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Pharmacology of Diabetes Dinushan Raveendran (BSc Endocrinology) dinushan.raveendran20@imperial.ac.uk -&"3/*/(▯0#+&$5*7&4▯ • Understand the pathophysiology of Type 2 Diabetes Mellitus. • To apply knowledge of the diseased state to understand why specific processes are the target for anti-diabetic drugs. • To recall common pharmacological interventions used in the treatment of diabetes, their usage, mechanisms of action and contraindications. 5ZQF▯▯▯%JBCFUFT▯.FMMJUVT▯▯"O▯0WFSWJFX • The combination of insulin- failure results in hyperglycaemicll- state. • Associated with obesity (visceral genetic predisposition to developave a the disease. • Unlike Type 1, it is potentially weight loss.ith lifestyle changes and • If not well controlled, then there is further decline and glucose required.therapy including insulin is&QJEFNJPMPHZ▯BOE▯3JTL▯'BDUPST • It has traditionally been regarded as a disease of late adulthood however recently it has been seen to be present across all decades of life • Rapidly increasing in prevalence among younger population. • Type 2 diabetes is the most common form of diabetes accounting for 90% of cases worldwide. • Risk factors include- High BMI, age, ethnicity, Family History, Inactivity, PCOS (polycystic ovary syndrome). Sattar et al. Circulation 20191IZTJPMPHJDBM▯DPOUSPM▯PG▯#MPPE▯(MVDPTF1IZTJPMPHJDBM▯DPOUSPM▯PG▯#MPPE▯(MVDPTF Glucagon and Insulin are ANTAGONISTIC to one another. GLUCAGON: INCREASES plasma glucose via gluconeogenesis, glycogenolysis and lipolysis. INSULIN: REDUCES plasma glucose via glycogenesis, protein and lipid synthesis Insulin effects on liver1IZTJPMPHJDBM▯DPOUSPM▯PG▯#MPPE▯(MVDPTF P L Insulin effects on Myocytes Insulin effects on Adipose Tissue 1BUIPQIZTJPMPHZ▯PG▯5ZQF▯▯▯%JBCFUFT▯.FMMJUVT Type 2 diabetes: decreased secretion of insulin for a given sensitivity (insulin resistance). There is also the unopposed action of GLUCAGON. Glucose UPTAKE INTO PERIPHERAL TISSUES IS REDUCED as they are less sensitive to This contributes to an increased HEPATIC GLUCOSE OUTPUT by insulin. increasing GLUCONEOGENESIS and GLYCOGENOLYSIS in the liver. The physiological response would be to produce MORE INSULIN however INSULIN SECRETION is also reduced. Combination of both these factors result in HYPERGLYCEMIA.1BUIPQIZTJPMPHZ▯PG▯5ZQF▯▯▯%JBCFUFT▯.FMMJUVT • Diabetic Ketoacidosis is a serious complication of TYPE 1 diabetes mellitus. • This is FAR LESS COMMON in TYPE 2 as some insulin present to prevent ketosis/lipolysis (acidosis), albeit insufficient levels to prevent hyperglycaemia. • Therefore type 2 is referred to as a RELATIVE insulin deficiency as opposed to type 1 which is an ABSOLUTE insulin deficiency. %JBHOPTJT Criteria for Pre-Diabetes Criteria for Type 2 Diabetes • Fasting plasma glucose ≥5.6 mmol/L • Fasting plasma glucose ≥7.0 mmol/L •Plasma glucose ≥7.7 mmol/L 2 hours after 75 g oral • Plasma glucose ≥11.1 mmol/L 2 hours after 75 g oral glucose glucose • Glycated haemoglobin (HbA1c) ≥48 mmol/mol • Glycated haemoglobin (HbA1c) ≥42 mmol/mol • In a symptomatic patient, random plasma glucose of ≥11.1 mmol/L OR HbA1c ≥48 mmol/mol is DIAGNOSTIC A repeat confirmatory test on a subsequent day is required in asymptomatic patients. From: BMJ Best Practice- Type 2 Diabetes4ZNQUPNT Pre-Diabetes Type 2 Diabetes • Usually asymptomatic and elevated blood glucose • Can also