IR Subjects Research Articles

Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.

BackgroundIt is increasingly recognized that intestinal cells can store lipids after a meal, yet the effect of this phenomenon on lipid absorption patterns in insulin resistance remains unknown.MethodsThe kinetics of meal fat appearance were measured in insulin-sensitive (IS, n = 8) and insulin-resistant (IR, n = 8) subjects after sequential, isotopically labeled lunch and dinner meals. Plasma dynamics on triacylglycerol-rich (TAG-rich) lipoproteins and plasma hormones were analyzed using a nonlinear, non–steady state kinetic model.ResultsAt the onset of dinner, IS subjects showed an abrupt plasma appearance of lunch lipid consistent with the “second-meal effect,” followed by slower appearance of dinner fat in plasma, resulting in reduced accumulation of dinner TAG of 48% compared with lunch. By contrast, IR subjects exhibited faster meal TAG appearance rates after both lunch and dinner. This effect of lower enterocyte storage between meals was associated with greater nocturnal and next-morning hyperlipidemia. The biochemical data and the kinetic analysis of second-meal effect dynamics are consistent with rapid secretion of stored TAG bypassing lipolysis and resynthesis. In addition, the data are consistent with a role for the diurnal pattern of plasma leptin in regulating the processing of dietary lipid.ConclusionThese data support the concept that intestinal lipid storage may be physiologically beneficial in IS subjects.Trial registrationClinicalTrials.gov NCT02020343.FundingThis study was supported by a grant from the American Diabetes Association (grant 1-13-TS-12).

Cytomegalovirus infection and allograft rejection among pediatric heart transplant recipients in the era of valganciclovir prophylaxis.

CMV infection remains a significant cause of morbidity among pediatric HTx recipients We explored the implications of CMV infection on post-transplant outcomes among CMV risk-stratified pediatric HTx recipients receiving VGC prophylaxis. Children who underwent HTx between January 2010 and October 2016 were stratified according to CMV risk at time of transplant and evaluated for evidence of post-transplant CMV infection, rejection, CAV, and graft loss. Among 97 children, 41 (42%) were considered HR or IR risk for CMV infection and received VGC prophylaxis. CMV DNAemia was observed in 34% of children, including 71% HR, 40% IR, and 18% LR individuals. Median time to CMV DNAemia following VGC prophylaxis was 32D among HR vs 277D in IR subjects (P=.042). No differencein overall graft loss was noted among groups, but CMV HR children had decreased rejection-free survival (3.5years) compared to IR (6years, P=.015) and LR children (8years, P=.0003). CMV was noted on EMB in 13% of children but was not associated with increased CAV, rejection or graft loss. High-risk CMV status was associated with decreased time to CMV infection despite VGC prophylaxis, compared to IR, and decreased rejection-free survival times compared to both IR and LR recipients. Detection of CMV on EMB was not associated with increased rejection, CAV or graft loss. Additional studies are needed to explore the impact of CMV infection on rejection-free survival in HTx recipients.

Systemic Cytokine Levels Do Not Predict CD4(+) T-Cell Recovery After Suppressive Combination Antiretroviral Therapy in Chronic Human Immunodeficiency Virus Infection.

Background. Subjects on suppressive combination antiretroviral therapy (cART) who do not achieve robust reconstitution of CD4+ T cells face higher risk of complications and death. We studied participants in the Women's Interagency HIV Study with good (immunological responder [IR]) or poor (immunological nonresponder [INR]) CD4+ T-cell recovery after suppressive cART (n = 50 per group) to determine whether cytokine levels or low-level viral load correlated with INR status.Methods. A baseline sample prior to viral control and 2 subsequent samples 1 and 2 years after viral control were tested. Serum levels of 30 cytokines were measured at each time point, and low-level human immunodeficiency virus (HIV) viral load and anti-HIV antibody levels were measured 2 years after viral suppression.Results. There were minimal differences in cytokine levels between IR and INR subjects. At baseline, macrophage inflammatory protein-3β levels were higher in IR subjects; after 1 year of suppressive cART, soluble vascular endothelial growth factor-R3 levels were higher in IR subjects; and after 2 years of suppressive cART, interferon gamma-induced protein 10 levels were higher in INR subjects. Very low-level HIV viral load and anti-HIV antibody levels did not differ between IR and INR subjects.Conclusions. These results imply that targeting residual viral replication might not be the optimum therapeutic approach for INR subjects.

