Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1

Recent epidemiologic studies have shown that abdominal obesity, characterized by a high waist to hip circumference ratio (WHR), is associated with increased cardiovascular morbidity and mortality. The present study examines components of the fibrinolytic system in obese and lean middle-aged women with a high and low WHR. Ten women in each group were carefully matched with respect to age, body weight, lean body mass, and body fat. Fibrinogen and endothelial type of plasminogen activator inhibitor -1 (PAI-1) were significantly elevated in the obese women with a high WHR compared with the obese women with a low WHR or with both groups of lean women. In addition, obese women with a high WHR exhibited a greater metabolic risk profile (elevated glucose, insulin, and triglyceride levels). When all subjects were pooled for the analyses, both fibrinogen and PAI-1 levels correlated positively with glucose and insulin levels. PAI-1 was also negatively related to degree of insulin sensitivity measured with the euglycemic clamp technique. In the obese groups, WHR but not body mass index (BMI), correlated with PAI-1 levels. No such correlations were seen in the lean groups. In conclusion, the data show that a high WHR in obese, but not lean middle-aged women, is associated with an impaired fibrinolytic activity. This perturbation becomes enhanced when it is associated with hyperinsulinemia and insulin resistance, which is a typical feature of abdominal obesity.     

Suppression of basal, but not of glucose-stimulated insulin secretion by human insulin in healthy and obese hyperinsulinemic subjects

To evaluate the suppressive effect of biosynthetic human insulin (BHI; 2.5 U/m2 . h) on basal and glucose-stimulated insulin secretion in healthy and obese hyperinsulinemic subjects, the plasma C-peptide response was measured during maintenance of euglycemia and hyperglycemia by means of the glucose clamp technique. In five healthy subjects in whom arterial insulin concentration was increased to 94 +/- 8 microU/mL, but euglycemia was maintained at the fasting level. C-peptide concentration fell from 1.3 +/- 1.0 ng/mL by 21 +/- 8% (P less than 0.05). When hyperglycemia of 7 mmol/L above basal was induced by a variable glucose infusion, the C-peptide response was similar in the control (5.0 +/- 0.6 ng/mL) and BHI experiments (4.7 +/- 0.6 ng/mL) and was paralleled by an identical increase in plasma insulin above the prevailing insulin concentration. In seven obese patients plasma C-peptide fell from 3.5 +/- 0.4 to 2.8 +/- 0.5 ng/mL (P less than 0.05) when BHI was infused at the same rate of euglycemia maintained as in the lean subjects. As in healthy subjects, however, the plasma C-peptide response to the hyperglycemic stimulus (8.7 +/- 0.9 ng/mL) was not altered by BHI (7.9 +/- 0.8 ng/mL). Glucose utilization as determined by the glucose infusion rate necessary to maintain the desired glucose level was reduced by half in the obese patients compared with that of normal subjects. From these data we conclude that in healthy as well as obese hyperinsulinemic subjects, insulin at concentrations capable of suppressing its basal secretion fails to suppress its glucose-stimulated secretion.     

Subcutaneous abdominal, but not femoral fat expression of plasminogen activator inhibitor-1 (PAI-1) is related to plasma PAI-1 levels and insulin resistance and decreases after weight loss

