scholarly journals Myeloid specific deletion of ferroportin impairs macrophage bioenergetics but is disconnected from systemic insulin action in adult mice

2021 ◽  
Author(s):  
Nathan C. Winn ◽  
Elysa M Wolf ◽  
Matthew A Cottam ◽  
Monica Bhanot ◽  
Alyssa H Hasty
Keyword(s):  
Insulin Resistance ◽  
Iron Overload ◽  
Mitochondrial Respiration ◽  
Insulin Action ◽  
Iron Chelation ◽  
Reserve Capacity ◽  
Adult Mice ◽  
Systemic Insulin Resistance ◽  
Tissue Iron

Tissue iron overload is associated with insulin resistance and mitochondrial dysfunction in rodents and humans; however, the mechanisms or cell types that mediate this phenotype are not completely understood. Macrophages (Mɸ)s are known to contribute to iron handling; thus, we hypothesized that perturbed iron handling by Mɸs impairs mitochondrial energetics and evokes systemic insulin resistance in mice. Male and female mice with myeloid targeted (LysMCre) deletion of the canonical iron exporter, ferroportin (Fpn, encoded by Slc40a1), floxed littermates and C57BL/6J wild-type mice were used to test our hypotheses. Myeloid-targeted deletion of Fpn evoked multi-tissue iron accumulation and reduced mitochondrial respiration in bone marrow-derived Mɸs, liver leukocytes, and Mɸ-enriched populations from adipose tissue (AT). In addition, a single bolus of exogenous iron administered to C57BL/6J mice phenocopied the loss of Fpn, resulting in a reduction in maximal and mitochondrial reserve capacity in Mɸ-enriched cellular fractions from liver and AT. In vivo exogenous iron chelation restored mitochondrial reserve capacity in liver leukocytes from Fpn LysMCre mice, but had no effect in AT myeloid populations. However, despite the impairments in mitochondrial respiration, neither loss of myeloid-specific Fpn, nor exogenous iron overload, perturbed glucose homeostasis or systemic insulin action in lean or obese mice; whereas, aging coupled with lifelong loss of Fpn unmasked glucose intolerance. Together these data demonstrate that iron handling is critical for the maintenance of macrophage mitochondrial function but perturbing myeloid iron flux via the loss of Fpn action is not sufficient to evoke systemic insulin resistance in young adult mice. These findings also suggest that if Mɸs are capable of storing iron properly, they have a pronounced ability to withstand iron excess without evoking overt collateral damage and associated insulin resistance that may be age dependent.

scholarly journals Endothelial insulin receptors differentially control insulin signaling kinetics in peripheral tissues and brain of mice

2017 ◽  
Vol 114 (40) ◽  
pp. E8478-E8487 ◽  
Author(s):  
Masahiro Konishi ◽  
Masaji Sakaguchi ◽  
Samuel M. Lockhart ◽  
Weikang Cai ◽  
Mengyao Ella Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Food Intake ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Insulin Receptors ◽  
Brain Regions ◽  
Peripheral Tissues ◽  
Systemic Insulin Resistance

Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb. At the level of the brain, the delay of insulin signaling was associated with decreased levels of hypothalamic proopiomelanocortin, leading to increased food intake and obesity accompanied with hyperinsulinemia and hyperleptinemia. The loss of endothelial IRs also resulted in a delay in the acute hypoglycemic effect of systemic insulin administration and impaired glucose tolerance. In high-fat diet-treated mice, knockout of the endothelial IRs accelerated development of systemic insulin resistance but not food intake and obesity. Thus, IRs on endothelial cells have an important role in transendothelial insulin delivery in vivo which differentially regulates the kinetics of insulin signaling and insulin action in peripheral target tissues and different brain regions. Loss of this function predisposes animals to systemic insulin resistance, overeating, and obesity.

scholarly journals Short-term K+ deprivation provokes insulin resistance of cellular K+ uptake revealed with the K+ clamp

