scholarly journals Hepatic deletion of p110α and p85α results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1600 ◽  
Author(s):  
Aditi Chaudhari ◽  
Katarina Ejeskär ◽  
Yvonne Wettergren ◽  
C. Ronald Kahn ◽  
Victoria Rotter Sopasakis
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Insulin Signaling ◽  
Kinase Activity ◽  
Tolerance Test ◽  
Metabolic Phenotype ◽  
Insulin Signal ◽  
Phosphatidylinositol Kinase ◽  
Insulin Tolerance

Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis. Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks. Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K. Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.

scholarly journals Hepatic deletion of p110α and p85α results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity

F1000Research ◽  
2018 ◽  
Vol 6 ◽  
pp. 1600
Author(s):  
Aditi Chaudhari ◽  
Katarina Ejeskär ◽  
Yvonne Wettergren ◽  
C. Ronald Kahn ◽  
Victoria Rotter Sopasakis
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Insulin Signaling ◽  
Kinase Activity ◽  
Tolerance Test ◽  
Metabolic Phenotype ◽  
Insulin Signal ◽  
Phosphatidylinositol Kinase ◽  
Insulin Tolerance

Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis. Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks. Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K. Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.

scholarly journals Up-Regulating the Heme Oxygenase System with Hemin Improves Insulin Sensitivity and Glucose Metabolism in Adult Spontaneously Hypertensive Rats

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 549-560 ◽  
Author(s):  
Joseph Fomusi Ndisang ◽  
Nina Lane ◽  
Noor Syed ◽  
Ashok Jadhav
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Essential Hypertension ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Insulin Signaling ◽  
Tolerance Test ◽  
Spontaneously Hypertensive ◽  
Insulin Tolerance

Accumulating clinical evidence indicates that impaired glucose tolerance is a common phenomenon in essential hypertension. Although recent evidence underscores the role of heme-oxygenase (HO) in diabetes, its effects on insulin sensitivity and glucose metabolism in spontaneously hypertensive rat (SHR), a model of essential hypertension with characteristics of metabolic syndrome including insulin resistance/impaired glucose metabolism remains largely unclear. Here we report the effects of the HO inducer, hemin, and the HO blocker, chromium-mesoporphyrin on insulin sensitivity and glucose metabolism in SHRs. Adult SHRs were severely hypertensive but normoglycemic. Hemin therapy lowered blood pressure, increased plasma insulin, decreased glycemia, and enhanced insulin sensitivity by improving glucose tolerance (ip glucose tolerance test) and insulin tolerance (ip insulin tolerance test) but reduced insulin resistance (homeostasis model assessment index). These effects were accompanied by increased gastrocnemius muscle HO-1, HO activity, cGMP, cAMP alongside antioxidants including bilirubin, ferritin, superoxide dismutase, catalase, and the total antioxidant capacity, whereas oxidative/inflammatory mediators like 8-isoprostance, nuclear-factor-κB, activating-protein-1, activating-protein-2, c-Jun-NH2-terminal-kinase, and heme were abated. Furthermore, hemin reduced proteinuria/albuminuria and enhanced the depressed levels of adiponectin, AMP-activated protein-kinase, and glucose transporter-4 in SHRs, suggesting that although SHRs are normoglycemic, insulin signaling and renal function may be impaired. Contrarily, the HO inhibitor chromium-mesoporphyrin exacerbated oxidative stress, aggravated insulin resistance, glucose tolerance, insulin tolerance and nephropathy. Hemin also enhanced HO signaling in Wistar Kyoto and Sprague Dawley rats and increased insulin sensitivity albeit less intensely than in SHRs, suggesting greater selectivity of HO in SHRs with dysfunctional insulin signaling. These results suggest that perturbations of insulin signaling may be a forerunner to hyperglycemia in essential hypertension. By concomitantly potentiating insulin-sensitizing agents, suppressing insulin/glucose intolerance, and abating oxidative stress, HO inducers may prevent metabolic and cardiovascular complications in essential hypertension.

scholarly journals PO-063 Exercise alleviates insulin resistance by regulating MG53 and IR/IRS/AKT/mTOR signaling in db/db mice skeletal muscle

2018 ◽  
Vol 1 (3) ◽  
Author(s):  
Yi Zhang ◽  
Shuzhe Ding ◽  
Yi Sun
Keyword(s):  
Insulin Resistance ◽  
Muscle Atrophy ◽  
Insulin Signaling ◽  
Skeletal Muscles ◽  
Treadmill Exercise ◽  
Tolerance Test ◽  
Exercise Group ◽  
Control Group ◽  
Insulin Tolerance ◽  
Lipid Parameters

