Steady-state Plasma Glucose Levels Research Articles

Relationship among obesity, insulin resistance, and hyperinsulinemia in the polycystic ovary syndrome.

To evaluate the relationship between obesity and insulin resistance among women with polycystic ovary syndrome (PCOS) using a gold standard test. A retrospective database analysis of 75 women with PCOS and 118 normal controls who underwent a modification of the insulin suppression test. The relationships between body mass index (BMI) and steady-state plasma glucose (SSPG) levels were investigated. Mean SSPG score for PCOS subjects was statistically similar than that of the controls at all BMI groupings. Only when PCOS subjects reached a BMI of ≥30 kg/m2 that the PCOS subjects had higher mean SSPG score than the control subjects, although not significantly so (p = 0.07). The distribution of PCOS and control subjects in each SSPG quartile grouping was investigated. When comparing all PCOS and control subjects, PCOS subjects were more likely to be in the higher quartiles of SSPG score (p = 0.0001). However, when comparing the PCOS and control subjects, at each BMI grouping (<25, 25-29.9, and ≥30 kg/m2), there was no difference in the likelihood that a larger percent of subjects fell into a different quartile (p = 0.12, 0.69, 0.32, respectively). PCOS subjects have increased magnitudes of insulin resistance when compared to ovulatory controls, when controlling for age, BMI, fasting glucose, and insulin levels. However, the magnitude of this insulin resistance in lean subjects is mild. Quantity of excess body fat, particularly subjects with a BMI of at least 30 kg/m2 is the primary predictor of insulin resistance of sufficient magnitude to put PCOS subjects at increased risk for metabolic abnormalities.

Genetic variation of SORBS1 gene is associated with glucose homeostasis and age at onset of diabetes: A SAPPHIRe Cohort Study

The SORBS1 gene plays an important role in insulin signaling. We aimed to examine whether common single-nucleotide polymorphisms (SNPs) of SORBS1 are associated with prevalence and incidence of diabetes, age at onset of diabetes, and the related traits of glucose homeostasis. A total of 1135 siblings from 492 ethnic Chinese families were recruited at baseline, and 630 were followed up for 5.19 ± 0.96 years. Nine SNPs including rs7081076, rs2281939, rs3818540, rs2274490, rs61739184, rs726176, rs2296966, rs17849148, and rs3193970 were genotyped and examined. To deal with correlated data of subjects within the same families, the generalized estimating equations approach was applied throughout all association analyses. The GG genotype of rs2281939 was associated with a higher risk of diabetes at baseline, an earlier onset of diabetes, and higher steady-state plasma glucose levels in the modified insulin suppression test. The minor allele T of rs2296966 was associated with higher prevalence and incidence of diabetes, an earlier onset of diabetes, and higher 2-h glucose during oral glucose tolerance test. These two SNPs revealed independent associations with age of diabetes onset as well as risk of diabetes at baseline. These findings supported that SORBS1 gene participates in the pathogenesis of diabetes.

Effect of Common Genetic Variants of Growth Arrest-Specific 6 Gene on Insulin Resistance, Obesity and Type 2 Diabetes in an Asian Population

ObjectivesGrowth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been implicated in systemic inflammation, obesity, and insulin resistance (IR). Data from recent studies suggest that polymorphisms in the Gas6 gene are associated with cardiovascular disorders and type 2 diabetes (T2D). However, the association of Gas6 gene variants with obesity, IR, and T2D development has not been explored.Materials and MethodsFour common single nucleotide polymorphisms (SNPs) in the Gas6 gene were genotyped in 984 participants from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. An insulin suppression test was performed to determine IR based on steady-state plasma glucose (SSPG). Associations between IR indices and obesity, and SNP genotypes, based on previously-reported data for this cohort (Phase I), were analyzed. In the present follow-up study (Phase II), the effects of gene variants of Gas6 on the progression to T2D were explored in individuals who were free of T2D in Phase I. The mean follow-up period for Phase II was 5.7 years.ResultsThe mean age of the study population in Phase I was 49.5 years and 16.7% of individuals developed T2D during follow-up. After adjusting for covariates, three SNPs (rs8191973, rs8197974, and rs7323932) were found to be associated with SSPG levels (p = 0.007, p = 0.03, and p = 0.011, respectively). This association remained significant after multiple testing and showed a significant interaction with physical activity for SNP rs8191973. However, no other significant correlations were observed between Gas6 polymorphisms and other indices of IR or obesity. A specific haplotype, AACG (from rs8191974, rs7323932, rs7331124, and rs8191973), was positively associated with SSPG levels (p = 0.0098). None of the polymorphisms were associated with an increased risk of T2D development.ConclusionsOur results suggest that Gas6 gene variants are associated with IR, although their effects on subsequent progression to T2D were minimal in this prospective Asian cohort.

