mellitus** *[Diagnosis]* Generally, two abnormal test results that demonstrate hyperglycaemia are required to make the diagnosis of diabetes: - either two fasting venous blood glucose levels of equal to or over 7.0 mmol/L, or two random venous blood glucose levels of equal to or over 11.1 mmol/L. The diagnosis can also be made with just one abnormal fasting or random blood glucose level if symptoms of hyperglycaemia are present. A plasma fasting blood glucose level of less than 6.1 mmol/L indicates diabetes is unlikely. Diabetes can also be indicated by the presence of glucose in the urine (glycosuria), but this should be confirmed using blood tests. *[Oral Glucose Tolerance Test]* Requires overnight fasting followed by consumption of a glucose drink which contains 75 grams of glucose; blood glucose levels are monitored after fasting and then again 2 hours after glucose ingestion. [Result:] If the person does not have diabetes, the blood glucose level will rise as the glucose drink is absorbed into the bloodstream, but should then decrease to below 7.8 mmol/L after 2 hours. In a person with diabetes, the fasting blood glucose level is raised, and the blood glucose level remains over 11.1 mmol/L after 2 hours. **Pre-Diabetes** A condition in which glucose homeostasis is between the normal level of control and that seen with diabetes. *[Impaired fasting glucose]* - the fasting blood glucose level is raised, but the response to the oral glucose tolerance test appears normal. *[Impaired glucose tolerance]* - the fasting blood glucose level is normal, and there is a hyperglycaemic response to the oral glucose tolerance test, but to a lesser extent than seen with diabetes. Pre-diabetes should be considered as a warning that type 2 diabetes is developing and modifiable lifestyle factors should be changed. **Pathophysiology** *[Insulin Deficiency]* -- shortage of insulin *[Insulin resistance]* -- Ineffective response to insulin at the target cells. Obesity - insulin is less able to facilitate the entry of glucose into the liver, skeletal muscles and adipose tissue. Excessive energy intake predisposes an individual to type 2 diabetes by contributing to obesity.  **Monitoring Blood Glucose Control** *[Glucometer]* - allows patients to monitor the effectiveness of their lifestyle measures and diabetes medications. *[HbA1c]* Measuring glycated haemoglobin (HbA1c) is used as a general indication of glycaemia over recent weeks. - Glucose molecules bind to haemoglobin, to form glycated haemoglobin - this is an irreversible reaction, so once the glucose is bound, it remains attached. A build-up of glycated Hb within the red cells reflects the average level of glucose to which the cells have been exposed during their 120-day life. **Complications** +-----------------------------------+-----------------------------------+ | **ACUTE** | **CHRONIC** | +===================================+===================================+ | - Hypoglycaemia | - Neuropathy | | | | | - Diabetic ketoacidosis | - Nephropathy | | | | | - Hyperglycaemic hyperosmolar | - Retinopathy | | state | | +-----------------------------------+-----------------------------------+ **Hypoglycaemic shock** Excess insulin, beyond what is required, leads to hypoglycaemia, which can result in severe activation of sympathetic nervous system responses. If the liver can produce sufficient glucose through gluconeogenesis, then the blood glucose can return to normal. However, if the hypoglycaemia becomes too low, without sufficient glucose to balance, this can lead to severe neuronal dysfunction, which may lead to coma and death. **Diabetic ketoacidosis** The inability of glucose to enter cells can lead to usage of lipids as cell fuel instead of glucose. As a result, ketone bodies are formed, which are highly acidic, and can lead to ketoacidosis. The severe lack of glucose in cells can also lead to production of glucose, which can occur by both glycogenolysis --- breakdown of glycogen stores into glucose, and by gluconeogenesis --- creation of glucose from non-glucose sources. This may lead to hyperglycaemia, which causes glycosuria and polyuria, with the dehydration contributing to acidosis. **Hyperglycaemic hyperosmolar state** Hyperglycaemic hyperosmolar state or HHS is an uncommon but significant complication of type 2 diabetes with a high overall mortality of approximately 15%. The hyperglycaemic hyperosmolar state, there is sufficient insulin to prevent breakdown of fat stores for production of glucose and therefore ketoacidosis is avoided. HHS is a medical emergency, as it can lead to drowsiness, stupor, coma and death. Treatment mandates aggressive fluid and electrolyte resuscitation and strict control of serum glucose level. **Chronic complications** **[Cardiovascular disease]** *[Dyslipidaemia]* - relates to the development of atherosclerosis. Elevated triglycerides and low-density lipoprotein (LDL) cholesterol are more prevalent in those with diabetes than those without the condition. *[High density lipoprotein]* - tends to protect vessels, is present in only low concentrations in individuals with diabetes compared with the general population. This overall lipid profile is more atherogenic in those with diabetes. The presence of other risk factors, including [hypertension,] increases vulnerability to [atherosclerosis].  **Thyroid Dysfunction** *[Hyperthyroidism]* It is a condition where thyroid hormone levels are higher than normal. When these high levels result in a hypermetabolic state, this is known as [thyrotoxicosis]. All forms of thyrotoxicosis share common physiological effects on the individual that are caused by the high thyroid hormone level. These effects are the result of an increase in adrenergic stimulation and increased metabolic effects: - Tachycardia - Palpitations - Nervousness - Insomnia - Heat tolerance - Moist skin - Tremor - Increased systolic blood pressure  *[Grave's Disease]* - is the most common cause of hyperthyroidism. It is an *[autoimmune]* condition. **Clinical Manifestations** All signs and symptoms of thyrotoxicosis; plus Immunological stimulation causes several physiological changes unique to Graves\' disease: - TSH receptor antibodies stimulate thyroid cells, increasing gland size and vascularity. - TSH receptors are found on tissue within the orbit. This causes enlargement of the ocular muscles, and results in eyeball protrusion, paralysis of extraocular muscles and damage to the retina and optic nerve which can lead to blindness. These changes result in exophthalmos (protrusion of the eyeball), periorbital oedema and extraocular muscle weakness leading to diplopia (double vision).  **Diagnosis** Thyroid hormone is measured as the hormones that are not protein bound, namely free thyroxine (T4) and free triiodothyronine (T3). In primary hyperthyroidism (which is the most common form of hyperthyroidism) thyroid hormone levels are raised and as a result TSH will decrease. **Treatment** Treatment needs to consider two issues: 1. achieve symptom control 2. reduce thyroid hormone levels where possible. To reduce thyroid hormone, antithyroid medication is commonly the first- line therapy: Carbimazole and propylthiouracil (PTU) interfere with thyroid hormone production and secretion from the thyroid cells. Both medications can cause liver disturbances and monitoring of liver function is essential Could cause agranulocytosis, patients are to immediately report sore throats, mouth ulcers and other signs of infection [Radioactive iodine therapy or surgery may be required.] Thyroidectomy when performed by experienced thyroid surgeons carries a small risk of permanent hypoparathyroidism of \< 2% and recurrent laryngeal nerve damage of \< 1%. Current treatment for Graves\' disease does not reverse the ocular changes. Corticosteroids and surgical intervention may be required in severe cases. *[Thyrotoxic crisis]* rare but dangerous worsening of the thyrotoxic state, in which death occurs within 48 hours without treatment. usually occurs in individuals who have undiagnosed or partially treated Graves\' disease. *[The systemic symptoms of thyrotoxic crisis include: ]* - hyperthermia - tachycardia - high-output heart failure - agitation or delirium - nausea, vomiting - diarrhoea contributing to fluid volume depletion **Hypothyroidism** *[Primary causes ]* 1. congenital defects 2. defective hormone production resulting from autoimmune thyroiditis, iodine deficiency or antithyroid drugs 3. Inadvertent loss of thyroid tissue after surgical or radioactive treatment for hyperthyroidism. 4. Causes of secondary hypothyroidism are related to either pituitary or hypothalamic failure **Clinical manifestations -- affects all body systems** The decrease in thyroid hormone lowers energy metabolism, heat production and delays neuromuscular processes within the body. The individual develops a low basal metabolic rate, cold intolerance, lethargy, tiredness, constipation, thinning brittle hair and slightly lowered basal body temperature. The decrease in thyroid hormone leads to excessive TSH production and goitre. **Evaluation and Treatment** The clinical symptoms of hypothyroidism, a decrease in serum-free T4 is nearly always present. TSH concentration increases because of loss of negative feedback from thyroid hormone. [Hormone replacement therapy] is the treatment of choice. Therapy may be increased gradually over months to avoid precipitating acute cardiac events in the elderly. Thyroxine needs to be taken separately from food, vitamins and mineral supplements to ensure adequate absorption.