1. Journal Club 亀田メディカルセンター 糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田 昌文 Matsuda, Masafumi 2008 年１月 10 日 8:20-8:50 B 棟８階 カンファレンス室

3. Objective: To assess the contribution of decreased glucose clearance to the rise in fasting plasma glucose (FPG) in the non-diabetic range. Research Design and Methods: 120 subjects with normal glucose tolerance received an OGTT and euglycemic insulin clamp with 3-[ 3 H] glucose. The basal and insulin-stimulated rates of glucose appearance, glucose disappearance, glucose clearance, and basal hepatic insulin resistance index were calculated. Simple Pearson correlation was used to assess the relationship between variables. Results: The increase in FPG (range= 75 to 125 mg/dl) correlated (r=0.32, p<0.0001) with the increase in BMI (range = 20-50 kg/m 2 ). The fasting plasma insulin concentration (FPI) also increased progressively with the increase in BMI (r=0.62, p<0.0001). However despite increasing FPI, the basal glucose clearance rate declined and correlated with the increase in BMI (r =-0.56, p<0.0001). Basal hepatic glucose production (HGP) decreased with increasing BMI (r = -0.51, p<0.0001) and correlated inversely with the increase in FPI (r= -0.32, p< 0.0001). The hepatic insulin resistance (basal HGP x FPI) increased with rising BMI (r=0.52, p<0.0001). During the insulin clamp, glucose disposal declined with increasing BMI (r= -0.64, p<0.0001) and correlated with the basal glucose clearance (r=0.39, p<0.0001). Conclusion: These results demonstrate that, in non-diabetic subjects, rising FPG is associated with a decrease (not an increase) in basal hepatic glucose production and is explained by a reduction in glucose clearance. ABSTRACT

4. FPG = fasting plasma glucose; FPI = fasting plasma insulin; HGP = hepatic glucose production. rHGP= residual hepatic glucose production during insulin clamp; SSPI steady state plasma insulin.

5. OGTT. Before the start of the OGTT, a small polyethylene catheter was placed into an antecubital vein and blood samples were collected at –30, –15, 0, 30, 60, 90, and 120 min for the measurement of plasma glucose and insulin concentrations. On the day of the OGTT lean body mass was measured with Dual Energy X-ray Absorptiometry (DEXA)

6. Euglycemic Insulin Clamp. Before the start of the insulin clamp, a catheter was placed into an antecubital vein for the infusion of all test substances. A second catheter was inserted retrogradely into a vein on the dorsum of the hand, and the hand was placed into a thermoregulated box heated to 70°C. At 0800 h, all subjects received a primed (25 μCi)- continuous (0.25 μCi/min) infusion of 3-[ 3 H] glucose (DuPont NEN Life Science Products, Boston, MA), which was continued for the 4 hour duration of the study. Two hours after the start of tritiated glucose, subjects received a primed-continuous insulin infusion at the rate of 240 pmol (40 mU) · min –1 · m –2 for 120 min. During the last 30 min of the basal equilibration period (90-120 min), blood samples were taken at 5- to 10- min intervals for the determination of plasma glucose and insulin concentrations and tritiated glucose radioactivity. During the insulin infusion, plasma glucose concentration was measured every 5 min, and a variable infusion of 20% glucose was adjusted, based on the negative feedback principle, to maintain the plasma glucose concentration at each subject’s fasting plasma glucose level with a coefficient of variation <5%. Blood samples were collected every 15 min from 120 to 210 min and every 5–10 min from 210 to 240 min for the determination of plasma glucose and insulin concentrations and tritiated glucose radioactivity.

7. Figure 1. Relationship between BMI and fasting plasma glucose concentration (A), hepatic glucose production (B), and fasting plasma insulin concentration (C).

10. Figure 2. Relationship between the hepatic insulin resistance index, measured as the product of fasting plasma insulin concentration (FPI) and hepatic glucose production (HGP) (A) and the rate of glucose clearance (B).

12. Figure 3. Relationship between fasting plasma glucose concentration and glucose clearance rate (A) and hepatic glucose production (B).

14. The results of the present study demonstrate that the decrease in noninsulin dependent glucose clearance is the primary factor that contributes to the increase in fasting plasma glucose concentration within the nondiabetic range. The decline in basal HGP observed with rising BMI is explained by the increase in fasting plasma insulin concentration that represents a compensatory response to the obesity- related insulin resistance. SUMMARY