Aims/hypothesis: Abdominal fat produces plasminogen activator inhibitor-1 (PAI-1) and could contribute to increased plasma PAI-1 values in human obesity associated with insulin resistance. Femoral fat, which is not associated with insulin resistance, is thought to be metabolically different from the abdominal fat. This study aimed to assess PAI-1 expression in these two fat territories in obese and lean subjects and to determine if concomitant changes of plasma and adipose tissue PAI-1 values occur after weight reduction. Methods: In 24 obese and 16 lean subjects, PAI-1 expression in abdominal and femoral subcutaneous fat, plasma PAI-1, insulin, triglyceride concentrations and insulin resistance were determined at the start of the study and in obese subjects after a 3-month weight reduction programme as well. Results: PAI-1 mRNA content in the abdominal subcutaneous fat was higher in obese than in lean subjects and positively correlated with plasma PAI-1 values (p < 0.01) and markers of insulin resistance (p < 0.05). In 18 obese subjects, re-examined after successful dieting, PAI-1 mRNA content decreased in the abdominal subcutaneous fat along with plasma PAI-1. However, the absolute changes of these two variables were not associated. In contrast, PAI-1 mRNA content in the femoral subcutaneous fat did not differ between lean and obese subjects, was not associated with plasma PAI-1 values or with markers of insulin resistance, and did not change after weight loss. Conclusion/interpretation: Only the abdominal, but not the femoral subcutaneous fat PAI-1 expression is a potential contributor to increases in plasma PAI-1 in obesity. Both plasma and abdominal subcutaneous fat PAI-1 values decreased significantly after weight reduction, although their absolute changes were not associated. [Diabetologia (2001) 44: 2025–2031] Received: 19 March 2001and in revised form: 3 August 2001     

Troglitazone improves insulin-stimulated glucose utilization associated with an increased muscle glycogen content in obese Zucker rats

Recent studies have demonstrated that troglitazone has the capacity to improve insulin resistance. The present study was undertaken to determine the effect of troglitazone on in vivo insulin action, the activities of the pyruvate dehydrogenase (PDH) complex and 3-hydroxyacyl-CoA dehydrogenase (3-HADH) in muscle, and muscle GLUT-4 and glycogen content in obese and lean Zucker rats. Rats were fed a normal chow diet with and without troglitazone as a food admixture (0.2%) for 3 weeks. In vivo insulin action was measured by the sequential euglycemic clamp technique at two different insulin infusion rates (6 and 30 mU/kg BW/min). At the basal (fasting) state and after the clamp studies, the activities of PDH complex and 3-HADH, and the amounts of GLUT-4 and glycogen contained in the red gastrocnemius muscles were determined. Troglitazone treatment produced a significant rise in the metabolic clearance rate of glucose (MCR) during the 6-mU/kg BW/min insulin clamp study (19.5+/-3.9 vs 9.9+/-1.5 ml/kg BW/min, mean+/-SE, P<0.05) in obese rats, but not in lean rats. Troglitazone significantly increased the muscle glycogen content after the clamp study, compared to non-treated rats, in obese rats (9.9+/-0.5 vs 6.5+/-0.4 mg/g tissue, P<0.05) and has the tendency to increase the activity state of PDH complex in obese and lean rats at the fasting state. However, no effect of the drug on muscle GLUT-4 content was found. These results indicate that troglitazone may improve insulin sensitivity associated with increased muscle glycogen content.     

Differential effects of insulin resistance on leucine and glucose kinetics in obesity

The effects of insulin resistance on glucose and amino acid metabolism were studied in obese nondiabetic women (body mass index [BMI], (32.8 +/- 2) and in lean controls. Glucose disposal rate, hepatic glucose production, and leucine carbon flux and oxidation were simultaneously measured during the postabsorptive state and during euglycemic hyperinsulinemia, by means of primed, constant infusions of D-[6,6-2H2]glucose and L-[1-13C]leucine. Each subject participated in two insulin clamp studies on separate days, at infusion rates of 10 and 40 mU (m2.min)-1, producing plasma insulin levels of 20 to 25 and 70 to 80 microU/mL, respectively. Fat-free mass (FFM) was calculated from underwater weighing measurements. Insulin-mediated glucose disposal rate was significantly slower in the obese group: 2.05 +/- 0.05 versus 3.84 +/- 0.18 mg (kg.min)-1 in controls during the 10-mU insulin clamp, and 3.80 +/- 0.23 versus 9.16 +/- 0.47 mg (kg.min)-1 during the 40-mU clamp. The insulin-induced decrease in plasma levels of branched chain amino acids was also significantly blunted in the obese group. Baseline leucine flux was similar in lean and obese subjects (78 +/- 3 and 71 +/- 2 mumol (kg.h)-1, respectively), and its decline in response to insulin infusion was also comparable (8% and 10% during the 10-mU/m2 clamp, and of 17% and 18% during the 40-mU/m2 clamp in lean and obese, respectively). Basal leucine carbon oxidation (from [13C]leucine and [13C]alpha ketoisocaproate [alpha-KIC] plasma enrichments) was also similar in lean and obese, and did not change significantly with insulin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Brain-derived neurotrophic factor ameliorates hepatic insulin resistance in Zucker fatty rats