The Effects of Bariatric Surgery-Induced Weight Loss on Adipose Tissue in Morbidly Obese Women Depends on the Initial Metabolic Status.

Adipose tissue (AT) dysfunction in obesity is commonly linked to insulin resistance and promotes the development of metabolic disease. Bariatric surgery (BS) represents an effective strategy to reduce weight and to improve metabolic health in morbidly obese subjects. However, the mechanisms and pathways that are modified in AT in response to BS are not fully understood, and few information is still available as to whether these may vary depending on the metabolic status of obese subjects. Abdominal subcutaneous adipose tissue (SAT) samples were obtained from morbidly obese women (n = 18) before and 13.3 ± 0.37months after BS. Obese women were stratified into two groups: normoglycemic (NG; Glu < 100mg/dl, HbA1c <5.7%) or insulin resistant (IR; Glu 100-126mg/dl, HbA1c 5.7-6.4%) (n = 9/group). A multi-comparative proteomic analysis was employed to identify differentially regulated SAT proteins by BS and/or the degree of insulin sensitivity. Serum levels of metabolic, inflammatory, and anti-oxidant markers were also analyzed. Before surgery, NG and IR subjects exhibited differences in AT proteins related to inflammation, metabolic processes, the cytoskeleton, and mitochondria. BS caused comparable weight reductions and improved glucose homeostasis in both groups. However, BS caused dissimilar changes in metabolic enzymes, inflammatory markers, cytoskeletal components, mitochondrial proteins, and angiogenesis regulators in NG and IR women. BS evokes significant molecular rearrangements indicative of improved AT function in morbidly obese women at either low or high metabolic risk, though selective adaptive changes in key cellular processes occur depending on the initial individual's metabolic status.

Obesity Associated Modulation of miRNA and Co-Regulated Target Transcripts in Human Adipose Tissue of Non-Diabetic Subjects.

Objective: Micro RNAs (miRNAs) are a class of non-coding regulatory RNAs. We performed a transcriptome-wide analysis of subcutaneous adipose tissue and in vitro studies to identify miRNAs and co-regulated target transcripts associated with insulin sensitivity (SI) and obesity in human. Methods: We selected 20 insulin-resistant (IR, SI=2.0±0.7) and 20 insulin-sensitive (IS, SI=7.2±2.3) subjects from a cohort of 117 metabolically characterized non-diabetic Caucasians for comparison. Results: After global profiling, 3 miRNAs had marginally different expressions between IR and IS subjects. A total of 14 miRNAs were significantly correlated with %fat mass, body mass index (BMI), or SI. The qRT-PCR validated the correlation of miR-148a-3p with BMI (r=-0.70, P=2.73X10-6). MiRNA target filtering analysis identified DNA methyltransferase 1 (DNMT1) as one of the target genes of miR-148a-3p. DNMT1 expression in adipose tissue was positively correlated with BMI (r=0.47, p=8.42X10-7) and was inversely correlated with miR-148a-3p (r=-0.34). Differentiation of SGBS preadipocytes showed up-regulation of miR-148a-3p and down-regulation of DNMT1 in differentiated adipocytes. After transfecting miR-148a-3p mimics into HeLa-S3 cells, DNMT1 was down-regulated, while transfection of adipose stem cells with miR-148a-3p inhibitor up-regulated DNMT1. Conclusions: Our results indicate that miR-148a-3p-mediated regulation of DNMT1 expression may play a mechanistic role in obesity.

Insulin-resistant subjects have normal angiogenic response to aerobic exercise training in skeletal muscle, but not in adipose tissue.

