Acute insulin response and beta-cell compensation in normal subjects treated with olanzapine or risperidone for 2 weeks.
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Benzodiazepines↗
Biomedical subjects
Helmut O Steinberg
Publications and source records attributed to Helmut O Steinberg.
Adipose tissue production of hepatocyte growth factor contributes to elevated serum HGF in obesity.
Serum HGF is elevated in obese individuals. This study examined the contribution of excess adipose tissue to increased circulating HGF levels in obesity. Serum HGF was measured by ELISA before and after weight loss due to bariatric surgery or a 24-h fast. At 6.1 +/- 0.1 mo following surgery, BMI (50.6 +/- 1.6 vs. 35.1 +/- 1.3 kg/m(2); P < 0.0001) and serum HGF were significantly decreased (1,164 +/- 116 vs. 529 +/- 39 pg/ml, P < 0.001). A 24-h fast did not change serum HGF, but serum leptin was significantly reduced (67.7 +/- 7.1 vs. 50.3 +/- 8.3 ng/ml, P = 0.02). HGF secretion in vitro from adipocytes of obese (BMI 40.3 +/- 2.8 kg/m(2)) subjects was significantly greater (80.9 +/- 10.4 vs. 21.5 +/- 4.0 pg/10(5) cells, P = 0.008) than release from adipocytes of lean (BMI 23.3 +/- 1.4 kg/m(2)) subjects. HGF mRNA levels determined by real-time RT-PCR were not different in adipocytes from lean (BMI 24.0 +/- 0.8 kg/m(2)) and obese (45.7 +/- 3.0 kg/m(2)) subjects, but serum HGF was significantly elevated in the obese individuals studied (787 +/- 61 vs. 489 +/- 49 pg/ml, P = 0.001). TNF-alpha (24 h treatment) significantly increased HGF release from subcutaneous adipocytes 23.6 +/- 8.3% over control (P = 0.02). These data suggest that elevated serum HGF in obesity is in part attributable to excess adipose tissue and that this effect can be reversed by reducing adipose tissue mass through weight loss. Increased HGF secretion from adipocytes of obese subjects may be due to posttranscriptional events possibly related to adipocyte size and stimulation by elevated TNF-alpha in the adipose tissue of obese individuals.
Adipocytes↗
Insulin sensitivity is preserved despite disrupted endothelial function.
It is well established that endothelial dysfunction and insulin resistance go hand in hand. However, it is unclear whether endothelial dysfunction per se is sufficient to impair insulin-mediated glucose uptake. We have previously reported that 4 wk of administration of the human immunodeficiency virus (HIV)-1 protease inhibitor indinavir to HIV-negative subjects induces endothelial dysfunction. Hence, we hypothesized that indinavir-induced endothelial dysfunction was associated with impaired insulin-mediated glucose disposal. We measured insulin-mediated glucose disposal at the level of the whole body, skeletal muscle, and vasculature by performing hyperinsulinemic euglycemic clamp, and vascular function studies, in a separate group of HIV-negative healthy nonobese subjects (n = 13) before and after 4 wk of daily oral indinavir. Four weeks of indinavir resulted in a 113 +/- 29% (P < 0.01) reduction of endothelium-dependent vasodilation, consistent with our earlier findings. In addition, there was a significant impairment of insulin-mediated vasodilation (101 +/- 14% before indinavir vs. 35 +/- 15% after indinavir; P < 0.05). However, there was no significant change in insulin-mediated glucose disposal at the level of the whole body (8.9 +/- 0.5 before indinavir vs. 8.5 +/- 0.6 mgxkg(-1)xmin(-1) after indinavir; P = 0.4), or skeletal muscle. Furthermore, in a separate group of four HIV-negative healthy nonobese subjects, we found that 4 wk of indinavir has no sustained effect on insulin-stimulated glucose uptake in adipose tissue. Thus our findings indicate that 1) endothelial dysfunction alone is insufficient to impair insulin-mediated glucose disposal, and 2) indinavir-induced endothelial dysfunction is likely due to a direct effect of the drug on the endothelium and is not coupled to the induction of insulin resistance.
Adipose Tissue↗
FFAs: do they play a role in vascular disease in the insulin resistance syndrome?
