Lect 15 Endocrine Pancreas, Diabetes & Therapeutics PDF

THE ENDOCRINE PANCREAS, DIABETES MELLITUS & PHARMACOTHERAPEUTICS PANCREATIC ISLETS The pancreas is a flattened organ located posterior and slightly inferior to the stomach and can be classified as both an endocrine and an exocrine gland Histologically, it consists of pancreatic islets...

THE ENDOCRINE PANCREAS, DIABETES MELLITUS & PHARMACOTHERAPEUTICS PANCREATIC ISLETS The pancreas is a flattened organ located posterior and slightly inferior to the stomach and can be classified as both an endocrine and an exocrine gland Histologically, it consists of pancreatic islets or islets of Langerhans and clusters of cells (acini) (enzyme-producing exocrine cells)  Anatomy of Pancreas Organ (5 inches) consists of head, body & tail Cells (99%) in acini produce digestive enzymes Endocrine cells in pancreatic islets produce hormones Cell Organization in Pancreas Exocrine acinar cells surround a small duct Endocrine cells secrete near a capillary Histology of the Pancreas 1 to 2 million pancreatic islets per human pancreas (1-2% of weight) Contains 4 types of endocrine cells Cell Types in the Pancreatic Islets (Islets of Langerhans) Alpha cells (20%) produce glucagon Beta cells (70%) produce insulin (+ amylin) Delta cells (5%) produce somatostatin PP cells produce pancreatic polypeptide Human pancreas contains 8 mg of insulin; secretes 0.5 to 1 mg per day. Insulin rapidly destroyed by liver & kidney (t½ in circulation about 6 minutes)  Regulation of Blood Glucose When blood glucose increases, pancreas secretes a hormone called INSULIN to bring glucose to normal levels. Glucose enters ß-cells via GLUT2 glucose transporter ATP synthesis increases ATP-sensitive potassium (KATP) channels close Insulin is released Insulin reduces blood glucose When blood glucose is low, pancreas secretes a hormone called GLUCAGON to maintain the levels constant. Glucagon increases blood glucose Insulin and glucagon have opposing actions.  Primary targets for insulin action Liver Skeletal muscle Adipose tissue Pancreatic alpha cells (to inhibit glucagon release) NB: skeletal muscle and fat dependent on insulin for glucose uptake Insulin promoting + counter-regulatory hormones Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), from GI tract, increase prandial insulin release (= “incretin” effect) Amylin inhibits hepatic gluconeogenesis Glucagon, catecholamines (i.e. noradrenaline, adrenaline), glucocorticoids (e.g. cortisol) & growth hormone oppose insulin action Regulation Regulation of glucagon and insulin secretion is via negative feedback mechanisms Low blood glucose stimulates release of glucagon High blood glucose stimulates secretion of insulin INSULIN Isolated in 1921 by Banting and Best Sequenced in 1955 by Sanger Gene on chromosome 11 in humans Human gene isolated and used to make human insulin from bacteria Insulin contains 2 chains. A chain 21 amino acids and B chain 30 amino acids. Only one amino acid different between pig & man. STRUCTURE OF BOVINE INSULIN SYNTHESIS OF INSULIN Insulin synthesised in RER of ß islet cells as preproinsulin 23 amino acids removed to form proinsulin in RER In Golgi apparatus proinsulin packed into vesicles where it is cleaved into insulin & C peptide Released by exocytosis when high blood sugar present in blood. INSULIN ACTIONS Hormone of abundance (anabolic hormone) Actions via insulin receptor include: Stimulated uptake of glucose in insulin-sensitive tissue like skeletal muscle and fat (via GLUT4 glucose transporter) Stimulated glycogen synthesis Stimulated lipid synthesis Stimulated protein synthesis Stimulated DNA/RNA synthesis Stimulated glycolysis AMYLIN 37 amino acid protein Co-released with insulin Actions in CNS Inhibits glucagon release Slows gastric emptying Decreases food intake Cleared by kidneys (t½ in circulation about 10 minutes) GLUCAGON Fasting hormone & hormone of energy release (catabolic) Secreted by α islet cells 29 amino acid linear polypeptide Synthesized as preproglucagon Degraded by liver and kidneys (t½ in circulation about 6 minutes) Actions (mainly on liver): Increases glycogen breakdown in liver Lipolytic action Increases ketone body formation by liver Increases gluconeogenesis in liver INSULIN ACTIONS Synthesis Breakdown Protein ↑ ↓ Lipid ↑ ↓ Glycogen ↑ ↓ DNA/RNA ↑ ↓ Liver Gluconeogenesi Glycolysis↑ s↓ GLUCOSE TRANSPORTERS GLUCOSE TRANSPORT PANCREAS SUMMARY The endocrine pancreas