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophins, has been reported to ameliorate hyperglycemia in obese diabetic animal models. To elucidate the mechanism of BDNF on glucose metabolism, we determined the glucose turnover under basal and euglycemic hyperinsulinemic (insulin infusion rate, 54 pmol. kg(-1). min(-1)) clamp conditions in obese insulin-resistant rats, male Zucker fatty rats, which had been acutely administered a subcutaneous injection of BDNF (20 mg/kg) (n = 9, BDNF) or vehicle (n = 8, vehicle). Under the basal condition, acute administration of BDNF did not affect the blood glucose level, plasma insulin level, rate of glucose disappearance (Rd), and endogenous glucose production (EGP). Under the clamp condition, the glucose infusion rate (GIR) was significantly higher in BDNF than in vehicle (mean +/- SD, 61.4 +/- 19.1 v 41.4 +/- 4.9 micromol. kg(-1). min(-1), P <.05). There was no significant difference in Rd and EGP between the 2 groups under the clamp condition, but the insulin-mediated suppression ratio of endogenous glucose production in BDNF was significantly greater than in vehicle (48.9 +/- 22.2 v 22.4% +/- 20.6%, P <.05). In BDNF, mRNA expressions of hepatic phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were comparable to those of vehicle, while hepatic glucokinase (GK) mRNA expression was significantly higher (1.57 +/- 0.33 v 1.03 +/- 0.17, P <.05). We conclude that BDNF mainly improves hepatic insulin resistance in obese insulin-resistant rats, probably by affecting the hepatic GK flux. Copyright 2003, Elsevier Science (USA). All rights reserved.     

The antilipolytic action of insulin in obese subjects with resistance to its glucoregulatory action

To compare the ability of insulin to regulate lipolysis in lean and obese subjects, free fatty acid (FFA) suppression was compared in groups of six lean [body mass index, 25.7 +/- 1.1 (+/-SEM) kg/m2] and six obese (body mass index, 48.8 +/- 3.1) Pima Indians during euglycemic hyperinsulinemic clamps which increased plasma insulin levels approximately 10, 20, and 100 microU/ml above basal concentrations. Basal FFA concentrations were slightly, but not significantly, elevated in the obese group (445 +/- 35 vs. 406 +/- 40 mu eg/liter). The mean decline in FFA from basal after 60-90 min of insulin infusion in the obese group was somewhat less than that in the lean group at the lower doses [67 +/- 23 vs. 132 +/- 32 (P = NS) during the 10-microU clamp, and 144 +/- 39 vs. 217 +/- 20 (P = NS) during the 20-microU clamp] and was almost identical in the two groups during the 100-microU clamp (226 +/- 29 vs. 229 +/- 51). In contrast, insulin-mediated glucose disposal at all insulin increments was much lower in the obese group (0.33 +/- 0.03, 0.56 +/- 0.04, and 1.39 +/- 0.04 mg/kg X min) than in the lean group (0.78 +/- 0.06, 1.67 +/- 0.12, and 4.96 +/- 0.26; P less than 0.001). The data suggest that although the obese subjects exhibited significant resistance to the glucoregulatory action of insulin, there were only small changes in insulin's antilipolytic effects. Relative maintenance of sensitivity to the antilipolytic action of insulin in the presence of resistance to insulin's glucoregulatory action could maintain fat deposition in obese individuals.     

