Situations Of Insulin Resistance Research Articles

Mutltifaceted biological roles of adiponectin

Adiponectin is a major adipokine involved in energy homeostasis that exerts insulin-sensitizing properties. The level of adiponectin is reduced in situations of insulin resistance and is negatively associated with several pathophysiological situations including abdominal obesity, metabolic syndrome, steatosis and non-alcoholic steatohepatitis, type 2 diabetes, some cancers and cognitive diseases. These aspects are discussed in this review.

Metformin attenuates the TLR4 inflammatory pathway in skeletal muscle of diabetic rats.

Inflammation induced by hyperglycemia triggers the toll-like receptor (TLR) pathway into cells. Our hypothesis was that metformin treatment attenuates the TLR signaling pathways triggered by inflammation in skeletal muscle of hypoinsulinemic/hyperglycemic STZ-induced rats. Thus, we examined TLR signaling under hypoinsulinemia and hyperglycemia conditions and its correlation with insulin resistance in muscle of diabetic rats treated with metformin. Ten-day diabetic rats were submitted to 7days of saline (D group) or metformin (500mg/kg once per day) (D+M group). The skeletal muscle was collected before the insulin tolerance test. Then, Western blotting analysis of skeletal muscle supernatant was probed with TLR4, TLR2, NF-κB, IκB, p-AMPK and p-JNK. TNF-α and CXCL1/KC content was analyzed by ELISA. Metformin treatment increased whole-body insulin sensitivity. This regulation was accompanied by a parallel change of p-AMPK and by an inverse regulation of TLR4 and NF-κB contents in the soleus muscle (r=0.7229, r=-0.8344 and r=-0.7289, respectively, Pearson correlation; p<0.05). Metformin treatment increased IκB content when compared to D rats. In addition, metformin treatment decreased p-JNK independently of TLR2 signal in diabetic rats. In summary, the results indicate a relationship between muscular TLR4, p-AMPK and NF-κB content and insulin sensitivity. The study also highlights that in situations of insulin resistance, such as in diabetic subjects, metformin treatment may prevent attenuation of activation of the inflammatory pathway.

C1qTNF-related protein 1 improve insulin resistance by reducing phosphorylation of serine 1101 in insulin receptor substrate 1.

C1qTNF-related protein 1 (CTRP1) is independently associated with type 2 diabetes. However, the relationship between CTRP1 and insulin resistance is still not established. This study aimed to explore the role of CTRP1 under the situation of insulin resistance in adipose tissue. Plasma CTRP1 level was investigated in type 2 diabetic subjects (n = 35) and non-diabetic subjects (n = 35). The relationship between CTRP1 and phosphorylation of multi insulin receptor substrate 1 (IRS-1) serine (Ser) sites was further explored. Our data showed that Plasma CTRP1 was higher and negative correlation with insulin resistance in diabetic subjects (r = -0.283, p = 0.018). Glucose utilisation test revealed that the glucose utilisation rate of mature adipocytes was improved by CTRP1 in the presence of insulin. CTRP1 was not only related to IRS-1 protein, but also negatively correlated with IRS-1 Ser1101 phosphorylation (r = -0.398, p = 0.031). Furthermore, Phosphorylation levels of IRS-1 Ser1101 were significantly lower after incubation with 40 ng/mL CTRP1 in mature adipocytes than those with no intervention (p < 0.05). There was no significant correlation between CTRP1 and other IRS-1 serine sites (Ser302, Ser307, Ser612, Ser636/639, and Ser789). Collectively, our results suggested that CTRP1 might improve insulin resistance by reducing the phosphorylation of IRS-1 Ser1101, induced in the situation of insulin resistance as a feedback adipokine.

Recovery of insulin sensitivity and Slc2a4 mRNA expression depend on T3 hormone during refeeding