Effect of Growth Hormone on Dawn Phenomenon in Healthy Adults

The purpose of this study was to investigate the involvement of growth hormone in the diurnal variation of insulin sensitivity in healthy adults. Afternoon (16:00 hr) or night (23:00 hr) pretreatment with a subcutaneous injection of normal saline, human growth hormone to mimic the normal nocturnal rise in growth hormone, or octreotide to inhibit endogenous growth hormone secretion to create a state of relative nocturnal growth hormone deficiency, was given 16 hours before undergoing the modified insulin suppression test in healthy subjects. The morning and evening experiments were separated by an interval of at least 3 days. Thus, each subject was tested on six separate occasions arranged in a random order. A higher value of the steady-state plasma glucose (SSPG) is indicative of lower insulin sensitivity. Plasma glucose, serum insulin, insulin-like growth factor-1, nonesterified fatty acids (NEFA), and metabolic clearance rate of insulin (MCRI) were measured. In the normal saline and human growth hormone groups, SSPG levels were lower in the morning than in the evening. Evening SSPG levels, MCRI, and NEFA concentrations were higher in the participants treated with normal saline and growth hormone than in the octreotide group. Differences in SSPG levels between the morning and evening values were higher in the participants pretreated with normal saline and growth hormone than in those treated with octreotide. A diurnal variation in insulin sensitivity existed in healthy subjects. These results provided direct evidence that the role of growth hormone in regulating insulin sensitivity might be related to changes in the MCRI and the metabolism of NEFA in healthy subjects.

Depression is not associated with peripheral insulin resistance in patients with chronic hepatitis C infection.

Depression is common in individuals infected with hepatitis C virus (HCV), and both depression and HCV infection are independently associated with insulin resistance (IR). To evaluate the relationship between depression and IR, among other factors, in an HCV-infected cohort. In this cross-sectional analysis, seventy-four non-type 2 diabetic, noncirrhotic, HCV-infected patients underwent comprehensive clinical, histologic and metabolic evaluation. IR was assessed directly with an insulin suppression test by measuring steady-state plasma glucose (SSPG) levels during continuous infusions of octreotide, glucose and insulin. Logistic regression modelling was used to evaluate predictors associated with depression. Thirty-nine (53%) patients were depressed, and 21 (54%) depressed patients were on at least one antidepressant. A higher estimated proportion of depressed patients were Caucasian (51% vs 20%, P = 0.005), unemployed (69% vs 49%, P = 0.07), heavier smokers (18 pack-years vs 13 pack-years, P = 0.07), on substance abuse therapy (16% vs 3%, P = 0.06) and had lower HDL levels (1.2 mmol/L vs 1.4 mmol/L, P = 0.01). The mean SSPG levels in depressed and nondepressed patients were 7.3 and 8.3 mmol/L (P = 0.45), respectively. In multipredictor adjusted analysis, only Caucasian race (OR 4.19, 95% CI 1.42-12.35, P = 0.009) and lower HDL (OR 0.95, 95% CI 0.89-0.99, P = 0.046) were associated with depression. In conclusion, although prevalent, depression was not associated with peripheral IR in this HCV-infected cohort. Attention to other modifiable factors associated with depression in the HCV-infected population is warranted.

