1. Possible Medical Interventions to Overcome Insulin Resistance January 26, 2011 15:55-17:10 Room No. 205, 2F, XICC Xiamen International Conference & Exhibition Center, Xiamen, China BIT’s 1st World Congress of Endocrinology and Metabolism 2011 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University, Kawagoe-shi, Saitama-ken, JAPAN Matsuda, Masafumi Session 5-1: Genetics and Pathophysiology of Diabetes Chair: Dr. Dieter Schmoll, Professor, Sanofi-Aventis, Diabetes division, R&D, Innovation & External Networking, Industriiepark Hoechst, Germany

2. Insulin secretion/resistance index (disposition index) Insulin resistance Without intervention: Complication Increased plasma glucose conc. What is “Diabetes Mellitus”?

3. Classical Triumvirate: Muscle, Liver, and Panc.  -cells Dysharmonious Quartet: Fat Quintessential Quintet: Gastrointestinal tract (incretin) Setaceous Sextet: Panc.  -cells Septicidal Septet: Kidney Ominous Octet: Brain DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting Lecture]. Diabetes. 2009;58:773-795. To mange diabetic complications, management of plasma glucose is not enough.

4. Evaluation of Insulin Sensitivity / Resistance

5. Control of Plasma Glucose Pancreas Liver Muscle Brain Insulin ↑ 200 g/day 120g/day Lactic acid Glycogen Glycogen Glycogen Glycogen (Food)(Food)Adipocytes Plasma Glucose Blood Glucose Urinary glucose Plasma glucose conc. is strictly controlled. Even small increase is out of this control.

6. Insulin resistance in the liver, and reduced insulin sensitivity in the muscle are features of type 2 diabetes mellitus (T2DM). Liver Muscle Insulin resistance reduced insulin sensitivity

8. Insulin Resistance Resistance to “Insulin Treatment” Resistance to “Insulin Action” Failure to lower plasma glucose conc.Failure to lower plasma glucose conc. Himsworth HP: Diabetes mellitus: Its differentiation into insulin- sensitive and insensitive types. Lancet i:127-130, 1936. Insulin conc. was Higher in diabetic subjects !Insulin conc. was Higher in diabetic subjects ! Yalow R, Berson S: Immunoassay of endogenous plasma insulin in man. J Clin Invest 39:1157-1175, 1960. More than 100 units per dayMore than 100 units per day More than 1.4 units / kg body weightMore than 1.4 units / kg body weight Flier JS, Kahn CR, Roth J: Receptors, antireceptor antibodies and mechanisms of insulin resistance. N Engl J Med 300:413-9, 1979.

9. Bergman RN, Ider YZ, Bowden CR: Quantitative estimation of insulin sensitivity. Am J Physiol 236:E667-E677, 1979. Bergman RN, Ider YZ, Bowden CR: Quantitative estimation of insulin sensitivity. Am J Physiol 236:E667-E677, 1979. (Glucose load: non-steady) Turner RC, Holman RR, Matthews D, et al: Insulin deficiency and insulin resistance interaction in diabetes: estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations. Metabolism 28:1086-1096, 1979. (Basal ： steady) Lundbaek K: Intravenous glucose tolerance as a tool in definition and diagnosis of diabetes mellitus. Br Med J 1:1507-13, 1962. (Insulin: non-steady) HOMA-IR Minimal model DeFronzo RA, Tobin J, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214-E223, 1979. (insulin & glucose: steady) ［ Indirect methods ］ ［ Direct methods ］ Insulin clamp Insulin tolerence test Assessment of Insulin Resistance/Sensitivity

10. Lundbaek K: Intravenous glucose tolerance as a tool in definition and diagnosis of diabetes mellitus. Br Med J 1:1507-13, 1962. (insulin: non-steady) Insulin Clamp Composite Index Insulin tolerance test Matsuda M, DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462-1470, 1999. (Basal ： steady & Glucose load: non-steady ～ steady) DeFronzo RA, Tobin J, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214-E223, 1979. (insulin & glucose: steady) ［ Indirect methods ］ ［ Direct methods ］