The insulin resistance syndrome, otherwise known as the metabolic syndrome, describes a cluster of cardiovascular and metabolic abnormalities, which are strongly associated with overweight and obesity. The importance of the syndrome is due to its increased rates of cardiovascular morbidity and mortality. Insulin resistance is also characterized by elevated free fatty acid (FFA) levels. In otherwise healthy human subjects, elevation of FFA impairs endothelial function. This appears to be largely the result of blunting of nitric oxide-dependent tone, most likely at the level of the endothelial isoform of nitric oxide synthase (eNOS). Some of the potential mediatory mechanisms include oxidative stress, proinflammatory cytokines, C-reactive protein, or endogenous inhibitors of eNOS. Regardless of the mechanism(s) that mediates the effects of increased FFA on the vasculature, impaired vascular function is likely to account, at least in part, for the increase in cardiovascular mortality in subjects with the insulin resistance syndrome.
Blood Flow Velocity↗
Indinavir impairs endothelial function in healthy HIV-negative men.
BACKGROUND: Potent antiretroviral treatment has drastically reduced mortality in HIV-infected patients but may accelerate atherosclerotic disease, which could be partially mediated via endothelial dysfunction. METHODS: In 8 HIV-negative healthy males, leg blood flow responses to intraartery infusions of methacholine chloride (Mch), sodium nitroprusside, and NG-mono-methyl-L-arginine (L-NMMA) were measured before and after 4 weeks of daily oral indinavir. In the same subjects, we also assessed the effect of indinavir on lipids, insulin sensitivity, markers of inflammation, as well as oxidative stress. RESULTS: After 4 weeks of indinavir, the endothelium-dependent response to methacholine chloride was impaired (195% +/- 38% vs 83% +/- 13%, P < .05), the response to NG-mono-methyl-L-arginine (nitric oxide-dependent tone) was nearly abrogated (-30% +/- 4% vs -1% +/- 11%, P < .05), whereas the endothelium-independent response to sodium nitroprusside remained unchanged. Fasting insulin levels increased from 5.8 +/- 1.2 to 7.0 +/- 1.4 microU/mL (P < .05), and HOMA-IR scores increased from 1.3 +/- 0.3 to 1.6 +/- 0.3 U (P < .05). There were no changes in blood pressure, lipids, markers of inflammation, or oxidative stress. CONCLUSIONS: Four weeks of the HIV-1 protease inhibitor indinavir, in the absence of HIV-1 infection, causes vascular dysfunction most likely at the level of endothelial nitric oxide production. The vascular dysfunction may be mediated partially by the concomitant induction of insulin resistance but other mechanisms cannot be ruled out.
Adult↗
Obesity and endothelial dysfunction.
Obesity is becoming more prevalent in the developed world because of the abundance of food and the decrease of physical activity. Obesity is a risk factor for a host of diseases from arthritis to cardiovascular disease. The precise mechanisms by which obesity promotes cardiovascular disease are not well understood but are likely to include metabolic and inflammatory responses to the increased amount of stored fat. The endothelium plays a pivotal role in maintaining vascular health. Impaired endothelial function is an independent predictor of cardiovascular disease. Most studies of vascular function in obese subjects have demonstrated impaired endothelial function. This impairment of endothelial function becomes obvious early on, long before any vascular abnormalities become clinically relevant and detectable. Better understanding of the mediators of obesity-induced endothelial dysfunction may lead to the identification of new targets for interventions that may prevent or postpone the development of obesity-related cardiovascular disease.
Adult↗
Women and heart disease: the role of diabetes and hyperglycemia.
Cardiovascular disease (CVD) is the primary cause of death in women, and women with type 2 diabetes mellitus are at greater risk of CVD compared with nondiabetic women. The increment in risk attributable to diabetes is greater in women than in men. The extent to which hyperglycemia contributes to heart disease risk has been examined in observational studies and clinical trials, although most included only men or did not analyze sex differences. The probable adverse influence of hyperglycemia is potentially mediated by impaired endothelial function, and/or by other mechanisms. Beyond high blood glucose level, a number of other common risk factors for CVD, including hypertension, dyslipidemia, and cigarette smoking, are seen in women with diabetes and require special attention. Presentation and diagnosis of CVD may differ between women and men, regardless of the presence of diabetes. Recognizing the potential for atypical presentation of CVD in women and the limitations of common diagnostic tools are important in preventing unnecessary delay in initiating proper treatment. Based on what we know today, treatment of CVD should be at least as aggressive in women-and especially in those with diabetes-as it is in men. Future trials should generate specific data on CVD in women, either by design of female-only studies or by subgroup analysis by sex.
