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Pharmacology of Diabetes sm4619@ic.ac.uk LEARNING OBJECTIVES: • Understand the pathophysiology of Type 2 Diabetes Mellitus. •specific processes are the target for anti-diabetic drugs.y • To recall common pharmacological interventions used in the treatment of Diabetes, their usage, mechanisms of action and contraindications. Type 2 Diabetes Mellitus: An Overview • The combination of insulin- resistance and Pancreatic Beta cell- failure results in hyperglycaemic state. • Associated with obesity,though not always the case. Certain individuals have a genetic predisposition to develop the disease. • Unlike Type 1, it is potentially reversible withlifestyle changes and weight loss. • If not well controlled, then there is lowering therapy including insulin is required.Epidemiology and Risk Factors • It has traditionally been regarded as a disease of lateadulthood however recently it has been seen to be present across all decades of life • Rapidly increasing inprevalence among youngerpopulation. • 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. Circulation2019Physiological control of Blood Glucose Physiological control of Blood Glucose Glucagonand Insulin are ANATAGONISTIC to one another. GLUCAGON: INCREASESplasmaglucosevia gluconeogenesis,glycogenolysisand lipolysis. INSULIN:REDUCESplasmaglucose via glycogenesis,proteinand lipidsynthesis and promotingbreakdown of glucose in aerobic respiration. Insulineffects of LiverPhysiological control of Blood Glucose P L Insulineffects on Myocytes Insulineffects on Adipose TissuePathophysiology of Diabetes Mellitus Type 2 • and insulin secretiondefects.al tissues Genes Macrovascular Obesity/FA • Unopposed actionof glucagon. Insulin Resistance Mitogenic Adipocytokines Metabolic • Combined these result in a Dyslipidaemia HYPERGLYCEMICstate. IUGR Inflam • Fatty acids importantin pathogenesis and B cell failure complications Hyperglycaemia • heterogenouspresentation.Individuals Insulin requirement develop diabetes a variable BMIs,ages Microvascular and progressionof the disease is variable. Pathophysiology of Diabetes Mellitus Type 2 InType2diabetes thereis a decreasedsecretion ofinsulin fora given sensitivity. GlucoseUPTAKEINTOPERIPHERALTISSUESIS REDUCEDasthey areless sensitiveto Thereis also theunopposedaction of GLUCAGON. insulin. This contributesto an increasedHEPATICGLUCOSEOUTPUTby Thephysiologicalresponsewouldbeto produceMOREINSULINhoweverINSULIN increasingGLUCONEOGENESISandGLYCOGENOLYSISintheliver. SECRETIONisalso reduced.Combination of both thesefactorsresultin HYPERGLYCEMIA.Pathophysiology of Diabetes Mellitus Type 2 • Diabetic Ketoacidosisis a serious complicationof TYPE1 diabetes mellitus. • This is FAR LESSCOMMONin TYPE 2 Diabetes Mellitus as thereis some insulin present, albeit insufficientlevels toprevent hyperglycaemia. • Thereforetype 2 is referred toas a RELATIVEinsulin deficiency as opposedtotype 1 whichis an ABSOLUTEinsulin deficiency. Diagnosis Criteriafor DiagnosisPre-Diabetes Criteriafor Diabetestype 2 •Fasting plasmaglucose≥5.6 mmol/L •Fasting plasmaglucose≥7.0 mmol/L •Plasmaglucose ≥7.7 mmol/L2 hoursafter75 g oral •Plasmaglucose ≥11.1 mmol/L 2 hoursafter 75 goral glucose glucose •Glycated haemoglobin(HbA1c) ≥48 mmol/mol •Glycated haemoglobin(HbA1c) ≥42 mmol/mol •In a symptomaticpatient,random plasmaglucoseof ≥11.1 mmol/L (thisaloneisdiagnostic). A repeatconfirmatoryteston a subsequentdayisrequiredin asymptomaticpatients. In practice, a patientwith severesymptomsandelevated test resultsdoesnot usuallyneed a repeat test. From: BMJBest Practice- Type 2DiabetesSymptoms Pre- Diabetes Type 2 Diabetes • Usually asymptomatic and elevated blood glucose • Can also present asymptomatically and be discovered by (but not severe enough to cause symptoms). routine investigations. However common symptoms include fatigue, blurred vision, UTI’s, Skin infections and fungal • Usually discovered