Historic Perspectives of Drug Development for Diabetes 糖尿病研究进展课件.ppt

Historic Perspectives of Drug Development for Diabetes,Yuguang Shi,Ph.D.Professor of PhysiologyDept of Cellular and Molecular PhysiologyPennsylvania State University College of MedicineHershey,PA 17033Email:yus11 psu.edu,23.0 M36.2 M57.0%,14.2 M26.2 M85%,48.4 M58.6 M21%,43.0 M 75.8 M 79%,7.1M15.0 M111%,39.3 M81.6 M108%,M=million,AFR=Africa,NA=North America,EUR=Europe,SACA=South and Central America,EMME=Eastern Mediterranean and Middle East,SEA=South-East Asia,WP=Western PacificDiabetes Atlas Committee.Diabetes Atlas 2nd Edition:IDF 2003.,Global Projections for the Diabetes Epidemic:2003-2025,World2003=194 M2025=333 M 72%,AFR,NA,SACA,EUR,SEA,WP,19.2 M39.4 M105%,EMME,2003 2025,2005.American College of Physicians.All Rights Reserved.,To diabetes,Metabolic Syndrome?,Diabetes,R.Heine MD,2005.American College of Physicians.All Rights Reserved.,Hepatic glucose output,Insulin resistanceGlucose uptake,Glucagon(a cell),Insulin(beta cell),Pancreas,Hyperglycemia,Islet-cell dysfunction,Major Pathophysiologic Defects in Type 2 Diabetes,Insulin,Synthesized in the b cells of the islets of Langerhans80%of the islet cell mass must be surgically removed before diabetes becomes clinically apparentProinsulin,is transported from the endoplasmic reticulum to the Golgi complex where it is packaged into granules and cleaved into insulin and a residual connecting peptide,or C peptide,Oskar Minkowski(18581931),Pancreas and Diabetes,Their landmark study in 1889 in dogs induced diabetes by removing their pancreas.It was Minkowski who performed the operation and made the crucial link to recognize that the symptoms of the treated dogs were due to diabetes.,Josef von Mering(1849-1908),Insulin and Analogues,Insulin,Rapid actingLispro,Aspart,Glulisine,Inhaled*Short actingRegularIntermediate actingNPH(Neutral Protamine Hagedorn)Long actingGlargineDetemir,Insulin,AdvantagesMimics normal pancreatic response to glucoseCan achieve normal blood glucose levelsNewer delivery options,DisadvantagesHypoglycemiaWeight gainPatient resistance to injectionsFrequent blood glucose monitoringExpensive cost of inhaled insulinSpirometry needed for inhaled insulin,Metformin,Decreases hepatic glucose productionImproves insulin sensitivity in peripheryDecreases intestinal absorption of glucose,Metformin,AdvantagesConsiderable A1c reductionUsed in combination with orals and insulinAvailable as extended release tablet and liquid formulationInexpensive,DisadvantagesGastrointestinal adverse effectsAvoid in heart failure,renal and hepatic insufficiencyRisk for lactic acidosis,Thiazolidinediones(TZDs),Insulin sensitizer(improves target cell response to insulin)Does not increase pancreatic insulin secretionAvailable products:Avandia(rosiglitazone),Actos(pioglitazone),Thiazolidinediones(TZDs),AdvantagesUse as monotherapy or in combination with other medicationsNo hypoglycemia(monotherapy or with metformin)Once or twice daily dosingIncrease in HDLDecrease in Triglycerides,DisadvantagesSeveral weeks of therapy before optimal glucose reductionPeripheral edemaWeight gainMacular edema,heart problemsMonitoring of liver functionIncrease in LDL(Avandia)Expensive,Alpha-Glucosidase Inhibitors,Starch blockers(delay glucose absorption and decrease postprandial glucose)Glyset(Miglitol)and Precose(Acarbose),Alpha-Glucosidase Inhibitors,AdvantagesReduces postprandial glucose,DisadvantagesGastrointestinal adverse effectsDosed with first bite of each mealPure glucose must be used to treat hypoglycemiaDrug