11. Direct Evaluation (insulin administration) 1 Therapeutic insulin resistance Dose of insulindose of insulin (Himsworth HP: Lancet i:127, 1936.) Insulin tolerance test Change of PGKITT (Lundbaek K: Brit Med J 1:1507, 1962) Insulin suppression test PGSSPG (Shen S-W et al: J Clin Invest 49:2151, 1970) Insulin suppression test (modified by somatostatin infusion) PGSSPG (Harano Y et al: J Clin Endocrinol Metab 45:1124, 1977) Co-administration of glucose and insulin IRI and PG during glucose and insulin infusion SSPG (Johnston C et al: Diabetic Med 7:110, 1990)

12. Direct Evaluation (insulin administration) 2 Forearm perfusion PG, blood flow(PGa-PGv) x Flow (Zierler K et al: J Clin Invest 40:2111, 1961) Euglycemic hyperinsulinemic clamp (insulin clamp) Glucose infusionGIR (DeFronzo RA et al: Am J Physiol 237:E214, 1979) Measurement of Ra of glucose by a tracer Specific activity of glucose, GIRRd, EGP (Groop LC et al: J Clin Invest 84:205, 1989) Pancreatic clamp Specific activity of glucose, GIREGP (Matsuda M et al: Metabolism 51:1111-1119, 2002) Analysis of insulin effectiveness Insulin and glucose infusionISI-delta, IRI- absolute (Matsuda M et al: Diabetologia 50:S276, 2007)

13. Indirect Evaluation (measurement of plasma insulin concentration) 1 Fasting insulin Fasting IRIFasting insulin (Yalow R et al: J Clin Invest 39:1157, 1960) Fasting insulin Fasting IRI (specific)Fasting insulin (Olefsky JM et al: Diabetes 22:507, 1973) HOMA method Fasting IRI, fasting PGHOMA-IR (Turner R et al: Diabetologia 28:1086, 1979) HOMA method updated Fasting IRI, fasting PGHOMA-%S (Levy JC et al: Diabetes Care 21:2191, 1998) QUICKI Fasting IRI, fasting PGQUICKI (Katz A et al: J Clin Endocrinol Metab 85:2402) HOMA-AD (*) Fasting IRI, fasting PG, adiponectinHOMA-AD (Matsuhisa M et al: Diabetes Res Clin Pract, 77:151, 2007) *: Regressed algorithm For sensitivity; 1/FI

14. Indirect Evaluation (measurement of plasma insulin concentration) 2 CIGMA IRI and PG during glucose infusionCIGMA (Hosker JP et al: Diabetologia 28:401, 1985) OGTT product IRI and PG during oral glucose loadaverage PG x average IRI (Levine R et al: N Engl J Med 283:237, 1970) SI IRI and PG during oral glucose loadSI (Cederholm J et al: Diabetes Res Clin Pract 10:167, 1990) Composite index or Matsuda index IRI and PG during oral glucose loadISI(Comp) (Matsuda M et al: Diabetes Care 22:1462, 1999) Si calculated from fasting and post oral glucose load IRI and PG during oral glucose loadSib, Si2h, SiM (Avignon A et al: Int J Obes Relat Metab Disord. 23:512, 1999) ISI (*) BMI, IRI at 120 min, PG at 90 minISI (Stumvoll M et al: Diabetes Care 23:295, 2000) *: Regressed algorithm

