Gut microbiota alterations in adult individuals with obesity and insulin resistance: Its association with metabolic parameters and body compositions

Insulin resistance may contribute to the pathogenesis of hypertension and progressive chronic kidney disease (CKD), however, few clinical studies have explored the role of insulin resistance in predicting the deterioration of renal function in CKD patients. Enrolled in the study were non-diabetic hypertensive patients with CKD Stage 3. Insulin resistance was assessed by a homeostasis model assessment of insulin resistance (HOMA-R) measured at the entry to the study. Patients were followed for 3 years and comparisons of renal and metabolic parameters were made in conjunction with HOMA-R between entry and the end of the study period. The insulin-resistant (IR) group was defined as patients with HOMA-R 2.0 and more, and the insulin-sensitive (IS) group as those with HOMA-R < 2.0. Blood pressure in both groups was equally controlled below 130/80 mmHg throughout the observation period. The degree of insulin resistance HOMA-R and immunoreactive insulin (IRI) remained unchanged in the IS group, however, both were ameliorated in the IR group (HOMA-R, from 3.4 +/- 1.5 - 3.0 +/- 1.1, p = 0.022 and IRI, from 14.4 +/- 6.1 microU/ml - 12.6 +/- 6.8 microU/ml, p = 0.012). Creatinine clearance (CCr) and estimated glomerular filtration rate (e-GFR) decreased and serum creatinine (Cr) concentration increased in all patients. The decline in CCr calculated as the slope of the reciprocal of serum Cr concentration (1/Cr) was greater in the IR group (0.007 +/- 0.004 (1/Cr/dl/mg/month) than in the IS group (0.003 +/- 0.002 (1/Cr/dl/mg/month), p < 0.001). Linear regression analysis showed that the slope of 1/Cr was negatively correlated with HOMA-R, IRI, BMI, respectively. Furthermore, stepwise regression analysis showed that the independent variables to explain the decline in renal function were HOMA-R and IRI. Insulin resistance is a significant risk factor for the deterioration of renal function in hypertensive non-diabetic patients with CKD.

PurposeThere is an increasing understanding that adipose tissue not only serves as an energy storage depot but also acts as a powerful endocrine organ. Various studies have shown that important...

Acute hyperinsulinemia reduces plasma leptin levels in insulin-sensitive Japanese men

Introduction: Weight loss is attenuated in individuals with insulin resistance (IR) who follow a traditional high-carbohydrate, calorie-restricted diet. However, the type of carbohydrate may modulate this response. We studied the effects of whole grains vs. refined grains on weight loss in individuals with increased waist circumference (M: &gt;102 cm, F: &gt;88 cm) and at least 1 other metabolic syndrome characteristic. Hypothesis: In a secondary analysis, we hypothesized that IR individuals (estimated by a triglyceride:high-density lipoprotein cholesterol ratio &gt; 3.5) would lose more weight on a hypocaloric diet with whole grains vs. refined grains. Methods: Overweight or obese (BMI 25–42 kg/m2) men and women (n=50) 35–55 yrs were randomized to a controlled-feeding diet with whole vs. refined grains for 12 weeks [6 weeks isocaloric then 6 weeks hypocaloric (∼500 kcal/d)]. Results: [All comparisons represented as IR mean±SEM vs. insulin sensitive (IS) mean±SEM, p-value)]. Compared to the IS group (n=29), the IR group (n=21) was predominately male (14 M/7 F vs. 11M/18F, p=0.04), weighed more (107.5±3.3 vs. 93.9±3.0 kg, p=0.005), and had increased waist circumference (113±2.2 vs. 106±1.5 cm, p=0.02). IR status did not affect overall percent body weight (%BW) lost over the course of the study (−4.0±0.4 vs. −4.5±0.3 %BW; p for interaction, time x IR status = 0.34). However, IR status did affect %BW lost when the type of carbohydrate was considered (p for interaction, time x IR status x diet = 0.04; Figure ). Post-hoc analysis revealed that within the refined grain group, IR participants lost less %BW than the IS participants (−4.14±0.4 vs. −5.84±0.5 %BW, adjusted p=0.04). On the whole grains diet, %BW lost was similar in the IS and IR groups. Conclusion: In conclusion, IR individuals lost less %BW than IS individuals on the hypocaloric refined grain diet. Limiting refined grains may improve the efficacy of traditional weight loss diets in IR individuals. Figure. %BW lost in IR and IS groups on refined grain diet, *p=0.04.