present asymptomatically but common symptoms (but not severe enough to cause symptoms). include fatigue, blurred vision, UTI’s, skin infections and fungal infections. • Usually discovered on routine investigation • The osmotic symptoms typically found in Type 1 diabetes • At this stage the disease progression is REVERSIBLE (polyuria, polydipsia, glycosuria and nocturia) present less but action should be taken to control blood glucose, frequently in type 2 diabetes unless very advanced and poorly otherwise insulin-dependent diabetes and controlled. associated complications. From: BMJ Best Practice- Type 2 Diabetes$PNQMJDBUJPOT ACUTE :Hyperosmolar Hyperglycemic state (HHS) Usually presents with renal failure due to dehydration (hypovolaemia due to osmotic diuresis), no significant metabolic acidosis. • Often caused by a precipitating factor e.g. infection, MI or dehydration. • Symptoms are severe hyperglycaemia and dehydration e.g. dry mucous membranes, polyuria, polydipsia, confusion, drowsiness, blurred vision (late-stage neurological symptoms). • Treatment: fluid resuscitation, correct electrolyte imbalance, intravenous insulin. CHRONIC: • Microvascular : Nephropathy, Retinopathy and Neuropathy • Macrovascular : Ischaemic heart disease, Cerebrovascular events and Peripheral vascular disease. • These are irreversible complications of chronic uncontrolled hyperglycaemia • Treatments depend on the complication..BOBHFNFOU LIFESTYLE CHANGES (1 line): • Weight loss • Structured education on nutrition - diet high in fiber and low in refined carbohydrates. If not sufficient to control blood glucose (HbA1c ≥48mmol/mol): • ORAL MEDICATION • May need insulin injections1PTTJCMF▯ESVH▯NFDIBOJTNT▯UP▯USFBU▯5ZQF▯▯▯ EJBCFUFT AIM: lower blood glucose to a normal physiological range. Pathological mechanisms Counteractive measure Drugs INSULIN RESISTANCE Increase peripheral tissue sensitivity to Metformin insulin DECREASED INSULIN SECRETION FOR Increase insulin secretion • Sulphonylureas GIVEN RESISTANCE • DPP-4 inhibitors EXCESS HEPATIC GLUCOSE OUTPUT Reduce hepatic glucose output Metformin (GLUCONEOGENESIS AND GLYCOGENOLYSIS VIA GLUCAGON). EXCESS GLUCOSE IN THE CIRCULATION Reduce glucose absorption from GI tract SGLT-2 Inhibitors and increase glucose excretion from Kidneys.%36(▯5"3(&54▯ 3*1& ▯ Receptors Ion Channels Transport Proteins Enzymes "QQSPBDI▯UP▯MFBSOJOH▯BCPVU▯OFX▯ESVHT • Drug (class) • Examples • Primary mechanism of action • Drug target • Side effects and Contraindications • Extra information .FUGPSNJO▯▯%SVH▯$MBTT▯BOE▯.FDIBOJTN▯PG▯"DUJPO • Belongs to a class of drugs known as BIGUANIDES. • First line treatment if dietary and lifestyle changes unsuccessful in lowering blood glucose. • Exact mechanism of action remains unclear. It is thought to activate the enzyme AMP (Adenosine Monophosphate) Kinase, which regulates cellular metabolism. This enzyme inhibits adenylate cyclase which prevents fat oxidation. This in turn reduces gluconeogenesis (hepatic glucose output). • Metformin increases peripheral tissue sensitivity to insulin, thus increasing glucose uptake into tissues, although the mechanism of how it does this remains unclear. .FUGPSNJO▯▯%SVH▯5BSHFU • Primary Drug Target: 5ʹ-AMP-activated protein kinase (AMPK) in the hepatocyte mitochondria. • Metformin is a highly polar molecule and therefore can only access tissue via a transport protein: Organic