Reduced vessel density in adipose tissue and skeletal muscle is associated with obesity and may result in decreased perfusion, decreased oxygen consumption, and insulin resistance. In the presence of VEGFA, Angiopoietin-2 (Angpt2) and Angiopoietin-1 (Angpt1) are central determinants of angiogenesis, with greater Angpt2:Angpt1 ratios promoting angiogenesis. In skeletal muscle, exercise training stimulates angiogenesis and modulates transcription of VEGFA, Angpt1, and Angpt2. However, it remains unknown whether exercise training stimulates vessel growth in human adipose tissue, and it remains unknown whether adipose angiogenesis is mediated by angiopoietin signaling. We sought to determine whether insulin-resistant subjects would display an impaired angiogenic response to aerobic exercise training. Insulin-sensitive (IS, N = 12) and insulin-resistant (IR, N = 14) subjects had subcutaneous adipose and muscle (vastus lateralis) biopsies before and after 12 weeks of cycle ergometer training. In both tissues, we measured vessels and expression of pro-angiogenic genes. Exercise training did not increase insulin sensitivity in IR Subjects. In skeletal muscle, training resulted in increased vessels/muscle fiber and increased Angpt2:Angpt1 ratio in both IR and IS subjects. However, in adipose, exercise training only induced angiogenesis in IS subjects, likely due to chronic suppression of VEGFA expression in IR subjects. These results indicate that skeletal muscle of IR subjects exhibits a normal angiogenic response to exercise training. However, the same training regimen is insufficient to induce angiogenesis in adipose tissue of IR subjects, which may help to explain why we did not observe improved insulin sensitivity following aerobic training.

Adaptation of β-Cell and Endothelial Function to Carbohydrate Loading: Influence of Insulin Resistance.

High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive [IS] [n = 64] or insulin-resistant [IR] [n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater β-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction.

Impaired Immune Phenotype of Circulating Endothelial-Derived Microparticles in None-Diabetic Patients with Chronic Heart Failure: Impact on Insulin Resistance

Background: The causality role of different immune phenotype in IR developing among chronic heart failure (CHF) subjects has not determined obviously. The aim of the study was to assess relationship between IR and immune phenotype of circulating endothelial-derived microparticles (EMPs) in patients with CHF. Methods: The study retrospectively involved 300 CHF patients aged 48 to 62 years. All the patients have given written informed consent for participation in the study. Biomarkers were measured at baseline of the study. Results: These were not significant differences between both cohort patients in EMPs labeled as CD144+/CD31+, CD144+/annexin V+, and CD62E+ microparticles. Higher concentrations of CD144+/CD31+/annexin V+ EMPs and CD31+/annexin V+ EMPs were found in IR subjects when compared with none IR patients. Using multivariate logistic regression analyses, we found that HOMA-IR (OR = 1.14, 95% CI=1.08-1.21, P = 0.001), NT-proBNP (OR = 1.07, 95% CI=1.04-1.10, P = 0.001), hs-CRP (OR = 1.04, 95% CI=1.02-1.07, P = 0.001), and NYHA class (OR = 1.03, 95% CI=1.01-1.05, P = 0.001) were predictors for increased CD31+/annexin V+ EMPs. Therefore, HOMA-IR (OR = 1.10, 95% CI=1.05-1.17, P = 0.001), NT-proBNP (OR = 1.08, 95% CI=1.04-1.12, P = 0.001), and NYHA class (OR = 1.05, 95% CI=1.02-1.09, P = 0.001) significantly predicted elevation of CD144+/CD31+/annexin V+ EMPs. Conclusion: we found that IR remains statistically significant predictor for increased apoptotic-derived EMPs labelled as CD144+/CD31+/annexin V+ and CD31+/annexin V+ EMPsin none-diabetic patients with CHF patients and that these findings reflect exiting impaired phenotype of circulating EMPs in this patient population.

Insulin Resistance Is Associated with Lower Acetylcholine-Induced Microvascular Reactivity in Nondiabetic Women