β2-Adrenoceptor Polymorphisms Relate to Insulin Resistance and Sympathetic Overactivity as Early Markers of Metabolic Disease in Nonobese, Normotensive Individuals

Mitochondrial dysfunction plays a role in the development of muscle insulin resistance (IR) and the accumulation of intramyocellular lipid (IMCL) in skeletal muscle that can, in turn, interfere with insulin signaling. The purpose of this study was to assess mitochondrial function (MF) and IMCL in obese adolescent girls with and without IR to determine whether: (1) Girls with IR have impaired MF, and (2) impaired MF in girls with IR is related to higher IMCL. We examined 22 obese girls aged 13-21 years old for IR [defined as a homeostasis model assessment of insulin resistance (HOMA-IR) value >4. Phosphorus magnetic resonance spectroscopy (31P-MRS) and proton magnetic resonance spectroscopy (1H-MRS), respectively, were used to determine MF and IMCL of the soleus muscle along with magnetic resonance imaging (MRI) measures of visceral, subcutaneous, and total adipose tissue (VAT, SAT, and TAT) in girls with HOMA-IR >4 (insulin-resistant group) versus HOMA-IR ≤ 4 (insulin-sensitive group). Serum lipids and waist-to-hip ratio (W/H) were also measured. Girls with IR (n=8) did not differ from the insulin-sensitive group (n=14) for age, bone age, weight, VAT, SAT, TAT, or IMCL. However, the insulin-resistant group had higher W/H. Additionally the insulin-resistance group had a lower log rate of postexercise phosphocreatine (PCr) recovery (ViPCr) and a higher log PCr recovery constant (tau), indicative of impaired MF. Obese girls with increased IR have impaired mitochondrial function. This association is not mediated by alterations in IMCL or adipose tissue. Further studies are necessary to determine whether there is a causal relation between impaired mitochondrial function and IR in obesity and mediators of such a relationship.

Insulin increases limb blood flow in a time- and dose-dependent manner. This effect can be blocked by inhibiting nitric oxide synthesis. These data raise the possibility that insulin resistance is associated with endothelial dysfunction. To examine whether endothelial function and insulin sensitivity are interrelated we quantitated in vivo insulin-stimulated rates of whole body and forearm glucose uptake at a physiological insulin concentration (euglycaemic hyperinsulinaemic clamp, 1 mU.kg-1.min-1 insulin infusion for 2 h) and on another occasion, in vivo endothelial function (blood flow response to intrabrachial infusions of sodium nitroprusside, acetylcholine, and N-monomethyl-L-arginine) in 30 normal male subjects. Subjects were divided into an insulin-resistant (IR) and an insulin-sensitive (IS) group based on the median rate of whole body glucose uptake (31 +/- 2 vs 48 +/- 1 mumol.kg-1.min-1, p < 0.001). The IR and IS groups were matched for age, but the IR group had a slightly higher body mass index, percentage of body fat and blood pressure compared to the IS group. The IR group also had diminished insulin-stimulated glucose extraction (p < 0.05) compared to the IS group, while basal and insulin-stimulated forearm blood flow rates were identical. There was no difference between the IR and IS groups in the forearm blood flow response to endothelium-dependent (acetylcholine and N-monomethyl-L-arginine) or -independent (sodium nitroprusside) vasoactive drugs. In conclusion, the ability of insulin to stimulate glucose uptake at physiological insulin concentrations and endothelium-dependent vasodilatation are distinct phenomena and do not necessarily coexist.