Abstract 65: ABCA1 Ligand Peptides That Stimulate Cellular Cholesterol Efflux With High Potency Increase Insulin Sensitivity in Metabolic and Genetic Mouse Models of Obesity and Type 2 Diabetes

Anti-diabetic activities of HDL apolipoprotein(apo)s have been described, complementing ability to reduce atherosclerosis. These effects have been attributed, in part, to apos stimulating cholesterol efflux from cells via ABCA1. This suggests apo mimetic peptides that promote ABCA1 cholesterol efflux may be useful to combat diabetes and its cardiovascular complications. Two such peptides (CS6253 and T6991-2) with optimized safety features (NOAEL = 500 mg/kg) and little TG elevating effects have been designed by us through structure-activity studies of a prototypic ABCA1 ligand peptide, ATI-5261, derived from the C-terminal (CT) domain of apoE. Glucose lowering and insulin sensitizing effects of these new peptides were presently evaluated in mouse models of obesity and diabetes. Peptides CS6253 and T6991-2 stimulated cholesterol efflux from macrophages via ABCA1 with high potency similar to the native apoE CT domain (Km= 0.33±0.14, 0.24±02, 0.21±0.02 μM). Administration of CS6253 at a dose of 30 mg/kg (SC) on alternate days for 6 weeks reduced atherosclerosis by 32% in apoE deficient mice fed high-fat, Western diet for 14 weeks (15±2 vs. 22±4% plaque lesions, CS6253 vs. control, p&lt;0.01). T6991-2 administered (SC) at a dose of 10 mg/kg for 6 weeks in chow-fed ob/ob mice showed little effect on steady-state plasma glucose levels vs. controls (126±22 vs. 135±11 mg/dl, respectively); however, the levels of glucose were greatly attenuated with peptide treatment vs. controls in response to GTT (1.8±0.5 vs. 2.8±0.4 fold increases in plasma glucose at 60 min, respectively, p&lt;0.01). Treatment of C57BL/6J mice fed high-fat diet (HFD) with T6991-2 (6 weeks, 30 mg/kg) also enhanced insulin sensitivity by 2.2±0.7 fold vs. controls (55±17 vs. 25±5% reduction in basal glucose levels, respectively, at 15 minutes post insulin, 0.75 Units/kg, p&lt;0.01). The favorable anti-diabetic effects of T6991-2 were not due to changes in total body weight or β-cell function (i.e. unchanged plasma C-peptide levels). Our data indicate that single amphipathic α-helix peptides derived from apoE CT domain are sufficient to confer potent cellular cholesterol efflux and anti-diabetic activities, with therapeutic potential for diabetes and cardiovascular disease.

Identification of Insulin Resistance in Subjects with Normal Glucose Tolerance

Decreased insulin action (insulin resistance) is crucial in the pathogenesis of type 2 diabetes. Decreased insulin action can even be found in normoglycaemic patients, and they still bear increased risks for cardiovascular disease. In this study, we built models using data from metabolic syndrome (Mets) components and the oral glucose tolerance test (OGTT) to detect insulin resistance in subjects with normal glucose tolerance (NGT). In total, 292 participants with NGT were enrolled. Both an insulin suppression test (IST) and a 75-g OGTT were administered. The steady-state plasma glucose (SSPG) level derived from the IST was the measurement of insulin action. Participants in the highest tertile were defined as insulin-resistant. Five models were built: (i) Model 0: body mass index (BMI); (ii) Model 1: BMI, systolic and diastolic blood pressure, triglyceride; (iii) Model 2: Model 1 + fasting plasma insulin (FPI); (iv) Model 3: Model 2 + plasma glucose level at 120 minutes of the OGTT; and (v) Model 4: Model 3 + plasma insulin level at 120 min of the OGTT. The area under the receiver operating characteristic curve (aROC curve) was observed to determine the predictive power of these models. BMI demonstrated the greatest aROC curve (71.6%) of Mets components. The aROC curves of Models 2, 3, and 4 were all substantially greater than that of BMI (77.1%, 80.1%, and 85.1%, respectively). A prediction equation using Mets components and FPI can be used to predict insulin resistance in a Chinese population with NGT. Further research is required to test the utility of the equation in other populations and its prediction of cardiovascular disease or diabetes mellitus.

