Insulin resistance and angiographical characteristics of coronary atherosclerosis.

Insulin resistance (IR) is frequently observed in patients with coronary heart disease (CHD). The relationship between IR and the angiographical characteristics of coronary atherosclerosis were investigated in 66 patients with coronary artery lesions. Insulin resistance was assessed by a 75-g oral glucose tolerance test and homeostasis model assessment (HOMA). The angiographical characteristics of coronary atherosclerosis (i.e., the severity of CHD) were defined by both Gensini's score (GS) (a higher degree of coronary artery stenosis or a proximal lesion was assigned a higher score than a distal lesion) and the number of significantly stenosed vessels. When GS was examined as a categorical variable classified by tertile values (Group A, n = 22: 1< or =GS< or =14; Group B, n = 22: 15< or =GS< or =32; and Group C, n = 22: 33< or =GS), patients with a high GS (Group C) had significantly (p<0.05) higher values of fasting plasma insulin, insulin response, and HOMA IR than patients with a low GS (Group A) (12.6+/-1.2 microU/ml vs. 6.9+/-1.2 microU/ml, 122.2+/-11.9 microU ml(-1) h(-1) vs. 72.9+/-12.9 microU ml(-1) h(-1), and 2.9+/-0.3 vs. 1.5+/-0.3, respectively).The values in Group B patients (9.4+/-1.2,microU/mI, 108.5+/-12.5 microU ml(-1) h(-1), and 2.1+/-0.3, respectively) were intermediate between those in Groups A and C. The area of insulin/area of glucose ratio was significantly (p<0.05) higher in Groups B and C than in Group A (0.54+/-0.06 microU/mg, 0.54+/-0.06 microU/mg, and 0.32+/-0.06 microU/mg, respectively). However, no significant differences were observed in variables of glucose tolerance, serum lipid, lipoproteins, fibrinogen, uric acid, and blood pressure among the 3 groups. Significant (p<0.05) positive associations were found between GS, the number of diseased coronary arteries, and fasting immunoreactive insulin, insulin response, the area of insulin/area of glucose ratio and HOMA IR by logistic regression analysis. After adjusting for the number of diseased coronary arteries, the association between GS and IR was not significant, suggesting that IR contributed to the severity of coronary atherosclerosis but not to the distribution of lesions. In conclusion, IR was associated with the severity of CHD as measured by both Gensini's score and the number of diseased coronary arteries, and increased the risk of CHD regardless of the location of the lesions.     

Dose-response relationship of insulin to glucose fluxes in the awake and unrestrained mouse.

The purpose of the study was to use the hyperinsulinemic-euglycemic clamp technique to generate insulin dose-response curves for insulin suppression of endogenous glucose output (EGO) and stimulation of the glucose disposal rate (GDR) in conscious unstressed mice. Five groups of male ICR (Institute for Cancer Research) mice were studied (N = 43). The animals underwent surgery for implantation of a jugular vein catheter 2 to 3 days before the clamp and were fasted 6 hours before the study. Each group was clamped at a different insulin infusion rate of 0, 2.5, 10, or 20 mU/kg/min. 3H-3-glucose was infused for measurement of the glucose turnover rate (rate of appearance [Ra]). Blood samples were collected by milking a severed tail-tip. EGO was calculated as the difference between the Ra and glucose infusion rate (GIR), and the glucose clearance rate (GCR) as the GDR divided by the plasma glucose concentration. From the curves generated, half-maximal EGO and GCR were obtained at a plasma insulin concentration of 20 to 30 microU/mL, which was achieved at an insulin infusion rate of about 4 to 5 mU/kg/min. Maximal suppression of EGO and stimulation of the GCR occurred at an insulin infusion rate of 10 mU/kg/min. The establishment of normative curves for insulin-stimulated glucose metabolism in conscious mice facilitates the evaluation of glucose metabolism in a variety of mouse models of insulin resistance.     

Glucose intolerance and insulin resistance in cirrhosis are normalized after liver transplantation.