15. Indirect Evaluation (measurement of plasma insulin concentration) 3 OGIS IRI and PG after oral glucose loadOGIS (Mari A et al: Diabetes Care 24:539, 2001) S I (oral) : minimal model index IRI and PG during meal loadS I (oral) (Caumo A et al: J Clin Endocrineol Metab 85:4396, 2000) S I (oral) : minimal model index IRI and PG during oral glucose loadS I (oral) (Brenda E et al: Diabetes 50:150, 2001) SIis OGTT IRI and PG after oral glucose loadSIis (Bastard JP et al.: Diabetes Metab 33:261, 2007) Minimal model (FSIVGTT) PG and IRI after iv glucose infusionS I (Bergman RN et al: Am J Physiol 236:E667, 1979) Minimal model (dynamic analysis) PG and IRI after iv glucose infusionS I D (Pillonetto G et al: IEEE Trans Biomed Eng 53:369, 2006) *: Regressed algorithm

16. Induction of HOMA-IR (1) (Radziuk J: J Clin Endocrinol Metab 85: 4426-4433, 2000) positive constant plasma glucose, insulin conc. Insulin sensitivity the fractional disappearance rate of glucose (insulin action) the volume of distribution of glucose the glucose input rate

17. Insulin sensitivity （ steady state ） Steady state: (Radziuk J: J Clin Endocrinol Metab 85: 4426-4433, 2000) Induction of HOMA-IR (2)

18. MCR (metabolic clearance rate) Dose of glucose AUC of PG conc. (non- steady state) = Glucose Dose PG 0 ~180min mean MCR After glucose administration

19. Insulin Sensitivity during OGTT MCR of glucose Average Insulin conc. Dose of glucose PG × Insulin = can be estimated by After glucose administration

20. Insulin sensitivity indices obtained from oral glucose tolerance testing (FPG X FPI)X(G X I) 10,000 ISI(comp)= 120 G= ∫ g(t)dt 0 120 1 I= ∫ i(t)dt 0 120 1 0 mean Matsuda M, DeFronzo RA.: Diabetes Care 22(9):1462-70, 1999.

22. World Diabetes Day Picture by Kawagoe City Public Relations Office November 14, 2009

23. Intervention to Overcome Insulin Resistance DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting Lecture]. Diabetes. 2009;58:773-795.

24. ● Life style modification ・ Malmö feasibility study(Eriksson, 1991) ・ Malmö Prfevention Trial(Eriksson, 1998) ・ DaQing IGT and Diabetes Study(Pan, 1997) ・ Finnish Diabetes Prevnetion Study(Tuomilehto, 2001) ・ Japan Diabetes Prevention Study(Kuzuya) ・ Stockholm Diabetes Prevention Program(Bjärås) ● Drug intervention ・ Diabetes Prevention Program(DPP Research Group, 2002) ・ STOP-NIDDM(Chiasson, 2002) ・ TRIPOD(Buchanan, 2001) ・ EDIT(Holman, 2003) ・ NAVIGATOR(Rury R. Holman, 2010) negative ・ DREAM(Boche, 2006) ・ ACT NOW(DeFronzo ， 2008) ・ ONTARGET(ONTARGET group, 2008) STOP-NIDDM ： Study To Prevent NDDM, TRIPOD ： Troglitazone In Prevention of Diabetes EDIT ： Early Diabetes Intervention Trial, NAVIGATOR ： Natglinide and Valsartan in Impaired Glucose Tolerance Outcome Reaserach DREAM ： Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications Primary Prevention of Type 2 Diabetes Mellitus

25. Intervention Lifestyle modification itself is a procedure to cancel insulin resistance. Anti-obesity medications should have favorable effects.

26. 58%less 31%less ~1,000 per group Cumulative Incidence of Diabetes According to Study Groups In the Diabetes Prevention Program Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group.: N Engl J Med. 2002 Feb 7;346(6):393-403.