Differential blood pressure effects of oral glucose and intravenous L-arginine in healthy lean normotensive and obese hypertensive subjects

We investigated the role of insulin and glucose in the pathophysiology of hypertension associated with obesity. The comparative effects of an oral glucose load and of an L-arginine infusion on plasma glucose, plasma insulin and blood pressures (BP) were assessed in lean normotensive and in obese hypertensive males. Oral glucose (75 g in 1-2 min) induced a small but significant lowering of BP in lean normotensives, but failed to modify BP in obese hypertensives. L-arginine infusion (30 min, 500 mg/kg total dose) reduced BP; significantly greater reductions in systolic and diastolic BP were observed in obese hypertensives than in the control group. Both oral glucose and L-arginine induced greater increases in plasma insulin in obese hypertensives than in lean normotensives. Endothelial dysfunction which accompanies the insulin resistant state of obesity, glucose intolerance and hypertension, may account for the different BP effects induced by glucose and L-arginine in obese hypertensives and lean normotensives.     

Evidence of proatherogenic inflammation in polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) have chronic low-level inflammation that can increase the risk of atherogenesis. We measured circulating proatherogenic inflammatory mediators in women with PCOS (8 lean: body mass index, 18-25 kg/m²; 8 obese: body mass index, 30-40 kg/m²) and weight-matched controls (8 lean, 8 obese). Blood samples were obtained fasting and 2 hours after glucose ingestion to measure interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemotactic protein-1 (MCP-1), C-reactive protein (CRP), matrix metalloproteinase-2, plasminogen activator inhibitor-1 (PAI-1), and activated nuclear factor κB in mononuclear cells. Truncal fat was determined by dual-energy x-ray absorptiometry. Fasting MCP-1 levels were elevated in lean women with PCOS compared with lean controls (159.9 ± 14.1 vs 121.2 ± 5.4 pg/mL, P < .02). Hyperglycemia failed to suppress matrix metalloproteinase-2 in lean women with PCOS compared with lean controls (1.7 ± 1.2 vs −4.8 ± 1.6 pg/mL, P < .002). Among women with PCOS, obese individuals exhibited higher fasting sICAM-1 (16.1 ± 0.8 vs 10.5 ± 1.0 ng/mL, P < .03) and PAI-1 (6.1 ± 0.7 vs 3.4 ± 0.8 ng/mL, P < .03) levels. Trend analysis revealed higher (P < .005) IL-6, sICAM-1, CRP, PAI-1, systolic and diastolic blood pressures, triglycerides, fasting insulin, and homeostasis model assessment of insulin resistance index in women with PCOS compared with weight-matched controls, and the highest levels in the obese regardless of PCOS status. Fasting MCP-1 levels correlated with activated nuclear factor κB during hyperglycemia (P < .05) and androstenedione (P < .004). Truncal fat correlated with fasting IL-6 (P < .004), sICAM-1 (P < .006), CRP (P < .0009), and PAI-1 (P < .02). We conclude that both PCOS and obesity contribute to a proatherogenic state; but in women with PCOS, abdominal adiposity and hyperandrogenism may exacerbate the risk of atherosclerosis.     

Lifelong sequential changes in glucose tolerance and insulin secretion in genetically obese Zucker rats (fa/fa) fed a diabetogenic diet

