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1、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.edu23.0 M36.2 M57.0%14.2 M26.2 M85%48.4 M58.6 M21%43.0 M 75.8 M 79% 7.1M15.0 M11
2、1%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
3、 Epidemic: 2003-2025World2003 = 194 M2025 = 333 M 72%AFRNASACAEURSEAWP19.2 M39.4 M105%EMME2003 20252005. American College of Physicians. All Rights Reserved.To diabetesMetabolic Syndrome?DiabetesR. Heine MD2005. American College of Physicians. All Rights Reserved.Hepatic glucose outputInsulin resist
4、anceGlucose uptakeGlucagon (a a cell)Insulin(beta cell)PancreasLiverHyperglycemiaIslet-cell dysfunctionMajor Pathophysiologic Defects in Type 2 DiabetesMuscleMuscleAdipose Adipose tissuetissueInsulinSynthesized in the cells of the islets of Langerhans80% of the islet cell mass must be surgically rem
5、oved 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 peptideOskar Minkowski Oskar Minkowski (18581931)(18581931)Pancreas and D
6、iabetesPancreas and DiabetesTheir landmark study in 1889 in dogs induced diabetes by Their landmark study in 1889 in dogs induced diabetes by removing their pancreas. It was Minkowski who performed the removing their pancreas. It was Minkowski who performed the operation and made the crucial link to
7、 recognize that the operation and made the crucial link to recognize that the symptoms of the treated dogs were due to diabetes. symptoms of the treated dogs were due to diabetes. Josef von MeringJosef von Mering(1849-1908)(1849-1908)Insulin and AnaloguesInsulin and AnaloguesInsulinRapid actingLispr
8、o, Aspart, Glulisine, Inhaled*Short actingRegularIntermediate actingNPH (Neutral Protamine Hagedorn)Long actingGlargineDetemirInsulinAdvantagesMimics normal pancreatic response to glucoseCan achieve normal blood glucose levelsNewer delivery options DisadvantagesHypoglycemiaWeight gainPatient resista
9、nce to injectionsFrequent blood glucose monitoringExpensive cost of inhaled insulinSpirometry needed for inhaled insulinMetforminDecreases hepatic glucose productionImproves insulin sensitivity in peripheryDecreases intestinal absorption of glucoseMetforminAdvantagesConsiderable A1c reductionUsed in
10、 combination with orals and insulinAvailable as extended release tablet and liquid formulationInexpensiveDisadvantagesGastrointestinal adverse effectsAvoid in heart failure, renal and hepatic insufficiencyRisk for lactic acidosisThiazolidinediones (TZDs)Insulin sensitizer (improves target cell respo
11、nse 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 dosingIncreas
12、e in HDLDecrease in TriglyceridesDisadvantagesSeveral weeks of therapy before optimal glucose reductionPeripheral edemaWeight gainMacular edema, heart problemsMonitoring of liver functionIncrease in LDL (Avandia)ExpensiveAlpha-Glucosidase InhibitorsStarch blockers (delay glucose absorption and decre
13、ase postprandial glucose)Glyset (Miglitol) and Precose (Acarbose) Alpha-Glucosidase InhibitorsAdvantagesReduces postprandial glucoseDisadvantagesGastrointestinal adverse effectsDosed with first bite of each mealPure glucose must be used to treat hypoglycemiaDrug InteractionsExpensiveGLP-1GLP-1The St
14、imulus-Secretion Pathways in Pancreatic b b-CellsSulfonylureasStimulates insulin release from pancreatic beta cellsReduces glucose output from liverImproves insulin sensitivity in peripheryAvailable products: Glyburide, Glipizide, Glimepiride (Amaryl)SulfonylureasAdvantages:Rapid, pronounced decreas
15、e in glucoseOnce or twice daily dosingInexpensiveAvailable in combination with other oral agentsDisadvantages:HypoglycemiaDrug InteractionsConcern for effectiveness after several years of treatmentMeglitinidesStimulates insulin release of pancreatic beta cellsDifferent chemical structure than sulfon
16、ylureasAvailable products: Prandin (repaglinide), Starlix (nateglinide)MeglitinidesAdvantagesShort half life/duration of actionMeal time glucose coverageLess hypoglycemia compared to sulfonylureasDisadvantagesShort duration of actionDosed with each mealDrug InteractionsExpensivePramlintideAmylin ana
