Insulin Resistance In Non-obese Research Articles

Distinct Effects of Carrageenan and High-Fat Consumption on the Mechanisms of Insulin Resistance in Nonobese and Obese Models of Type 2 Diabetes.

Exposure to low concentration of the common food additive carrageenan (10 mg/L) for only six days led to glucose intolerance and insulin resistance in the C57BL/6J mouse. Longer exposure produced fasting hyperglycemia but with no increase in weight, in contrast to the HFD. Glucose intolerance was attributable to carrageenan-induced inflammation and to increased expression of GRB10. Both HFD and carrageenan increased p(Ser32)-IκBα and p(Ser307)-IRS1, and the increases were greater following the combined exposure. The effects of carrageenan were inhibited by the combination of the free radical inhibitor Tempol and BCL10 siRNA, which had no impact on the HFD-mediated increase. In contrast, the PKC inhibitor sotrastaurin blocked the HFD-induced increases, without an effect on the carrageenan-mediated effects. HFD had no impact on the expression of GRB10. Both carrageenan and high fat increased hepatic infiltration by F4/80-positive macrophages. Serum galectin-3 and galectin-3 binding to the insulin receptor increased by carrageenan and by HFD. Tyrosine phosphorylation of the insulin receptor declined following either exposure and was further reduced by their combination. Carrageenan reduced the activity of the enzyme N-acetylgalactosamine-4-sulfatase (ARSB; arylsulfatase B), which was unchanged following HFD. Dietary exposure to both high fat and carrageenan can impair insulin signaling through both similar and distinct mechanisms.

Voluntary exercise opposes insulin resistance of skeletal muscle glucose transport during liquid fructose ingestion in rats.

We have recently reported that male rats given liquid fructose ingestion exhibit features of cardiometabolic abnormalities including non-obese insulin resistance with impaired insulin signaling transduction in skeletal muscle (Rattanavichit Y et al. Am J Physiol Regul Integr Comp Physiol 311: R1200-R1212, 2016). While exercise can attenuate obesity-related risks of cardiometabolic syndrome, the effectiveness and potential mechanism by which exercise modulates non-obese insulin resistance have not been fully studied. The present investigation evaluated whether regular exercise by voluntary wheel running (VWR) can reduce cardiometabolic risks induced by fructose ingestion. Moreover, the potential cellular adaptations following VWR on key signaling proteins known to influence insulin-induced glucose transport in skeletal muscle of fructose-ingested rats were investigated. Male Sprague-Dawley rats were given either water or liquid fructose (10% wt/vol) without or with access to running wheel for 6weeks. We demonstrated that VWR restored insulin-stimulated glucose transport in the soleus muscle by improving the functionality of several signaling proteins, including insulin-stimulated IRβ Tyr1158/Tyr1162/Tyr1163 (82%), IRS-1 Tyr989 (112%), Akt Ser473 (56%), AS160 Thr642 (76%), and AS160 Ser588 (82%). These effects were accompanied by lower insulin-stimulated phosphorylation of IRS-1 Ser307 (37%) and JNK Thr183/Tyr185 (49%), without significant changes in expression of proteins in the renin-angiotensin system. Intriguingly, multiple cardiometabolic abnormalities were not observed in fructose-ingested rats with access to VWR. Collectively, this study demonstrates that the development of cardiometabolic abnormalities as well as insulin resistance of skeletal muscle and defective signaling molecules in rats induced by fructose ingestion could be opposed by VWR.

Angiotensin II induces differential insulin action in rat skeletal muscle.

Angiotensin II (ANGII) is reportedly involved in the development of skeletal muscle insulin resistance. The present investigation evaluated the effects of two ANGII doses on the phenotypic characteristics of insulin resistance syndrome and insulin action and signaling in rat skeletal muscle. Male Sprague-Dawley rats were infused with either saline (SHAM) or ANGII at a commonly used pressor dose (100 ng/kg/min; ANGII-100) or a higher pressor dose (500 ng/kg/min; ANGII-500) via osmotic minipumps for 14 days. We demonstrated that ANGII-100-infused rats exhibited the phenotypic features of non-obese insulin resistance syndrome, including hypertension, impaired glucose tolerance and insulin resistance of glucose uptake in the soleus muscle, whereas ANGII-500-treated rats exhibited diabetes-like symptoms, such as post-prandial hyperglycemia, impaired insulin secretion and hypertriglyceridemia. At the cellular level, insulin-stimulated glucose uptake in the soleus muscle of the ANGII-100 group was 33% lower (P < 0.05) than that in the SHAM group and was associated with increased insulin-stimulated IRS-1 Ser307 and decreased Akt Ser473 and AS160 Thr642 phosphorylation and GLUT-4 expression. However, ANGII-500 infusion did not induce skeletal muscle insulin resistance or impair insulin signaling elements as initially anticipated. Moreover, we found that insulin-stimulated glucose uptake in the ANGII-500 group was accompanied by the enhanced expression of ACE2 and MasR proteins, which are the key elements in the non-classical pathway of the renin-angiotensin system. Collectively, this study demonstrates for the first time that chronic infusion with these two pressor doses of ANGII induced differential metabolic responses at both the systemic and skeletal muscle levels.