Analysis of Integrated Insulin-mTOR Signalling Network -Diabetes Perspective

The regulatory action of insulin on the blood glucose homeostasis is mediated by the Insulin signalling pathway. To quantify this regulation, we have integrated the models of Insulin secretion, insulin signalling, mTOR signalling and blood glucose uptake by various tissues. We have analyzed the effect of perturbations in the integrated insulin-mTOR signalling pathway on blood glucose levels. These effects were studied in the tissues in which glucose uptake is dependent on insulin (i.e. muscle, adipose and heart). Seventy five rate parameters in the integrated network were perturbed and the corresponding steady state plasma glucose levels were recorded. The fold changes in these parameters leading to pre-diabetic and diabetic states were characterized. Perturbations in 22 parameters elicited diabetic effect and 31 parameters showed pre-diabetic effects for certain fold change in basal parameter values. In the insulin signalling pathway, the concentrations and phosphorylation states of PTP and PIP3 were most effective in leading to diabetic state with only 3 and -3 fold change in their parameters, respectively. While increasing concentrations of PTEN by five folds also led to diabetic state, decreasing the phosphorylation of IRS, AKT and GSK3 unto 10 folds resulted in diabetic state. In the mTOR pathway, increasing the influence of amino acid on Rheb-GTP localization to the inhibitory complex by 4 folds elicited diabetic state. On the other hand decreasing conversion of RhebGTP to RhebGDP and formation of mTOR-raptor-PRAS40 complex also resulted in diabetic state. This demonstrates the influence of excess amino acid intake on diabetic state. Overall, it was noted that only 2 to 3 fold change in sensitive parameters resulted in pre-diabetic state.

Early insulin sensitivity after restrictive bariatric surgery, inconsistency between HOMA-IR and steady-state plasma glucose levels

BackgroundThe low-grade inflammatory condition present in morbid obesity is thought to play a causative role in the pathophysiology of insulin resistance (IR). Bariatric surgery fails to improve this inflammatory condition during the first months after surgery. Considering the close relation between inflammation and IR, we conducted a study in which insulin sensitivity was measured during the first months after bariatric surgery. Different methods to measure IR shortly after bariatric surgery have given inconsistent data. For example, the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) levels have been reported to decrease rapidly after bariatric surgery, although clamp techniques have shown sustained insulin resistance. In the present study, we evaluated the use of steady-state plasma glucose (SSPG) levels to assess insulin sensitivity 2 months after bariatric surgery. MethodsInsulin sensitivity was measured using HOMA-IR and SSPG levels in 11 subjects before surgery and at 26% excess weight loss (approximately 2 months after restrictive bariatric surgery). ResultsThe SSPG levels after 26% excess weight loss did not differ from the SSPG levels before surgery (14.3 ± 5.4 versus 14.4 ± 2.7 mmol/L). In contrast, the HOMA-IR values had decreased significantly (3.59 ± 1.99 versus 2.09 ± 1.02). ConclusionDuring the first months after restrictive bariatric surgery, we observed a discrepancy between the HOMA-IR and SSPG levels. In contrast to the HOMA-IR values, the SSPG levels had not improved, which could be explained by the ongoing inflammatory state after bariatric surgery. These results suggest that during the first months after restrictive bariatric surgery, HOMA-IR might not be an adequate marker of insulin sensitivity.

Short-term Overfeeding Induces Insulin Resistance in Weight-stable Patients After Bariatric Surgery

Short time overfeeding of rats rapidly leads to insulin resistance (IR). A study with healthy human volunteers, which we suggest are less susceptible for developing IR after short time overfeeding, did not show these effects on IR. Therefore a study population of weight-stable, former morbidly obese subjects (BMI 31.3 kg/m2), which were treated with bariatric surgery approximately 3 years ago was selected. Eleven subjects were submitted to a 7-day overfeeding study, resulting in a 53% increase in caloric intake (1,227 +/- 394.4 to 1,879.2 +/- 298.4 kcal/day). During normal diet and after overfeeding, insulin sensitivity was measured using steady state plasma glucose (SSPG) levels. At these time points, BMI and waist/hip ratio together with plasma levels of inflammatory markers (CRP, AGP, LBP, and TNF-alpha receptors) and plasma leptin values were also measured. SSPG levels after overfeeding increased from 8.2 +/- 3.2 to 10.6 +/- 2.6 mmol/l (P < 0.05), indicating decreased insulin sensitivity after overfeeding. Fasting plasma insulin, glucose, circulating levels of inflammatory markers, BMI, and waist/hip ratio remained unchanged. This study shows that overfeeding in a group of weight-stable, former morbidly obese subjects 3 years after bariatric surgery results in decreased insulin sensitivity. The mechanisms behind decreased insulin sensitivity induced by overfeeding are poorly understood, but the present results reveal that a unique human model is available to study these mechanisms, leading to a better understanding of the pathophysiology of IR.