Objective In the current study, we aim to investigate whether 12-week treadmill exercise alleviates insulin resistance and muscle atrophy, and to explore whether MG53 along with IR/IRS/AKT/mTOR cascade play a role in the physiopathological changes of db/db mice. Methods 20 db/db mice and 20 age-matched non-diabetic m/m mice were assigned to 4 groups as MC (m/m control) group, ME (m/m exercise) group, DC (db/db control) group and DE (db/db exercise) group. After an intervention of treadmill exercise of moderate intensity for 12 weeks, glucose and insulin tolerance tests, insulin resistance index (HOMA-IR, homeostasis model assessment of insulin resistance) and lipid metabolic profile were determined using blood samples. Skeletal muscles were utilized for determination of cross-sectional area (CSA), protein level detection of MG53 and insulin signaling pathway. Results Compared with MC mice, the AUC (areas under curve) of IPGTT (intraperitoneal glucose tolerance test) and IPITT (intraperitoneal insulin tolerance test) as well as HOMA-IR were significantly increased, and lipid parameters (serum triglyceride and total cholesterol) increased significantly in DC group. The upregulation of MG53 protein in different skeletal muscles (quadriceps, gastrocnemius and soleus muscle) could be observed in DC mice. Phosphorylated proteins of IR-β (β subunit of insulin receptor), IRS1, AKT (protein kinase B), mTOR (mammalian target of rapamycin), p70S6k and S6 ribosomal protein after acute insulin stimulation were downregulated with significance, whereas no significant difference was found in total protein levels of IR-β and AKT except IRS1 in DC group. The results of AUC of IPGTT and IPITT, HOMA-IR and serum lipid parameters in DE group were significantly decreased compared with DC group. 12-week moderate exercise was sufficient to downregulate the expression of MG53 in skeletal muscles of diabetic db/db mice. In addition, treadmill exercise-induced improvement of insulin signal transduction and insulin-dependent protein synthesis may partially account for the heavier muscle mass and larger muscle size. Conclusions In summary, insulin resistance and muscle atrophy of diabetic db/db mice could be effectively attenuated by 12-week moderate treadmill exercise by regulating MG53, MG53-mediated ubiquitin-dependent degradation of IRS1 and insulin signaling transduction.

scholarly journals A fifty percent leucine-restricted diet reduces fat mass and improves glucose regulation

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Ziheng Zhou ◽  
Hanrui Yin ◽  
Yajie Guo ◽  
Yuanyuan Fang ◽  
Feixiang Yuan ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Fat Mass ◽  
Insulin Signaling ◽  
Lipid Synthesis ◽  
Tolerance Test ◽  
Glucose Regulation ◽  
Control Group ◽  
Reduced Fat ◽  
Proper Group

Abstract Background Leucine deprivation modulates the dietary amino acid composition, reducing the fat content and improving the glucose tolerance, thus protecting the organism against obesity. However, a complete deprivation of leucine can lead to an extremely rapid fat loss in mice, accompanied by prolonged adverse effects such as weakness and mental fatigue. Therefore, in this study we aimed to seek the optimal concentration of dietary leucine that can reduce fat mass and improve the metabolism without the onset of severe effects. Methods To investigate whether there is a better concentration of diet leucine restriction (LR), based on the diet we conducted (A10021B), that can reduce fat mass and improve metabolism status without taking many negative effects, we fed 8 weeks old male C57Bl/6J mice with increasing degrees of leucine restriction diet 0% LR (control group), 25% LR, 50% LR, and 75% LR groups (4–6 mice each group). Fat mass and blood glucose levels were measured. The expression levels of genes involved in lipid metabolism in white adipose tissue (WAT) and liver, and proteins in insulin signaling were assessed in WAT, liver and muscle. Results We found that the 50% LR group is the most proper group here at the lowest leucine effective concentration, which reduced fat mass (p < 0.05) and improved glucose regulation in mice over a 90 days feeding. Further studies revealed that lipid synthesis pathway (Fas, Scd1and Srebp1, p < 0.05) was downregulated and lipolysis (Atgl, p < 0.05) was upregulated in WAT in 50% LR group, compared to that in control group. Furthermore, glucose regulation (glucose tolerance test, p < 0.05) was also improved, and insulin signaling (p < 0.05) in the muscle was enhanced in 50% LR group while in WAT and liver were not changed. Conclusions Collectively, a 50% LR in mice reduced fat mass and improved glucose regulation, which may function through modulating lipid synthesis and lipolysis pathway in adipose tissue as well as enhancing insulin signaling in muscle. So far, we provide a further consideration for carrying out the diet of leucine restriction to reduce fat and improve metabolism status before clinical study.

