SBI242 - Week 9.docx

**SBI242 -- Week 9** **Drugs affecting the endocrine system** **Review of the pancreas** **Exocrine Function** contain digestive enzymes, enzyme precursors and electrolytes, and are discharged into the pancreatic ducts and then into the gastrointestinal tract **Endocrine Function** The product...

**SBI242 -- Week 9** **Drugs affecting the endocrine system** **Review of the pancreas** **Exocrine Function** contain digestive enzymes, enzyme precursors and electrolytes, and are discharged into the pancreatic ducts and then into the gastrointestinal tract **Endocrine Function** The production of hormones controlling blood glucose levels (BGLs) and some gastrointestinal functions. - Insulin is produced by beta cells - Glucagon produced by alpha cells - Simatostatin (GHRIF) produced by delta cells -- Somatostatin inhibits release of growth hormone and inhibits release of insulin and glucagon. **Insulin** Protein hormone consisting of two polypeptide chains joined by disulfide bridges. Insulin is synthesised from a larger protein, proinsulin, which acts as the storage form. *[Insulin release]* - There is a low basal release in pulses every 15--30 minutes into the portal circulation to the liver. Release is increased within 30--60 seconds after absorption of glucose from a meal, a rapid initial rise due to release of stored insulin, then a slower delayed phase over 60--90 minutes when newly synthesised insulin is also released. *[Stimuli to insulin secretion:]* - Raised blood amino acid levels - Glucagon - Incretins (glucose-dependent insulinotropic peptides, glucagon-like peptides) released from the digest tract in response to food - Vagal stimulation; due to increased parasympathetic activity in response to a meal - B-adrenoceptor stimulation - Some oral hypoglycaemic agents *[Insulin release is inhibited by:]* - Falling blood glucose levels - Fasting - Somatostatin - Adrenaline (epinephrine; via a2-receptors) - Thiazide diuretics *[Deficiencies of insulin release:]* - Diabetes mellitus - Pancreatitis - Tumours insulin is rapidly digested in the gut if given orally, with a half-life of only a few minutes insulin must be administered parenterally to treat diabetes. Its biological duration of action is 2--4 hours, as it is bound to receptors in tissues where it acts. *[Mechanism of action -- insulin]* Insulin facilitates removal of glucose from the blood into muscle and fat cells via biochemical reactions affecting uptake, utilisation and storage of carbohydrates, fats and amino acids in liver, adipose and muscle cells. Insulin binds to specific membrane receptors on target cells and activates tyrosine kinase enzyme. - Initiates cascades of phosphorylation reactions leading to many kinase and phosphatase activities, as well as DNA transcription and cell replication. - Intracellular vesicles containing a glucose transporter (GLUT-4) fuse with the plasma membrane leading to a rapid 10- to 30-fold increase in glucose uptake into the cell, where it is 'trapped' as glucose-6-phosphate. Insulin inhibits glycogenolysis, lipolysis and proteolysis. The actions of insulin are physiologically inhibited by the catabolic hormones -- adrenocorticotrophic hormone (ACTH), glucocorticoids, adrenaline, growth hormone (GH) and thyroxine. **CONTROL OF BLOOD-GLUCOSE LEVELS**\ Carbohydrate metabolism and blood glucose levels are controlled by finely balanced interactions between the anterior pituitary, pancreas, adrenal and thyroid glands, maintaining the plasma glucose level around the optimum. **Glucagon** A hormone secreted by alpha cells in the pancreas in response to hypoglycaemia and high-protein meals, and stimulated by exercise, stress and infections. Its actions include: - stimulating hepatic glycogenolysis gluconeogenesis (the conversion of glycerol and amino acids to glucose), lipolysis and ketogenesis - inhibiting glycogen synthesis - stimulating release of catecholamines, hence inhibiting tone and motility in GIT smooth muscle - Increasing release of GH, ACTH (Adrenocorticotropic Hormone), and insulin. Secretion of glucagon is inhibited by insulin, hyperglycaemia and incretins **Incretins** Peptide hormones secreted from the intestinal mucosa into the circulation in the presence of food. Incretins increase insulin secretion via G-protein-coupled receptor activation, raised cAMP levels and calcium-induced exocytosis, mediating much of the β-cell response to an ingested meal. Incretins regulate islet hormone secretion, glucose concentrations, lipid metabolism, gut motility, appetite and body weight. **Central Nervous System** Nutrient availability is sensed in the arcuate nucleus of the hypothalamus and contains high densities of insulin receptors; neural signals are relayed via efferent vagal fibres to the liver where glucose production is inhibited. In T2DM and obesity, the brain incorrectly perceives and responds to peripheral signals of low nutrient availability.  **Diabetes Mellitus** characterised by polyuria associated with a chronic disorder of carbohydrate and lipid metabolism and an inappropriate rise in glucose level in the blood, due to a relative or absolute lack of insulin. - *[Type 1 -]* there is complete lack of insulin; believed to be an autoimmune disease where insulin producing cells beta cells are destroyed by the immune system. - *[Type 2 -]* where there is a relative lack of insulin or defects of the insulin receptors due to poor diet/lifestyle, obesity, positive family history, cardiovascular disease, metabolic syndrome, and tobacco use. **Hyperglycaemia** A lack of insulin means glucose cannot be taken up into cells. Excess glucose is circulated in blood, and excess glucose is secreted by the kidneys (glycosuria). Signs and symptoms - Polyphagia -- increased appetite - Polydipsia -- increased thirst - Polyuria - Ketosis - Anorexia/weight loss - Abdominal pain - Nausea/vomiting - Dry mouth - Weakness **Diagnosis of diabetes** Diagnosis is by signs and symptoms, by measurement of high BGL (casual \>11.1 mmol/L, fasting \>7.0 mmol/L), by glucose tolerance testing after overnight fasting, and/or by glycated haemoglobin levels. - Blood glucose glycosylates haemoglobin in RBC (average life-span 120 days) → more blood glucose = higher HbA1c. - HbA1c (blood test) is used to determine blood glucose levels for the past 3 months (appropriate treatment for/control of diabetes) *[Treatment]*: is with diet, exercise, hypoglycaemic drugs, insulin. **Hypoglycaemia** BGL \