2001 ◽  
Vol 280 (1) ◽  
pp. F95-F102 ◽  
Author(s):  
Cheol S. Choi ◽  
Curtis B. Thompson ◽  
Patrick K. K. Leong ◽  
Alicia A. McDonough ◽  
Jang H. Youn
Keyword(s):  
Insulin Resistance ◽  
Atpase Activity ◽  
Infusion Rate ◽  
Insulin Action ◽  
Insulin Dose ◽  
Short Term ◽  
Conscious Rat ◽  
Physiological Concentration ◽  
Glucose Clearance

We aimed to test the feasibility of quantifying insulin action on cellular K+ uptake in vivo in the conscious rat by measuring the exogenous K+ infusion rate needed to maintain constant plasma K+ concentration ([K+]) during insulin infusion. In this “K+ clamp” the K+ infusion rate required to clamp plasma [K+] is a measure of insulin action to increase net plasma K+ disappearance. K+ infusion rate required to clamp plasma [K+] was insulin dose dependent. Renal K+ excretion was not significantly affected by insulin at a physiological concentration (∼90 μU/ml, P > 0.05), indicating that most of insulin-mediated plasma K+ disappearance was due to K+ uptake by extrarenal tissues. In rats deprived of K+ for 2 days, plasma [K+] fell from 4.2 to 3.8 mM, insulin-mediated plasma glucose clearance was normal, but insulin-mediated plasma K+ disappearance decreased to 20% of control, even though there was no change in muscle Na-K-ATPase activity or expression, which is believed to be the main K+ uptake route. After 10 days K+ deprivation, plasma [K+] fell to 2.9 mM, insulin-mediated K+ disappearance decreased to 6% of control (glucose clearance normal), and there were 50% decreases in Na-K-ATPase activity and α2-subunit levels. In conclusion, the present study proves the feasibility of the K+ clamp technique and demonstrates that short-term K+ deprivation leads to a near complete insulin resistance of cellular K+uptake that precedes changes in muscle sodium pump expression.

Sepsis-induced changes in in vivo insulin action in diabetic rats

1989 ◽  
Vol 257 (3) ◽  
pp. E301-E308 ◽  
Author(s):  
C. H. Lang ◽  
C. Dobrescu
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Plasma Concentrations ◽  
Diabetic Rats ◽  
Hepatic Insulin Resistance ◽  
Blood Levels ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Glucose Output

The present study examined whether sepsis exacerbates the diabetes-induced peripheral and hepatic insulin resistance. Vascular catheters were placed in diabetic (70 mg/kg streptozotocin, 4-wk duration) and nondiabetic rats, and sepsis was produced by subcutaneous injections of live Escherichia coli. Basal glucose metabolism was determined with the use of [3-3H]glucose initiated 18 h after the first injection of bacteria. Thereafter, in vivo insulin action was assessed with the use of the euglycemic hyperinsulinemic clamp technique. Sepsis in nondiabetic rats produced a 57% reduction in the maximal responsiveness for the insulin-induced increase in total glucose utilization compared with nondiabetic nonseptic animals. Diabetes alone decreased both insulin sensitivity and responsiveness. When the septic insult was superimposed on the diabetic condition, the maximum responsiveness was unchanged compared with non-septic diabetic rats, but the 50% maximally efficient dose was reduced from 817 to 190 microU/ml, suggesting an improvement in insulin sensitivity. Sepsis did not alter the insulin-induced suppression of hepatic glucose output in either nondiabetic or diabetic animals. Sepsis increased the plasma concentrations of epinephrine, norepinephrine, glucagon, and corticosterone in both nondiabetic and diabetic rats; however, the elevation in catecholamines and glucagon was 65 to 250% greater in the diabetic animals. These results indicate that hypermetabolic sepsis produces peripheral insulin resistance in nondiabetic rats but does not worsen the preexisting insulin resistance in diabetic animals, despite the higher prevailing blood levels of glucagon and catecholamines.

scholarly journals Overexpression of the ped/pea-15 Gene Causes Diabetes by Impairing Glucose-Stimulated Insulin Secretion in Addition to Insulin Action

2004 ◽  
Vol 24 (11) ◽  
pp. 5005-5015 ◽  
Author(s):  
Giovanni Vigliotta ◽  
Claudia Miele ◽  
Stefania Santopietro ◽  
Giuseppe Portella ◽  
Anna Perfetti ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Transgenic Mice ◽  
Insulin Action ◽  
Glucose Levels ◽  
Beta Cell Line ◽  
Protein Kinase Cα ◽  
Glucose Stimulated Insulin Secretion