Impact of Clinical Characteristics of Individual Metabolic Syndrome on the Severity of Insulin Resistance in Chinese Adults

The impact the metabolic syndrome (MetS) components on the severity of insulin resistance (IR) has not been reported. We enrolled 564 subjects with MetS and they were divided into quartiles according to the level of each component; and an insulin suppression test was performed to measure IR. In males, steady state plasma glucose (SSPG) levels in the highest quartiles, corresponding to body mass index (BMI) and fasting plasma glucose (FPG), were higher than the other three quartiles and the highest quartiles, corresponding to the diastolic blood pressure and triglycerides, were higher than in the lowest two quartiles. In females, SSPG levels in the highest quartiles, corresponding to the BMI and triglycerides, were higher than in all other quartiles. No significant differences existed between genders, other than the mean SSPG levels in males were greater in the highest quartile corresponding to BMI than that in the highest quartile corresponding to HDL-cholesterol levels. The factor analysis identified two underlying factors (IR and blood pressure factors) among the MetS variables. The clustering of the SSPG, BMI, triglyceride and HDL-cholesterol was noted. Our data suggest that adiposity, higher FPG and triglyceride levels have stronger correlation with IR and subjects with the highest BMI have the highest IR.

Association between insulin resistance and endothelial dysfunction in type 2 diabetes and the effects of pioglitazone

Endothelial dysfunction is regarded as an early stage of atherosclerosis, and plays a role in the development of atherosclerotic diseases. Insulin resistance is related to the atherosclerotic process. In this study, we examined the association between endothelial function and insulin resistance in 48 subjects with type 2 diabetes. In addition, the effects of pioglitazone treatment on endothelial function and insulin resistance were investigated in a subgroup of subjects. Endothelial function of the brachial artery was non-invasively assessed using ultrasound technique. We measured flow-mediated endothelium-dependent vasodilation (FMD) and glyceryl trinitrate-induced endothelium-independent vasodilation (GTN). Insulin sensitivity was measured by the steady-state plasma glucose (SSPG) method. High SSPG levels indicate insulin resistance. There was a significant inverse correlation ( r = −0.462, p < 0.001) between SSPG and FMD. Systolic blood pressure was inversely correlated with FMD ( r = −0.360, p < 0.013). By multiple regression analysis, insulin resistance was the sole predictor of FMD. The effects of chronic treatment with pioglitazone were assessed in 10 subjects with type 2 diabetes. The increase in FMD significantly correlated with the decrease in SSPG. There is a significant association between vascular endothelial dysfunction and insulin resistance in type 2 diabetes. This result was supported by the effects of the insulin sensitizer, pioglitazone.

Sibutramine improves insulin sensitivity without alteration of serum adiponectin in obese subjects with Type 2 diabetes