P704Nanoliposomal anti-PCSK9 vaccine ameliorates glucose intolerance and insulin resistance in diabetic rats

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A A Momtazi-Borojeni ◽  
M R Jaafari ◽  
E Abdollahi ◽  
M Banach ◽  
A Sahebkar
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Glucose Intolerance ◽  
Tolerance Test ◽  
Diabetic Rats ◽  
Pcsk9 Inhibitors ◽  
Insulin Tolerance ◽  
Pcsk9 Inhibition ◽  
Histopathology Examination

Abstract Background PCSK9 inhibitors have emerged as an effective lipid-lowering approach. Although the results of available studies suggest a positive association of plasma PCSK9 levels with glycemic parameters and risk of DM, the effects of PCSK9 inhibitors on glucose intolerance and insulin resistance as the key features of DM remain unclear. Purpose The present study was directed to determine effect of vaccine-mediated PCSK9 inhibition on glucose intolerance and insulin resistance in experimental diabetic rats. Methods Nanoliposomal vaccine composing from PCSK9-linked nanoliposome particles mixed in Alum adjuvant was subcutaneously injected four times with bi-weekly intervals in Wistar-Albino rats. Two weeks after the last immunization, vaccinated and non-vaccinated rats were subjected to diabetes experiment induced by single intraperitoneal injection of streptozotocin (STZ). One week after STZ injection, glucose tolerance ability of each animal was evaluated by using oral glucose tolerance test (OGTT) on the overnight fasted rats with glucose dose at 2 g/kg. Two weeks after STZ injection, insulin tolerance test (ITT) viaintraperitoneal injection of insulin (0.8 U/kg) was performed to determine the measure of peripheral utilization of glucose. The plasma concentrations of total cholesterol (TC), LDL-C, HDL-C, and TG were measured. Results Nanoliposomal vaccine exposing PCSK9 peptide was found to provoke high-titers IgG antibody response against PCSK9 in rats, which was associated with the decrease plasma levels and function of plasma PCSK9. During the first week after STZ injection, it was indicated that the fasting blood glucose (FBG) level was 49% (−171.7±35 mg/dL, p<0.0001) lower in the vaccinated diabetic (VD) rats, when compared to the diabetic control (DC) rats. OGTT assessment revealed that the VS rats had significantly improved glucose tolerance ability and recorded significant reduction in the level of blood glucose over the period of 180 min, when compared with the DC rats. Measurement of integrated areas under the glucose curve values demonstrated that blood glucose levels were significantly (p<0.0001) decreased by 34.5% in the VS rats than the DC rats. In addition, ITT analysis showed that after insulin administration blood glucose level was decreased by 49.3% in the VS group compared with the DC group. The VS rats showed significantly lower (−26.65%, p=0.02) plasma LDL-C levels than the DC rats (Figure). Histopathology examination indicated that the pancreatic islet of the VS rats had a slightly decreased population of β-cells and few α-cells. Histopathology examination of the liver tissues of both VS and DC rats exhibited the normal histology with the normal hepatic architecture composed of hepatic lobules with normal central vein. Conclusions PCSK9 inhibition using liposomal vaccine can protect from glucose and insulin tolerance impairments in diabetic rats through an unknown and pancreatic-independent mechanism.

Chronic infusion of angiotensin-(1–7) improves insulin resistance and hypertension induced by a high-fructose diet in rats

2009 ◽  
Vol 296 (2) ◽  
pp. E262-E271 ◽  
Author(s):  
Jorge F. Giani ◽  
Marcos A. Mayer ◽  
Marina C. Muñoz ◽  
Ezequiel A. Silberman ◽  
Christian Höcht ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
Tolerance Test ◽  
Akt Pathway ◽  
Sprague Dawley ◽  
Chronic Infusion ◽  
Inhibitory Site