mainly produces insulin and glucagon Insulin and glucagon control blood glucose levels Lack of insulin results in diabetes mellitus Diabetes mellitus can be divided into Type 1 & 2 Diabetes mellitus can be treated with diet, exogenous insulin and additionally in Type 2 DM, various hypoglycaemic drugs. DIABETES Two diseases: Diabetes insipidus (posterior pituitary disease) Diabetes mellitus (pancreas disease) first described by the Egyptians in 550 BC “diabetes” is Greek meaning pass through or siphon used in 200 AD “mellitus” means honey sweet, added in 1700s Two major types of diabetes mellitus: Type 1 Type 2  Diabetes Mellitus Main Signs & Symptoms are: Polyuria (increase urine volume) Polydipsia (increase drinking) Polyphagia (increased appetite) Hyperglycaemia (raised blood sugar) Glycosuria (glucose in urine) Ketosis (ketone bodies in blood & urine)* Acidosis (excess acid in blood) Rapid weight loss* Weakness, drowsiness, fatigue Skin problems (e.g. infections, diabetic dermopathy) Visual problems (e.g. blurred vision) Coma Due to absolute (type 1) or relative (type 2) lack of insulin *particularly in uncontrolled Type 1 DM  Criteria for diagnosing diabetes Diabetes symptoms plus: a random venous plasma glucose concentration ≥ 11.1 mM or a fasting plasma glucose ≥ 7 mM or 2h plasma glucose concentration ≥ 11.1 mM 2h after 75g anhydrous glucose in an oral glucose tolerance test (OGTT) NB: in situations where HbA1c testing is appropriate, an HbA1c of 48 mmol/mol (6.5%) is recommended as the cut- off point for diagnosing diabetes CAUSES OF DIABETES MELLITUS 1. Autoimmune – destruction of B cells (Type 1 DM often) 2. Excess insulin “antagonists” e.g. growth hormone 3. Insulin receptor problems / insulin resistance (Type 2 DM often) 4. Defective insulin release (Type 2 DM often) 5. Abnormal insulin produced 6. Drug & chemical damage 7. Pancreatitis 8. Problems with glucose transport TYPES OF DIABETES MELLITUS TYPE 1 TYPE 2 Onset Under 30yr Over 40yr Type of onset Abrupt Gradual Obesity at onset Rare Common Symptoms Polyuria etc. Often none Ketosis Frequent Rare Endogenous insulin Negligible Present ß islet cells Few Normal Insulin therapy All need 20-30% need Hypoglycaemic drugs Not used Can help Diet Must control Must control % diabetic 10 90 Family history Uncommon Common HLA associated Yes No Seasonal trends Yes No Possible causes ß-cell loss (viral, chemical Insulin resistance (defective means) insulin receptor signalling) Vascular problems Microvascular Macrovascular Sex ratio Same More female  DIABETES MELLITUS acute complications e.g.: diabetic ketoacidosis (particularly uncontrolled Type 1 DM) hyperglycaemia Hyperosmolar Hyperglycaemic State (HHS) (associated with Type 2 DM) iatrogenic hypoglycaemia  DIABETES MELLITUS chronic complications e.g.: retinopathy (eye problems) neuropathy (nerve damage) nephropathy (kidney problems) heart attack & stroke (atherothrombotic problems) diabetic foot (circulatory problems) gum disease (infection & circulatory problems) increased cancer risk (tumorigenesis problems) sexual dysfunction (nervous & circulatory problems) DIABETES MELLITUS THERAPY Type 1 DM - treat with exogenous insulin + diet control - compensates for absolute lack of endogenous insulin Type 2 DM – various possibilities: 1. Dietary therapy especially if overweight 2. Drug therapy + diet control 3. Exogenous insulin + diet control - addresses e.g. insulin resistance, inappropriate hepatic glucose production & insulin secretory defect  PHARMACOTHERAPEUTIC MANAGEMENT OF DIABETES: CLASSES OF ANTI-DIABETIC AGENTS Exogenous insulin preparations** e.g. REGULAR INSULIN, INSULIN LISPRO, INSULIN GLARGINE Inhibitors of glucose absorption (“starch blockers”)* a-glucosidase inhibitors, e.g. ACARBOSE Enhancers of glucose excretion* gliflozins e.g. DAPAGLIFLOZIN Insulin secretagogues* sulfonylureas e.g. TOLBUTAMIDE, GLIPIZIDE meglitinides (glinides) e.g. REPAGLINIDE Glucagon-like peptide 1 (GLP-1), “incretin”-based therapy GLP-1 agonists** e.g. EXENATIDE, LIRAGLUTIDE inhibitors of dipeptidyl peptidase-4 (DPP-4)* e.g. SITAGLIPTIN Insulin sensitisers* thiazolidinediones (TZDs) (aka glitazones) - PIOGLITAZONE biguanides - METFORMIN *orally active; **administered by injection  Common insulin preparations Prandial bolus (short / *rapid acting) Regular (unmodified insulin) Lispro* Aspart* Glulisine* Basal (intermediate / **long acting) Neutral Protamine Hagedorn (NPH) Glargine** Detemir** Insulin