27. Hazard rates for diabetes by metabolic variables at baseline and mean changes from baseline Diabetes Hazard rates (per 1000) Change from base line Standardized baseline value The Diabetes Prevention Program Research Group: Role of Insulin Secretion and Sensitivity in the Evolution of Type 2 Diabetes in the Diabetes Prevention Program Effects of Lifestyle Intervention and Metformin Diabetes 54:2404–2414, 2005

28. Metformin Metformin overcomes insulin resistance through activation of AMPK.

29. Rory Curtis, Bard J.Geesaman & Peter S.DiStefano: Nature Reviews Drug Discovery 4, 569-580, 2005.

30. Hyperglycemia TREATMENT OF TYPE 2 DIABETES: A SOUND APPROACH BASED UPON ITS PATHOPHYSIOLOGY Impaired Insulin Secretion Hyperglycemia Decreased Glucose Uptake Increased Lipolysis DPP-IV Inhibitors SU/glinides  Metformin TZDs GLP-1 analogues Increased HGP TZDs Metformin 

31. Pioglitazone Pioglitazone, PPARgamma against, is able to ameliorate the defective problems in the liver and the muscle, thus preserves pancreatic beta cells, resulting prolonged good plasma glucose control.

32. Intramuscular Fat Intrahepatic Fat Intraabdominal Fat Subcutaneous Fat Effect of Thiazolidinediones on Fat Topography High FFA FFA TZD Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78.. Intra-arterial Fat Artery

33. Mechanisms of pioglitazone to preserve beta-cells Adipocytes Muscle Pioglitazone Beta-cell preservation Improvement of beta- cell function pancreas Reduced TNF-  Reduced oxidative stress Glucotoxicity Lipotoxicity Improvement Liver b ABCA1 (ATP-binding cassette transporter ) PPAR 

34. P<0.0001 mean -0.3 MET （ n=588 ） -2 0 1 3 2 -3 -4 （ μU/mL ） -2.4 -2.8 +2.1 P<0.001 PIO （ n=588 ） PIO （ n=616 ） GLIC （ n=616 ） Campbell I.W.:Int.J.Clin.Pract.,58 （ 2 ）,192,2004 -1.41 -1.43 -0.5 0 -1.5 MET （ n=588 ） PIO （ n=588 ） PIO （ n=616 ） GLIC （ n=616 ） -1.50 -1.35 （%）（%） NS HbA 1C F-IRI -2.0 change from baseline Pioglitazone Reduces Serum Insulin Level Randomized into PIO 15~45mg/day or MET 850~2,550mg/day or GLIC 80~320mg/day and followed 52 weeks.

35. Kawasaki F, Matsuda, M et al: Am. J. Physiol Endocrinol Metab 288:E510-E518, 2005  -cell protective effect of pioglitazone (db/db) mice ） No treatment Pioglitazone 12 week 18 week

36. TIME TO OCCURRENCE OF DIABETES (KAPLAN MEIER) 0.30 0.25 0.20 0.15 0.10 0.05 0 10 0 20 3040 50 HR = 0.19 (95%, CI)= 0.09,0.39 p<0.00001 6.8% per year 1.5% per year Pioglitazone Placebo # at risk PLAC 299 PIO 303 215 220 Cumulative Hazard Months

37. EFFECT OF PIOGLITAZONE AND PLACEBO ON MATSUDA INDEX OF INSULIN SENSITIVITY 4 6 8 10 2 0 PlaceboPioglitazone PrePostPrePost Matsuda Index P<0.001

38. EFFECT OF PIOGLITAZONE AND PLACEBO ON INSULIN SECRETION / INSULIN RESISTANCE INDEX 3 4 5 6 2 1 0 PrePostPrePost  I/  G xMatsuda (0-120) PlaceboPioglitazone P<0.005