High-fructose and high-fat feeding correspondingly lead to the development of lysoPC-associated apoptotic cardiomyopathy and adrenergic signaling-related cardiac hypertrophy

BackgroundThe heart is a highly adaptive organ that demonstrates remarkable structural, functional, and metabolic remodeling in response to physiological and pathological stimuli. We hypothesize that the heart undergoes differential adaptations in high-fat and high-fructose diet, resulting in a distinct phenotype. MethodsHigh-fat and high-fructose diet-induced obese and non-obese insulin resistance (IR) rat models were used to understand how the heart adapts to long-term (12-week) overnutrition. ResultsRats fed the high-fat diet developed obese IR, whereas high-fructose diet developed non-obese IR. Obese IR rats developed fibrotic hypertrophy with impairment of preload-independent contractility. The sympathetic and renin–angiotensin–aldosterone (RAA) systems and myocardial adrenergic signaling were activated in obese IR rats. Non-obese IR rats developed apoptotic cardiomyopathy with severe systolic dysfunction. Myocardial calcium cycling regulatory proteins (CCRPs) were dysregulated in non-obese IR rats; specifically, troponin I protein expression was downregulated. Moreover, compared with the controls, lipidomics analysis revealed substantial differences in lipid metabolites in non-obese IR and obese IR rats. The overproduction of lysophosphatidylcholine (lysoPC) and fatty acids was observed in non-obese IR rat hearts. A strong correlation was observed between the myocardial lysoPC and plasma troponin I levels. Treatment of cardiomyocytes with lysoPC resulted in cell death in a dose- and time-dependent manner. The overproduction of myocardial lysoPCs was associated with circulating sPLA2 levels. ConclusionObese IR rats developed severe fibrotic hypertrophy with the activation of adrenergic signaling and sympathetic and RAA systems. The sPLA2–lysoPC may play a crucial role in the induction of apoptotic cardiomyopathy in high fructose-induced non-obese IR rats.

Asymmetric dimethylarginine (ADMA) elevation and arginase up-regulation contribute to endothelial dysfunction related to insulin resistance in rats and morbidly obese humans.

The presence of insulin resistance (IR) is determinant for endothelial dysfunction associated with obesity. Although recent studies have implicated the involvement of mitochondrial superoxide and inflammation in the defective nitric oxide (NO)-mediated responses and subsequent endothelial dysfunction in IR, other mechanisms could compromise this pathway. In the present study, we assessed the role of asymmetric dimethylarginine (ADMA) and arginase with respect to IR-induced impairment of endothelium-dependent vasodilatation in human morbid obesity and in a non-obese rat model of IR. We show that both increased ADMA and up-regulated arginase are determinant factors in the alteration of the l-arginine/NO pathway associated with IR in both models and also that acute treatment of arteries with arginase inhibitor or with l-arginine significantly alleviate endothelial dysfunction. These results help to expand our knowledge regarding the mechanisms of endothelial dysfunction that are related to obesity and IR and establish potential therapeutic targets for intervention. Insulin resistance (IR) is determinant for endothelial dysfunction in human obesity. Although we have previously reported the involvement of mitochondrial superoxide and inflammation, other mechanisms could compromise NO-mediated responses in IR. We evaluated the role of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) and arginase with respect to IR-induced impairment of l-arginine/NO-mediated vasodilatation in human morbid obesity and in a non-obese rat model of IR. Bradykinin-induced vasodilatation was evaluated in microarteries derived from insulin-resistant morbidly obese (IR-MO) and non-insulin-resistant MO (NIR-MO) subjects. Defective endothelial vasodilatation in IR-MO was improved by l-arginine supplementation. Increased levels of ADMA were detected in serum and adipose tissue from IR-MO. Serum ADMA positively correlated with IR score and negatively with pD2 for bradykinin. Gene expression determination by RT-PCR revealed not only the decreased expression of ADMA degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH)1/2 in IR-MO microarteries, but also increased expression of arginase-2. Arginase inhibition improved endothelial vasodilatation in IR-MO. Analysis of endothelial vasodilatation in a non-obese IR model (fructose-fed rat) confirmed an elevation of circulating and aortic ADMA concentrations, as well as reduced DDAH aortic content and increased aortic arginase activity in IR. Improvement of endothelial vasodilatation in IR rats by l-arginine supplementation and arginase inhibition provided functional corroboration. These results demonstrate that increased ADMA and up-regulated arginase contribute to endothelial dysfunction as determined by the presence of IR in human obesity, most probably by compromising arginine availability. The results provide novel insights regarding the mechanisms of endothelial dysfunction related to obesity and IR and establish potential therapeutic targets for intervention.