on routine investigation infections. • At this stage the disease progression is REVERSIBLE • The osmotic symptoms typically found in Type 1 diabetes but action should be taken to control blood sugar. If (polyuria, polydipsia, glycosuria and nocturia) present less not the individual will go on to develop insulin- frequently in type 2 diabetes unless the disease is far advanced dependent diabetes and potentially develop all and very poorly controlled. associated complications. • Can also be discovered upon the appearance of micro and macrovascular complications (kidney failure, nephropathy and vision loss) indicating damage caused by long-term poorly controlled hyperglycaemia and hypertension. From: BMJBest Practice- Type 2Diabetes COMPLICATIONS ACUTE: Hyperosmolar Hyperglycemic state. Usuallypresents with renalfailuredueto dehydration (Not the same as diabetic nephropathy however both affectthe kidneys).There is not enough insulinto suppress hyperglycaemia but enough to prevent ketogenesis/lipolysis,therefore no acidosis present. • Often causedby a precipitating factor e.g. infection,MI or dehydration. • Symptoms are severehyperglycaemia and dehydration e.g.dry mucous membranes, polyuria, polydipsia (osmotic symptoms) confusion, drowsiness and blurred vision(late-stageneurological symptoms). • Treat via fluidresuscitation,correcting electrolyte imbalance and intravenous insulin. CHRONIC: Microvascular:Nephropathy, Retinopathy and neuropathy Macrovascular:Ischaemic heartdisease,cerebrovascularevents and peripheral vasculardisease. Theseare irreversiblestagecomplications ofchronic uncontrolled highblood glucoseleading to nerve and blood vessel damage. Various treatments depending on the complication.COMPLICATIONS- SUMMARY Treatment • Lifestyle changes:Weight loss,diet high in fiber and low in refined carbohydrates. • Structured education aroundnutrition. If not sufficient to control blood glucose: • ORAL MEDICATION • Injected doses of insulin • Maygointo remission. Where could we target to treat the disease? OurAIM isto lower bloodglucose to a normalphysiologicalrange. Counteractivemeasure Pathologicalmechanisms Drugs INSULINRESISTANCE Increase peripheral tissue sensitivity totformin insulin Sulphonylureas DECREASED INSULINSECRETION FOR GIVEN Increase levels of insulin secretion DPP4-inhibitors RESISTANCE GLP-1 Agonists(Injectable) EXCESS HEPATIC GLUCOSE OUTPUT Reduce hepatic glucose output (GLUCONEOGENESIS AND GLYCOGENOLYSIS Metformin VIA GLUCAGON). EXCESS GLUCOSE IN THE CIRCULATION Reduce glucose absorption from GI tractSGLT-2 Inhibitors and increase glucose excretion from Kidneys.DRUG TARGETS ARE ONE OF 4 THINGS: Enzymes Ion Channels Transport Proteins Receptors Approach to learning about new drugs • Drug (class) • Examples • Primary mechanism of action • Drug target • Side effects and Contraindications • Extra informationMETFORMIN- Drug Class and Mechanism of Action • Belongsto a classof drugs knownasBIGUANIDES. Otherexamplesof these drugs includePhenformin andBuformin, howeverthese are no longerin usedue to theirhigh risk of causinglactic acidosis. • Firstline treatmentifdietaryandlifestyle changeshavenot helpedlowerbloodglucose. • Exact mechanismof actionremainsunclear.It isthought to activatetheenzymeAMP (Adenosine Monophosphate)Kinase,which regulatescellularmetabolism.The accumulationofthisenzyme then inhibitsadenylate cyclasewhich preventsfatoxidation.These inturn reducesthe generationofglucose from notcarbohydratesubstances(gluconeogenesis)andreducesHepatic glucoseoutput, leadingtoa lowerblood sugar. • Metformin isalso thoughtto increaseperipheraltissuesensitivity to insulin,thusincreasingthe uptake of glucose into tissues,althoughthe mechanism ofhow it doesso remainsunclear. METFORMIN- Drug T arget • PrimaryDrugTarget: 5′-AMP-activatedproteinkinase(AMPK) in the hepatocytemitochondria. • Metformin isa highlypolarmoleculeandtherefore canonlyaccess tissue viaa transportprotein: OrganicCation Transporter1 • Present inenterocytes(small bowel), hepatocytes (liver)andProximalTubules(Kidney nephrons).Thisallows absorptionvia the GI tract, transportto the liverviathe portalveinfor its therapeutic effect andexcretion viathe kidneys.METFORMIN- Side effects and Contraindications to use • OCT-1 allowsmetformin to accumulatein the liverfor itstherapeuticeffect howeverdueto the presenceof OCT-1 in the smallbowelit can causeadverseGI side-effectsincludinganorexia(no appetite), nausea , abdominaldiscomfortanddiarrhoea.Thiscan be mitigatedby givinga smallerdose and slowlyincreasinguntil the drug istoleratedandtherapeuticbenefitis achieved. • Metformin shouldnot be given to individualswhohave liver failure,renal impairmentorcardiacfailure because ofthe high risk of lacticacidosis. • Metformin isused intype 2 diabetesasit ismost effective in the presence of some residualendogenousinsulin. METFORMIN Summary Drug (class) Biguanide Examples Metformin (only oneused now). Phenformin and Buformin (no longerused asthey cause lacticacidosis) Drug Target 5′-AMP-activatedproteinkinase (AMPK) in the hepatocytemitochondria Primary Mechanismof InhibitsGluconeogenesisandincreasesperipheraltissue sensitivityto insulin.Highly Action polartherefore canonlyaccess tissues viaspecialisttransport proteinOCT-1 present in smallbowel, liverandkidneynephrons. Side Effects GI Side-effects includingnausea, anorexia,abdominalpainanddiarrhoea Contraindications Do not use in cardiac,renalorliverfailuredue to increased risk of lacticacidosis.SBA 1: Metformin 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 secretionSBA 1: Metformin 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) DPP-4 INHIBITORS- Mechanism of Action • Dipeptidyl Peptidase-4 (DPP4) inhibitors • 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- Agonists). • Incretins e.g. GLP 1 (glucagon-like peptide) are gut hormones responsible for enhancing insulin secretion and suppressing glucagon secretion. They are secreted from the enteroendocrine cells of the small intestine e.g. after a meal when insulin needs increasing and glucagon needs to decreasing. These aid digestion and reduce appetite. They are broken down by the enzyme dipeptidyl peptidase 4 (DPP4) which is present in the vascular endothelium. • DPP4 Inhibitors therefore inhibit this enzyme and increase the half-life of circulating incretins.DPP-4 INHIBITORS- Incretin effectDPP4 INHIBITORS- Drug Target, Side-effects and Contraindications • The Primary drug target ofthese inhibitorsisthe DPP4enzymesthemselves, present in the vascular endothelium. • Side effects includeflu-like symptomse.g. sore throatand headacheand nasaldischarge.Occasionally respiratorytract infections • Nausea • Severe allergicreactions(SERIOUS COMPLICATION) • Maycause acute Pancreatitis(SERIOUS COMPLICATION). • DPP4 inhibitorswork by augmentinginsulinsecretiontherefore shouldbe used when there isstillthe productionof endogenousinsulin. DPP4- Inhibitors Summary Drug (class) DPP4 Inhibitors Examples Sitagliptin,Saxagliptin,AlogliptinandLinagliptin(-gliptins). Drug Target DPP4 enzyme invascularendothelium Primary Mechanismof Enhancesincretineffect by inhibitingthe enzyme DPP4 whichis responsiblefor Action metabolizingincretinse.g., GLP-1. Enhancesinsulinsecretionand suppressed glucagon. Side Effects Upperrespiratorytract infections, flu-likesymptoms. SERIOUS: Severe allergicreactionandacute pancreatitis. Contraindications Administerthe drug onlyifsome residualfunction left inthe pancreaticisletscell. Avoidin patientswith pancreatitis.SBA 2: DPP4 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.SBA 2: DPP4 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)Sulfonylureas- Mechanisms of Action • Drug Class: Sulfonylureas • Examples:Gliclazide, Glimepiride and Glipizide. • Mechanism of Action:the drug binds tothe sulfonylurea receptoron theBeta islet cell membrane. This inhibits the