To evaluate the effect of sibutramine on weight loss, insulin sensitivity and serum adiponectin levels in obese patients with Type 2 diabetes. This study is a randomized, double-blind, placebo-controlled parallel comparison study of sibutramine 15 mg/day and placebo. Forty-eight eligible obese patients with Type 2 diabetes (age between 30 and 75 years with body mass index > or = 27 kg/m(2)) were randomly assigned to receive either placebo (n = 24) or sibutramine (15 mg/day) (n = 24) for 6 months. Fifteen subjects in each group underwent meal tests and modified insulin suppression tests before and after 6 months' treatment. After 6 months of sibutramine treatment statistically significant changes from baseline were observed for body weight (85.4 +/- 2.5 vs. 82.9 +/- 2.4 kg, P < 0.005) and body mass index (32.0 +/- 0.7 vs. 31.4 +/- 0.6 kg/m(2), P < 0.05) without a significant alteration of waist-hip ratio (W/H), blood pressure, heart rate, glycaemic parameters or lipid profiles. The steady-state plasma glucose (SSPG) level during the modified insulin suppression test was significantly reduced in the sibutramine group (17.33 +/- 2.92 vs. 14.29 +/- 4.19 mmol/l, P < 0.05) despite similar steady-state plasma insulin (SSPI) concentrations. In addition, serum adiponectin and C-reactive protein (CRP) levels remained unchanged, although modest weight reduction was achieved after sibutramine treatment. There were also no significant correlations between changes in serum adiponectin and reduction of SSPG or body weight. Daily ambient plasma insulin and glucose concentrations in response to a test meal were not significantly different in subjects receiving sibutramine treatment. We conclude that treatment with sibutramine 15 mg once daily effectively reduces weight and enhances insulin sensitivity without alteration of serum adiponectin levels in obese patients with Type 2 diabetes.

Increased plasma concentration of nitric oxide in type 2 diabetes but not in nondiabetic individuals with insulin resistance

Insulin resistance (IR) is a key element in the pathogenesis of type 2 diabetes. The results of recent experiments on insulin-mediated vasodilatation have suggested that vascular insensitivity is a component of IR. However, it is still controversial that patients with type 2 diabetes have a decreased ability of insulin to increase endothelial nitric oxide (NO) release. Plasma concentration of NO was examined in 26 patients with type 2 diabetes and 78 nondiabetic volunteers during an insulin suppression test. The test measured the efficacy of insulin in promoting disposal of the infused glucose load, in which the steady state plasma glucose (SSPG) during the 150-180 min of the test was used as an index of IR. Plasma NO levels were assayed by measurement of the stable end products of their metabolism. Comparison of plasma NO levels between groups were performed by Mann-Whitney test and relationships between SSPG and different variables were analyzed by partial correlations. Our results showed that the plasma NO levels were significantly higher in the diabetic group. When the nondiabetic subjects were analyzed according to their SSPG levels, there was no difference of plasma NO levels between those with SSPG>160 mg/dl and those with SSPG<160 mg/dl. There were also no difference of NO levels between those with a family history of type 2 diabetes and those without. In the nondiabetic group, SSPG correlated with BMI, fasting insulin, triglyceride and HDL-cholesterol, but neither with plasma NO levels nor fasting plasma glucose. Our data suggests that the impairment of NO activity in patients with type 2 diabetes is due to an impaired effect rather than its production. This altered NO signaling pathway is not an early event in insulin resistant individuals. Any such changes will not be apparent until type 2 diabetes with overt hyperglycemia develops.

Close association of endothelial dysfunction with insulin resistance and carotid wall thickening in hypertension

Background Endothelial dysfunction has been regarded as an early stage in the atherosclerotic process. Endothelial dysfunction and insulin resistance were observed in hypertensive subjects and were associated with carotid wall thickening. Methods We examined the determinants of endothelial dysfunction including insulin sensitivity and carotid wall thickening. A total of 41 subjects with nondiabetic essential hypertension were studied. Endothelial function of brachial artery and carotid wall thickening were assessed noninvasively using ultrasound technique. In brachial artery, we measured flow-mediated endothelium-dependent vasodilation (FMD) and glyceryl trinitrate–induced endothelium-independent vasodilation (GTN). We estimated intima-media thickness of the common carotid artery (IMT). Insulin sensitivity was measured according to the steady-state plasma glucose (SSPG) method. High SSPG levels indicated insulin resistance. Results On univariate analysis, there were significant negative correlations between FMD and SSPG ( r = −0.695, P < .0001) or IMT ( r = −0.449, P < .004). The FMD was negatively correlated significantly with age and with systolic and diastolic blood pressures (BP). A significant negative correlation was observed between GTN and SSPG. There was a significant positive relation between SSPG and IMT. On multiple regression analysis including systolic BP, SSPG, and age as independent variables and FMD as a dependent variable, FMD was independently related to SSPG ( P < .03) and systolic BP ( P < .02). If the presence of SSPG, diastolic BP, and age were entered as independent variables against FMD, FMD was independently related to SSPG ( P < .002). Conclusions One of the major determinants of endothelial function was insulin resistance. Our findings suggest that endothelial dysfunction and early structural vascular changes were related to insulin resistance.