The association between insulin resistance and microvascular dysfunction is well established in obese individuals with type 2 diabetes. It is unclear whether this relationship is dependent on obesity and body fat in insulin-resistant persons. This study investigated acetylcholine (ACh)-induced microvascular reactivity in apparently healthy women (n=37, 20-45 years), with and without insulin resistance. Body fat mass (dual X-ray absorptiometry), waist circumference (WC), blood pressure, fasting glucose, insulin, and free fatty acid concentrations were measured. Insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR), and subjects were divided into insulin-resistant (IR, n=16) and insulin-sensitive (IS, n=21) groups. ACh-induced forearm microvascular reactivity was measured by laser Doppler imagery using iontophoresis of ACh and compared between groups adjusting for WC and skin resistance (SR). The IR group had a higher body mass index (BMI) (30.7 ± 6.4 vs. 22.9 ± 7.3 kg/m(2), P < 0.01), fat mass (34.7 ± 11.9 vs. 19.7 ± 9.6 kg, P < 0.01), WC (89.9 ± 13.6 vs. 74.4 ± 9.7 cm, P < 0.01), and a lower SR (0.24 ± 0.08 vs. 0.32 ± 0.08 Ω, P < 0.05) than the IS group. Microvascular reactivity, expressed as percentage increase in perfusion from baseline, was significantly lower in IR subjects after adjusting for differences in WC and SR (420.9 ± 166.5 vs. 511.6 ± 214.8%, P < 0.05). There were associations between microvascular reactivity and SR (r=-0.34, P < 0.05) and systolic blood pressure (r=-0.36, P < 0.05), but not BMI, body fat mass, WC, or HOMA-IR. ACh-induced microvascular reactivity was different between IR and IS apparently healthy, nondiabetic women once differences in WC and SR were accounted for.

Impaired hemodynamic response to meal intake in insulin-resistant subjects: an impedance cardiography approach

In the postprandial state, insulin regulates metabolic and cardiovascular responses. In insulin resistance, the insulin action is impaired at both levels. However, postprandial hemodynamic responses are poorly characterized in this setting. We investigated fasting and postprandial cardiac and vascular hemodynamic responses in subjects with and without insulin resistance. Sixty-six atherosclerosis-free, healthy volunteers were studied in a fasted state and ≤180 min after ingestion of a mixed meal. The insulin sensitivity index was determined by using a minimal model analysis; hemodynamic response was monitored by using continuous impedance cardiography that allowed a reliable beat-to-beat noninvasive evaluation of stroke volume, cardiac contractility, and several derived variables. Subjects were divided into insulin-resistant (IR; n = 33) and insulin-sensitive (IS; n = 33) groups. After fasting, IR subjects had significantly higher values of systolic and diastolic blood pressures and the systemic vascular resistance index (SVRI) than did IS subjects. In the postprandial state, acute vasodilatation was comparable and synchronous (at 30 min) in IR and IS subjects (P = 0.209), but subsequent vascular tone recovery (30-180 min) was significantly impaired in IR subjects (P = 0.018), even after adjustment for age and sex (P = 0.031). Hemodynamic dysregulation was directly correlated with metabolic disturbances in the postprandial state. In basal and postprandial states, hemodynamic variables related to cardiac function were not significantly different in IR and IS subjects. IR subjects had a worse fasting vascular performance than did IS subjects. In the postprandial phase, insulin resistance was associated with a shorter duration of vasodilatation in the absence of an altered cardiac performance. Peripheral hemodynamic alterations in fasting and postprandial states may have a negative effect on cardiovascular performance in IR patients.

Insulin Resistance Is Associated With Higher Intramyocellular Triglycerides in Type I but Not Type II Myocytes Concomitant With Higher Ceramide Content

OBJECTIVEWe tested the primary hypotheses that sphingolipid and diacylglycerol (DAG) content is higher within insulin-resistant muscle and that the association between intramyocellular triglycerides (IMTG) and insulin resistance is muscle fiber type specific.RESEARCH DESIGN AND METHODSA nested case-control analysis was conducted in 22 obese (BMI >30 kg/m2) women who were classified as insulin-resistant (IR; n = 12) or insulin-sensitive (IS; n = 10), determined by hyperinsulinemic-euglycemic clamp (>30% greater in IS compared with IR, P < 0.01). Sphingolipid and DAG content was determined by high-performance liquid chromatography–tandem mass spectrometry. Fiber type–specific IMTG content was histologically determined. Gene expression was determined by quantitative PCR.RESULTSTotal (555 ± 53 vs. 293 ± 54 pmol/mg protein, P = 0.004), saturated (361 ± 29 vs. 179 ± 34 pmol/mg protein, P = 0.001), and unsaturated (198 ± 29 vs. 114 ± 21 pmol/mg protein, P = 0.034) ceramides were higher in IR compared with IS. DAG concentrations, however, were similar. IMTG content within type I myocytes, but not type II myocytes, was higher in IR compared with IS subjects (P = 0.005). Insulin sensitivity was negatively correlated with IMTG within type I myocytes (R = −0.51, P = 0.026), but not with IMTG within type II myocytes. The proportion of type I myocytes was lower (41 vs. 59%, P < 0.01) in IR subjects. Several genes involved in lipid droplet and fatty acid metabolism were differentially expressed in IR compared with IS subjects.CONCLUSIONSHuman skeletal muscle insulin resistance is related to greater IMTG content in type I but not type II myocytes, to greater ceramide content, and to alterations in gene expression associated with lipid metabolism.