Cirrhosis is often associated with insulin resistance and glucose intolerance. We evaluated if these alterations are restored by liver transplantation (LT). Glucose tolerance (oral glucose tolerance test [OGTT]), peripheral insulin sensitivity (euglycemic insulin clamp technique), glucose oxidation (indirect calorimetry), nonoxidative glucose disposal, and insulin secretion (hyperglycemic clamp technique) were measured in 6 patients (Group 1) before and 6 months after LT, in 12 patients (Group 2) who underwent LT 6 to 30 months previously, and in 6 healthy individuals (controls). In Group 1, glucose tolerance and insulin sensitivity (3.24 +/- 0.37 mg/kg/min) were normalized after LT (8.6 +/- 0.77 mg/kg/min; P <.0001; P = not significant vs. controls). The improved insulin-mediated glucose uptake was the result of a normalization of nonoxidative glucose disposal. Fasting insulin and C-peptide decreased from 24.6 +/- 3.3 microU/mL and 4.37 +/- 0.46 ng/dL, respectively, to 12.7 +/- 1.9 microU/mL and 2.46 +/- 0.5 ng/dL (controls: 10.0 +/- 3 microU/mL and 1.45 +/- 0.34 ng/dL). The glucose-induced increase of insulin concentration, which was higher before LT, showed a significant reduction, although the first phase of beta-cell secretion remained significantly higher compared with that of controls. All these findings were also confirmed in Group 2. The present data indicate that LT normalizes glucose tolerance and insulin sensitivity in cirrhotic patients through an improvement of both hepatic glucose clearance and the peripheral glucose disposal. The latter effect may be the result of the correction of chronic hyperinsulinemia. An increased first-phase beta-cell insulin secretion in response to high glucose levels persists, suggesting that a memory of previous insulin resistance is maintained.     

Subject index

The goals of this study were twofold: (1) to determine the in vivo dose-response relationship in the conscious, unstressed rat between the plasma insulin concentration and total body glucose uptake, and between plasma insulin and suppression of endogenous glucose production; and (2) to develop a physiologic compartmental model to describe the kinetics of plasma glucose in the rat in the basal state. In order to perform repeat insulin clamp studies in the same rat, chronic catheters were implanted in the aortic arch (via the carotid artery) and in the cardiac atrium (via the jugular vein), exteriorized, and fixed to the back of the skull with a dental cement cap. Insulin was infused at rates of 1.2, 2.4, 4.8, 12, and 24 mU/min.kg, and the plasma glucose was held constant at the basal level by a variable glucose infusion (euglycemic insulin clamp). The resulting steady-state plasma insulin concentrations ranged from 40 to 1,300 microU/mL. The dose-response curve for glucose uptake was sigmoidal in shape: in the basal state, total glucose utilization averaged 6.8 mg/min.kg at an insulin concentration of 9 microU/mL, half-maximal glucose uptake (18.3 mg/kg.min) occurred at a plasma insulin concentration between 70 and 80 microU/mL, and maximal uptake (36.6 mg/kg.min) was seen at an insulin level in excess of 100 microU/mL. Residual endogenous glucose production was evaluated by a prime-continuous infusion of (3-3H)-glucose. The dose-response curve for suppression of endogenous glucose output also was sigmoidal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial infarction before the age of 40 years is associated with insulin resistance

Insulin resistance is associated with atherosclerosis, and hyperinsulinemia is predictive of coronary heart disease. However, a quantitative estimation of in vivo insulin sensitivity in juvenile myocardial infarction is still lacking and the mechanism of hyperinsulinemia is unknown. We estimated insulin sensitivity, beta-cell secretion, and hepatic insulin extraction using the minimal model analysis of a frequently sampled intravenous glucose tolerance test (FSIGT) in 25 normal-weight subjects without glucose intolerance and hypertension who had an acute myocardial infarction before the age of 40 years, and 10 control subjects comparable for age, sex, body mass index, and blood pressure. All patients underwent a coronary angiography. Insulin sensitivity was significantly lower in patients than in control subjects (mean +/- SEM, 4.6 +/- 0.6 v8.5 +/- 1.2 10(-4). min(-1)(microU/mL), P = .002). The basal C-peptide secretion rate (P = .02), total C-peptide secretion (P = .005), area under the curve (AUC) of insulin (P = .04) and C-peptide (P = .01), and hepatic insulin extraction (P = .04) were higher in patients versus control subjects. In conclusion, insulin resistance is evident in subjects with early myocardial infarction accurately selected to avoid the influence of other factors known to reduce insulin sensitivity, and hyperinsulinemia is due to an increase in beta-cell secretion rather than a decrease in hepatic insulin extraction.     