39. Matsuda M.;GEKKAN TOUNYOUBYOU;2,16-22,2010 2:16-22, 2010. Prevention of Diabetes Mellitus Trialpublication follow-up, year drug No. of new on-set of DM No.(total) event per 1000 person-years control No. of new on-set of DM No.(total) event per 1000 person-years Thiazolidine *DPP20050.9Troglitazone1038728.7 Placebo Metformin ILS 37 21 16 391 397 393 105.1 58.8 45.2 TRIPOD20022.5Troglitazone1711459.6Placebo37122121.3 PIPOD20063.0Pioglitazone118642.6- *DREAM20063.0Rosiglitazone306236543.1Placebo686263486.8 *ACTNOW20084.0Pioglitazone103038.3Placebo4529937.6 *CANOE20103.9Met+Rosi1410334.9Placebo41104101.1 Other (α-GI, statin, fibrate, glinide) WOSCOP20015Pravastation5729993.8Placebo8239755.5 *STOP- NIDDM20023.3Acarbose22168298.2Placebo285686125.9 BIP20046.2Bezafibrate6615668.2Placebo8014787.8 *VICTORY20094Voglibose5089713.9Placebo10688130.0 *NAVIGATOR20106.5Nateglinide1674372669.1Placebo1580374764.9

40. GLP-1 agonists/DPP4-inhibitors GLP-1 agonists and DPP4-inhibitors can suppress increased glucagon secretion in T2DM patients, resulting apparent reduction of insulin resistance.

41. Postprandial glucagon and glucose levels in subjects with NGT, patients with T2DM, and patients with T1DM during infusions of saline or GLP-1. Incremental AUC from -30 to 180 min for glucagon (A) and glucose (B) during a standardized meal consumed during infusion of saline (open bars) or GLP-1 (0.75 pmol/kg_min; filled bars) in subjects with NGT, T2DM, or T1DM. Mean ± SEM, n = 8–9 subjects per group. Gutniak M, Ørskov C, Holst JJ, Ahre´n B, Efendic S: Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med 326:1316–1322, 1992. Effect of GLP-1 to type 1 and type 2 diabetic patients

42. Ralph A. DeFronzo, Ted Okerson, Prabhakar Viswanathan, Xuesong Guan, John H. Holcombe and Leigh MacConell: CURRENT MEDICAL RESEARCH AND OPINION 24, 2943–2952, 2008. 100mg 10  g Postprandial glucagon concentration during meal ingestion at baseline and after treatment with exenatide or sitagliptin ?

43. Suppression of RAS Suppression of renin-angiotensin system is alternative way to improve insulin sensitivity, and ARB or ACEI is a choice of medication in T2DM patients with hypertension.

44. P110 PI 3-kinase P-Ser- -Tyr-P P-Ser- AⅡAⅡ AT-R P-Ser- -Tyr-P α β Insulin Receptor IRS-1 P85 Diagram of A Ⅱ signaling interactions with the insulin receptor, IRS-1, and PI 3 kinase in RASMC Folli et al: J. Clin. Invest. 100:2158–2169, 1997

45. Trialpublication follow-up, year drug No. of new on-set of DM No.(total) event per 1000 person-years control No. of new on-set of DM No.(total) event per 1000 person-years antihypertensive drug CAPPP 19996.1ACEI337518310.7β blocker380523011.9 STOP-2 19994.0ACEI93197011.8 β blocker Diuretic CCB 97 95 1960 1935 12.4 12.1 HOPE 20014.5ACEI10228378.0Placebo155288311.9 ALLHAT 20024.0ACE11940967.3 CCB Diuretic 154 302 3954 6766 9.7 11.2 PEACE 20044.8ACEI335343220.3Placebo399347223.9 ANBP-2 20054.1ACEI138280012.0Diuretic200282617.3 AASK 20063.8ACEI4541028.9 β blocker CCB 70 32 405 202 45.5 41.7 *DREAM 20063.0ACEI449262357.1Placebo489264661.6 LIFE 20024.8ARB242402012.5β blocker320397916.8 *ALPINE 20031.0ARB11965.1Diuretic819640.8 CHARM 20033.1ARB163271519.4Placebo202272123.9 SCOPE 20033.7ARB93216711.6Placebo115217514.3 VALUE 20044.2ARB690508732.3CCB845507439.7 CASE-J 20073.2ARB3813438.8CCB59134213.7 *ProFESS 20082.5ARB12573066.8Placebo15172838.3 *ONTARGET 20084.7ARB399854210.0ACEI36685769.2 *ONTARGET 20084.7 ARB +ACEI 32385028.1ACEI36685769.2 *TRANSCEND 20084.7ARB319295426.4Placebo395297228.8 *HIJ-CREATE 20094.2ARB76452.6Placebo186246.9 *Kyoto Heart 20093.27ARB+X58111651.6X8699876.7 *NAVIGATOR 20106.5ARB1532374862.9Placebo1722372571.1 Matsuda M.; Endocrinology ＆ Diabetology;26,1,35-41,2008. Prevention of Diabetes Mellitus

