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

Evaluation of Insulin Sensitivity / Resistance

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

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

Resistance to “Insulin Treatment” Resistance to “Insulin Action” Insulin Resistance Resistance to “Insulin Treatment” Failure to lower plasma glucose conc. Himsworth HP: Diabetes mellitus: Its differentiation into insulin-sensitive and insensitive types. Lancet i:127-130, 1936. More than 100 units per day More 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. Resistance to “Insulin Action” 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.

Assessment of Insulin Resistance/Sensitivity ［Indirect methods］ ［Direct methods］ 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 tolerance test 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) Insulin clamp 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) HOMA-IR Bergman RN, Ider YZ, Bowden CR: Quantitative estimation of insulin sensitivity. Am J Physiol 236:E667-E677, 1979.　 (Glucose load: non-steady) Minimal model

Assessment of Insulin Resistance/Sensitivity ［Indirect methods］ ［Direct methods］ 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 tolerance test 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) Insulin Clamp 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) Composite Index

Direct Evaluation (insulin administration) 1 Therapeutic insulin resistance Dose of insulin dose of insulin (Himsworth HP: Lancet i:127, 1936.) Insulin tolerance test Change of PG KITT (Lundbaek K: Brit Med J 1:1507, 1962) Insulin suppression test PG SSPG (Shen S-W et al: J Clin Invest 49:2151, 1970) Insulin suppression test (modified by somatostatin infusion) (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) 次のスライドお願いします。

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 infusion GIR (DeFronzo RA et al: Am J Physiol 237:E214, 1979) Measurement of Ra of glucose by a tracer Specific activity of glucose, GIR Rd, EGP (Groop LC et al: J Clin Invest 84:205, 1989) Pancreatic clamp Specific activity of glucose, GIR EGP (Matsuda M et al: Metabolism 51:1111-1119, 2002) Analysis of insulin effectiveness Insulin and glucose infusion ISI-delta, IRI-absolute (Matsuda M et al: Diabetologia 50:S276, 2007) 次のスライドお願いします。

Indirect Evaluation (measurement of plasma insulin concentration) 1 Fasting insulin Fasting IRI Fasting insulin (Yalow R et al: J Clin Invest 39:1157, 1960) Fasting IRI (specific) Fasting insulin (Olefsky JM et al: Diabetes 22:507, 1973) HOMA method Fasting IRI, fasting PG HOMA-IR (Turner R et al: Diabetologia 28:1086, 1979) HOMA method updated Fasting IRI, fasting PG HOMA-%S (Levy JC et al: Diabetes Care 21:2191, 1998) QUICKI Fasting IRI, fasting PG QUICKI (Katz A et al: J Clin Endocrinol Metab 85:2402) HOMA-AD (*) Fasting IRI, fasting PG, adiponectin HOMA-AD (Matsuhisa M et al: Diabetes Res Clin Pract, 77:151, 2007) *: Regressed algorithm For sensitivity; 1/FI 次のスライドお願いします。

Indirect Evaluation (measurement of plasma insulin concentration) 2 CIGMA IRI and PG during glucose infusion CIGMA (Hosker JP et al: Diabetologia 28:401, 1985) OGTT product IRI and PG during oral glucose load average PG x average IRI (Levine R et al: N Engl J Med 283:237, 1970) SI IRI and PG during oral glucose load SI (Cederholm J et al: Diabetes Res Clin Pract 10:167, 1990) Composite index or Matsuda index IRI and PG during oral glucose load ISI(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 load Sib, Si2h, SiM (Avignon A et al: Int J Obes Relat Metab Disord. 23:512, 1999) ISI (*) BMI, IRI at 120 min, PG at 90 min ISI (Stumvoll M et al: Diabetes Care 23:295, 2000) *: Regressed algorithm 次のスライドお願いします。

Indirect Evaluation (measurement of plasma insulin concentration) 3 OGIS IRI and PG after oral glucose load OGIS (Mari A et al: Diabetes Care 24:539, 2001) SI (oral) : minimal model index IRI and PG during meal load SI (oral) (Caumo A et al: J Clin Endocrinol Metab 85:4396, 2000) IRI and PG during oral glucose load SI (oral) (Brenda E et al: Diabetes 50:150, 2001) SIis OGTT IRI and PG after oral glucose load SIis (Bastard JP et al.: Diabetes Metab 33:261, 2007) Minimal model (FSIVGTT) PG and IRI after iv glucose infusion SI (Bergman RN et al: Am J Physiol 236:E667, 1979) Minimal model (dynamic analysis) PG and IRI after iv glucose infusion SID (Pillonetto G et al: IEEE Trans Biomed Eng 53:369, 2006) *: Regressed algorithm 次のスライドお願いします。