InteractionsExpensive,GLP-1,The Stimulus-Secretion Pathways in Pancreatic b-Cells,Sulfonylureas,Stimulates insulin release from pancreatic beta cellsReduces glucose output from liverImproves insulin sensitivity in peripheryAvailable products:Glyburide,Glipizide,Glimepiride(Amaryl),Sulfonylureas,Advantages:Rapid,pronounced decrease in glucoseOnce or twice daily dosingInexpensiveAvailable in combination with other oral agents,Disadvantages:HypoglycemiaDrug InteractionsConcern for effectiveness after several years of treatment,Meglitinides,Stimulates insulin release of pancreatic beta cellsDifferent chemical structure than sulfonylureasAvailable products:Prandin(repaglinide),Starlix(nateglinide),Meglitinides,AdvantagesShort half life/duration of actionMeal time glucose coverageLess hypoglycemia compared to sulfonylureas,DisadvantagesShort duration of actionDosed with each mealDrug InteractionsExpensive,Pramlintide,Amylin analog(co-secreted with insulin from beta cells)Prolongs gastric emptying timeReduces postprandial glucagon secretionReduces food intake(centrally-mediated appetite suppressionAvailable product:Symlin,Pramlintide,Advantages:Use in Type 1 and Type 2 diabetesImproves postprandial glucose,Disadvantages:Multiple injectionsSmall dosing in insulin syringeGastrointestinal adverse effectsHypoglycemiaDrug InteractionsExpensiveCannot be mixed with insulin in same syringe,Incretins,Peptide hormones secreted by enteroendocrine cells in the GI tractModulate pancreatic islet secretions as part of the“enteroinsular axis”Other effects on nutrient homeostasisTwo major incretins that affect glucose metabolism-GLP-1:glucagon-like peptide-1;GIP:glucose-dependent insulinotropic peptide(gastric inhibitory polypeptide),2005.American College of Physicians.All Rights Reserved.,GLP-1 is Derived FromProglucagon,GRPP,Glucagon,IP-1,GLP-1,IP-2,GLP-2,Glicentin,MPGF,Pancreas,Intestine,GlucagonMPGF,GlicentinOxyntomodulinGLP-1GLP-2IP-2,Drucker DJ.Mol Endocrinol 2003;17:161-171,2005.American College of Physicians.All Rights Reserved.,GLP-1 Modes of Action in Humans,GLP-1 is secretedfrom the L-cellsin the intestine,This in turn,Stimulates glucose-dependent insulin secretion,Suppresses glucagon secretion,Slows gastric emptying,Long term effectsdemonstrated in animals,Increases beta-cell mass and maintains beta-cell efficiency,Improves insulin sensitivity,Reduces food intake,Upon ingestion of food,Drucker DJ.Curr Pharm Des 2001;7:1399-1412Drucker DJ.Mol Endocrinol 2003;17:161-171,2005.American College of Physicians.All Rights Reserved.,Incretin Effect,Normal Weight:Non-Diabetic Subjects,Normal Weight:Diabetic Subjects,Plasma Insulin Responses to Oral and Intravenous Glucose,Non-Diabetic Subjects(glucose range 3.9-6.7 mmol/L)Diabetic Subjects(glucose range 4.7-12.2 mmol/L),Oral GlucoseIntravenous Glucose,Oral GlucoseIntravenous Glucose,60,Plasma Insulin(U/mL),30,0,0,60,120,180,30,90,150,0,60,120,180,30,90,150,90,Plasma Insulin(U/mL),60,30,0,90,Time(min),Time(min),Postprandial GLP-1 Levels are Decreased in Subjects With IGT and Type 2 Diabetes,Data from:Toft-Nielsen M,et al.J Clin Endocrinol Metab 2001;86:3717-3723,20,15,10,5,0,0,60,120,180,240,Time(min),Mean(SE)GLP-1(pmol/L),*,*,*,*,*,*,*,*,Meal,2005.American College of Physicians.All Rights Reserved.,Glucose Dependent Actions of GLP-1in Patients With Type 2 Diabetes,Data from:Nauck MA,et al.Diabetologia 1993;36:741-744,25,20,15,10,5,0,Glucagon(pmol/L),Time(min),-30,0,60,120,180,240,*,*,*,*,17.5,15.0,12.5,10.0,7.5,5.0,2.5,0.0,*,Glucose(mmol/L),GLP-1/PBO