Adipose tissue, hepatic, and skeletal muscle insulin sensitivity in extremely obese subjects with acanthosis nigricans

We evaluated insulin action in skeletal muscle (glucose disposal), liver (glucose production), and adipose tissue (lipolysis) in 5 extremely obese women with acanthosis nigricans (AN), who had normal oral glucose tolerance, and 5 healthy lean subjects, by using a 5-stage pancreatic clamp and stable isotopically labeled tracer infusion. Basal plasma insulin concentration was much greater in obese subjects with AN than lean subjects (54.8 +/- 4.5 vs 8.0 +/- 1.3 microU/mL, P < .001), but basal glucose and free fatty acid concentrations were similar in both groups. During stage 1 of the clamp, glucose rate of appearance (R(a)) (2.6 +/- 0.3 vs 3.7 +/- 0.3 micromol x kg FFM(-1) x min(-1), P = .02) and palmitate R(a) (2.4 +/- 0.6 vs 7.0 +/- 1.5 micromol x kg FFM(-1) x min(-1), P < .05) were greater in obese subjects with AN than lean subjects despite slightly greater plasma insulin concentration in subjects with AN (3.0 +/- 0.7 vs 1.1 +/- 0.4 microU/mL, P < .05). The area under the curve for palmitate R(a) (1867 +/- 501 vs 663 +/- 75 micromol x kg FFM(-1) x 600 min(-1), P = .03) and glucose R(a) (1920 +/- 374 vs 1032 +/- 88 micromol x kg FFM(-1) x 600 min(-1), P = .02) during the entire clamp procedure was greater in subjects with AN than lean subjects. During intermediate insulin conditions (plasma insulin, approximately 35 microU/mL), palmitate R(a) was 5-fold greater in subjects with AN than in lean subjects (2.6 +/- 1.1 vs 0.5 +/- 0.2 micromol x kg FFM(-1) x min(-1), P = .05). Maximal glucose disposal was markedly lower in obese subjects with AN than in lean subjects (13.0 +/- 0.8 vs 23.4 +/- 1.8 mg x kg FFM(-1) x min(-1), P = .01) despite greater peak plasma insulin concentration (1842 +/- 254 vs 598 +/- 38 microU/mL, P < .05). These data demonstrate obese young adults with AN have marked insulin resistance in multiple tissues. However, marked insulin hypersecretion can compensate for impaired insulin action, resulting in normal glucose and fatty acid metabolism during basal conditions.     

阿昔单抗降低急性心肌梗死直接PTCA术缺血危险性的观察

目的　探讨血小板Ⅱb/Ⅲa受体拮抗剂阿昔单抗在急性心肌梗死直接经皮冠状动脉腔内成形术 (PTCA)术中应用的安全性 ,合理性和对PTCA术后缺血并发症及预后的影响。方法　对 6 0例胸痛小于 2h施行直接PTCA治疗的急性心肌梗死患者 ,随机分成对照组 30例和阿昔单抗组 30例 ,对照组静脉注射常规剂量肝素 10 0U/kg ,阿昔单抗组静脉注射小剂量肝素 70U/kg和阿昔单抗 0 .2 5mg/kg,随后以阿昔单抗 10 μg/min持续静脉滴注 12h ,观察 30d时两组死亡率、心肌梗死、再次急诊冠脉血运重建术和出血发生率。结果　随访 30d ,两组均未见出血并发症 ,对照组复合终点事件发生率为 10 %;阿昔单抗组无 1例死亡 ,也未发生心肌梗死和施行再次冠脉血运重建术。结论　在急性冠脉缺血综合征中 ,应用血小板Ⅱb/Ⅲa受体拮抗剂是安全合理的 ,血小板Ⅱb/Ⅲa受体拮抗剂阿昔单抗能降低急性心肌梗死患者直接PTCA术后缺血并发症 ,改善患者预后。     

Glucose metabolism in noninsulin-dependent diabetic patients with experimental hyperthyroidism