Metabolism is sex-different, and the direct link between gut microbiota and aging-associated metabolic changes needs to be established in both sexes. Gene expression, metabolic and inflammatory signaling, gut microbiota profile, and metabolome were studied during aging and after fecal microbiota transplantation (FMT) in mice of both sexes. Our data revealed young female mice and aged male mice were the most insulin sensitive and resistant group, respectively. In addition, aging reduced sex difference in insulin sensitivity. Such age- and sex-dependent metabolic phenotypes were accompanied by shifted gut microbiota profile and altered abundance of bacterial genes that produce butyrate, propionate, and bile acids. After receiving feces from the aged males (AFMT), the most insulin-resistant group, recipients of both sexes had increased hepatic inflammation and serum endotoxin. However, AFMT only increased insulin resistance in female mice and abolished sex difference in insulin sensitivity. Additionally, such changes were accompanied by narrowed sex difference in metabolome. Metabolomics data revealed that age-associated insulin resistance in males was accompanied by increased sugar alcohols and dicarboxylic acids as well as reduced aromatic and branched-chain amino acids. Further, receiving feces from the young females (YFMT), the most insulin-sensitive group, reduced body weight and fasting blood glucose in male recipients and improved insulin sensitivity in females, leading to enhanced sex differences in insulin sensitivity and metabolome. Aging systemically affected inflammatory and metabolic signaling based on the sex. Gut microbiome is age and sex-specific, which affects inflammation and metabolism in a sex-dependent manner.

Characterization of Circulating miRNAs in Insulin Sensitive and Insulin Resistant Arab Individuals in Qatar

Impact of insulin resistance and obesity on elevated blood pressure in Chinese children and adolescents: The BCAMS study

Insulin resistance increases circulating malondialdehyde-modified LDL and impairs endothelial function in healthy young men

Objective: To investigate the relationship between serum secreted frizzled-related protein 5(sfrp5) levels, insulin resistance, and airway inflammation in patients with chronic obstructive pulmonary disease(COPD). Method: A total of 178 COPD patients visiting our respiratory outpatient clinic from February 2015 to January 2017 were enrolled, and 99 healthy control subjects from the same time period were selected. Serum sfrp5 levels were compared between the 2 groups. Serum sfrp5 and inflammatory cytokines in induced sputum were observed in the 4 subgroups: insulin resistant COPD group [homeostasis model assessment of insulin resistance (HOMA-IR)≥2.29], non-insulin resistant COPD group, non-COPD insulin resistant group, and healthy control group. Results: Serum sfrp5 levels were found to be significantly higher in the COPD group as compared to the healthy control group (t=-14.29, P<0.001). Serum sfrp5 levels in the insulin resistant COPD group [(8±3)ng/ml] were significantly lower than that of the non-insulin resistant COPD group [(10±5)ng/ml], non-COPD insulin resistant group [(13±3)ng/ml], and normal control group [(14±4)ng/ml, F=35.85, P<0.01]. The insulin resistant COPD group had higher levels of In(Homa-IR), as well as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in induced sputum as compared to the non-insulin resistant COPD group, non-COPD insulin resistant group, and healthy control group (F values were 64.968, 41.40, 64.15, respectively, P value <0.01 for all items). The non-insulin resistant COPD group had higher levels of In(HOMA-IR) as well as TNF-α and IL-6 in induced sputum as compared to the non-COPD insulin resistant group and healthy control group. FEV(1)/FVC and FEV(1)% predicted were significantly lower in the insulin resistant COPD group as compared to those of non-insulin resistant COPD group and non-COPD insulin resistant group, and healthy control group (F values were 2.481 and 8.37, respectively, P value<0.05 for all items). FEV(1)/FVC and FEV(1)% predicted were significantly lower in the non-insulin resistant COPD group as compared to those of the healthy control group and non-COPD insulin-resistant group. Serum sfrp5 levels were positively correlated to FEV(1)/FVC and FEV(1) predicted (r values were 0.466 and 0.412, respectively; P values were <0.001 and 0.007, respectively) and inversely correlated to In(HOMA-IR) and TNF-α and IL-6 in induced sputum (r values were -0.304, -0.459, -0.517, respectively; P values were <0.001, 0.002, <0.001, respectively). BMI, ln(HOMA-IR), and IL-6 in induced sputum were independent related factors (r(2) values were 0.286, 0.176, 14.69, respectively; P values were <0.01 for all items) Conclusion: Sfrp5 may be concurrently associated with COPD and insulin resistance; insulin resistance may be associated with airway inflammation and airflow limitation. Sfrp5 may be involved in the development of COPD and may be the key link by which insulin resistance exerts its effects on airway inflammation.

