Normal Effect of Insulin to Stimulate Leg Blood Flow in NIDDM Flemming Dela, Jens J. Larsen, Kari J. Mikines, and Henrik Galbo In patients with non-insulin-dependent diabetes mellitus (NIDDM), a decreased effect of insulin in stimulating leg blood flow (LBF) has been reported. We reinvestigated the effect of insulin on LBF and validated our data by use of other measures. Eight healthy men (control group) and seven men with NIDDM were studied (age 59 ± 1 and 58 ± 3 years, weight 83 ± 3 and 86 ± 6 kg, fat-free mass 66 ± 1 and 64 ± 3 kg, respectively [mean ± SE, allP > 0.05]; body mass index 26 ± 1 and 29 ± 1 kg/m 2 , fasting plasma insulin 72 ± 7 and 187 ± 22 pmol/1, fasting plasma glucose 5.8 ± 0.2 and 10.2 ± 1.7 mmol/1 [all P < 0.05]). A three-step hyperinsulinemic glucose clamp (ambient glu- cose level) was performed, combined with catheteriza- tion of an artery and both femoral veins. Expiratory air was collected, LBF was measured by thermodilution, and blood was sampled and analyzed for oxygen content. Insulin concentration was increased to 416 ± 22 and 509 ± 43 (step I), 1,170 ± 79 and 1,299 ± 122 (step II), and 15,936 ± 1,126 and 16,524 ± 1,916 (step III) pmol/1 in control and NIDDM subjects, respectively (P > 0.05). LBF increased similarly (P > 0.05) in the two groups (from 287 ± 23 and 302 ± 12 [basal] to 308 ± 31 and 362 ± 9 [I], 371 ± 29 and 409 ± 17 [II], and 434 ± 32 and 472 ± 29 [III] mlmiiTMeg" 1 in control and NIDDM sub- jects, respectively). Leg oxygen uptake always increased in the face of constant venous Po 2 (JP > 0.05; 4.3 ± 0.2 and 4.5 ± 0.2 [basal], 4.3 ± 0.2 and 4.6 ± 0.2 [I], 4.8 ± 0.2 and 4.6 ± 0.2 [II], and 4.7 ± 0.1 and 4.4 ± 0.2 [III] kPa in control and NIDDM subjects, respectively). Both leg and whole body O 2 uptake increased similarly in the two groups. In conclusion, at ambient glucose levels, the effect of insulin in stimulating LBF is normal in NIDDM. Moreover, insulin-mediated vasodilation is closely linked to muscle metabolic rate. Diabetes 44:221-226, 1995 I n healthy subjects, extremity blood flow has been reported to increase in response to increasing plasma insulin concentrations (1-5). The mechanism by which insulin acts as a vasodilator is not fully understood, and both systemic and local mechanisms have been pro- posed (6). In patients with non-insulin-dependent diabetes mellitus (NIDDM), Laakso et al. (7) have found an impaired From the Department of Medical Physiology, The Panum Institute, University of Copenhagen; Department of Urology and Endocrine Surgery D2112, Rigshospita- let; and Copenhagen Muscle Research Centre, Copenhagen, Denmark. Address correspondence and reprint requests to Dr. Flemming Dela, Depart- ment of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. Received for publication 1 June 1994 and accepted in revised form 6 October 1994. NIDDM, non-insulin-dependent diabetes mellitus; LBF, leg bloodflow;ANOVA, analysis of variance. insulin-mediated increase in leg blood flow (LBF). Based on the defective ability of insulin to increase LBF in patients with NIDDM, the authors have noted that insulin-stimulated muscle glucose uptake rates in NIDDM could be improved by up to 40% if the blood flow response to insulin is normalized (7). This issue is therefore important for our understanding of the pathophysiology of the decreased insulin sensitivity in NIDDM, particularly in the skeletal muscle. In contrast to the findings of Laakso et al. (7), we have now found that insulin-stimulated blood flow in the legs does not differ between healthy subjects and patients with NIDDM. Our blood flow measurements are supported by measure- ments with other techniques, which, in addition, elucidate the mechanism behind the vasodilator action of insulin. RESEARCH DESIGN AND METHODS Eight healthy men (control group; age 59 ± 1 years [mean ± SE]) and seven men with NIDDM (age 58 ± 3 years) gave their informed consent to participate in the study, which was approved by the Ethical Commit- tee of Copenhagen. All subjects in the control group had normal glucose tolerance (assessed by a 75-g oral glucose tolerance test), and none were taking any medication. The duration of diabetes in the NIDDM group was on average 5 years 1 month (range 1.5-12.0 years). Three subjects were treated by diet alone, and four subjects were treated with both diet and oral antidiabetic drugs (subject 1: gliklazide, 3 x 80 mg; subject 3: metformin 3 x 1 g + chlorpropamide 1 x 250 mg; subject 5: glipizide 2 x 3.5 mg + metformin 2 x 500 mg; subject 7: tolbutamide 2 X 500 mg). In none of the groups did the subjects have clinical or laboratory evidence of any other endocrine diseases. In the NIDDM group, one subject (subject 5) was treated for hypertension (diltiazem 2 x 120 mg) as well. Clinical and laboratory characteristics of both groups are shown in Table 1. On the 3 days before the experimental day, the subjects were fed a diet containing a least 250 g carbohydrate per day. The subjects were studied postabsorptive (10 h) at 8 A.M. and had abstained from unusual physical activity and intake of alcohol the day before. On the day of experiments, no medication was taken. After arrival in the laboratory, the subjects were weighed, their height was measured, and they went to bed. Electrocardiogram and heart rate were monitored by precordial electrodes. A cannula was inserted into a brachial or radial artery and used for blood sampling and measurement of arterial blood pressure. Another cannula was inserted in the medial cubital vein for later infusion of insulin and glucose. After application of local anesthesia, Teflon catheters were inserted in both femoral veins (Seldinger tech- nique) 5-7 cm below the inguinal ligament and advanced so that the tip of the catheter was located ~2 cm distal to the inguinal ligament. The catheters were conical, with the hole at the tip being just wide enough for a thermistor to pass through. Four small (0.3 mm in diameter) side holes were drilled 1.5 cm from the tip, allowing blood drawing and injection of cold saline (see below). A thermistor (Edslab probe 94-030- 2.5F, Baxter) was inserted into the catheter and advanced 6-8 cm beyond the catheter tip. All cannulas were kept patent with a slow drip of saline (artery and cubital vein) or Na/KCl (femoral veins). After a 45-min rest, expiratory air was collected in Douglas bags through a respiratory valve. Subjects were accustomed to the respiratory valve for at least 4 min before collection of air (~10 min). Basal blood samples were then drawn simultaneously from the arterial and venous catheters. This was done twice, with an interval of 10 min. Immediately after blood DIABETES, VOL. 44, FEBRUAEY 1995 221 Downloaded from http://diabetesjournals.org/diabetes/article-pdf/44/2/221/361208/44-2-221.pdf by guest on 04 November 2022