ObjectiveGLUT4 protein, encoded by the Slc2a4 gene, plays a key role in muscle glucose uptake, and its expression decreases in muscles under insulin resistance. Slc2a4/GLUT4 decreases with fasting and rapidly increases with refeeding and the same occurs to plasma glucose, amino acids, insulin and T3. Thus, they might be potential regulators of the Slc2a4 gene, which makes them promising targets for strategies to improve GLUT4 expression. Herein, we investigate the role of metabolic–hormonal parameters triggered by refeeding upon the Slc2a4 expression. Materials/MethodsPlasma glucose/insulin/T3, and gastrocnemius Slc2a4 mRNA contents were measured in rats studied at the end of 48-h fasting, and subsequently at: i) 2–4h after spontaneous refeeding; ii) 2–4h after T3 injection, without refeeding; and iii) 0.5–2h after intravenous infusion of insulin, insulin+glucose and insulin+amino acids, without refeeding. ResultsRefeeding increased plasma glucose/insulin/T3 and muscle Slc2a4 mRNA, reverting insulin resistance. Post-fasting infusions surprisingly induced a further Slc2a4 mRNA decrease (~20%, P<0.05 vs. fasting), but T3 injection induced a ~2-fold increase in Slc2a4 mRNA, 2–4h later (P<0.001). Moreover, T3 increased glycemia and insulinemia to the 2h-refed rats levels, suggesting that T3 elevation is a key factor to the mechanisms of metabolic balance during refeeding. ConclusionsRefeeding induces a rapid increase in muscle Slc2a4 expression, not associated with increased plasma glucose, insulin or amino acids, but highly correlated to increased plasma T3 concentration. This result points out T3 hormone as a powerful Slc2a4 enhancer, an effect that may be acutely explored in situations of insulin resistance.

Effects of RNA interference targeting angiotensin-converting enzyme on glucose metabolism in type 2 diabetic rats

Objective To investigate the effects of RNA interference (RNAi) targeting angiotensinconverting enzyme (ACE) on blood glucose,insulin resistance,as well as oxidative stress in type 2 diabetic rats.Methods Type 2 diabetic rats were divided into diabetes control group (caudal intravenation with control adenovirus named Ad5),gene treatment group (caudal intravenation with recombinant adenoviral vectors named Ad5-ACE-shRNA,expressing ACE gene-specific shRNA),and enalapril group (intragastric administration with enalapril every day).At the same time,the normal blood glucose control group was set up.All rats were injected two times during the experiment period.Blood glucose was measured before and after the intervention.At the third day of the experiment,expressions of ACE mRNA and protein in pancreas were evaluated by RT-PCR and Western blot,and serum concentrations of ACE and Ang Ⅱ were measured by ELISA.By the end of the experiment,insulin sensitivity index was calculated and expressions of glucose transporter 4 (GLUT4) protein of epididymal adipose tissue and NAD (P) H (p22phox) protein of pancreas were measured.Results Blood glucose levels in the gene treatment group [(17.8 ±1.1) mmol/L] and the enalapril group [(17.9 ± 1.2) mmol/L] were lower than that in the diabetes control group [(24.9 ± 1.3) mmol/L] when the experiment was finished.ACE mRNA and protein expressions in pancreas of the gene treatment group were significantly decreased compared with the diabetes control group (P ＜ 0.05).Serum concentrations of ACE and Ang Ⅱ in the gene treatment group were (16.37 ± 3.01) ng/ml and (18.24 ± 3.69)pg/ml,significantly lower than those of the diabetes control group [(46.67 ± 3.92) ng/ml and (44.93 ± 4.12) pg/ml respectively,both P＜0.05].Insulin sensitivity indexes of the gene treatment group and the enalapril group were (-5.14 ± 0.41) and (-5.17 ± 0.38),being all significantly higher than that of the diabetes control group (-6.18 ±0.46,both P＜0.05).Expressions of GLUT4 protein in epididymal adipose tissue were higher and expressions of p22phox protein in pancreas were lower in the gene treatment group and the enalapril group than those of the diabetes control group (both P＜0.05).Conclusions RNAi targeting ACE gene may delay the progress of hyperglycaemia and improve the situation of insulin resistance and oxidative stress.The RNAi technology may be used as a new strategy of gene therapy for diabetes mellitus. Key words: Angiotensin-converting enzyme; RNA interference; Diabetes mellitus ; Rats

Le lactate, substrat énergétique en réanimation ?

Glucose is an energy substrate because its total oxidation to CO2 and H2O allows the synthesis of adenosine triphosphate (ATP). Glucose is converted to pyruvate and lactate during its metabolism. If not oxidized by the mitochondria to produce ATP, pyruvate and lactate leave the cell. They can then spread to other cells where they are converted into glucose or oxidized in the mitochondria. From a biochemical point of view, pyruvate and lactate are thus carbohydrates perfectly usable for energy metabolism. Compared to glucose, lactate is easily metabolized by all tissues even in situations of insulin resistance. It requires no activation step by ATP and prevents the deleterious effects of hypoglycemia. In addition, sodium lactate is an alkalizing solute with anti-edematous properties. Furthermore, hypertonic sodium lactate solutions have good capacity for intravascular volume expansion. This review attempts to promote lactate and its use in the intensive care unit.