ABSTRACT Overexpression of the ped/pea-15 gene is a common feature of type 2 diabetes. In the present work, we show that transgenic mice ubiquitously overexpressing ped/pea-15 exhibited mildly elevated random-fed blood glucose levels and decreased glucose tolerance. Treatment with a 60% fat diet led ped/pea-15 transgenic mice to develop diabetes. Consistent with insulin resistance in these mice, insulin administration reduced glucose levels by only 35% after 45 min, compared to 70% in control mice. In vivo, insulin-stimulated glucose uptake was decreased by almost 50% in fat and muscle tissues of the ped/pea-15 transgenic mice, accompanied by protein kinase Cα activation and block of insulin induction of protein kinase Cζ. These changes persisted in isolated adipocytes from the transgenic mice and were rescued by the protein kinase C inhibitor bisindolylmaleimide. In addition to insulin resistance, ped/pea-15 transgenic mice showed a 70% reduction in insulin response to glucose loading. Stable overexpression of ped/pea-15 in the glucose-responsive MIN6 beta-cell line also caused protein kinase Cα activation and a marked decline in glucose-stimulated insulin secretion. Antisense block of endogenous ped/pea-15 increased glucose sensitivity by 2.5-fold in these cells. Thus, in vivo, overexpression of ped/pea-15 may lead to diabetes by impairing insulin secretion in addition to insulin action.

scholarly journals Hepatoprotective Role of Phlogacanthus thyrsiflorus Nees as a Potential Iron Chelating Drug

2019 ◽  
Vol 12 ◽  
pp. 12-22
Author(s):  
Queen Saikia ◽  
Manas Das ◽  
Archana Saikia
Keyword(s):  
Iron Overload ◽  
Radical Scavenging ◽  
Iron Chelation ◽  
The Body ◽  
Oral Drug ◽  
Histopathological Analysis ◽  
Dependent Manner ◽  
North East

Exceeding iron levels in the body get accumulated in the liver and other vital organs that induce oxidative stress in the affected areas , which is clinically diagnosed as “iron overload”. Present study was undertaken to investigate the role of Phlogacanthus thyrsiflorus Nees, an endemic species of North-east India, in ameliorating such diseased conditions. Our results indicate that the methanolic leaf extract of Phlogacanthus thyrsiflorus (PTME) exhibits excellent iron chelation and antioxidant activities in dose dependent manner in vitro. To understand the in vivo conditions, thirty six mice were divided into six groups which were treated with differing doses of PTME. Levels of serum markers ALT and AST significantly elevates during diseased conditions but PTME treated mice have shown a marked decrease in the group (S200) by 39.24 and 17.24%. On the contrary lowering levels of liver antioxidant enzymes (GST, GSH, SOD and CAT) indicates stress. But 200mg/kg b.w of PTME treated groups restored the enzyme to optimum levels. Morphological changes were observed through histopathological analysis of liver tissues and we found significant differences in them . PTME was found to be completely nontoxic in the in vivo treatment, suggesting its feasibility as a safe oral drug. The above study suggests that PTME contributed to its free radical scavenging and iron chelation activity; however, further studies are required for the assessment of the phytoconstituents and the pathways through which it act to treat iron-overload diseases.

scholarly journals Hyperinsulinemia promotes HMGB1 release leading to inflammation induced systemic insulin resistance: An interplay between pancreatic beta-cell and peripheral organs

2019 ◽  
Author(s):  
Abhinav Choubey ◽  
Aditya K Kar ◽  
Khyati Girdhar ◽  
Tandrika Chattopadhyay ◽  
Surbhi Dogra ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Pancreatic Beta Cell ◽  
Underlying Mechanism ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Extracellular Milieu ◽  
Peripheral Organs ◽  
Systemic Insulin Resistance

SummaryInsulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. Pancreatic β-cells hypersecretion (hyperinsulinemia), is a central hallmark of peripheral insulin resistance. However, the underlying mechanism by which hyperinsulinemia perpetuates towards the development of insulin resistance remains unclear and is still a bigger therapeutic challenge. Here, we found hyperinsulinemia triggers inflammation and insulin resistance by stimulating TLR4-driven inflammatory cascades. We show that hyperinsulinemia activates the TLR4 signaling through HMGB1, an endogenous TLR4 ligand emanating from hyperinsulinemia exposed immune cells and peripheral organs like adipose tissue and liver. Further, our observation suggests hyperinsulinemia ensuring hyperacetylation, nuclear-to-cytoplasmic shuttling and release of HMGB1 into the extracellular space. HMGB1 was also found to be elevated in serum of T2DM patients. We found that extracellular HMGB1 plays a crucial role to promote proinflammatory responses and provokes systemic insulin resistance. Importantly, in-vitro and in-vivo treatment with naltrexone, a TLR4 antagonist led to an anti-inflammatory phenotype with protection from hyperinsulinemia mediated insulin resistance. In-vitro treatment with naltrexone directly enhanced SIRT1 activity, blocked the release of HMGB1 into extracellular milieu, suppressed release of proinflammatory cytokines and ultimately led to insulin-sensitizing effects. These observations elucidate a regulatory network between pancreatic β-cells, macrophage and hepatocytes and assign an unexpected role of TLR4 - HMGB1 signaling axis in hyperinsulinemia mediated systemic insulin resistance.Graphical Abstract

scholarly journals Ameliorating Iron Overload in Intestinal Tissue of Adult Male Rats: Quercetin vs Deferoxamine

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Arwa A. El-Sheikh ◽  
Shimaa Hamed Ameen ◽  
Samaa Salah AbdEl-Fatah
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Adult Male ◽  
Caspase 3 ◽  
Iron Chelation ◽  
Male Rats ◽  
Albino Rats ◽  
Tissue Iron ◽  
Small Intestinal

Objective. The aim of our study is to compare the role of the new natural alternative (Quercetin) with the current iron-chelation therapy (Deferoxamine (DFO)) in the effect of iron overload on small intestinal tissues and to investigate the possible underlying molecular mechanisms of such toxicity. Methods. Forty-two adult male albino rats were divided into six groups: control groups, DFO, Quercetin, iron overload, iron overload+DFO, and iron overload+Quercetin groups. Animals received daily intraperitoneal injection of Deferoxamine (125 mg /kg), Quercetin (10 mg/kg), and ferric dextran (200 mg/kg) for 2 weeks. Results. Iron overloaded group showed significant increase in serum iron, total iron binding capacity (TIBC), transferrin saturation percentage (TS %) hepcidin (HEPC), serum ferritin, nontransferrin bound iron (NTBI), and small intestinal tissues iron levels. Iron overload significantly increased the serum oxidative stress indicator (MDA) and reduced serum total antioxidant capacity (TAC). On the other hand, iron overload increased IL6 and reduced IL10 in small intestinal tissues reflecting inflammatory condition and increased caspase 3 reactivity indicating apoptosis and increased iNOs expressing cell indicting oxidative stress especially in ileum. In addition, it induced small intestinal tissues pathological alterations. The treatment with Quercetin showed nonsignificant differences as compared to treatment with DFO that chelated the serum and tissue iron and improved the oxidative stress and reduced tissue IL6 and increased IL10 and decreased caspase 3 and iNOs expressing cells in small intestinal tissues. Moreover, it ameliorated the iron overload induced pathological alterations. Conclusion. Our study showed the potential role of Quercetin as iron chelator like DFO in case of iron overload induced small intestinal toxicity in adult rats because of its serum and tissue iron chelation, improvement of serum, and small intestinal oxidative stress, ameliorating iron induced intestinal inflammation, apoptosis, and histopathological alterations.