Mutations in the peroxisome proliferator-activated receptor-gamma 2 (PPAR-gamma 2) gene may cause obesity and insulin resistance. Therefore we investigated whether known variants in the PPAR-gamma 2 gene are associated with obesity and extreme insulin resistance in obese patients with impaired glucose tolerance (IGT). The Pro115 Gln, Pro12Ala, Pro467Leu, Val290Met and a silent polymorphism C478 T were examined in 48 subjects with IGT and insulin resistance (IR), characterized by euglycemic hyperinsulinemic clamps, and in 52 healthy insulin sensitive (IS) controls. We found one proband in the IR group with the Pro115 Gln variant. This subject showed a lower whole body glucose uptake (18 micromol/kg per min) compared to the entire IR group (29 micromol/kg per min). The body weight of the proband (BMI 28.5 kg/m2) was within the average of the IR group (30.3 +/- 0.8 kg/m2). The Pro12Ala variant was not associated with differences in BMI, in the degree of insulin resistance between the IR and IS group. The Pro467Leu, Val290Met mutations and the silent polymorphism CAC478CAT were not detected in any group. In conclusion, the Pro115 Gln variant, but not the Pro12Ala mutation in the PPAR-gamma 2 gene, could be a rare cause of severe insulin resistance.

Most of what is known about the metabolically healthy obese phenomenon is derived from studies in the adult population and no standardized criteria to identify these individuals exist to date. The aim of this study was to determine if the preserved insulin sensitivity evaluated by homeostatic model assessment of insulin resistance (HOMA-IR) index is associated with favorable metabolic profile in the obese children. We studied a group of 248 children and adolescents (150 female, 98 male), aged 5.9-18.9years with diet-induced obesity (BMI >95th percentile). The entire cohort was divided into quartiles based on levels of insulin resistance determined by HOMA-IR index. Subjects in the lower quartile of HOMA-IR were classified as insulin-sensitive group (ISG), whereas children in the upper quartile were categorized as insulin-resistant group (IRG). The ISG subjects had values of HOMA-IR ≤2.75 while the children from the IRG group had HOMA-IR ≥6.16. Subjects from ISG group had lower basal β-cell activity and were less likely to have impaired fasting glucose or impaired glucose tolerance. Concentrations of LDL and total cholesterol, triglycerides, and transaminases were lower and HDL cholesterol levels were higher in ISG subjects. Findings obtained by the use of Matsuda index correlated well with the findings obtained by the use of HOMA-IR. Lower HOMA-IR values were significantly associated with favorable metabolic profile in studied children, which correlates with findings in the adult population and emphasizes the need for further, longitudinal studies of insulin resistance development in childhood obesity.

Ghrelin, an orexigenic hormone that may play a role in body weight regulation, is reduced in states of obesity. Because obesity is associated with insulin resistance and compensatory hyperinsulinemia, we determined whether these metabolic characteristics were independently associated with suppressed ghrelin concentrations. To investigate this hypothesis, using steady-state plasma glucose concentrations, we identified 20 insulin-resistant (IR) and 20 insulin-sensitive (IS) individuals who were equally obese. The mean body mass indexes were 32.5 +/- 0.4 and 32.0 +/- 0.4 kg/m(2) for the IR and IS groups, respectively. Fasting insulin concentrations were 19.5 and 7.4 micro U/ml (P < 0.001), respectively. Ghrelin concentrations were suppressed in the IR group (252 +/- 19 pg/ml) relative to the IS group (412 +/- 35 pg/ml; P < 0.001). Ghrelin correlated inversely with both insulin resistance (r = -0.64; P < 0.001) and fasting insulin concentration (r = -0.58; P < 0.001). Multivariate analysis confirmed that both insulin resistance and hyperinsulinemia independently predicted low ghrelin concentrations. Our results demonstrate that in obese individuals, insulin resistance and hyperinsulinemia are inversely associated with ghrelin concentrations. Thus, insulin resistance or related metabolic abnormalities may constitute part of a feedback mechanism by which body weight is regulated in humans.