therapy Indicated in Type 1 DM + Type 2 DM insufficiently responsive to diet and oral hypoglycaemic agents Administered by subcutaneous injection Typically, basal preparation to provide constant, low-level, background insulin throughout day/night + prandial bolus preparation before meals Regimen (e.g. insulin preparation, dose, frequency) personalised and adjusted for e.g. patient’s activity, meals, blood glycaemia SULPHONYLUREAS Insulin secretagogues, i.e. stimulate islet ß cells to release insulin (in glucose-independent manner) E.g. tolbutamide, glipizide, glimepiride Bind to SUR1 subunit on ATP-dependent potassium (KATP) channel, thus blocking channel leading to depolaristion and stimulating (glucose-independent) insulin release Main side effects e.g.: raised insulin levels, hypoglycaemia (especially in elderly), weight gain, appetite stimulation, GI upset, skin rash, blood dyscrasias MEGLITINIDES (GLINIDES) Insulin secretagogues, i.e. stimulate islet ß cells to release insulin (in glucose-independent manner) E.g. repaglinide Similar site and mechanism of action as sulphonylureas, but more selective for ß cell KATP channels Rapid onset and offset kinetics with short duration of action Less potent than sulphonylureas Reduce postprandial hyperglycaemia Usually administered before main meal Similar main side effect profile as for sulphonylureas, but lower risk of hypoglycaemia and weight gain BIGUANIDES Metformin Insulin sensitiser, inhibitor of hepatic glucose output (predominant action in liver to reduce glycogenolysis and gluconeogenesis) and inhibitor of glucose absorption from gut Activates hepatic adenosine 5’-monophosphate (5-AMP)-activated protein kinase (AMPK) Increases insulin receptor activity and reduces insulin resistance Enhances insulin effects in target tissues (muscle, fat, liver) and increases insulin-dependent glucose uptake (muscle and fat) No weight gain/some weight loss; reduces insulin levels and appetite; low risk of hypoglycaemia (monotherapy); reduces lipids and glucagon levels Main side effects e.g.: GI upset, altered taste, decreased appetite, vitamin B12 deficiency, lactic acidosis STARCH BLOCKERS Inhibit α-glucosidase enzymes in gut, blocking starch and sucrose breakdown and reducing/delaying glucose absorption from gut E.g. acarbose No weight gain Low risk of hypoglycaemia (monotherapy) Reduces postprandial hyperglycaemia Main side effects: GI upset, flatulence, aminotransferase elevation, raised triglycerides Poorly tolerated, but tolerance can develop THIAZOLIDINEDIONES (TZDs)/GLITAZONES Pioglitazone Insulin sensitiser Stimulate nuclear hormone receptor PPAR-g (peroxisome proliferator activated receptor g), with predominant action in muscle Reduce peripheral insulin resistance Low risk of hypoglycaemia (monotherapy); reduces insulin levels, triglycerides and free fatty acids Main side effects e.g.: weight gain, fluid retention, oedema, anaemia, GI upset, headache, fatigue, potential liver toxicity (need to monitor), heart failure, raised LDL cholesterol  GLIPTINS Inhibit dipeptidyl peptidase-4 (DPP-4) enzyme “Incretin”-based therapy (“incretin” enhancers) raise levels of GLP-1 E.g. sitagliptin, saxagliptin, vildagliptin, linagliptin Enhance glucose-dependent insulin release, decrease glucagon release + hepatic glucose production, delay gastric emptying Low risk of hypoglycaemia (monotherapy); no weight gain Main side effects e.g.: upper respiratory tract infection, headache, GI upset, nasopharyngitis, raised creatinine levels  GLP-1 agonists Analogues of GLP-1 (DPP-4 resistant) “Incretin”-based therapy (“incretin” agonists) mimic actions of GLP-1 E.g. exenatide, lixisenatide, liraglutide, dulaglutide, semaglutide, tirzepatide* Enhance glucose-dependent insulin release, decrease glucagon release + hepatic glucose production, delay gastric emptying Appetite suppression; weight loss Main side effects e.g.: GI disturbances, gastro-oesophageal reflux disease, hypoglycaemia, headache, dizziness * also a GIP agonist GLIFLOZINS Sodium glucose-linked transporter-2 (SGLT-2) inhibitors E.g. dapagliflozin, canagliflozin, empagliflozin, ertugliflozin Prevent proximal tubular reabsorption of filtered glucose from renal filtrate Low risk of hypoglycaemia (monotherapy); weight loss Main side effects e.g.: polyuria, dehydration, aggravated glycosuria, genital yeast infection, urinary tract infection, skin infection (Fournier’s gangrene), diabetic ketoacidosis