ATP-sensitivepotassium ion channels and blockspotassiumefflux. This causesdepolarization of the cell membrane which opens Calcium ion channels and Calcium ions enterthe cell. This causes exocytosis of vesicles containinginsulin. Sulfonylureas- Mechanisms of Action • Normalinsulinrelease requiresthe Rate-limitingstep closureof the ATP sensitive Potassium channels. • ATPin the cell isgeneratedby the breakdownof glucosevia aerobic respiration.Glucose entersthe cell via GLUT-2 receptorwhich hasextremely high affinityfor it. • Sulfonylureasbindto the Potassium channel andclose them without the need for ATP, therefore increasing insulineffluxfora given concentration of glucose.Sulfonylureas- Side-effects and Contraindications • Commonside-effectsinclude weight gain and hypoglycaemia. • Weight gain can be mitigatedby concurrent administering of metformin. • Risks of hypoglycaemia shouldbe discussedwith thepatient, especially when administeringotherglucose-loweringdrugs. They shouldreceive appropriate education on howto reverse hypoglycemic states. • Sulfonylureas augment insulin secretion thereforeare only effectivewhen thereis still someresidual function of the pancreatic betacells. Sulfonylureas Summary Drug (class) Sulfonylureas Examples Gliclazide,GlimepirideandGlipizide Drug Target ATP- sensitivepotassiumchannelon Betaislet cell inpancreas. Primary Mechanismof Inhibitionofpotassiumchannelandsubsequentdepolarizationofcell membrane.Leads Action to openingofcalciumion channels.Calciumenterscellcausinginsulinvesicle exocytosis. Side Effects Weight gainand Hypoglycemia Contraindications Prescribe with cautionin those with liveror renaldisease (increasedrisk ofsevere hypoglycemiadueto drug metabolismand excretion defects.)SBA 3: Sulfonylureas Q1: In which of the following circumstances should you NOT prescribe sulfonylureas to a patient? A. Diabetic Ketoacidosis B. Type 1 Diabetes Mellitus C. Diabetes Insipidus D. A patient on hemodialysis E. CirrhosisSBA 3: Sulfonylureas Q1: In which of the following circumstances should you NOT prescribe sulfonylureas to a patient? A. Diabetic Ketoacidosis B. Type 1 Diabetes Mellitus C. Diabetes Insipidus D. A patient on hemodialysis E. Cirrhosis SGLT2 inhibitors- Mechanism of Action • Belongto the drugclass Sodium-GlucoseCo- transporter2 inhibitors. • Examplesinclude Dapagliflozin,Empagliflozinand Canagliflozin. • Itsmechanismof action includes reversibly inhibitingthe sodium-glucosecotransporterin the renalproximalconvolutedtubule.This reducesthe amountof glucosereabsorbedback into the blood and increasesthe amountexcreted in the urine.SGLT2 inhibitors- Drug T arget, Side-effects and Contraindications • The drugbindsto SGLT2 proteinin the PCT of the nephron. • Side-effects are often relatedto the increasedglucose collectingin the urine.There is anincreased risk of uro- genitalinfections,UTIs anddehydration. • Rare complicationsincludediabeticketoacidosisandFournier’sgangrene. • These drugs helpwith weight loss, improverenaldysfunctionandreduce the risk ofadverse cardiacevents (common comorbiditywithtype 2 diabetes).Exact mechanism unknownbut thoughtto do thisvia: - Increasingnatriuresisleadingto fluid lossandsmall reductionsin systolicbloodpressure - Increasingproductionofketonesactingasa superfuel for the heart. - VasodilationthroughblockadeofRAS (renin-angiotensin)system - Direct effects onheart SGLT2 inhibitors-Summary Drug (class) SGLT2 Inhibitors Examples Dapagliflozin,EmpagliflozinandCanagliflozin. Drug Target SGLT 2on the renal proximalconvolutedtubule. Primary Mechanismof Inhibitsthe transport proteinthat reabsorbsglucose from the blood.Thismeans less Action glucose isreabsorbed inthe bloodandmore islost inthe urine. Side Effects UTIs, dehydration,genitourinaryinfections.Rarely KetoacidosisandFournier’sGangrene. Contraindications Those who havea historyof diabeticketoacidosisandin severe renalfailure(e.g. undergoingdialysis).SBA 4: SGLT2 Inhibitors Which