Cation Transporter 1 (OCT-1) • OCT-1 present in enterocytes (small bowel), hepatocytes (liver) and Proximal Tubules (Kidney nephrons). This allows absorption via the GI tract, transport to the liver via the portal vein for its therapeutic effect and excretion via the kidneys..FUGPSNJO▯▯4JEF▯FGGFDUT▯▯▯$POUSBJOEJDBUJPOT▯UP▯VTF Side-effects: • OCT-1 presence in small bowel can cause adverse GI side-effects including anorexia (no appetite), nausea, abdominal discomfort and diarrhoea. This can be mitigated by starting at a smaller dose and slowly increasing to improve tolerability. Contraindications: • Metformin SHOULD NOT be given to individuals who have liver failure, renal impairment or cardiac failure because of the high risk of lactic acidosis. • Metformin is used in type 2 diabetes as it is most effective in the presence of some residual endogenous insulin. .FUGPSNJO▯4VNNBSZ▯UBCMF Drug (class) Biguanide Examples Metformin (only one used now). Phenformin and Buformin (no longer used as they cause lactic acidosis) Drug Target 5ʹ-AMP-activated protein kinase (AMPK) in the hepatocyte mitochondria Primary Mechanism of Inhibits Gluconeogenesis and increases peripheral tissue sensitivity to insulin. Highly Action polar therefore can only access tissues via specialist transport protein OCT-1 present in small bowel, liver and kidney nephrons. Side Effects GI side-effects including nausea, anorexia, abdominal pain and diarrhoea Contraindications Do not use in cardiac, renal or liver failure due to increased risk of lactic acidosis.4#"▯▯▯▯.FUGPSNJO Q1: Which of these pathological processes contributing to the disease state is a target for Metformin? A. Increased insulin resistance in peripheral tissues B. Increase Glucose in the urine C. Increased Hepatic Glucose Output D. Autoimmune destruction of the pancreatic beta cells E. Decreased insulin secretion4#"▯▯▯▯.FUGPSNJO Q1: Which of these pathological processes contributing to the disease state is a target for Metformin? A. Increased insulin resistance in peripheral tissues B. Increase Glucose in the urine (side effect of SGLT2 inhibitors) C. Increase Hepatic Glucose Output D. Autoimmune destruction of the pancreatic beta cells (Type 1 Diabetes) E. Decreased insulin secretion (Target for DPP4 and sulfonylureas)Dipeptidyl Peptidase-4 ( %11▯▯ ▯*OIJCJUPST▯▯.FDIBOJTN▯PG▯ "DUJPO • Examples include Sitagliptin, Saxagliptin, Alogliptin and Linagliptin (- gliptins). • One of two drug classes that work by enhancing the ‘incretin effect’ (the other drug class being GLP-1 Agonists e.g. exenatide). • Incretins e.g. GLP-1 are gut hormones secreted from enteroendocrine cells that stimulate insulin secretion, suppress glucagon secretion, induce satiety (feeling full) e.g. after a meal. • GLP-1 broken down by the enzyme dipeptidyl peptidase 4 (DPP-4), present in the vascular endothelium. • DPP-4 Inhibitors inhibit this enzyme and increase the half-life of circulating incretins.