Diabetes Mellitus↗
L-carnitine may attenuate free fatty acid-induced endothelial dysfunction.
We have recently shown that elevated levels of free fatty acid (FFA) seen in insulin-resistant obese subjects are associated with endothelial dysfunction. L-carnitine, which is required for mitochondrial FFA transport/oxidation, has been reported to improve vascular function in subjects with diabetes and heart disease. Here, we tested the hypothesis that L-carnitine attenuates FFA-induced endothelial dysfunction. We studied leg blood flow (LBF) responses and leg vascular resistance (LVR) to graded intrafemoral artery infusions of the endothelium-dependent vasodilator, methacholine chloride (MCh). A group (n = 7) of normal lean subjects was studied under basal conditions (saline), after 2 h of FFA elevation (FFA), and then after 2 h of superimposing L-carnitine on FFA elevation. FFA elevation caused the maximal LBF increment in response to MCh to decrease from 0.388 +/- 0.08 to 0.212 +/- 0.071 L/min (P < 0.05). Similarly, FFA blunted the maximum decrease in LVR in response to MCh from -315 +/- 41 U to -105 +/- 46 U (P < 0.05). The superimposed L-carnitine restored the LBF increment in response to MCh to 0.488 +/- 0.088 L/min (P < 0.05 vs. FFA) and the maximum fall in LVR to -287 +/- 75 U (P < 0.05 vs. FFA), indicating that L-carnitine elevation may attenuate FFA-induced endothelial dysfunction. In conclusion, our data suggest that increasing L-carnitine levels may improve FFA-induced and obesity-associated endothelial dysfunction. This improved endothelial function may delay or prevent the development of excess cardiovascular disease.
Adult↗
Interactions between endothelin and nitric oxide in the regulation of vascular tone in obesity and diabetes.
Endothelial dysfunction reflects an imbalance of vasodilators and vasoconstrictors. Endogenous endothelin activity seems to be increased in human obesity and type 2 diabetes, and cellular studies suggest that this factor may itself reduce bioavailable nitric oxide (NO). We studied 20 lean, 20 obese, and 14 type 2 diabetic individuals under three protocols, measuring leg vascular responses to intra-arterial infusions of NG-monomethyl-l-arginine (l-NMMA; an inhibitor of NO synthase) alone or in combination with BQ123 (an antagonist of type A endothelin receptors) or phentolamine (used as a control vasodilator). NO synthase inhibition alone (study 1) produced an approximately 40% increase in leg vascular resistance (LVR) in all three participant groups, which was not statistically different across groups (increase in LVR: lean, 135 +/- 28; obese, 140 +/- 32; type 2 diabetic, 184 +/- 51 units; NS). By design, BQ123 at the infused rate of 3 micromol/min produced equivalent approximately 35% reductions in LVR across groups. The subsequent addition of l-NMMA produced a greater increase in LVR among obese participants than lean or type 2 diabetic participants (study 2: lean, 182 +/- 48; obese, 311 +/- 66; type 2 diabetic, 186 +/- 40; P = 0.07). Compared with study 1, the effect of l-NMMA was magnified by BQ123 in obese participants but not in lean or type 2 diabetic participants (P = 0.005, study 1 vs. 2; P = 0.03 for group effect). Phentolamine (75 mg/min) produced vasodilation in obese participants comparable to that seen with BQ123 but failed to augment the L-NMMA response. Endothelin antagonism unmasks or augments NO synthesis capacity in obese but not type 2 diabetic participants. This suggests that impaired NO bioavailability as a result of endogenous endothelin may contribute to endothelial dysfunction in obesity, in addition to direct vasoconstrictor effects of endothelin. In contrast, endothelin antagonism alone is insufficient to restore impaired NO bioavailability in diabetes.
Blood Pressure↗
Coupling of metabolism and cardiovascular response represents normal physiology.