The current study was undertaken to determine whether Ang-(1–7) is effective in improving metabolic parameters in fructose-fed rats (FFR), a model of metabolic syndrome. Six-week-old male Sprague-Dawley rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water. For the last 2 wk of a 6-wk period of either diet, control and FFR were implanted with subcutaneous osmotic pumps that delivered Ang-(1–7) (100 ng·kg−1·min−1). A subgroup of each group of animals (control or FFR) underwent a sham surgery. We measured systolic blood pressure (SBP) together with plasma levels of insulin, triglycerides, and glucose. A glucose tolerance test (GTT) was performed, with plasma insulin levels determined before and 15 and 120 min after glucose administration. In addition, we evaluated insulin signaling through the IR/IRS-1/PI3K/Akt pathway as well as the phosphorylation levels of IRS-1 at inhibitory site Ser307 in skeletal muscle and adipose tissue. FFR displayed hypertriglyceridemia, hyperinsulinemia, increased SBP, and an exaggerated release of insulin during a GTT, together with decreased activation of insulin signaling through the IR/IRS-1/PI3K/Akt pathway in skeletal muscle, liver, and adipose tissue, as well as increased levels of IRS-1 phospho-Ser307 in skeletal muscle and adipose tissue, alterations that correlated with increased activation of the kinases mTOR and JNK. Chronic Ang-(1–7) treatment resulted in normalization of all alterations. These results show that Ang-(1–7) ameliorates insulin resistance in a model of metabolic syndrome via a mechanism that could involve the modulation of insulin signaling.

scholarly journals Resveratrol reduces the inflammatory response in adipose tissue and improves adipose insulin signaling in high-fat diet-fed mice

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5173 ◽  
Author(s):  
Shibin Ding ◽  
Jinjin Jiang ◽  
Zhe Wang ◽  
Guofu Zhang ◽  
Jianli Yin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Inflammatory Response ◽  
Glucose Tolerance ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Density Lipoprotein ◽  
High Fat

Background Obesity-induced glucose metabolism disorder is associated with chronic, low-grade, systemic inflammation and is considered a risk factor for diabetes and metabolic syndrome. Resveratrol (RES), a natural anti-inflammatory compound, is observed to improve glucose tolerance and insulin sensitivity in obese rodents and humans. This study aimed to test the effects of RES administration on insulin signaling and the inflammatory response in visceral white adipose tissue (WAT) caused by a high-fat diet (HFD) in mice. Methods A total of 40 wild-type C57BL/6 male mice were divided into four groups (10 in each group): the standard chow diet (STD) group was fed a STD; the HFD group was fed a HFD; and the HFD-RES/L and HFD-RES/H groups were fed a HFD plus RES (200 and 400 mg/kg/day, respectively). The L and H in RES/L and RES/H stand for low and high, respectively. Glucose tolerance, insulin sensitivity, circulating inflammatory biomarkers and lipid profile were determined. Quantitative PCR and Western blot were used to determine the expression of CC-chemokine receptor 2 (CCR2), other inflammation markers, glucose transporter 4 (GLUT4), insulin receptor substrate 1 (IRS-1) and pAkt/Akt and to assess targets of interest involving glucose metabolism and inflammation in visceral WAT. Results HFD increased the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol and proinflammatory cytokines in serum, decreased the high-density lipoprotein cholesterol level in serum, and induced insulin resistance and WAT inflammation in mice. However, RES treatment alleviated insulin resistance, increased the expressions of pAkt, GLUT4 and IRS-1 in WAT, and decreased serum proinflammatory cytokine levels, macrophage infiltration and CCR2 expression in WAT. Conclusion Our results indicated that WAT CCR2 may play a vital role in macrophage infiltration and the inflammatory response during the development of insulin resistance in HFD-induced obesity. These data suggested that administration of RES offers protection against abnormal glucose metabolism and inflammatory adaptations in visceral WAT in mice with HFD-induced obesity.

scholarly journals Mifepristone Improves Adipose Tissue Insulin Sensitivity in Insulin Resistant Individuals

2021 ◽  
Author(s):  
Sriram Gubbi ◽  
Ranganath Muniyappa ◽  
Susmeeta T Sharma ◽  
Shivraj Grewal ◽  
Raven McGlotten ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Hepatic Insulin Resistance ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Insulin Sensitivity Index

Abstract Background Increased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance. Methods We conducted a randomized, double-blinded, placebo-controlled, crossover study in overweight/obese individuals (n = 16, 44% female) with prediabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 h) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT [primary outcome: insulin sensitivity index (SI)] and OGTT [Matsuda index (MI) and oral glucose insulin sensitivity index (OGIS)]. Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT. Results Mifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7 ± 32.9 vs 42.8 ± 23.9; P = 0.002) and reduced adipo-IR (49.9 ± 45.9 vs 65.5 ± 43.8; P = 0.004), and HIRI (50.2 ± 38.7 vs 70.0 ± 44.3; P = 0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or β-cell glucose sensitivity. Conclusion Short-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism.

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