Hyperthyroidism is known to further impair carbohydrate metabolism in diabetic patients. In the present study we examined in noninsulin-dependent (type 2) diabetic patients the effect of T3-induced hyperthyroidism on glucose utilization and endogenous glucose production by means of the hyperinsulinemic and hyperglycemic clamp technique in combination with [3H]3-glucose kinetic analysis. Administration of T3 for 1 week increased the mean serum T3 concentration from 1.0 +/- 0.1 (SEM) to 4.1 +/- 0.2 ng/ml, and the mean fasting plasma glucose from 8.7 +/- 0.7 to 9.9 +/- 0.9 mmol/liter. Basal hepatic glucose production (HGP) rose from 3.23 +/- 0.23 to 3.98 +/- 0.25 mg/kg X min, whereas basal MCR of glucose (MCRG) increased only slightly from 2.12 +/- 0.24 to 2.30 +/- 0.14 ml/kg X min. When the plasma insulin concentration was acutely raised and maintained at 82 +/- 8 microU/ml (hyperinsulinemic clamp study), HGP decreased to 0.71 +/- 0.29 mg/kg X min and MCRG increased to 3.16 +/- 0.47 ml/kg X min. After T3 administration suppression of HGP by insulin was reduced (1.55 +/- 0.37 mg/kg X min), but at the same time MCRG was only slightly affected (3.64 +/- 0.54 ml/kg X min). In the hyperglycemic clamp study the plasma glucose concentration was maintained 7 mmol/liter above the individual fasting level. MCRG was again slightly higher after T3 administration (1.98 +/- 0.18 vs. 1.66 +/- 0.15 ml/kg X min), but insufficient to completely compensate for the higher residual HGP at the hyperthyroid as compared to the euthyroid state (2.42 +/- 0.24 vs. 1.45 +/- 0.36 mg/kg X min). Thus, deterioration of metabolic control in noninsulin-dependent diabetic patients by hyperthyroidism is due primarily to enhancement of basal HGP and its reduced suppressibility by insulin and glucose.     

Low-dose growth hormone treatment combined with diet restriction decreases insulin resistance by reducing visceral fat and increasing muscle mass in obese type 2 diabetic patients

OBJECTIVE: To evaluate the effects of low-dose growth hormone (GH) therapy combined with diet restriction on changes in body composition and the consequent change in insulin resistance in newly-diagnosed obese type 2 diabetic patients. DESIGN: Double-blind and placebo-controlled trial of 25-kcal/kg IBW diet daily with GH (n=9; rhGH, 0.15 IU/kg body weight/week) or placebo (n=9) for 12 weeks. SUBJECTS: Eighteen newly-diagnosed obese type 2 diabetic patients (age 42--56 y, body mass index 28.1+/-2.7 kg/m(2)). MEASUREMENTS: Body composition and fat distribution parameters (by bioelectrical impedance analyzer and CT scans), serum IGF-1; serum glucose, insulin and free fatty acid (FFA) during oral glucose tolerance test (OGTT); HbA(1c); serum lipid profiles; and glucose disposal rate (GDR) by euglycemic hyperinsulinemic clamp at baseline and after treatment. RESULTS: The fraction of body weight lost as fat lost was significantly greater (0.98+/-0.39 vs 0.52+/-0.32 kg/kg, P<0.05) and visceral fat area was decreased more in the GH-treated group compared to the placebo-treated group (27.9 vs 21.6%, P<0.05). Lean body mass and muscle area were reduced in the placebo-treated group, whereas an increase in both was observed in the GH-treated group. GDR the was significantly increased in only the GH-treated group (4.67+/-1.05 vs 6.95+/-0.91 mg/kg/min, P<0.05). The GH-induced increase in GDR was positively correlated with the decrease in the ratio of visceral fat area/muscle area (r=0.588, P=0.001). Serum glucose levels and insulin- and FFA-area under the curve during OGTT and HbA(1c) were significantly decreased after GH treatment. LDL-cholesterol level was decreased in only the GH-treated group. CONCLUSION: Low-dose GH treatment combined with dietary restriction resulted not only in a decrease of visceral fat but also in an increase of muscle mass with a consequent improvement of the insulin resistance observed in obese type 2 diabetic patients.     