%11▯▯▯*OIJCJUPST▯▯%SVH▯5BSHFU ▯4JEF▯FGGFDUT▯BOE▯ $POUSBJOEJDBUJPOT • Primary drug target: DPP-4 enzymes, present in the vascular endothelium. Side effects: • Upper respiratory tract infections • Flu-like symptoms e.g. sore throat, headache and nasal discharge • SERIOUS: Severe allergic reactions and acute pancreatitis Contraindications • DPP-4 inhibitors work by augmenting insulin secretion therefore should only be used when there is residual beta-cell function to produce endogenous insulin. • Avoid in patients with pancreatitis %11▯▯▯*OIJCJUPST▯4VNNBSZ▯UBCMF Drug (class) DPP-4 Inhibitors Examples Sitagliptin, Saxagliptin, Alogliptin and Linagliptin (-gliptins). Drug Target DPP-4 enzyme in vascular endothelium Primary Mechanism of Enhances incretin effect by inhibiting the enzyme DPP-4 which is responsible for Action metabolising incretins e.g. GLP-1. Enhances insulin secretion and suppresses glucagon. Side Effects Upper respiratory tract infections, flu-like symptoms. SERIOUS: Severe allergic reaction and acute pancreatitis. Contraindications Administer the drug only if some residual function in the pancreatic beta cells. Avoid in patients with pancreatitis.4#"▯▯▯▯%11▯ Q1: What is the role of incretins in control of plasma glucose levels? A. Increases lipolysis and proteolysis B. Stimulates release of somatostatin C. Contribute to satiety (feeling full after a meal) D. Decreases blood sugar via stimulating insulin secretion E. Emulsifying fats from the diet to be absorbed better.4#"▯▯▯▯%11▯ Q1: What is the role of incretins in control of plasma glucose levels? A. Increases lipolysis and proteolysis (Glucagon) B. Stimulates glycogenolysis (Glucagon) C. Contribute to satiety (feeling full after a meal) D. Decreases blood sugar via stimulating insulin secretion E. Emulsifying fats from the diet to be absorbed better. (Bile)4VMQIPOZMVSFBT▯ 46 ▯▯%SVH▯UBSHFU • Drug Class: Sulphonylureas • Examples: Gliclazide, Glimepiride and Glipizide. • Drug target: ATP-sensitive potassium ion (K+) channels of pancreatic beta islet cells 4VMQIPOZMVSFBT▯ 46 ▯▯.FDIBOJTNT▯PG▯"DUJPO • Glucose enters the cell via GLUT-2 receptor Rate-limiting step which has extremely high affinity for it. • ATP is generated by breakdown of glucose via aerobic respiration. • Normal insulin release requires closure of the ATP sensitive Potassium (K+) channels. • SU bind to, inhibit and close K+ channel without the need for ATP. This blocks K+ efflux, causing depolarisation of cell membrane, opening of Ca2+ channels and Ca2+ influx. This causes exocytosis of insulin-containing vesicles.4VMQIPOZMVSFBT▯ 46 ▯▯4JEF▯FGGFDUT▯BOE▯ $POUSBJOEJDBUJPOT • Common side-effects include weight gain and hypoglycaemia. • Weight gain can be mitigated by concurrent administering of metformin. • Risks of hypoglycaemia should be discussed with the patient, especially when administering other glucose-lowering drugs. They should receive appropriate education on how to reverse hypoglycemic states. • SU augment insulin secretion therefore are only effective when there is still some residual function of the pancreatic beta cells. 4VMQIPOZMVSFBT▯ 46 ▯4VNNBSZ▯UBCMF Drug (class) Sulphonylureas Examples Gliclazide, Glimepiride and Glipizide Drug Target ATP-sensitive potassium channel on Beta islet cell in pancreas. Primary Mechanism of Inhibition of potassium channel and subsequent depolarisation of cell membrane. Leads Action to opening of calcium ion channels. Calcium enters cell causing insulin vesicle exocytosis. Side Effects Weight gain and Hypoglycemia Contraindications Prescribe with caution in those with liver or renal disease (increased risk of severe hypoglycemia due to drug metabolism and excretion defects.)4#"▯▯▯▯4VMQIPOZMVSFBT Q1: In which of the following circumstances should you NOT prescribe sulphonylureas to a patient? A. Diabetic Ketoacidosis B. Type 