Life-long sequential changes in glucose tolerance and insulin secretion were investigated in genetically obese Zucker rats (fa/fa) fed a diabetogenic diet rich in lard and sucrose. Comparisons were made with lean littermates (Fa/-) receiving normal chow diet. At 3-month intervals, seven to nine lean and obese rats had two permanent venous catheters implanted, allowing stress- and pain-free sampling of blood before, during, and after substrate administration. Intravenous glucose, iv arginine, and oral glucose tolerance were tested. The obese rats progressively developed hyperglycemia and severe hyperinsulinemia; their basal glycemia reached 8.8 +/- 1.1 vs. 5.8 +/- 0.2 mmol/liter in the lean rats at 46 weeks of age; respective insulinemia was 287.7 +/- 61.9 and 18.1 +/- 2.8 mU/liter (mean +/- SD). In the obese rats a distinct loss in glucose tolerance was seen with progression of age in spite of rising stimulated insulin secretion, which suggests progressive development of insulin resistance without exhaustion of B-cell secretory capacity. Absence of insulin deficiency was also suggested by immunohistochemical staining of pancreatic tissue specimens from obese rats, which showed large populations of insulin-containing cells. Like the obese animals, lean rats exhibited a decrease in insulin sensitivity with age. Relating basal individual glycemia and insulinemia, a rise by 1 mmol/liter in glycemia was associated with a 8.8-fold rise in basal insulinemia in lean rats, but only with a 1.8-fold increase in obese rats. Similar correlations for stimulated glycemia and insulinemia suggest impaired glucose sensitivity of pancreatic B-cells in obese vs. lean rats. In conclusion, hyperglycemia and hyperinsulinemia in insulin-resistant obese Zucker rats on a diabetogenic diet are not characterized by quantitatively deficient B-cell secretory capacity, but, rather, by impaired B-cell sensitivity to glucose with qualitatively intact regulation of glycemia and insulinemia at elevated plasma concentrations.     

Adipose triglyceride lipase gene expression in human visceral obesity.

In comparison to subcutaneous (SC) fat, visceral adipose tissue is more sensitive to catecholamine-induced lipolysis and less sensitive to the antilipolytic effects of insulin. Variation in the expression of lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) have been reported. We therefore hypothesized that expression of adipose triglyceride lipase (ATGL) is different in visceral and SC depot and investigated whether ATGL mRNA expression is related to obesity, fat distribution and insulin sensitivity. ATGL, LPL, and HSL mRNA expression was measured in 85 paired samples of omental and subcutaneous adipose tissue in normal glucose tolerant lean and obese individuals. In addition, we included a subgroup of obese (BMI >30 kg/m2) individuals with either impaired or preserved insulin sensitivity determined by euglycemic-hyperinsulinemic clamps. ATGL mRNA levels are significantly decreased in insulin resistant obese subjects. Independently of body fat mass, omental ATGL mRNA correlates with fasting insulin concentration, glucose uptake during the steady state of the clamp and HSL mRNA expression. In obese, but not in lean subjects, LPL and HSL mRNA expression was significantly higher in omental compared to SC fat. In both depots, HSL mRNA was significantly lower in obese individuals. Visceral HSL mRNA expression is closely related to adipocyte size and fasting plasma insulin concentrations, whereas visceral fat area significantly predicts visceral LPL mRNA expression. ATGL mRNA expression is not significantly different between omental and SC fat. HSL, but not ATGL mRNA expression is closely related to individual and regional differences in adipocyte size. Impaired insulin sensitivity was associated with decreased ATGL and HSL mRNA expression, independently of body fat mass and fat distribution.     

The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: a magnetoencephalographic study

Animal studies have shown that the brain is an insulin-responsive organ and that central nervous insulin resistance induces obesity and disturbances in glucose metabolism. In humans, insulin effects in the brain are poorly characterized. We used a magnetoencephalography approach during a two-step hyperinsulinemic euglycemic clamp to (i) assess cerebrocortical insulin effects in humans, (ii) compare these effects between 10 lean and 15 obese subjects, and (iii) test whether the insulin receptor substrate (IRS)-1 Gly972Arg polymorphism in the insulin-signaling cascade modifies these effects. Both spontaneous and stimulated (mismatch negativity) cortical activity were assessed. In lean humans, stimulated cortical activity (P = 0.046) and the beta and theta band of spontaneous cortical activity (P = 0.01 and 0.04) increased with insulin infusion relative to saline. In obese humans, these effects were suppressed. Moreover, the insulin effect on spontaneous cortical activity correlated negatively with body mass index and percent body fat (all r < -0.4; all P < 0.05) and positively with insulin sensitivity of glucose disposal (theta band, r = 0.48, P = 0.017). Furthermore, insulin increased spontaneous cortical activity (beta band) in carriers of wild-type IRS-1, whereas, in carriers of the 972Arg allele, this insulin effect was absent (P = 0.01). We conclude that, in lean humans, insulin modulates cerebrocortical activity, and that these effects are diminished in obese individuals. Moreover, cerebrocortical insulin resistance is found in individuals with the Gly972Arg polymorphism in IRS-1, which is considered a type 2 diabetes risk gene.     

