Fig.1 Individual changes in peripheral insulin concentration and glucose infusion rate during euglycemic clamping with insulin infusion rates of 1.12

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2 Fig.1 Individual changes in peripheral insulin concentration and glucose infusion rate during euglycemic clamping with insulin infusion rates of 1.12 or 2.24 mu/kg/min in obese ( œ) and nonobese ( ) type 2DM.

3 Table 1 Subject clinical profiles (N=45) 103 ~dl/kg min per ƒêu/ml dur: duration FPG: fasting plasma glucose firi: fasting immunoreactive insulin GIR: glucose infusion rate SI: insulin sensitivity index BMI: body mass index TG: triglyceride TCho: total cholesterol OHA: oral hypoglycemic agent SU: sulfonyl urea a GI: a-glucosidase inhibitor BG: biguanide. Data is shown as Mean } SD *p<0.05 (obese DM vs nonobese DM) **p<0.01 (obese DM vs nonobese DM)

4 Fig.2 Mean peripheral insulin concentrations and glucose infusion rates during euglycemic clamping with insulin infusion rates of 1.12 or 2.24 mulkg/min in obese ( œ) and nonobese ( ) type 2 DM.

7 1) DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237: E ) Bergman RN, Ider YZ, Bowden CR, Cobelli C (1979) Quantitative estimation of insulin sensitivity. Am J Physiol 236: E ) Beard JC, Bergman RN, Ward WK, Porte D Jr (1986) The insulin sensitivity index in nondiabetic man: correlation between clamp-derived and IVGTT derived values. Diabetes 35: ) Bergman RN, Prager R, Volund A, Olefsky JM (1987) Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp. J Clin Invest 79: ) Coates PA, Luzio SD, Brunel P, Owens DR (1995) Comparison of estimates of insulin sensitivity from minimal model analysis of the insulin-modified frequently sampled intravenous glucose tolerance test and the isoglycemic hyperinsulinemic clamp in subjects with NIDDM. Diabetes 44: ) Kahn SE, Prigeon RL, Mcculloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JK, Palmer JP, Porte D Jr (1993) Quantification of the relationship between insulin sensitivity and ƒà-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 42: ) Raynaud E, Perez-Martin A, Brun JF, Benhaddad AA, Mercier J (1999) Revised concept for the estimation of insulin sensitivity from a single sample. Diabetes Care 22 (6): ) Working Group on Hypertension in Diabetes (1987) Statement on hypertension in diabetes mellitus: final report. Arch Intern Med 147: ) Kahn CR (1978) Insulin resistance, insulin insensitivity, and insulin unresponsiveness; a necessary distinction. Metabolism 27: ) Kolterman OG, Insel U, Saekow M, Olefsky JM (1980)

8 Mechanisms of insulin resistance in human obesity. Evidence for receptor and post-receptor defects. J Clin Invest 65: R (1982) Feedback inhibition of insulin secretion by insulin: relation to the hyperinsulinemia of obesity. N Engl J Med 306: ) Campbell PJ, Mandarino LJ, Gerich JE (1988) Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin dependent diabetes mellitus. Metabolism 37: ) DeFronzo RA, Simonson D, Ferrannini E (1982) Hepatic and peripheral insulin resistance: A common feature of type 2 (non-insulin dependent) and type 1 (insulin dependent) diabetes mellitus. Diabetologia 23: ) Rizza RA, Mandarino U, Gerich JE (1981) Doseresponse characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol 240: E 630-E ) Elahi D, Nagulesparan M, Hershcopf RI, Muller DC, Tobin JD, Blix PM, Rubenstein AH, Unger RH, Andres 20) Bergman RN, Finegood DT, Ader M (1985) Assessment of insulin sensitivity in vivo. Endocr Rev 6: ) DeFronzo RA (1988) The triumvirate: betacell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37:

9 Abstract Insulin Sensitivity Index Measured by Euglycemic Clamping as an Index for Insulin Resistance in Obese and Nonobese Type 2 Diabetes Mellitus Toshio Ono, Norihiro Shiga, Yoshinobu Taneda and Shuuka Umemura Department of Internal Medicine, Iwaki Kyouritsu General Hospital We compared the insulin sensitivity index (SI) measured by euglycemic clamping with the glucose infusion rate (GIR) and fasting insulin concentration. Euglycemic clamping was conducted at 2 insulin infusion rates (1.12 mu/kg/min and 2.24 mu/kg/min) in 45 patients with type 2 diabetes mellitus treated with diet or oral hypoglycemic drugs. Patients were 29 men and 16 women, 58 }11 years of age, and either obese (body mass index [BMI] 25 kg/m2, 17 patients) or nonobese (BMI<25 kg/m2, 28 patients). In obese patients, greater peripheral insulin concentrations (68 }18 ƒêu/ml, 133 }43 ƒêu/ml) than those of nonobese patients (55 }13 ƒêu/ml, 98 }27 ƒêu/ml) were required to maintain a quantitatively equivalent GIR (3.8 }1.4 mg/kg/min, 7.1 }2.1 mg/kg/min) to those of nonobese patients (4.1 }1.8 mg/kg/min, 6.7 }2.1 mg/kg/min). SI of obese patients (0.94 }0.73 ~10-3 dl /kg Emin/ƒÊU/ml) did not differ from that of nonobese patients (0.92 }0.57 ~10-3dl /kg Emin/ƒÊU/ml). SI and GIR/IRI correlated (r=0.52, p<0.05) in obese patients, but not in nonobese patients. Obese patients had much higher fasting insulin (8.9 }3.2 ƒêu/ml) than that of nonobese patients (6.9 }2.4 ƒêu/ml) and fasting insulin concentration correlated with the reciprocal of SI (r=0.52, p<0.05) or reciprocal of GIR (r= 0.69, p<0.01) at a fasting plasma glucose of<170 mg/dl. In conclusion, we showed that a while GIR or SI of obese type 2 DM subjects did not differ from that of nonobese DM subjects, insulin resistance was increased more in obese patients than in nonobese patients. Peripheral insulin concentration must therefore be cousidered during clamping for evaluating SI, b) Fasting insulin concentration is useful as a surrogate for GIR or SI in obese type 2 DM subjects when insulin-glucose feedback is operative. J. Japan Diab. Soc. 43 (11): , 2000

Fig. 1 A: Effects of intramuscular injection of glucagon on the blood glucose levels (changes from basal, ƒ BG) as compared with effects of scopolamin

Fig. 1 A: Effects of intramuscular injection of glucagon on the blood glucose levels (changes from basal, ƒ BG) as compared with effects of scopolamine butylbromide during upper gastrointestinal endoscopy.