Determination of insulin resistance in non-diabetic Saudi adults by including fasting free fatty acids into QUICKI

Most available diagnostic methods of insulin resistance are either unsuitable for screening or fail to detect marginal cases. It was reported that including plasma free fatty acids (FFA) into QUICK (quantitative insulin sensitivity check index) I improves its diagnostic power. The aim was to test the effectiveness of modified QUICK I against HOMA (homeostasis model assessment) and QUICK I in identifying insulin resistant subjects in the non-diabetic adult population. 357 healthy adults aged 18 - 50 years were recruited randomly. Their anthropometric and demographic information were taken. Biochemical parameters and FFA (free fatty acid) were measured in fasting blood samples and used to calculate modified QUICK I. Reported cut-off point was used to identify IR subjects, who were matched for age and sex to individuals from the rest of the subjects. 209 subjects satisfied the criteria. 97 individuals were identified to be IR. This group had statistically different anthropometric and biochemical parameters compared to NIR group. Biochemical parameters did not differ significantly when QUICK I was used to identify IR subjects. The modified QUICK I for all subjects correlated significantly (p = 0.01) with HOMA values (r = -0.756) and with QUICK I values (r = 0.758). Modified QUICK I is a more powerful diagnostic index of IR in Saudi non diabetic adults. Key words: Insulin resistance, non diabetic, QUICK, FFA.

Circadian rhythm of the autonomic nervous system in insulin resistant subjects with normoglycemia, impaired fasting glycemia, impaired glucose tolerance, type 2 diabetes mellitus

BackgroundIn type 2 diabetes mellitus both insulin resistance and hyperglycemia are considered responsible for autonomic dysfunction. The relation between the autonomic activity, impaired fasting glycemia and impaired glucose tolerance is, however, unclear. The purpose of this study was to evaluate and compare the circadian autonomic activity expressed as heart rate variability (HRV) measured by 24-hours ECG recording in insulin resistant subjects (IR) with characteristics as follow: IR subjects with normal oral glucose tolerance test results, IR subjects with impaired fasting glucose, IR subjects with impaired glucose tolerance and subjects with type 2 diabetes mellitus.MethodsEighty Caucasian insulin resistant subjects (IR) and twenty five control subjects were recruited for the study. IR subjects were divided into four groups according to the outcoming results of oral glucose tests (OGTTs): IR subjects with normal glucose regulation (NGR), IR subjects with impaired fasting glycemia (IFG), IR subjects with impaired glucose tolerance (IGT) and subjects with type 2 diabetes mellitus (DM). Autonomic nervous activity was studied by 24-hours ECG recording. Heart rate variability analysis was performed in time and frequency domains: SDNN, RMS-SD, low frequency (LF) and high frequency (HF) were calculated.ResultsThe total SDNN showed statistically significant reduction in all four groups with insulin resistant subjects (IR) when compared to the control group (p <0,001). During night LF normalized units (n.u.) were found to be higher in all four groups including IR subjects than in the control group (all p < 0,001) and subjects with normal glucose regulation (NGR), with impaired fasting glycemia (IFG) and with impaired glucose tolerance (IGT) were found to have higher LF n.u. than those in the type 2 diabetes mellitus group. The linear regression model demonstrated direct association between LF values and the homeostasis model assessment-index (HOMA-I), in the insulin resistant group (r = 0,715, p <0,0001).ConclusionThe results of our study suggest that insulin resistance might cause global autonomic dysfunction which increases along with worsening glucose metabolic impairment. The analysis of sympathetic and parasympathetic components and the sympathovagal balance demonstrated an association between insulin resistance and sympathetic over-activity, especially during night. The results indicated that the sympathetic over-activity is directly correlated to the grade of insulin resistance calculated according to the HOMA-I. Since increased sympathetic activity is related to major cardiovascular accidents, early diagnosis of all insulin resistant patients should be contemplated.