In this issue of Clinical Science, Fugmann and co-workers demonstrate a highly integrated cardiovascular response to changes in plasma concentrations of glucose, triacylglycerols (triglycerides), fatty acids and insulin. Since the different substrates, alone and combined, evoked these changes, this response is likely to be a physiological one and directed towards minimizing the extent and duration of substrate elevations that could cause vascular dysfunction.
Eating↗
Troglitazone therapy improves endothelial function to near normal levels in women with polycystic ovary syndrome.
Obese women with polycystic ovary syndrome (PCOS) exhibit impaired endothelial function, which is strongly and directly correlated with both testosterone levels and insulin resistance. Endothelial dysfunction is considered a potent risk factor for macrovascular disease. Because troglitazone (Tgz) improves both hormonal profiles and insulin sensitivity, we tested whether Tgz treatment ameliorates endothelial function in these patients. We studied leg blood flow (LBF) responses to graded intrafemoral artery infusion of the endothelium-dependent vasodilator methacholine chloride (MCh) and to a 4-h hyperinsulinemic euglycemic clamp (120 mU/m(2) x min) in 10 PCOS, before and after 3 months treatment with Tgz (600 mg/d). A group of 13 obese women (OBW) matched for age, weight, body fat (>40% in both groups), blood pressure, and total cholesterol served as controls. PCOS patients exhibited elevated free testosterone (fT) and triglycerides (TG) and lower high density lipoprotein cholesterol levels compared with OBW [14.0 +/- 1.0 vs. 3.7 +/- 0.6 pmol/liter (P < 0.0001), 1.60 +/- 0.28 vs. 0.94 +/- 0.09 mmol/liter (P < 0.02), and 0.91 +/- 0.04 vs. 1.1 +/- 0.04 mmol/liter (P < 0.005), respectively]. Tgz treatment reduced fT levels, but did not improve the TG and high density lipoprotein profile [to 9.7 +/- 2.8 pmol/liter (P < 0.007), 1.49 +/- 0.34 mmol/liter (P = NS), and 0.93 +/- 0.07 mmol/liter (P = NS), respectively]. Basal LBF was unchanged after Tgz. In PCOS compared with OBW, insulin stimulated glucose disposal (52.7 +/- 6.6 vs. 85.5 +/- 4.4 micromol/kg fat-free mass x min; P < 0.0005) and vasodilation (increase in LBF, 22 +/- 14% vs. 59 +/- 15%; P < 0.05) were significantly improved after Tgz treatment to 68.8 +/- 7.2 micromol/kg fat-free mass x min (P < 0.0001) and 101 +/- 48% (P < 0.03), respectively. The increase in LBF in response to MCh in PCOS was markedly more pronounced after treatment (P < 0.01, by ANOVA) and was similar to that observed in OBW. Before Tgz treatment, maximal LBF increments in response to MCh were 130 +/- 25% and 233 +/- 29% in PCOS and OBW, respectively (P < 0.01). After Tgz treatment, PCOS values improved, achieving increments similar to those in OBW (245 +/- 45%; P < 0.04). Tgz treatment in PCOS improves both hormonal and metabolic features. These modifications are associated with improvement of endothelial function, suggesting that Tgz could be a useful tool to reduce the risk of macrovascular disease in women with PCOS and perhaps in other insulin-resistant syndromes.
Blood Glucose↗
Weight loss and endothelial function in obesity.
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Diet, Reducing↗
Hyperglycemic clamp assessment of insulin secretory responses in normal subjects treated with olanzapine, risperidone, or placebo.
The goal of this study was to evaluate the effect of olanzapine or risperidone treatment on beta-cell function in healthy volunteers. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d; n = 17), risperidone (4 mg/d; n = 13), or placebo (n = 18) for 15-17 d. Insulin secretion was quantitatively assessed at baseline and the end of the study period using the hyperglycemic clamp. Weight increased significantly (P < 0.01) in the olanzapine (2.8 +/- 1.7 kg) and risperidone (3.1 +/- 2.1 kg) treatment groups. An increase ( approximately 25%) in the insulin response to hyperglycemia and a decrease ( approximately 18%) in the insulin sensitivity index were observed after treatment with olanzapine and risperidone. The change in insulin response was correlated (r = 0.5576; P = 0.019) with a change in body mass index. When the impact of weight change was accounted for by multivariate regression analyses, no significant change in insulin response or insulin sensitivity was detected after treatment with olanzapine or risperidone. We found no evidence that treatment of healthy volunteers with olanzapine or risperidone decreased the insulin secretory response to a prolonged hyperglycemic challenge. The results of this study do not support the hypothesis that olanzapine or risperidone directly impair pancreatic beta-cell function.