1 Diabetes Mellitus C. Diabetes Insipidus D. A patient on hemodialysis E. Cirrhosis4#"▯▯▯▯4VMQIPOZMVSFBT Q1: In which of the following circumstances should you NOT prescribe sulphonylureas to a patient? A. Diabetic Ketoacidosis B. Type 1 Diabetes Mellitus C. Diabetes Insipidus D. A patient on hemodialysis E. Cirrhosis 4(-5▯▯▯JOIJCJUPST▯▯.FDIBOJTN▯PG▯"DUJPO • Belong to the drug class Sodium-Glucose Co- transporter 2 inhibitors. • Examples include Dapagliflozin, Empagliflozin and Canagliflozin (-floxin) • SGLT-2i reversibly inhibit the sodium-glucose cotransporter in the renal proximal convoluted tubule. This reduces the amount of glucose reabsorbed back into the blood and increases the amount excreted in the urine.4(-5▯▯▯JOIJCJUPST▯▯%SVH▯5BSHFU ▯4JEF▯FGGFDUT▯BOE▯ $POUSBJOEJDBUJPOT Drug target: SGLT-2 co-transporter protein in the proximal convoluted tubule (PCT) of nephron Side-effects: • Increased glucose collecting in the urine -> increased risk of urogenital infections, UTIs and dehydration. • Rare complications include diabetic ketoacidosis and Fournier’s gangrene. Contraindications: • History of diabetic ketoacidosis • Severe renal failure (e.g: undergoing dialysis) 4(-5▯▯▯JOIJCJUPST▯4VNNBSZ▯UBCMF▯ Drug (class) SGLT2 Inhibitors Examples Dapagliflozin, Empagliflozin and Canagliflozin. Drug Target SGLT 2 on the renal proximal convoluted tubule. Primary Mechanism of Inhibits the transport protein that reabsorbs glucose from the blood. This means less Action glucose is reabsorbed in the blood and more is lost in the urine. Side Effects UTIs, dehydration, genitourinary infections. Rarely Ketoacidosis and Fournier’s Gangrene. Contraindications Those who have a history of diabetic ketoacidosis and in severe renal failure (e.g. undergoing dialysis).4#"▯▯▯▯4(-5▯▯▯*OIJCJUPST Which of the following are COMMON side-effects of SGLT-2 inhibitors use? A. Diabetic Ketoacidosis B. Fournier’s Gangrene C. Acute Pancreatitis D. Dehydration E. Urogenital infections4#"▯▯▯▯4(-5▯▯▯*OIJCJUPST Which of the following are COMMON side-effects of SGLT-2 inhibitors use? A. Diabetic Ketoacidosis (RARE complication) B. Fournier’s Gangrene (RARE complication) C. Acute Pancreatitis (complication of DPP-4 use) D. Dehydration E. Urogenital infectionsCase-based SBAs on Type 2 Diabetes Mellitus and its pharmacological interventions 4#"▯▯▯ A 57 year old gentleman is found to have a HbA1c of 44 mmol/mol and a fasting plasma glucose of 6.2 mmol/L. He has a BMI of 27. He has a 20-pack year smoking history. He has no other symptoms. What is the diagnosis? A. Type 2 Diabetes Mellitus B. Cushing’s Syndrome C. Pre-diabetes D. Acromegaly E. Hyperthyroidism 4#"▯▯▯ A 57 year old gentleman is found to have a HbA1c of 44 mmol/mol and a fasting plasma glucose of 6.2 mmol/L. He has a BMI of 27. He has a 20-pack year smoking history. He has no other symptoms. What is the diagnosis? A. Type 2 Diabetes Mellitus Criteria for Diagnosis Pre- Diabetes B. Cushing’s Syndrome C. Pre-diabetes • Fasting plasma glucose ≥5.6 mmol/L •Plasma glucose ≥7.7 mmol/L 2 hours after 75 g oral glucose D. Acromegaly • Glycated haemoglobin (HbA1c) ≥42 mmol/mol E. Hyperthyroidism (All of these are potential causes of secondary diabetes but would likely present with other symptoms). 