of the following are COMMON complications of SGLT2 inhibitors use? A. Diabetic Ketoacidosis B. Fournier’s Gangrene C. Acute Pancreatitis D. Dehydration E. Urogenital infectionsSBA 4: SGLT2 Inhibitors Which of the following are COMMON side effects of SGLT2 use? A. Diabetic Ketoacidosis (RARE complication) B. Fournier’s Gangrene (RARE complication) C. Acute Pancreatitis (complication of DPP4 use) D. Dehydration E. Urogenital infectionsSBAs on Type 2 Diabetes Mellitus and its pharmacological interventions SBA 5: Q1: 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. Diabetes Mellitus type 2 B. Cushing’s Syndrome C. Pre-diabetes D. Acromegaly E. Hyperthyroidism SBA 5: Q1: 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. Diabetes Mellitus type 2 Criteria for Diagnosis Pre-Diabetes B. Cushing’s Syndrome • Fasting plasmaglucose ≥5.6mmol/L C. Pre-diabetes •Plasmaglucose≥7.7 mmol/L 2 hoursafter 75g oralglucose D. Acromegaly E. Hyperthyroidism • Glycated haemoglobin (HbA1c)≥42mmol/mol (All of these are potentialcausesof secondarydiabetes but would likelypresentwith other symptoms).SBA 6: Q1: 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. 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.SBA 6: Q1: 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 diabetes. What would the first line treatment for this patient be?t he has pre- A. Gliclazide B. Injected insulin C. Metformin D. Sitagliptin E. Lifestyle changes: increased exercise and weight loss. Lifestyles changes are the first line management for pre-diabetes.SBA 7: Q1: Thepatientcomesbackthree monthslaterand with a HBA1C of 47mmol/mol Lifestylechangesarenot enough to lower blood sugar.What shouldhe be given next? A. Gliclazide B. Injected insulin C. Metformin D. Sitagliptin E. DapagliflozinSBA 7: Q1: Thepatientcomesbackthree monthslaterand with a HBA1C of 47mmol/mol Lifestylechangesarenot enough to lower blood sugar.What shouldhe be given next? A. Gliclazide (Sulfonylurea) B. Injected insulin (late- stage treatment for diabetes not pre-diabetes). C. Metformin- FIRST LINE ORAL GLUCOSE- LOWERINGTHERAPY D. Sitagliptin (DPP4 Inhibitors) E. Dapagliflozin (SGLT2 inhibitors)SBA 8: Q1: Thepatientis started Metforminbut hisHba1c is now 52mmol/mol(type 2 diabetes).He has also been recentlydiagnosed with COPD. Prescriptionof which oral-glucoseloweringtherapywouldbe contraindicated in this patient? A. Insulin B. Atorvastatin C. Gliclazide D. Dapagliflozin E. Sitagliptin SBA 8: Q1: Thepatientis started metforminbuthis Hba1cis now 52mmol/mol(type2 diabetes).He has also been recentlydiagnosed with COPD. Prescriptionof which oral-glucoseloweringtherapywouldbe contraindicated in this patient? A. Insulin B. Atorvastatin C. Gliclazide D. Dapagliflozin E. Sitagliptin- (DPP4 inhibitorscause upper respiratorytract infections and patient has COPD) SUMMARY INSULIN RESISTANCE DECREASED INSULIN SECRETION - Metformin - DPP4 inhibitors - Sulfonylureas INCREASEDHEPATICGLUCOSE OUTPUT EXCESS GLUCOSEIN CIRCULATION - Metformin - SGLT2 Inhibitors Other Aspects to Consider • Comorbidities of Type 2 diabetes include hypertension thereforeblood pressure managementis key. • Thereare clear benefits tousing anti-hypertensive drugs e.g. ACE-inhibitorsor ARBS. • Alsocommonfor type 2 diabetics to have dyslipidemia. Totalcholesterol and triglycerides are raised and HDL cholesterol is reduced. Lipid lowering therapies e.g. statinsare very beneficial. • Weight loss, increased physical activity and diet is superior toeverything! LEARNING OBJECTIVES: • Understand the pathophysiology of Type 2 Diabetes Mellitus. •specific processes are the target for anti-diabetic drugs.y • To recall common pharmacological interventions used in the treatment of Diabetes, their usage, mechanisms of action and contraindications. Extra Reading: 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.THANK YOU! Please fill in the Feedback form! Name: Shaarika Munshi Email: sm4619@ic.ac.uk