Lipidomics Reveals Associations of Phospholipids With Obesity and Insulin Resistance in Young Adults.

Obesity and related diseases have become a global public health burden. Identifying biomarkers will lead to a better understanding of the underlying mechanisms associated with obesity and the pathways leading to insulin resistance (IR) and diabetes. This study aimed to identify the lipidomic biomarkers associated with obesity and IR using plasma samples from a population-based cohort of young adults. The Western Australian Pregnancy Cohort (Raine) study enrolled 2900 pregnant women from 1989 to 1991. The 20-year follow-up was conducted between March 2010 and April 2012. Participants and Samples: Plasma samples from 1176 subjects aged 20 years were analyzed using mass spectrometry-based metabolomics. Associations of analytes with markers of obesity and IR including body mass index, waist circumference, homeostasis model assessment (HOMA-IR), and insulin were examined. Analyses were stratified by body mass index and adjusted for lifestyle and other factors. Waist circumference was positively associated with seven sphingomyelins and five diacylphosphatidylcholines and negatively associated with two lysophosphatidylcholines. HOMA-IR was negatively associated with two diacylphosphatidylcholines and positively with one lysophosphatidylcholine and one diacylphosphatidylcholine. No significant association was found in the obese/overweight group of the HOMA-IR model. In the normal-weight group, one lysophosphatidylcholine was increased. A possible discriminative effect of sphingomyelins, particularly those with two double bonds, and lysophosphatidylcholines was identified between subjects with normal weight and obesity independent of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol concentrations. Our results suggest weight status-dependent mechanisms for the development of IR with lysophosphatidylcholine C14:0 as a key metabolite in nonobese IR.

Circadian-clock system in mouse liver affected by insulin resistance

Circadian rhythms are exhibited in the physiological and behavioral processes of all mammals; they are generated by intracellular levels of circadian oscillators, which are named as a set of circadian-clock genes. These genes compose the transcriptional/translational feedback loops to regulate not only circadian rhythmicity, but also energy metabolism. Previous studies have shown that obesity and diabetes cause the dysregulation of the circadian-clock system, and vice versa. However, some diabetes subjects are lean with insulin resistance and the mechanisms of insulin resistance without obesity are much less well known. Therefore, whether insulin resistance alone is enough to influence the expression of circadian-clock genes is uncertain. This study employs a neonatal streptozotocin (STZ)-treated paradigm in mice to model the molecular and physiological progress of nonobese insulin resistance. A single injection of STZ into 2-d-old male C57BL/6 mice induces nonobese, hyperglycemic and hyperinsulinemic conditions, and the levels of gene expression in the liver by a real-time quantitative polymerase chain reaction are then measured. Although the levels of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2), and Cry1 (cryptochrome 1) mRNA expression in the liver change during the progress of insulin resistance conditions, the gene expression patterns still show circadian rhythmicity. This study suggests that changes in the hepatic circadian-clock gene expression mark an early event in the metabolic disruption associated with insulin resistance. Furthermore, 2 wks of treatment with the thiazolidinedione, pioglitazone, fully resolve the dysfunction in metabolic parameters and the changes in circadian-clock gene expression from early insulin resistance conditions. These results indicate that the circadian-clock system is sensitive to insulin resistance, and that treatment with thiazolidinediones can resolve changes in the circadian-clock system in a timely manner. Thus, strengthening the peripheral circadian-clock system may counteract the adverse physiological consequences in the metabolic syndrome.