TNF—α诱导的胰岛素抵抗小鼠胰岛素敏感性及糖脂代谢的变化

目的探讨TNF-α诱导的胰岛素抵抗（IR）小鼠胰岛素敏感性及糖脂代谢的变化。方法23只健康雄性C57BL／6J小鼠随机分为4组：高剂量（H）组、中剂量（M）组、低剂量（L）组分别给予腹腔注射6、3、1μg·kg^-1·d^-1的TNF-α，正常对照（NC）组注射等体积的生理盐水，共7天。采用静脉葡萄糖耐量试验（IVGTT）和3-[^3H]葡萄糖为示踪剂的扩展胰岛素钳夹技术，评价小鼠胰岛素敏感性和糖脂代谢的变化。结果TNF-α处理后，小鼠FBG、血浆胰岛素（Ins）和FFA水平均增高，且H组明显高于NC、M和L组。IVGTT结果显示H组糖耐量减低，Ins释放水平明显高于其他组。在胰岛素钳夹术中，H组基础葡萄糖清除率（GDR）和肝糖输出率（HGP）明显高于NC组（P＜50.01）。在钳夹稳态时，H组血浆Ins水平明显高于NC组（P＜0.01），Ins对FFA的抑制作用较NC组明显降低（P＜0.01），H组葡萄糖输注率（GIR）明显低于NC组（P＜0.01）；钳夹稳态时小鼠GDR明显增加，但H组GDR的增加仍明显低于NC组（P＜0.01）；钳夹结束时，NC组HGP被完全抑制，而H组仅被抑制59％。结论高剂量TNF-α（6μg·kg^-1·d^-1）处理可导致小鼠糖脂代谢紊乱以及肝和外周组织的球。     

Triglyceride and glucose intolerance as a risk factor for coronary heart disease

The electrophoresis of plasma lipoproteins frequently showed midbands between beta- and pre-beta-lipoproteins in survivors of myocardial infarction. There were increases in intermediate-density-lipoprotein (IDL) cholesterol and triglycerides with an increase in IDL cholesterol/triglycerides in the very-low-density-lipoprotein fraction, even if the increase in cholesterol was not so significant. Impaired glucose tolerance (IGT) was also frequently found in these patients. Among the patients with an apparently normal glucose tolerance, the coronary atherosclerosis scores judged by the American Heart Association reporting system on coronary angiography increased as the total insulin area by 75 g oral glucose tolerance test increased. The correlation between the atherosclerosis score and the insulin area was still significant even after adjustment for body mass index and plasma triglyceride level. Our data suggest that hypertriglyceridemia, IGT, and hyperinsulinemia may become independent risk factors for atherosclerosis in addition to cholesterol. Another study showed that the morbidity of coronary heart disease increased with an elevation of plasma triglyceride levels among patients with familial hypercholesterolemia.     

Hepatic and peripheral insulin resistance following streptozotocin-induced insulin deficiency in the dog

Insulin resistance and insulin deficiency are both present in many patients with diabetes mellitus. We tested the hypothesis that insulin resistance can evolve from a primary lesion of the beta-cell secretory function. Insulin-mediated glucose uptake (insulin clamp), endogenous glucose production, and glucose-stimulated insulin secretion (hyperglycemic clamp) were measured in awake dogs before and four to six weeks after streptozotocin-induced diabetes mellitus. Streptozotocin (30 mg/kg) resulted in a significant rise in the mean fasting plasma glucose concentration from 104 +/- 2 mg/100 mL to 200 +/- 34 mg/100 mL, (P less than 0.05), and a slight decrease in the mean fasting plasma insulin concentration (from 21 +/- 2 microU/mL to 15 +/- 2 microU/mL). Under conditions of steady-state hyperglycemia (+75 mg/100 mL hyperglycemic clamp, insulin secretion was reduced by 75% in the streptozotocin-treated dogs (P less than 0.025), and the total amount of glucose metabolized decreased from 13.56 +/- 1.04 to 4.74 +/- 0.70 mg/min X kg (P less than 0.001). In the postabsorptive state, endogenous glucose production was slightly, although not significantly, higher in the diabetic dogs (3.05 +/- 0.46 v 2.51 +/- 0.22 mg/min . kg), while the glucose clearance rate was 35% lower (P less than 0.001). When the plasma insulin concentration was increased to approximately 45 microU/mL (insulin clamp) while holding plasma glucose constant at the respective fasting levels (99 +/- 1 and 186 +/- 30 mg/100 mL), endogenous glucose production was completely suppressed in control dogs but suppressed by only 51% (1.46 +/- 0.37 mg/min . kg, P less than 0.025) in diabetic animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of hypocaloric diet and insulin therapy on metabolic control and mechanisms of hyperglycemia in obese non-insulin-dependent diabetic subjects