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

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

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

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

Induction of Composite Index ISI(comp) Inverse of Geometric Mean 次のスライドお願いします。 Inverse of Geometric Mean

∫ ∫ 10,000 (FPG X FPI)X(G X I) ISI(comp)= G= g(t) dt I= i(t) dt Insulin sensitivity indices obtained from oral glucose tolerance testing 10,000 ISI(comp)= (FPG X FPI)X(G X I) 次のスライドお願いします。 240 1 ∫ G= g(t) dt mean 240 1 240 ∫ I= i(t) dt 240 240 Response up to 240 minutes or time that is necessary to reach basal state. Matsuda M, DeFronzo RA.: Diabetes Care 22(9):1462-70, 1999.

∫ ∫ 10,000 (FPG X FPI)X(G X I) ISI(comp)= G= g(t) dt I= i(t) dt Insulin sensitivity indices obtained from oral glucose tolerance testing 10,000 ISI(comp)= (FPG X FPI)X(G X I) 次のスライドお願いします。 120 1 ∫ G= g(t) dt mean 120 1 120 ∫ I= i(t) dt 120 120 Usually we have OGTTs with 120 minutes. And the initial validation was done from the data up to 120 min. Matsuda M, DeFronzo RA.: Diabetes Care 22(9):1462-70, 1999.

ISI(comp) (Composite Index, Matsuda’s Index) Mean (range, ±SD) in healthy young persons New Haven, CT (n=37) 5.43 (2.7-9.6, ±1.9) San Antonio, TX (n=62) 4.34 (1.0-11.0, ±2.6) Correlation with clamp: r ≧ 0.73 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.

Cut off value for Insulin Resistance 2,321 (2,138 nondiabetic) euglycemic insulin clamp studies European Group for the Study of Insulin Resistance (EGIR) project (n = 1,436) Pima Indian Study (n = 597) San Antonio (n = 288, of whom 99 were Mexican American) The EGIR studies were performed on Caucasians from 17 European sites (Athens, Greece; Baden, Heidelberg, Kreisha, and Munich,Germany; Belgrade, Serbia; Geneva, Switzerland; Goteborg, Sweden; Helsinki and Kuopio, Finland; Odense, Denmark; and Naples, Padova, Pisa, Rome,Torino, and Verona, Italy). Mixture model for whole-body glucose disposal measured by the euglycemic insulin clamp technique. Dashed line, histogram including diabetic subjects; solid line, histogram excluding diabetic subjects; dotted line, normal mixture density estimate. Cut off Value Rd: <28 mmol/min per kg LBM 　　　　(5.0 mg/min per kg LBM) 　　　　(200 mg/min per m2) ISI(comp): < ~ 3.1 HOMA-IR: > ~ 2.8 Diagnosis of insulin resistance (if any of the following conditions are met) BMI >28.9 kg/m2 HOMA-IR>4.65 BMI >27.5 kg/m2 and HOMA-IR >3.60 (Sensitivity 84.9%, Specificity 78.7%) Insulin Sensitivity Diabetes 54:333–339, 2005

Cut off Value Calculation from the data set used to introduce ISI(comp) Rd<200mg/m2 per min as the gold standard Sensitivity Specificity BMI≧28.0 83% 65% BMI≧30.0 66% 80% (Rd vs BMI: r=-0.45) HOMA-IR≧2.50 84% 69% HOMA-IR≧2.80* 80% 77% (Rd vs HOMA-IR: r=-0.44) ISI(comp)＜3.1 76% 71% ISI(comp)＜2.6* 71% 84% (Rd vs ISI(comp): r=0.73) Model 91% (85%¶) 62% (79%¶) BMI >28.9 kg/m2 or HOMA-IR>4.65 or (BMI >27.5 kg/m2 and HOMA-IR >3.6) *:best value by ROC analysis ¶: shown in Diabetes 54:333–339, 2005 (Data set used in Diabetes Care 22: 1462, 1999) ISI(comp)=2.5 was used as a cut-off in Kerman WN, et al: Pioglitazone improves insulin sensitivity among non diabetic patients with a recent transient ischemic attach or ischemic stroke. Stroke 34:1431-6, 2003

Homeostatic Model Assessment HOMA Homeostatic Model Assessment

Anyone Should Appreciate the Danger of Interpreting Ratios Is it possible that inulin resistance can be assessed by the ratio of fasting plasma insulin to fasting plasma glucose concentration? A: PG 90mg/dl IRI 5mU/ml Ratio 90/5=18 Product 90x5=450 B: IRI 10mU/ml Ratio 90/10=9 Product 90x10=900 C: PG 120mg/dl Ratio 120/10=12 Product 120x10=1200 次のスライドお願いします。 The order of insulin resistance has to be C, B, A! Insulin Resistance can be assessed by the product of FPG and fasting insulin conc.