ISP27: Omega 3 PUFA chain length: a key factor of their efficiency on cardiovascular risk factors in experimental metabolic syndrome

Background and aims The impact of dietary n-3 polyunsaturated fatty acids (PUFA), on cardiometabolic risk prevention was evaluated according to chain length, in two rat models of non-obese insulin resistance and hypertension. Materials and Methods Fructose-fed rat was used as a model of acquired metabolic syndrome (MS) and spontaneously hypertensive rat (SHR) rat as a model of inherited MS. The rats were submitted to a diet containing either no n-3 PUFAs (control) or α-linolenic acid (ALA) as single n-3 PUFA source or a mix of ALA and its two main longer chain metabolites (LC), eicosapentaenoic and docosahexaenoic acids. During the dietary period, glucose and insulin tolerance tests were performed and serum triglycerides concentration was quantified. Arterial blood pressure was evaluated punctually by tail-cuff or continuously by implanted telemetry. After 10 weeks of feeding, the fatty acid (FA) composition of insulin-sensitive tissues was analysed. Results The 2 experimental models developed insulin resistance and hypertension, associated to an alteration of the specific FA pattern in insulin sensitive tissues. Insulin resistance was also associated to a high cardiovascular risk as evaluated by the increase in blood pressure parameters and especially by the increase in pulse pressure in the fructose-fed rats. LC n-3 PUFA significantly affected the development of insulin resistance, impaired glucose tolerance, blood pressure rise and hypertriglyceridemia, in relation with a strong limitation of the FA composition in the insulin sensitive tissue phospholipids. Conversely, ALA alone affected only hypertriglyceridemia. Conclusion Whatever the etiology of insulin resistance, the significant beneficial effects of n-3 PUFAs on the prevention of cardiometabolic risk factors can be attributed to the long chain n-3 PUFAs but not to the precursor.

Pathogenesis of insulin resistance syndrome in Western‐style diets‐induced obese and non‐obese experimental animal models

Western diet induces obesity and consequently leads to insulin resistance, diabetes, and cardiovascular disease (CVD) is threatening to become a global epidemic. Although, more than 70 % of insulin resistance patient is obese, insulin resistance also occurs in non‐obese individuals. Hence, the present study was aimed to characterize the insulin resistance syndrome in obese and non‐obese and further explore its pathogenesis. The animals were fed with different western‐styles diet for 12 week and divided into five groups: (1) chow diet control group, control; (2) high fat diet, HFat; (3) high fructose diet, HFru; (4) high cholesterol diet, HC; (5) high cholesterol diet plus with 10% fructose in drinking water, HCF. The insulin resistance syndrome was observed in both HFat‐obese and HCF‐nonobese rats. The phosphorylated Akt (thr308) protein level was increased in adipose tissues of four western‐styles diets compared to chow diet control. The phosphorylated Akt (Ser473) protein level was increased in the adipose tissues of HFat, whereas it was reduced in the adipose tissues of HC and HCF. The GLUT4 level was downregulated in the adipose tissue of HFat, HC and HCF. The crown‐like structures around adipocytes were observed especially in HC and HCF groups. Up‐regulated NFκB/IκB ratio showed the higher inflammation degree in HFat, HC, and HCF groups. The lower MnSOD and Cu/ZnSOD proteins exhibited a weaker antioxidative ability and resulted raising of in superoxide anion in HC and HCF adipose tissues. The cleaved caspase 3 protein increased implying that adipocytes underwent apoptosis process especially in HC groups. In conclusion, our results indicate the causal relationships between inflammation and insulin resistance in non‐obese insulin resistance.

Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects.

Early reports suggested that resistin is associated with obesity and insulin resistance in rodents. However, subsequent studies have not supported these findings. To our knowledge, the present study is the first assessment in human subjects of serum resistin and insulin sensitivity by the insulin clamp technique. Thirty-eight nonobese subjects [age, 23 +/- 4 yr; body mass index (BMI), 25.4 +/- 4.3 kg/m(2)], 12 obese subjects (age, 54 +/- 8 yr; BMI, 33.0 +/- 2.5 kg/m(2)), and 22 obese subjects with type 2 diabetes (age, 59 +/- 7 yr; BMI, 34.0 +/- 2.4 kg/m(2)) were studied. Serum resistin concentrations were not different among nonobese (4.1 +/- 1.7 ng/ml), obese (4.2 +/- 1.6 ng/ml), and obese diabetic subjects (3.7 +/- 1.2 ng/ml), and were not significantly correlated to glucose disposal rate during a hyperinsulinemic glucose clamp across groups. Serum resistin was, however, inversely related to insulin sensitivity in nonobese subjects only (r = -0.35; P = 0.05), although this association was lost after adjusting for percent body fat. Serum resistin was not related to percent fat, BMI, or fat cell size. A strong correlation was observed between serum resistin and resistin mRNA expression from abdominal sc adipose tissue in a separate group of obese subjects (r = 0.62; P < 0.01; n = 56). Although the exact function of resistin is unknown, we demonstrated only a weak relationship between resistin and insulin sensitivity in nonobese subjects, indicating that resistin is unlikely to be a major link between obesity and insulin resistance in humans.