We studied the effects of hypocaloric diet (500 kcal/d) and insulin therapy in 15 obese (body mass index greater than 30.0 kg/m2) non-insulin-dependent diabetic patients with secondary drug failure and poor metabolic control. The patients were randomly allocated either to hypocaloric diet (n = 8) or to insulin treatment (n = 7). After 2 weeks of treatment there was a significant improvement in the fasting blood glucose, in the mean diurnal glucose, in glucosuria, and in glucose response to a 75-g oral glucose load in both groups. No change in insulin secretion was seen in either group. Glucose disposal rates (GDR) improved significantly both in the diet-treated group (from 2.34 +/- 0.15 to 4.01 +/- 0.40 mg/kg/min, P less than .01) and in the insulin-treated group (from 2.46 +/- 0.33 to 2.77 +/- 0.29 mg/kg/min, P less than .01). The improvement was greater in the diet-treated group (71%) than in the insulin-treated group (13%, P less than .05). The increase of GDR in the diet-treated group was due to an increase of nonoxidative GDR (from 1.18 +/- 0.17 to 2.98 +/- 0.39 mg/kg/min, P less than .001) as assessed by indirect calorimetry. In the insulin-treated group there was a small increase both in oxidative and nonoxidative GDR, but the changes were not statistically significant. Hepatic glucose output (HGO) in a postabsorptive state decreased significantly both in the diet-treated group (from 2.49 +/- 0.15 to 2.04 +/- 0.10 mg/kg/min, P less than .01) and in the insulin-treated group (from 2.63 +/- 0.23 to 2.05 +/- 0.12 mg/kg/min, P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic hyperinsulinemia decreases insulin action but not insulin sensitivity

Hyperinsulinemia and insulin resistance are commonly seen in obese and non-insulin-dependent diabetes mellitus (NIDDM) patients, suggesting a causal link exists between hyperinsulinemia and insulin resistance. In a previous study, we demonstrated that chronic (28 days) intraportal hyperinsulinemia (50% increase in basal insulin levels) resulted in a decrease in insulin action as assessed by a one-step euglycemic hyperinsulinemic clamp. Since only one dose of insulin was used during the clamp, it was not possible to determine if the decrease in insulin action was due to a change in insulin sensitivity and/or maximal insulin responsiveness. In the present study, insulin resistance was induced as before, but insulin action was assessed in overnight fasted conscious dogs using a four-step euglycemic hyperinsulinemic clamp (1, 2, 10, and 15 mU/kg/min). Insulin responsiveness was assessed before the induction of chronic hyperinsulinemia (day 0), and after 28 days of hyperinsulinemia (day 28). Transhepatic glucose balance and whole-body glucose utilization were measured to allow assessment of both the hepatic and peripheral effects of insulin. Chronic hyperinsulinemia increased basal insulin levels from 13 +/- 2 to 21 +/- 4 microU/mL. After 4 weeks of chronic hyperinsulinemia, maximal insulin-stimulated glucose utilization was decreased 23% +/- 4% (P less than .05) and insulin sensitivity (ED50) was not significantly altered. During the four-step clamp, the liver was a major site of glucose utilization. The liver was responsible for 13% of the total glucose disposal rate on day 0 (2.9 mg/kg/min) at the highest insulin infusion rate (15 mU/kg/min; 2,000 microU/mL).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hyperglycemia reduces myocardial blood flow reserve and the magnitude of reduction is associated with insulin resistance: a study in nondiabetic humans using contrast echocardiography

The effect of acute hyperglycemia per se on coronary perfusion in humans is undefined. We evaluated the effects of short-term hyperglycemia on myocardial blood flow reserve (MBFR) in healthy nondiabetic volunteers. Twenty-one nondiabetic volunteers (76 % females, mean ± SD, age 48 ± 5 years) had noninvasive MBFR assessment while exposed to pancreatic clamp with somatostatin and replacement glucagon and growth hormone infusions, with frequent interval plasma glucose (PG) monitoring. Insulin was infused at 0.75 mU/kg/min to mimic postprandial plasma insulin concentrations, and glucose was infused to maintain euglycemia (PG 93.9 ± 7.3 mg/dl) followed by hyperglycemia (PG 231.5 ± 18.1 mg/dl). Myocardial contrast echocardiography (MCE) was performed during each glycemic steady state using continuous infusion of Definity at rest and during regadenoson (Lexiscan 5 ml (400 μg) intravenous bolus) infusion to quantify myocardial blood flow (MBF) and determine MBFR. Insulin resistance (IR) was assessed by glucose infusion rate (GIR; mg/kg/min) at euglycemia. Median stress MBF, MBFR, and β reserve were significantly reduced during acute hyperglycemia versus euglycemia (stress MBF 3.9 vs 5.4, P = 0.02; MBFR 2.0 vs 2.7, P < 0.0001; β reserve 1.45 vs 2.4, P = 0.007). Using a median threshold GIR of 5 mg/kg/min, there was a correlation between GIR and hyperglycemic MBFR (r = 0.506, P = 0.019). MBFR, as determined noninvasively by MCE, is significantly decreased during acute hyperglycemia in nondiabetic volunteers, and the magnitude of this reduction is modulated by IR.     