Insulin resistance, but normal basal rates of glucose production in patients with newly diagnosed mild diabetes mellitus

Fasting hyperglycemia in Type II (non-insulin-dependent) diabetes has been suggested to be due to hepatic overproduction of glucose and reduced glucose clearance. We studied 22 patients (10 lean and 12 obese) with newly diagnosed mild diabetes mellitus (fasting plasma glucose less than 15 mmol/l, urine ketone bodies less than 1 mmol/l), and two age- and weight-matched groups of non-diabetic control subjects. Glucose turnover rates and sensitivity to insulin were determined using adjusted primed-continuous [3-3H]glucose infusion and the hyperinsulinemic euglycemic clamp technique. Insulin-stimulated glucose utilization was reduced in both diabetic groups (lean patients: 313 +/- 35 vs 531 +/- 22 mg.m-2.min-1, p less than 0.01; obese patients: 311 +/- 28 vs 453 +/- 26 mg.m-2.min-1, p less than 0.01). Basal plasma glucose concentrations decreased 0.43 +/- 0.05 mmol/l per h (p less than 0.01). Glucose production rates were smaller than glucose utilization rates (lean patients: 87 +/- 3 vs 94 +/- 3 mg.m-2.min-1, p less than 0.01; obese patients: 79 +/- 5 vs 88 +/- 5 mg.m-2.min-1, p less than 0.01), were not correlated to basal glucose or insulin concentrations, and were not different from normal (lean controls: 87 +/- 4 mg.m-2.min-1; obese controls: 80 +/- 5 mg.m-2.min-1). These results suggest that the basal state in the diabetic patients is a compensated condition where glucose turnover rates are maintained near normal despite defects in insulin sensitivity.     

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.     

Anti-inflammatory effects of troglitazone in nondiabetic obese subjects independent of changes in insulin sensitivity

BACKGROUND: Obesity is characterised by insulin resistance and by elevated levels of proinflammatory markers. We investigated whether, in the absence of changes in glucose, thiazolidinediones (TZDs) have anti-inflammatory effects and whether improvement of insulin sensitivity correlates with suppression of inflammatory markers. METHODS: We performed a randomised double-blind placebo-controlled crossover study with troglitazone (400 mg daily for eight weeks) in 15 normoglycaemic obese subjects. We measured plasma high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), leptin, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and tumour necrosis factor-alpha (TNF-alpha) after each of the two treatment periods and in 13 age- and sex-matched lean individuals. RESULTS: Obese subjects were insulin resistant (decreased glucose infusion rate (GIR) during euglycaemic hyperinsulinaemic clamp) and had higher plasma levels of hsCRP, IL-6, leptin, tPA, and PAI-1 compared with lean subjects. TNF-alpha also tended to be higher. Troglitazone improved insulin sensitivity (mean increase in whole body glucose uptake 23.1 +/- 10.5% (p = 0.047)) and normalised plasma concentrations of hsCRP, tPA and TNF-alpha, whereas it did not significantly change IL-6, leptin and PAI-1. Changes in GIR did not correlate with changes in inflammatory markers. CONCLUSION: Troglitazone induces suppression of some of the inflammatory markers that are elevated in normoglycaemic obese subjects. The suppression of inflammatory markers, however, does not correlate with improvement in insulin sensitivity, suggesting involvement of partially differential mechanisms in these effects of TZDs.     