4#"▯▯▯▯ A 57-year-old gentleman is found to have a HbA1c of 44 mmol/mol and a fasting plasma glucose of 6.2 mmol/L. He has a BMI of 27. He has no other symptoms. He has a 20-pack year smoking history. Having established that he has pre-diabetes, what is the first line management? A. Gliclazide B. Injected insulin C. Metformin D. Sitagliptin E. Lifestyle changes: increased exercise and weight loss. 4#"▯▯▯▯ A 57-year-old gentleman is found to have a HbA1c of 44 mmol/mol and a fasting plasma glucose of 6.2 mmol/L. He has a BMI of 27. He has no other symptoms. We have established that he has pre-diabetes. What would the first line treatment for this patient be? A. Gliclazide B. Injected insulin C. Metformin D. Sitagliptin E. Lifestyle changes: increased exercise and weight loss Lifestyle changes = first line management for pre-diabetes.4#"▯▯▯▯ The patient comes back three months later and with a HbA1c of 49mmol/mol Lifestyle changes are not enough to lower blood sugar. What should he be given next? A. Gliclazide B. Injected insulin C. Metformin D. Sitagliptin E. Dapagliflozin4#"▯▯▯▯ The patient comes back three months later and with a HbA1c of 49mmol/mol Lifestyle changes are not enough to lower blood sugar. What should he be given next? A. Gliclazide (Sulfonylurea) B. Injected insulin (late-stage treatment for diabetes) C. Metformin- FIRST LINE oral glucose-lowering therapy D. Sitagliptin (DPP4 Inhibitors) E. Dapagliflozin (SGLT2 inhibitors)4#"▯▯▯ The patient is started Metformin but his HbA1c is now 58mmol/mol. He has also been recently diagnosed with COPD. Prescription of which oral-glucose lowering therapy would be contraindicated in this patient? A. Insulin B. Atorvastatin C. Gliclazide D. Dapagliflozin E. Sitagliptin4#"▯▯▯ The patient is started Metformin but his HbA1c is now 58mmol/mol. He has also been recently diagnosed with COPD. Prescription of which oral-glucose lowering therapy would be contraindicated in this patient? A. Insulin B. Atorvastatin C. Gliclazide D. Dapagliflozin E. Sitagliptin- (DPP4 inhibitors cause upper respiratory tract infections and patient has COPD) 46.."3: INSULIN RESISTANCE DECREASED INSULIN SECRETION • DPP-4 inhibitors • Metformin • Sulphonylureas INCREASED HEPATIC GLUCOSE OUTPUT EXCESS GLUCOSE IN CIRCULATION • Metformin • SGLT-2 inhibitors 0UIFS▯"TQFDUT▯UP▯$POTJEFS • Comorbidities of Type 2 diabetes include hypertension therefore blood pressure management is key. • There are clear benefits to using anti-hypertensive drugs e.g. ACE-inhibitors or ARB. • Also common for type 2 diabetics to have dyslipidemia. Total cholesterol and triglycerides are raised and HDL cholesterol is reduced. Lipid lowering therapies e.g. statins are very beneficial. • Weight loss, increased physical activity and diet is superior to everything! -&"3/*/(▯0#+&$5*7&4▯ • Understand the pathophysiology of Type 2 Diabetes Mellitus. • To apply knowledge of the diseased state to understand why specific processes are the target for anti-diabetic drugs. • To recall common pharmacological interventions used in the treatment of diabetes, their usage, mechanisms of action and contraindications. &YUSB▯3FBEJOH▯ Revise pharmacology within the context of the disease! This will help give a wholistic understanding of the disease itself as opposed to memorising individual segments. • Khan Academy- Pharmacology • Osmosis: Pharmacology • Kumar and Clark’s Clinical Medicine: Chapter on Diabetes Mellitus.5)"/,▯:06▯ Please fill in the Feedback form! Dinushan Raveendran dinushan.raveendran20@imperial. ac.uk