Insulin antibody does not cause insulin resistance during glucose clamping in rats.

Although it has often been stated that insulin antibodies cause insulin resistance, this concept is still controversial. The effect of insulin antibody GP30, commonly used in insulin radioimmunoassay, on insulin action was investigated in Wistar rats in vivo by the euglycemic glucose clamp technique. As a preliminary experiment, the equilibrium time required for insulin antibody to bind with endogenous insulin was examined. One hundred microliters/kg insulin antibody took 60 min or more to attain equilibrium, but 10 microliters/kg insulin antibody almost immediately equilibrated with endogenous insulin. During a 60-min glucose clamp study, 2 mU/kg/min porcine insulin was infused with 100 microliters/kg insulin antibody. At steady state, during the last 20-min period, the mean glucose infusion rate was 2.10 +/- 0.85 mg/kg/min (n = 5, mean +/- SD), significantly lower than the 5.77 +/- 1.61 mg/kg/min of the control, indicating insulin resistance before equilibrium was reached. However, the glucose infusion rates during the clamp with 10 microliters/kg insulin antibody and 100 microliters/kg insulin antibody infused 75 min before the insulin were 6.10 +/- 1.44 and 7.12 +/- 1.19 mg/kg/min, respectively, no different from the control. In these instances, free insulin levels measured by radioimmunoassay using the polyethyleneglycol method were 43.8 +/- 20.4 and 15.4 +/- 6.1 microU/ml, respectively, lower than the control (77.0 +/- 16.1 microM/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of insulin sensitivity by 90 min isoglycaemic hyperinsulinaemic glucose clamp in healthy young men

We aimed to perform a detailed analysis of the isoglycaemic hyperinsulinaemic glucose clamp in relation to the time spent in performing the procedure, and analysed two series performed by independent investigators on different groups (n = 19 and n = 28) of healthy, young men. We calculated glucose disposal rates (GDR) during 20-min periods at different time points during the clamp. There was no difference in 90- and 120-min GDR when comparing the two series. The differences between 90- and 120-min GDR were (mean +/- SD) 0.48 +/- 1.10 mg/kg/min (p = 0.73) and 0.37 +/- 1.05 mg/kg/min (p = 0.71), respectively. The correlations between 90- and 120-min GDR were 0.94 (p < 0.001) and 0.89 (p < 0.001). Correlations between GDR during the second hour of the clamp and fasting plasma insulin ranged from -0.53 (p = 0.020) to -0.55 (p = 0.016) and from -0.44 (p = 0.020) to -0.54 (p = 0.003), respectively, and did not improve after 60 min of clamping. These data suggest that reliable indices of insulin sensitivity in healthy young men may appear even when the isoglycaemic hyperinsulinaemic clamp procedure is shortened from 120 to 90 min. A shorter procedure is time-effective and less expensive, but may be limited to healthy, young Caucasian men.     

Differential effects of troglitazone and D-chiroinositol on glucosamine-induced insulin resistance in vivo in rats

Troglitazone and D-chiroinositol have been shown to exert antidiabetic effects by either potentiating or mimicking insulin action. We studied whether pretreatment with these compounds can prevent the deleterious effects of glucosamine on insulin action that may play an important role in hyperglycemia-induced insulin resistance. Normal Wistar rats were pretreated with troglitazone (100 mg/kg/d), D-chiroinositol (100 mg/kg/d), or placebo (saline) for 7 days. Glucosamine (50 micromol/kg/min) was then infused for 210 minutes, and a euglycemic glucose clamp was performed during the last 120 minutes. Pretreatment with troglitazone or D-chiroinositol had no effect on fasting plasma glucose or insulin or basal hepatic glucose output (HGO). Under the euglycemic-hyperinsulinemic (956+/-93 pmol/L) clamp condition, HGO in glucosamine-infused placebo-treated rats was not suppressed, but instead was increased over the basal level, indicative of hepatic insulin resistance. In contrast, HGO failed to increase during glucosamine infusion in rats pretreated with troglitazone but was not normally suppressed. This may indicate a partial improvement in the hepatic insulin resistance. D-Chiroinositol pretreatment had no effect on the glucosamine-induced increase in HGO. The glucose disposal rate (GDR) was 25% lower in rats infused with glucosamine versus saline-infused rats (25.5+/-2.5 v 34.1+/-2.0 mg/kg/min), indicative of peripheral insulin resistance. Pretreatment with D-chiroinositol (34.5+/-2.3 mg/kg/min) prevented the glucosamine-induced decrease in the GDR, indicating an improvement in peripheral insulin resistance. Troglitazone (25.2+/-3.3 mg/kg/min) was without effect. In conclusion, (1) in normal control rats, glucosamine infusion induced hepatic and peripheral insulin resistance; (2) D-chiroinositol, but not troglitazone, pretreatment prevented glucosamine-induced peripheral insulin resistance; and (3) troglitazone, but not D-chiroinositol, partially blocked the glucosamine-induced hepatic insulin resistance. D-Chiroinositol may provide a novel pharmacological approach to hexosamine-induced peripheral insulin resistance.     