46. Giordano M, Matsuda M, Sanders L, Canessa ML, DeFronzo RA.: Effects of angiotensin-converting enzyme inhibitors, Ca2+ channel antagonists, and alpha-adrenergic blockers on glucose and lipid metabolism in NIDDM patients with hypertension. Diabetes. 1995 Jun;44(6):665-71. Insulin sensitivity after administration of ACE-I, CaCB, and alpha AB Insulin-medicated glucose uptake, glucose oxidation, and non-oxidative glucose disposal during the euglycemic clamp before (open bars) and after (solid bars) 3 months of treatment with doxazossin.

47. Improvement of Insulin Resistance Lender Am.J.Hypertens.,1999 Lender Am.J.Hypertens.,1999 CCB Amlodipine CCB Amlodipine normal glucose Hypertension normal glucose Hypertension Falkner Am.J.Hypertens.,1997 Falkner Am.J.Hypertens.,1997 ACE-I Lisinopril ACE-I Lisinopril normal glucose Black Hypertension normal glucose Black Hypertension Yamasaki J.Hum.Hypertens,1999 Yamasaki J.Hum.Hypertens,1999 α 1 -B Prazosin α 1 -B Prazosin normal glucose Hypertension normal glucose Hypertension Furuhashi Hypertension,2003 Furuhashi Hypertension,2003 ARB Candesartan ARB Candesartan normal glucose Hypertension normal glucose Hypertension 16w clamp 9% increase 16w clamp 9% increase 12w clamp 16% increase 12w clamp 16% increase 4w clamp 17% increase 4w clamp 17% increase 2w clamp 45% increase 2w clamp 45% increase

48. ARB protects β-cell function （ after 14 weeks ： db/db mice ） Shao J., Watada H. et al.:Biochem. Biophys. Res. Commun.,2006;344:1224.. 0 40 60 80 120 140 160 20 100 0 5 10 15 20 25 30 Normal (db/m) Control (db/db) Candesartan (db/db) （ mg ） （%）（%） Candesartan (db/db) Control (db/db)Normal(db/m) Insulin β-cell mass Staining density of Insulin （ % of Normal ） Normal (db/m) Control (db/db) Candesartan (db/db) p<0.05 （ n=11 each ）

49. High Quality Of Life same as healthy individuals, And the same duration of life as healthy individuals Prevention of Microvascular complications, and Macrovascular complications Good control of Blood glucose, Weight control, Blood pressure, Lipid Treatment Goal of Diabetic Patients ～ Japan Diabetes Society ： Treatment of Diabetes Guideline 2010 ～

50. Maintain the same QOL as healthy people, secure the same duration of life as healthy people Preventing onset and progression of diabetic microvascular disease （ retinopathy, nephropathy, neuropathy ） and macrovascular disease （ ischemic heart disease, cerebrovascular disease, arteriosclerosis obliterans ） Long-term persistence of tight blood glucose control and fundamental treatment of underlying pathophysiological condition Medical Interventions to Overcome Insulin Resistance Can Achieve the Goal of Diabetic Treatment Stain Suppression of RAS Not SU [Pio, Met, DPP4I] Slowing of Disease Progression through: Preservation of  -Cell Function and Lowering Blood Pressure (Never use glibenclamide)