An exercise intervention without weight loss decreases circulating interleukin-6 in lean and obese men with and without type 2 diabetes mellitus

Obesity and type 2 diabetes mellitus (T2DM) have been associated with a state of chronic low-grade inflammation. We examined the effect of exercise without weight loss on circulating inflammatory biomarkers in previously sedentary lean men and obese men with and without T2DM. Middle-aged men (8 lean, 8 obese, and 8 obese with T2DM) performed 60 minutes of aerobic exercise 5 times per week for 12 weeks without a reduction in body weight. Subjects underwent a hyperinsulinemic-euglycemic clamp before and after the 12-week exercise program to assess insulin sensitivity. Circulating interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), and C-reactive protein concentrations were measured by sandwich enzyme-linked immunosorbent assay before and after the exercise intervention. Body fat was measured using magnetic resonance imaging, and waist circumference was recorded for each subject pre- and postexercise intervention. Waist circumference and plasma IL-6 concentrations were significantly lower (P < .05) after exercise training despite no change in body weight or insulin sensitivity. There were no correlations between insulin sensitivity and IL-6. Fasting plasma PAI-1 concentration was significantly lower in the lean group compared with the obese group both pre- and postexercise intervention (P < .05). There were no changes in C-reactive protein or PAI-1 concentrations after exercise training. A 12-week exercise intervention led to reductions in waist circumference and fasting IL-6 concentrations in previously sedentary lean and obese men with or without T2DM, demonstrating significant changes in clinically relevant diabetes-related parameters despite no change in body weight.     

Central glucocorticoid regulation of parasympathetic drive to pancreatic B-cells in the obese fa/fa rat

The effects of glucocorticoids on the insulin secretory response to an intravenous glucose load have been studied in lean (Fa/?) and obese fa/fa Zucker rats. The role of parasympathetic drive to the pancreatic B-cells was assessed as that component of the insulin secretory response that was blocked by pretreatment of the rats with intravenous atropine. The insulin secretory response to the glucose load was greater in obese than in lean rats. Atropine significantly reduced basal and stimulated levels of insulin in obese but not in lean rats. Adrenalectomy reduced basal insulin levels and the secretory response in obese but not lean rats and also abolished the atropine-blockable component of the response. Peripheral corticosterone replacement of adrenalectomized fa/fa rats restored the hyperinsulinemia. Chronic infusion of dexamethasone intracerebroventricularly to adrenalectomized fa/fa rats increased basal insulin and the secretory response to glucose and this effect was blocked by atropine. In contrast, intracerebroventricular infusion of obese rats with corticotropin releasing factor reduced basal and stimulated insulin levels. It is concluded that the hypersecretion of insulin in obese fa/fa rats results, at least in part, from a central glucocorticoid-mediated stimulation of vagal drive to the pancreatic B-cells.     

Severe hepatic and peripheral insulin resistance as evidenced by euglycemic clamps in genetically obese fa/fa rats

The action of insulin on glucose metabolism and hepatic glucose production was studied in vivo over a wide range of insulin concentrations in lean and genetically obese (fa/fa) rats, using the euglycemic clamp technique. While total glucose metabolism was stimulated 3-fold by insulin in lean animals (half-maximal stimulation at 400 microU/ml insulin), the hormone had no significant effect on glucose metabolism in obese animals, whatever the concentration used. In lean rats, the endogenous (i.e. hepatic) glucose production was completely suppressed at a steady state insulin concentration of about 360 microU/ml. In obese rats, an insulin concentration as high as 10,000 microU/ml was needed to suppress the hepatic glucose production. These results suggest that, in obese rats 1) basal plasma insulin levels appear to maximally stimulate peripheral glucose metabolism, and the presence of postreceptor defects prevents any further stimulatory effect of the hormone on glucose metabolism; 2) grave impairments of the action of insulin on hepatic glucose production are present, despite a normal responsiveness obtained at pharmacological concentrations of the hormone. These hepatic alterations could be due to postbinding and/or intracellular defects, as well as to defects, yet to be defined, of the homeostasis of insulin counterregulatory hormones.