Glucose intolerance is associated with C-reactive protein and intima-media anatomy of the common carotid artery in patients with coronary heart disease.

AIMS: The purpose of this study was to examine the relationship between glucose intolerance and levels of hsCRP, calculated intima-media area (cIMa) of the carotid artery and flow-mediated dilation of the brachial artery in 122 patients with a myocardial infarction 1-12 months before inclusion and without known diabetes mellitus. METHODS: A standard oral glucose test (OGTT) was performed. Diabetes mellitus and impaired glucose tolerance (IGT) were defined according to the WHO criteria. Ultrasound measurement of cIMa of the carotid artery and flow-mediated dilation of the brachial artery were analyzed. RESULTS: Patients with diabetes mellitus had higher hs-CRP compared with patients with IGT and those patients with normal glucose tolerance (P < 0.05). The greater cIMa of the carotid artery in those with diabetes mellitus compared with normal subjects failed to reach conventional levels of significance (P = 0.058). hs-CRP and cIMa were associated with plasma glucose 120 min after the glucose load (P < 0.05). A multiple stepwise regression analysis, including all variables significantly associated with plasma-glucose 120 min after glucose ingestion as independent variables, revealed an independent and significant association between plasma-glucose 120 min after glucose ingestion in the OGTT and CRP (P < 0.05). No association was observed between glucose intolerance and endothelial function. CONCLUSION: Glucose intolerance was associated with hs-CRP and cIMa in patients with coronary heart disease without known diabetes mellitus. Thus, inflammation, atherosclerosis and impaired glucose tolerance are tightly interrelated disorders even in subjects without known diabetes mellitus.     

Non-oxidative glucose disposal is reduced in type 2 diabetes, but can be restored by aerobic exercise

Whole-body glucose utilization consists of mitochondrial glucose oxidation and non-oxidative glycogen synthesis. We examined whether reduction of both non-oxidative glucose disposal and glucose oxidation contributes to insulin resistance in type 2 diabetes. We also examined the effects of exercise on these two components. Whole-body glucose disposal rate (GDR, mg/kg/min) was evaluated in 37 type 2 diabetic (T2DM) and 17 non-diabetic (non-DM) subjects as the mean of glucose infusion rate during steady state in the euglycaemic–hyperinsulinaemic clamp study. Glucose oxidation rates were assessed by indirect calorimetry, and non-oxidative GDR was calculated by subtracting glucose oxidation rate from GDR. Intramyocellular lipid (IMCL) content of the soleus muscle was measured using ¹H-magnetic resonance spectroscopy. In 10 T2DM subjects, the changes in oxidative and non-oxidative glucose disposal during clamp were examined after 3-month exercise intervention. GDR (2.93 ± 1.55 vs. 4.55 ± 1.83, p = 0.001) and non-oxidative GDR (1.45 ± 1.52 vs. 3.01 ± 1.87, p = 0.002) were significantly lower in T2DM than in non-DM subjects. Glucose oxidation rate was comparable in the two groups, and inversely correlated with IMCL (n = 15, r =−0.565, p = 0.028). GDR (2.28 ± 1.67 to 4.63 ± 2.42, p = 0.021) and non-oxidative GDR (0.72 ± 1.27 to 2.26 ± 1.91, p = 0.047) were increased after exercise intervention, although the change in glucose oxidation rate was not significant. In summary, reduction of non-oxidative glucose disposal may contribute to decreased whole-body glucose utilization. In addition, exercise improves insulin resistance mainly by increasing non-oxidative glucose disposal in type 2 diabetes.