Description of the Original HOMA PERIPHERAL TISSUE Description of the Original HOMA BRAIN 次のスライドお願いします。 Metabolism 28:1086-1096, 1979

Homeostasis model analysis (HOMA) First description in 1979 Turner et al. Turner R, Holman RR, Matthews D, Hockaday TR, Peto J : Insulin deficiency and insulin resistance interaction in diabetes : estimation of relative contribution by feedback analysis from basal plasma insulin and glucose concentrations. (Metabolism 28:1086-1096, 1979.) HOMA INDEX( Insulin resistance )=rl=rp During basal steady state: 0= HGP & Splanchnic ( f PG,fIRI,rl) － Brain (fPG) － Muscle (fPG,fIRI, rp) 次のスライドお願いします。 This is converted to the below formula. The unit of PG is mmol/min. fIRI fIRI 0.4 0.4 1.2 1.2 1 1 1 1 0= 0= 3-1.86 3-1.86 × × log log -1.5 -1.5 × × log(fPG) log(fPG) - - - - × × × × rl rl 0.1 0.1 14 14 0.4 0.4 6 6 1+ 1+ 1+ 1+ 1+ 1+ fPG fPG fIRI fIRI fPG fPG +2 +2 rp rp Where fIRI : fasting insulin conc. [mU/L], fPG : fasting PG [mmol/L] rl : liver insulin resistance, rp : peripheral (or muscle) insulin resistance Assuming that rl=rp(=R), the above formula can be solved for R after substituting fPG and fIRI for actual measured values. NOTE: the function above is in steady state.

Calculation of HOMA-IR (example) fIRI fIRI 0.4 0.4 1.2 1.2 1 1 1 1 0= 0= 3-1.86 3-1.86 × × log log -1.5 -1.5 × × log(fPG) log(fPG) - - - - × × × × rl rl 0.1 0.1 14 14 0.4 0.4 6 6 1+ 1+ 1+ 1+ 1+ 1+ fPG fPG fIRI fIRI fPG fPG rl=rp(=R)，fIRI=8 [mU/ml] , fPG=6 [mmol/L] +2 +2 rp rp Then, R 8 1+ 0.4 0.1 6 14 +2 1.2 1 0= 3-1.86 × log -1.5 log(6) - 次のスライドお願いします。 R=2.1　　(when fIRI=8 mU/ml, fPG=108mg/dl(=6mmol/L)) Thus, Note: this calculation was estimated from the figures found in the original Metabolism paper published in 1979. It may possible that Dr. Turner used a different formuola. It was possible to solve this equation by a large frame computer in 1979. Now it is easy to solve this equation by an EXCEL file. M. Matsuda: index of insulin secretion and insulin resistance, Internal Medicine [Japanese] 105:39-44, 2010.

Induction of Simplified HOMA formula Reduced formula (1985 by Matthews D et al.) HOMA-IR= 次のスライドお願いします。 HOMA-b%= Diabetologia 28:412-419, 1985

QUICKI Kats A, Nambi SS, Mather K et al: Quantitative Insulin-Sensitivity Check Index (QUICKI): a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85:2402-2410, 2000.

INSULIN DOSE RESPONSE CURVE Ｓｓ INSULIN DOSE RESPONSE CURVE Difference found in HOMA-IR or QUICKI Total Glucose Disposal (mg/min・kg) Production (mg/min・kg) Hepatic Glucose Rd(t) Ra(t) Basal glucose metabolism ： ~2.2 mg/kg per min Plasma insulin concentration was conc. in portal vein for hepatic glucose production.

HOMA-IR vs Insulin Clamp Differences in Insulin Clamp 緑のグラフは正常対象者の糖利用のインスリン用量依存曲線であります。 さて，筋肉はインスリンに抵抗性があるのかは，インスリン濃度を変化させて その用量依存曲線が右下の黄色いグラフの方向にゆけば抵抗性があると言ってよろしいと思います。 実際に，肥満者や糖尿病患者では抵抗性があるわけです。 次のスライドお願いします。 Differences in HOMA-IR or QUICKI Insulin (mU/ml)