Modulation of Double‐Stranded RNA‐Activated Protein Kinase in Insulin Sensitive Tissues of Obese Humans

The double-stranded RNA-dependent protein kinase (PKR) was recently implicated in regulating molecular integration of nutrient- and pathogen-sensing pathways in obese mice. However, its modulation in human tissues in situations of insulin resistance has not been investigated. The present study was performed to first determine the tissue expression and phosphorylation levels of PKR in the liver, muscle, and adipose tissue in obese humans, and also the modulation of this protein in the adipose tissue of obese patients after bariatric surgery. Eleven obese subjects who were scheduled to undergo Roux-en-Y Gastric Bypass Procedure participated in this study. Nine apparently healthy lean subjects as a control group were also included. Our data show that PKR is activated in liver, muscle, and adipose tissue of obese humans and, after bariatric surgery, there is a clear reduction in PKR activation accompanied by a decrease in protein kinase-like endoplasmic reticulum kinase, c-Jun N-terminal kinase, inhibitor of kappa β kinase, and insulin receptor substrate-1 serine 312 phosphorylation in subcutaneous adipose tissue from these patients. Thus, it is proposed that PKR is an important mediator of obesity-induced insulin resistance and a potential target for the therapy.

Insulin-Resistance-Associated Compensatory Mechanisms of Pancreatic Beta Cells: A Current Opinion

Insulin-Resistance-Associated Compensatory Mechanisms of Pancreatic Beta Cells: A Current Opinion

Metabolomic study of plasma of patients with abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is an important health problem, both because of AAA rupture and death and because of increased cardiovascular mortality. Identification of new biomarkers of AAA may suggest novel pathological mechanisms and targets for new medical treatments to slow AAA progression. Metabolic changes in AAA patients were mainly related to carbohydrate and lipid metabolism and many of these changes can be associated with a situation of insulin resistance (which can be related to metabolic syndrome) together with altered amino acid metabolism. For the first time, metabolites that can be associated with differential metabolism by the gut microflora of AAA patients have also been found. Moreover, aminomalonic acid in plasma has been shown to be the metabolite with the biggest difference between patients suffering from large aneurysm (>5 cm) and controls.

Functions of AMP-activated protein kinase in adipose tissue.

AMP-activated protein kinase (AMPK) is involved in cellular energy homeostasis. Its functions have been extensively studied in muscles and liver. AMPK stimulates pathways which increase energy production (glucose transport, fatty acid oxidation) and switches off pathways which consume energy (lipogenesis, protein synthesis, gluconeogenesis). This has led to the concept that AMPK has an interesting pharmaceutical potential in situations of insulin resistance and it is indeed the target of existing drugs and hormones which improve insulin sensitivity. Adipose tissue is a key player in energy metabolism through the release of substrates and hormones involved in metabolism and insulin sensitivity. Activation of AMPK in adipose tissue can be achieved through situations such as fasting and exercise. Leptin and adiponectin as well as hypoglycaemic drugs are activators of adipose tissue AMPK. This activation probably involves changes in the AMP/ATP ratio and the upstream kinase LKB1. When activated, AMPK limits fatty acid efflux from adipocytes and favours local fatty acid oxidation. Since fatty acids have a key role in insulin resistance, especially in muscles, activating AMPK in adipose tissue might be found to be beneficial in insulin-resistant states, particularly as AMPK activation also reduces cytokine secretion in adipocytes.

Abnormalities in plasma fatty acid composition in human immunodeficiency virus‐infected children treated with protease inhibitors

To study plasma fatty acid composition in human immunodeficiency virus-infected children treated with protease inhibitors and its relation with other components of the metabolic syndrome observed after this therapy. Cross-sectional study from collected clinical database. 17 children with HIV infection treated with protease inhibitors. Nine patients received ritonavir (20-30 mg/kg/d) and the remaining eight received nelfinavir (60-90 mg/kg/d). Duration of protease inhibitors treatment was 711+/-208 d. As controls, we used 112 matched blood samples from apparently healthy children admitted for minor surgical procedures. Plasma fatty acids were determined using a Hewlett Packard GC 5890 gas chromatograph. Plasma levels of cholesterol and triglycerides and insulin-like growth factor 1 (IGF-1) tended to be high in protease inhibitor-treated patients. Plasma content of omega6 long-chain polyunsaturated fatty acids and, in particular, of the highly unsaturated 22ratio4omega6 and 22ratio5omega6, was significantly increased. Also, infected children had increased Delta6 and Delta4 desaturase activities and decreased Delta5 desaturase activity. Significant correlations were present between plasma IGF-1 level and plasma triglycerides, plasminogen activator inhibitor-1 activity and Delta6 desaturase activity. HIV-infected, protease inhibitor-treated children exhibit a metabolic syndrome which is associated with significant changes in plasma fatty acid composition. These changes are similar to those observed in situations of insulin resistance and are linked to variations in plasma IGF-1 concentration.