infusion,*,*,*,*,*,*,-30,0,60,120,180,240,350,300,250,200,150,100,50,0,Insulin(pmol/L),GLP-1/PBO infusion,Time(min),*,*,*,*,*,*,*,*,GLP-1/PBO infusion,Time(min),-30,0,60,120,180,240,2005.American College of Physicians.All Rights Reserved.,Effect of GLP-1 Infusion on Glucose Concentration in Patients With Type 2 Diabetes(Previously on Oral Agents),Glucose(mmol/L),0,2,4,6,8,10,12,14,16,Data from:Rachman J,et al.Diabetologia 1997;40:205-211,Clock Time(h),Breakfast,Lunch,Snack,24.00,02.00,04.00,06.00,08.00,10.00,12.00,14.00,22.00,16.00,2005.American College of Physicians.All Rights Reserved.,Strategies to Enhance Incretin Action in Diabetes,GLP-1 analogues Exendin 4 ExenatideDPP-IV inhibitors,2005.American College of Physicians.All Rights Reserved.,Exenatide(Byetta),A peptide from Gila monster saliva that shares 50%homology with human GLP-1Functions as an incretin mimeticIncreases insulin secretionIncreases beta cell growth/replicationSlows gastric emptyingDecreases food intakeCauses sustained weight loss in type 2 patients,Diabetes Care.2005 May;28(5):1092-100,Exenatide(Byetta)and Weight Loss,Exenatide(Byetta),Ongoing efforts for slow release formPotential usage as an antiobesity drugPotential usage for beta cell regeneration,Side effects include:nausea(common)and pancreatitis(very rare),A serine protease widely expressed on cell membranes,known as CD26DPP-IV also exists as a soluble form in plasmaPrefers proline or alanine at position 2 of the N-terminus for cleavage,but can also cleave at nonpreferred amino acidsOverlapping substrate specificity with several related enzymes,DPP-IV,2005.American College of Physicians.All Rights Reserved.,Dipeptidylpeptidase 4(DPP4)InactivatesGlucagon Like Peptide-1(GLP-1),GLP-1Inactive,GLP-1 Actions,Mixed meal,GLP-1Active,Plasma,IntestinalGLP-1release,DPP-IV,Rapid inactivation(80%of pool),Excreted by kidneys,Deacon et al.Diabetes.1995;44:1126.,2005.American College of Physicians.All Rights Reserved.,DPP-IV And GLP-1 Inactivation,Augmenting GLP-1 Levels by Inhibiting DPP-IV Activity,GLP-1Inactive,GLP-1 Actions,Mixed meal,Plasma,IntestinalGLP-1release,DPP-IV,Rapid inactivation(80%of pool),Excreted by kidneys,GLP-1Active,Deacon et al.Diabetes.1995;44:1126.,2005.American College of Physicians.All Rights Reserved.,Advantages of DPP-IV Inhibition,Low risk of hypoglycemiaOral therapy,providing dosing convenience to the patientEndogenous GLP-1 levels are increased in response to meal and are transient Avoid tolerability/immunogenicity issues with exogenous GLP-1 Multiple mechanisms of GLP-1 in T2DM Insulin release is glucose dependent Reduced hepatic glucose production Improved peripheral glucose utilization-cell preservation/neogenesis and restoration,Source:Drucker DJ.Diabetes Care 2003;26:2929-2940.,2005.American College of Physicians.All Rights Reserved.,DPP-IV Inhibitors,What are the advantages of DPP-IV inhibitors compared with GLP-1 analogues?,DPP-IV InhibitorsSitagliptin(Januvia),Orally availableMultiple targetsGLP-1 PK favorableShort vs long acting Drug overdose nontoxicNo CNS side effects,GLP-1 AnaloguesByetta,InjectableSingle known targetWeight lossBeta cell regenerationPancreatitisPotential for CNS side effects,Processing of substrates beyond GLP-1,GIPPotential toxicities due to non-selective inhibitionDPP-IV is a member of an emerging protease familyPotential role for DPP-IV(CD26)in T cell activationPotential risk of impaired immune function Role of catalytic function controversial,DPP-IV Inhibition:Key Safety Issues,2005.American College of Physicians.All Rights Reserved.,