Adult↗
Endothelin contributes to basal vascular tone and endothelial dysfunction in human obesity and type 2 diabetes.
Endothelium-dependent vasodilation is impaired in clinical states of insulin resistance such as obesity and type 2 diabetes. Individuals who have hyperinsulinemic insulin resistance have relatively elevated circulating levels of endothelin (ET)-1, suggesting that ET-1 may be important in the endothelial dysfunction and alterations of vascular tone in these conditions. In 8 lean subjects, 12 nondiabetic obese subjects, and 8 subjects with type 2 diabetes, we measured basal and methacholine-stimulated rates of leg blood flow (LBF) and total serum nitrates (NOx) before and after the intrafemoral arterial administration of BQ123, a specific blocker of ET(A) receptors. BQ123 produced significant vasodilation in the obese and type 2 diabetic subjects (leg vascular resistance = mean arterial pressure/LBF fell by 34 and 36%; P < 0.005) but not in the lean subjects (13%; P = NS, P = 0.018 comparing all groups). ET(A) blockade did not change basal NOx flux (NOx*LBF). This suggests increased basal ET-1 constrictor tone among obese and type 2 diabetic subjects. BQ123 corrected the baseline defect in endothelium-dependent vasodilation seen in obese and type 2 diabetic subjects, suggesting an important contribution of ET-1 to endothelial dysfunction in these subjects. In contrast to basal conditions, stimulated NOx flux was augmented by BQ123 in obese and type 2 diabetic subjects but not in L subjects (P = 0.04), suggesting a combined effect of ET(A) blockade to reduce constrictor tone and augment dilator tone. Endothelin seems to contribute to endothelial dysfunction and the regulation of vascular tone in human obesity and type 2 diabetes.
Adult↗
Role of amylin in insulin secretion and action in humans: antagonist studies across the spectrum of insulin sensitivity.
BACKGROUND: Amylin is a peptide co-secreted with insulin by pancreatic beta-cells. A role for amylin in the pathogenesis of type 2 diabetes mellitus (DM2) has been suggested by in vitro and in vivo studies indicating an effect of amylin to cause insulin resistance and/or inhibit insulin secretion. METHODS: We have determined the effect of endogenous amylin on insulin secretion and insulin action in humans by performing 4-h hyperglycemic clamps during infusion of placebo or a specific amylin receptor antagonist (ARA) in paired, double-blinded, crossover studies. We studied nine healthy lean, ten healthy obese (BMI>27) and ten obesity-matched DM2 subjects. RESULTS: Infusion of ARA alone had no effect on basal insulin, glucose or glucose turnover in any group. Under combined hyperglycemia and ARA infusion, lean subjects displayed a 32% augmentation in insulin levels [AUC 33,565+/-3556 (placebo) to 44,562+/-1379 (ARA) pmol/l/min, p<0.01]. The concomitant increase in glucose disposal rate (GDR) was proportionate, indicating no change in insulin sensitivity (ISI 27.7+/-2.7 vs 27.3+/-2.1, p=NS). In obese subjects, basal insulin and the rise in insulin during the clamp were greater (AUC I 44% increase from 82,054+/-15 407 to 117,922+/-27,085, p<0.01), and also accompanied by a proportionate rise in GDR reflecting an unchanged insulin sensitivity (ISI 12.1+/-2.9 vs 10.8+/-3.0, p=NS). In lean and obese subjects, the C-peptide response to hyperglycemia was also augmented by ARA (p=0.007). No effect of ARA on insulin secretion or action was observed in diabetic subjects. CONCLUSIONS: The present data are consistent with an effect of endogenous amylin on the beta-cell to modulate and/or restrain insulin secretion, and indicate that endogenous amylin does not affect insulin action. These observations provide the first human evidence that amylin plays a role in the modulation of insulin secretion.
Adult↗