Inpatient diabetes control: approaches to treatment.

This is the second of two articles on the Consensus Development Conference on Inpatient Diabetes Control, which was sponsored by the American College of Endocrinology and held in Washington, DC, 14–15 December 2003. Derek LeRoith (Bethesda, MD) and Irl Hirsch (Seattle, WA) discussed mechanisms by which metabolic control may improve outcomes. Both speakers reviewed physiological and cellular aspects of normal insulin action and glucose homeostasis and molecular aspects of insulin resistance in relation to situations of stress. Insulin has classic actions such as increased glucose uptake, decreased hepatic glucose production (HGP), and antilipolytic effects in skeletal muscle, liver, and adipose tissue, as well as nonclassical vasodilatory effects, proliferative actions on vascular smooth muscle cells (VSMCs), effects on the brain (perhaps related to learning and memory), β-cell actions, and general effects increasing growth and differentiation and decreasing apoptosis. Insulin levels range from <10 to 30–50 μU/ml in the fasting versus fed state. The liver is exposed to portal vein insulin levels triple that in the periphery, with HGP inhibited at levels of 20–25 μU/ml. Lipolysis increases during fasting and is inhibited at levels of 30–50 μU/ml, so that in the fasting state, free fatty acids (FFAs) are available for fuel. A doubling of insulin levels inhibits HGP by 80% and increases glucose utilization by 20%. The insulin-signaling pathway involves stimulation of cascades of intracellular kinases leading to insulin action. The insulin receptor substrates (IRSs) have metabolic as well as antiapoptotic effects, particularly due to IRS-1 phosphorylation via the phosphatidylinositol-3-hydroxy kinase (PI3K) pathway after activation of the insulin receptor—a process inhibited in situations of insulin resistance. The mitogen-activated protein kinase pathway is involved in gene expression, cell proliferation, and a variety of other anabolic actions. When insulin stimulates glucose uptake, particularly occurring in muscle, which mediates ∼80% of insulin-stimulated glucose uptake, PI3K …

Microarray Profiling of Human Skeletal Muscle Reveals That Insulin Regulates ∼800 Genes during a Hyperinsulinemic Clamp

Insulin action in target tissues involved precise regulation of gene expression. To define the set of insulin-regulated genes in human skeletal muscle, we analyzed the global changes in mRNA levels during a 3-h hyperinsulinemic euglycemic clamp in vastus lateralis muscle of six healthy subjects. Using 29,308 cDNA element microarrays, we found that the mRNA expression of 762 genes, including 353 expressed sequence tags, was significantly modified during insulin infusion. 478 were up-regulated and 284 down-regulated. Most of the genes with known function are novel targets of insulin. They are involved in the transcriptional and translational regulation (29%), intermediary and energy metabolisms (14%), intracellular signaling (12%), and cytoskeleton and vesicle traffic (9%). Other categories consisted of genes coding for receptors, carriers, and transporters (8%), components of the ubiquitin/proteasome pathways (7%) and elements of the immune response (5.5%). These results thus define a transcriptional signature of insulin action in human skeletal muscle. They will help to better define the mechanisms involved in the reduction of insulin effectiveness in pathologies such as type 2 diabetes mellitus, a disease characterized by defective regulation of gene expression in response to insulin.

Regulation of cardiac Jak-2 in animal models of insulin resistance.

Insulin induces phosphorylation and activation of JAK2 tyrosine, as well as its association with STAT1 and SHP2 in insulin-sensitive tissues of intact rats, thus demonstrating a new pathway in transduction of insulin signals. We investigated this pathway in hearts of rats in three situations of insulin resistance: 72 h of fasting, chronic treatment with dexamethasone, and acute treatment with epinephrine. The acute treatment with epinephrine showed no difference in insulin-induced JAK2 tyrosine phosphorylation or JAK2/STAT1 and JAK2/SHP2 association in comparison with the control. In fasted rats the JAK2 protein concentration decreased, accompanied by a decrease in the stoichiometry of the phosphorylation to 70%, an increase in association of JAK2/STAT1 to 160%, and a decrease in JAK2/SHP2 association to 85%. In the dexamethasone-treated group, the JAK2 protein concentrations increased but the stoichiometry of its phosphorylation decreased to 20%, whereas the JAK2/STAT1 and JAK2/SHP2 associations changed by 70% and 170%, respectively. In fasting and dexamethasone-treated rats, therefore, insulin-induced JAK2 tyrosine phosphorylation decreases, and the JAK2 protein expression is differentially regulated such that the insulin-induced JAK2 association with SHP2 and STAT1 shows opposite interactions with the kinase.