In vivo insulin action in genetic models of hypertension

1992 ◽  
Vol 262 (2) ◽  
pp. E191-E196 ◽  
Author(s):  
S. Frontoni ◽  
L. Ohman ◽  
J. R. Haywood ◽  
R. A. DeFronzo ◽  
L. Rossetti
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Glucose Uptake ◽  
Insulin Action ◽  
Hepatic Glucose Production ◽  
High Dose ◽  
Rat Models ◽  
Genetic Hypertension ◽  
Per Se

Insulin resistance has been described in nonobese subjects with essential hypertension. At present it is unknown whether hypertension per se may lead to the onset of insulin resistance. To examine this question we studied in vivo insulin action in two rat models of genetic hypertension. Four groups of conscious rats were studied: Milan hypertensive (MHS), Milan normotensive (MNS), spontaneously hypertensive (SHR), and Wistar-Kyoto (WKY). Mean arterial pressure was increased in SHR vs. WKY in both the fed (184 +/- 5 vs. 126 +/- 6 mmHg; P less than 0.001) and fasting (160 +/- 5 vs. 129 +/- 5; P less than 0.001) states. During high-dose insulin clamps, total body glucose uptake (mg.kg-1.min-1) was similar in MNS (28.7 +/- 1.4) vs. MHS (33.6 +/- 3.0) and in WKY (34.6 +/- 1.8) vs. SHR (35.7 +/- 2.4). During low-dose insulin clamps, suppression of hepatic glucose production (3.5 +/- 0.6 vs. 3.0 +/- 0.5 mg.kg-1.min-1) and stimulation of glycolysis (12.9 +/- 0.8 vs. 14.4 +/- 1.5 mg.kg-1.min-1) were similar in WKY vs. SHR, whereas glucose uptake (24.6 +/- 1.9 vs. 18.3 +/- 1.2 mg.kg-1.min-1; P less than 0.01) and muscle glycogenic rate (10.2 +/- 1.1 vs. 6.5 +/- 1.1 mg.kg-1.min-1; P less than 0.05) were increased in SHR vs. WKY. In conclusion, 1) feeding markedly augments blood pressure in hypertensive but not in normotensive rats, and 2) hepatic and muscle insulin sensitivity are normal or increased in two different rat models of genetic hypertension. These results provide evidence that high blood pressure per se does not invariably lead to the development of insulin resistance.

scholarly journals Peroxisome Proliferator-Activated Receptor (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid Uptake and Metabolism in Vivo—A Study Using the Novel PPARα/γ Agonist Tesaglitazar

Endocrinology ◽  
2004 ◽  
Vol 145 (7) ◽  
pp. 3158-3164 ◽  
Author(s):  
Bronwyn D. Hegarty ◽  
Stuart M. Furler ◽  
Nicholas D. Oakes ◽  
Edward W. Kraegen ◽  
Gregory J. Cooney
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
The Novel ◽  
High Fat

Abstract Agonists of peroxisome proliferator-activated receptors (PPARs) have emerged as important pharmacological agents for improving insulin action. A major mechanism of action of PPAR agonists is thought to involve the alteration of the tissue distribution of nonesterified fatty acid (NEFA) uptake and utilization. To test this hypothesis directly, we examined the effect of the novel PPARα/γ agonist tesaglitazar on whole-body insulin sensitivity and NEFA clearance into epididymal white adipose tissue (WAT), red gastrocnemius muscle, and liver in rats with dietary-induced insulin resistance. Wistar rats were fed a high-fat diet (59% of calories as fat) for 3 wk with or without treatment with tesaglitazar (1 μmol·kg−1·d−1, 7 d). NEFA clearance was measured using the partially metabolizable NEFA tracer, 3H-R-bromopalmitate, administered under conditions of basal or elevated NEFA availability. Tesaglitazar improved the insulin sensitivity of high-fat-fed rats, indicated by an increase in the glucose infusion rate during hyperinsulinemic-euglycemic clamp (P < 0.01). This improvement in insulin action was associated with decreased diglyceride (P < 0.05) and long chain acyl coenzyme A (P < 0.05) in skeletal muscle. NEFA clearance into WAT of high-fat-fed rats was increased 52% by tesaglitazar under basal conditions (P < 0.001). In addition the PPARα/γ agonist moderately increased hepatic and muscle NEFA utilization and reduced hepatic triglyceride accumulation (P < 0.05). This study shows that tesaglitazar is an effective insulin-sensitizing agent in a mild dietary model of insulin resistance. Furthermore, we provide the first direct in vivo evidence that an agonist of both PPARα and PPARγ increases the ability of WAT, liver, and skeletal muscle to use fatty acids in association with its beneficial effects on insulin action in this model.

Sign in / Sign up

Export Citation Format

Share Document