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 M111%39
2、.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:2003-2025World2003=
3、194 M2025=333 M 72%AFRNASACAEURSEAWP19.2 M39.4 M 105%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 resistanceGlucose uptakeGlucagon(a a cell)In
4、sulin(beta cell)PancreasLiverHyperglycemiaIslet-cell dysfunctionMajor Pathophysiologic Defects in Type 2 DiabetesInsulin Rapid acting Lispro,Aspart,Glulisine,Inhaled*Short acting Regular Intermediate acting NPH(Neutral Protamine Hagedorn)Long acting Glargine DetemirInsulin Advantages Mimics normal p
5、ancreatic response to glucose Can achieve normal blood glucose levels Newer delivery options Disadvantages Hypoglycemia Weight gain Patient resistance to injections Frequent blood glucose monitoring Expensive cost of inhaled insulin Spirometry needed for inhaled insulinMetformin Decreases hepatic gl
6、ucose production Improves insulin sensitivity in periphery Decreases intestinal absorption of glucoseMetformin Advantages Considerable A1c reduction Used in combination with orals and insulin Available as extended release tablet and liquid formulation Inexpensive Disadvantages Gastrointestinal adver
7、se effects Avoid in heart failure,renal and hepatic insufficiency Risk for lactic acidosisThiazolidinediones(TZDs)Insulin sensitizer(improves target cell response to insulin)Does not increase pancreatic insulin secretion Available products:Avandia(rosiglitazone),Actos(pioglitazone)Thiazolidinediones
8、(TZDs)Advantages Use as monotherapy or in combination with other medications No hypoglycemia(monotherapy or with metformin)Once or twice daily dosing Increase in HDL Decrease in Triglycerides Disadvantages Several weeks of therapy before optimal glucose reduction Peripheral edema Weight gain Macular
9、 edema,heart problems Monitoring of liver function Increase in LDL(Avandia)ExpensiveAlpha-Glucosidase Inhibitors Starch blockers(delay glucose absorption and decrease postprandial glucose)Glyset(Miglitol)and Precose(Acarbose)Alpha-Glucosidase Inhibitors Advantages Reduces postprandial glucose Disadv
10、antages Gastrointestinal adverse effects Dosed with first bite of each meal Pure glucose must be used to treat hypoglycemia Drug Interactions ExpensiveSulfonylureas Stimulates insulin release from pancreatic beta cells Reduces glucose output from liver Improves insulin sensitivity in periphery Avail
11、able products:Glyburide,Glipizide,Glimepiride(Amaryl)Sulfonylureas Advantages:Rapid,pronounced decrease in glucose Once or twice daily dosing Inexpensive Available in combination with other oral agents Disadvantages:Hypoglycemia Drug Interactions Concern for effectiveness after several years of trea
12、tmentMeglitinides Stimulates insulin release of pancreatic beta cells Different chemical structure than sulfonylureas Available products:Prandin(repaglinide),Starlix(nateglinide)Meglitinides Advantages Short half life/duration of action Meal time glucose coverage Less hypoglycemia compared to sulfon
13、ylureas Disadvantages Short duration of action Dosed with each meal Drug Interactions ExpensivePramlintide Amylin analog(co-secreted with insulin from beta cells)Prolongs gastric emptying time Reduces postprandial glucagon secretion Reduces food intake(centrally-mediated appetite suppression Availab
14、le product:SymlinPramlintide Advantages:Use in Type 1 and Type 2 diabetes Improves postprandial glucose Disadvantages:Multiple injections Small dosing in insulin syringe Gastrointestinal adverse effects Hypoglycemia Drug Interactions Expensive Cannot be mixed with insulin in same syringeIncretins Pe
15、ptide hormones secreted by enteroendocrine cells in the GI tract Modulate pancreatic islet secretions as part of the“enteroinsular axis”Other effects on nutrient homeostasis Two major incretins that affect glucose metabolism -GLP-1:glucagon-like peptide-1;GIP:glucose-dependent insulinotropic peptide
16、(gastric inhibitory polypeptide)2005.American College of Physicians.All Rights Reserved.GLP-1 is Derived FromProglucagon130646978107/8162158158123111726133GlicentinMPGFPancreasIntestineGlucagonMPGFGlicentinOxyntomodulinGLP-1GLP-2IP-2OxyntomodulinDrucker DJ.Mol Endocrinol 2003;17:161-1712005.American
17、 College of Physicians.All Rights Reserved.GLP-1 Modes 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
18、 and maintains beta-cell efficiency Improves insulin sensitivity 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 SubjectsNorma
19、l Weight:Diabetic SubjectsPlasma Insulin Responses 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)30006012018030901500601201803090150
20、90Plasma Insulin(U/mL)6030090Time(min)Time(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 subject
21、sIGT subjectsT2DM patients2005.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
22、College of Physicians.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.Amer
23、ican College 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 Mult
24、iple mechanisms 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.Source:Drucker DJ.Diabetes CareDiabetes Care 2003;26:2929-2940.2003;26:2929-2940.2005.Americ
25、an College of Physicians.All Rights Reserved.DPP-IV InhibitorsSitagliptin(Januvia)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 controversialDPP-IV Inhibition:Key Safety Issues2005.American College of Physicians.All Rights Reserved.