17、log (co-secreted with insulin from beta cells)Prolongs gastric emptying timeReduces postprandial glucagon secretionReduces food intake (centrally-mediated appetite suppressionAvailable product: SymlinPramlintideAdvantages:Use in Type 1 and Type 2 diabetesImproves postprandial glucoseDisadvantages:Mu
18、ltiple injectionsSmall dosing in insulin syringeGastrointestinal adverse effectsHypoglycemiaDrug InteractionsExpensiveCannot be mixed with insulin in same syringeIncretinsPeptide hormones secreted by enteroendocrine cells in the GI tractModulate pancreatic islet secretions as part of the “enteroinsu
19、lar 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 FromProglucagonG
20、RPPGRPPGlucagonGlucagon IP-1IP-1GLP-1GLP-1IP-2IP-2GLP-2GLP-2130646978107/8162158158123111726133GlicentinMPGFPancreasIntestineGlucagonMPGFGlicentinOxyntomodulinGLP-1GLP-2IP-2OxyntomodulinDrucker DJ. Mol Endocrinol 2003; 17:161-1712005. American College of Physicians. All Rights Reserved. GLP-1 Modes
21、of Action in HumansGLP-1 is secretedfrom the L-cellsin the intestineThis in turn Stimulates glucose-dependent insulin secretion Suppresses glucagon secretion Slows gastric emptyingLong term effectsdemonstrated in animals Increases beta-cell mass and maintains beta-cell efficiency Improves insulin se
22、nsitivity Reduces food intakeUpon ingestion of foodDrucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-1712005. American College of Physicians. All Rights Reserved.Incretin EffectNormal Weight: Non-Diabetic SubjectsNormal Weight: Diabetic SubjectsPlasma Insulin Respon
23、ses to Oral and Intravenous GlucoseNon-Diabetic Subjects (glucose range 3.9-6.7 mmol/L)Diabetic Subjects (glucose range 4.7-12.2 mmol/L)Oral GlucoseIntravenous GlucoseOral GlucoseIntravenous Glucose60Plasma Insulin ( U/mL)3000601201803090150060120180309015090Plasma Insulin ( U/mL)6030090Time (min)Ti
24、me (min)Postprandial GLP-1 Levels are Decreased in Subjects With IGT and Type 2 DiabetesData from: Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001; 86:3717-3723* P 0.05 between T2DM and NGT group.20151050060120180240Time (min)Mean (SE)GLP-1 (pmol/L)* *MealNGT subjectsIGT subjectsT2DM patients200
25、5. American College of Physicians. All Rights Reserved.Glucose Dependent Actions of GLP-1in Patients With Type 2 DiabetesData from: Nauck MA, et al. Diabetologia 1993; 36:741-744Data are mean SE.* P 80% of pool)Excreted by kidneysDeacon et al. Diabetes .1995;44:1126.2005. American College of Physici
26、ans. All Rights Reserved.DPP-IV And GLP-1 Inactivation Augmenting GLP-1 Levels by Inhibiting DPP-IV Activity GLP-1InactiveGLP-1 ActionsMixed mealPlasmaIntestinalGLP-1releaseDPP-IVRapid inactivation(80% of pool)Excreted by kidneysGLP-1ActiveDeacon et al. Diabetes .1995;44:1126.2005. American College
27、of Physicians. All Rights Reserved.Advantages of DPP-IV InhibitionLow 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 mechan
28、isms of GLP-1 in T2DM Insulin release is glucose dependent Reduced hepatic glucose production Improved peripheral glucose utilization -cell preservation / neogenesis and restorationSource: Drucker DJ. Diabetes Care 2003;26:2929-2940.2005. American College of Physicians. All Rights Reserved.DPP-IV In
29、hibitorsWhat are the advantages of DPP-IV inhibitors What are the advantages of DPP-IV inhibitors compared with GLP-1 analogues?compared with GLP-1 analogues?DPP-IV InhibitorsDPP-IV InhibitorsSitagliptin (Januvia)Orally availableOrally availableMultiple targetsMultiple targetsGLP-1 PK favorableGLP-1
30、 PK favorableShort vs long acting Short vs long acting Drug overdose nontoxicDrug overdose nontoxicNo CNS side effectsNo CNS side effectsGLP-1 AnaloguesGLP-1 AnaloguesByettaByettaInjectableInjectableSingle known targetSingle known targetWeight lossWeight lossBeta cell regenerationBeta cell regenerat
31、ionPancreatitisPancreatitisPotential for CNS side effectsPotential for CNS side effectsProcessing 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 controversialDPP-IV Inhibition: Key Safety Issues2005. American College of Physicians. All Rights Reserved.