Methods for quantifying insulin resistance in human immunodeficiency virus-positive patients

Various indirect indices have been used in human immunodeficiency virus (HIV)-infected individuals to assess insulin resistance, but the validity of these measures has not been rigorously assessed by comparison with physiologic methods of quantifying insulin-mediated glucose uptake (IMGU). We directly measured IMGU in 50 nondiabetic HIV-positive subjects by determining the steady-state plasma glucose (SSPG) concentration in response to a 3-hour continuous infusion of insulin, glucose, and somatostatin. Because steady-state plasma insulin concentrations were similar (∼60 μU/mL) in all subjects, the SSPG concentrations provided direct assessments of insulin action. Relationships between SSPG levels and various surrogate measures of IMGU derived from the 75-g oral glucose tolerance test (OGTT) were determined. The indirect measure of IMGU most closely related to SSPG concentrations was the total integrated insulin response to a 75-g glucose load ( r = 0.78, P < .01), accounting for approximately two thirds of the variability in SSPG ( r 2 = 0.61). Other indirect measures of IMGU, including the homeostasis assessment for insulin resistance (HOMA-IR), were also significantly related to SSPG values, but had lower magnitudes of correlation ( r = 0.43 to 0.61), thereby possessing limited ability to predict SSPG variability ( r 2 = 0.18 to 0.37). In conclusion, indirect measures of IMGU need to be applied with caution when evaluating insulin action in HIV-infected patients.

Improvement of insulin sensitivity by a long-acting nifedipine preparation (nifedipine-CR) in patients with essential hypertension

Background Nifedipine has been reported to cause impairment of insulin sensitivity. But recently a controlled-released formulation of nifedipine (nifedipine-GITS) has been reported that it could improve insulin sensitivity. Methods We evaluated insulin sensitivity in two groups of essential hypertensive subjects before and after treatment with either long-acting nifedipine (nifedipine-CR, Adalat CR tablets; Bayer Yakuhin, Osaka, Japan) ( n = 10) or metoprolol ( n = 9). Insulin sensitivity was evaluated from the steady-state plasma glucose (SSPG) level measured at the steady-state insulin level (20 to 30 μU/mL) using a modification of the SSPG method previously reported. Results The SSPG was initially high, but was significantly reduced by nifedipine-CR treatment (from 133 ± 14 mg/dL to 95 ± 8 mg/dL). However, SSPG was not significantly altered by treatment in the metoprolol group (from 103 ± 15 mg/dL to 119 ± 12 mg/dL). Conclusions Our results indicate that the long-acting nifedipine (nifedipine-CR) is associated with improved insulin sensitivity.

Quinapril treatment restores the vasodilator action of insulin in fructose-hypertensive rats.

1. Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve insulin-resistance both experimentally and clinically. We therefore investigated the effects of quinapril, which has high tissue specificity for ACE, regarding the contribution of insulin to vascular contractions, as well as insulin sensitivity in a dietary rat model of insulin resistance. 2. Male Sprague-Dawley rats were divided into three groups: (i) rats fed normal chow (normal diet group); (ii) rats fed fructose-rich chow containing 40% fructose and 7% lard (fructose diet group); and (iii) rats fed fructose-rich chow plus quinapril (10 mg/kg per day; quinapril-treated group). 3. After 2 weeks, we evaluated systolic blood pressure, insulin sensitivity as assessed by steady state plasma glucose (SSPG) levels, response of aortic rings to phenylephrine (10-9 to 10-6 mol/L) in the presence or absence of insulin and the response of aortic rings to acetylcholine. 4. Feeding rats fructose-rich chow resulted in an elevation of blood pressure (P < 0.01) and SSPG levels (P < 0.01). Quinapril treatment significantly prevented increases in both blood pressure and SSPG, with a return to the levels seen in the normal diet group. 5. In the absence of insulin, the maximal contractile response to phenylephrine did not differ between the three groups. However, in the presence of insulin (100 mU/mL), the contractile response to phenylephrine (10-6 mol/L) was reduced by 22.8 +/- 1.2% in the normal diet group, although no insulin effects were observed in the fructose diet group (P < 0.01). Quinapril restored the inhibitory effect of insulin on phenylephrine-induced contractions. 6. In addition, the reduction in relaxation induced by acetylcholine in the fructose diet group was significantly reversed by quinapril treatment. 7. It is concluded that the fructose diet impairs the vasodilator effects of insulin as well as acetylcholine-induced relaxation in rat thoracic aortas. Quinapril prevented deterioration in the responses of the aortic rings, suggesting that ACE inhibitors may be useful for treating vascular insulin resistance.

Weight Reduction Increases Plasma Levels of an Adipose-Derived Anti-Inflammatory Protein, Adiponectin

Adiponectin, an adipose tissue-specific plasma protein, was recently revealed to have anti-inflammatory effects on the cellular components of vascular wall. Its plasma levels were significantly lower in men than in women and lower in human subjects with obesity, type 2 diabetes mellitus, or coronary artery disease. Therefore, it may provide a biological link between obesity and obesity-related disorders such as atherosclerosis, against which it may confer protection. In this study, we observed the changes of plasma adiponectin levels with body weight reduction among 22 obese patients who received gastric partition surgery. A 46% increase of mean plasma adiponectin level was accompanied by a 21% reduction in mean body mass index. The change in plasma adiponectin levels was significantly correlated with the changes in body mass index (r = −0.5, P = 0.01), waist (r = −0.4, P = 0.04) and hip (r =− 0.6, P = 0.0007) circumferences, and steady state plasma glucose levels (r = −0.5, P = 0.04). In multivariate linear regression models, the increase in adiponectin as a dependent variable was significantly related to the decrease in hip circumference (β = −0.16, P = 0.028), after adjusting body mass index and waist circumference. The change in steady state plasma glucose levels as a dependent variable was related to the increase of adiponectin with a marginal significance (β =− 0.92, P = 0.053), after adjusting body mass index and waist and hip circumferences. In conclusion, body weight reduction increased the plasma levels of a protective adipocytokine, adiponectin. In addition, the increase in plasma adiponectin despite the reduction of the only tissue of its own synthesis suggests that the expression of adiponectin is under feedback inhibition in obesity.

Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin.

Adiponectin, an adipose tissue-specific plasma protein, was recently revealed to have anti-inflammatory effects on the cellular components of vascular wall. Its plasma levels were significantly lower in men than in women and lower in human subjects with obesity, type 2 diabetes mellitus, or coronary artery disease. Therefore, it may provide a biological link between obesity and obesity-related disorders such as atherosclerosis, against which it may confer protection. In this study, we observed the changes of plasma adiponectin levels with body weight reduction among 22 obese patients who received gastric partition surgery. A 46% increase of mean plasma adiponectin level was accompanied by a 21% reduction in mean body mass index. The change in plasma adiponectin levels was significantly correlated with the changes in body mass index (r = -0.5, P = 0.01), waist (r = -0.4, P = 0.04) and hip (r = -0.6, P = 0.0007) circumferences, and steady state plasma glucose levels (r = -0.5, P = 0.04). In multivariate linear regression models, the increase in adiponectin as a dependent variable was significantly related to the decrease in hip circumference (beta = -0.16, P = 0.028), after adjusting body mass index and waist circumference. The change in steady state plasma glucose levels as a dependent variable was related to the increase of adiponectin with a marginal significance (beta = -0.92, P = 0.053), after adjusting body mass index and waist and hip circumferences. In conclusion, body weight reduction increased the plasma levels of a protective adipocytokine, adiponectin. In addition, the increase in plasma adiponectin despite the reduction of the only tissue of its own synthesis suggests that the expression of adiponectin is under feedback inhibition in obesity.