Insulin sensitivity is inversely related to cellular energy status, as revealed by biotin deprivation

2014 ◽  
Vol 306 (12) ◽  
pp. E1442-E1448 ◽  
Author(s):  
Ana Salvador-Adriano ◽  
Sonia Vargas-Chávez ◽  
Alain de J. Hernández-Vázquez ◽  
Daniel Ortega-Cuellar ◽  
Armando R. Tovar ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Muscle Cells ◽  
Independent Effect ◽  
Ampk Activation ◽  
Energy Status ◽  
Biotin Deficiency ◽  
Deficient Diet ◽  
Insulin Tolerance

We have reported an early decrease in glycemia in rats fed a biotin-deficient diet with reduced cellular ATP levels, suggesting increased insulin sensitivity. Here, we show that biotin-deprived rats are more tolerant of glucose, as shown by both oral and intraperitoneal glucose tolerance tests, during which insulin plasma levels were significantly diminished in deficient rats compared with controls. Biotin-deficient rats had lower blood glucose concentrations during intraperitoneal insulin sensitivity tests than controls. Furthermore, more glucose was infused to maintain euglycemia in the biotin-deficient rats during hyperinsulinemic euglycemic clamp studies. These results demonstrate augmented sensitivity to insulin in biotin-deprived rats. They are most likely the consequence of an insulin-independent effect of AMPK activation on GLUT4 membrane translocation with increased glucose uptake. In biotin-deficient cultured L6 muscle cells, there was increased phosphorylation of the energy sensor AMPK. We have now confirmed the augmented AMPK activation in both biotin-deprived in vivo muscle and cultured muscle cells. In these cells, glucose uptake is increased by AMPK activation by AICAR and diminished by its knockdown by the specific siRNAs directed against its α1- and α2-catalytic subunits, with all of these effects being largely independent of the activity of the insulin-signaling pathway that was inhibited with wortmannin. The enhanced insulin sensitivity in biotin deficiency likely has adaptive value for organisms due to the hormone promotion of uptake and utilization of not only glucose but other nutrients such as branched-chain amino acids, whose deficiency has been reported to increase insulin tolerance.

ALY688 elicits adiponectin-mimetic signaling and improves insulin action in skeletal muscle cells

2021 ◽  
Author(s):  
Hye Kyoung Sung ◽  
Patricia L. Mitchell ◽  
Sean Gross ◽  
Andre Marette ◽  
Gary Sweeney
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Muscle Cells ◽  
Temporal Analysis ◽  
Skeletal Muscle Cells ◽  
Adiponectin Receptor ◽  
Metabolic Effects

Adiponectin is well established to mediate many beneficial metabolic effects, and this has stimulated great interest in development and validation of adiponectin receptor agonists as pharmaceutical tools. This study investigated the effects of ALY688, a peptide-based adiponectin receptor agonist, in rat L6 skeletal muscle cells. ALY688 significantly increased phosphorylation of several adiponectin downstream effectors, including AMPK, ACC and p38MAPK, assessed by immunoblotting and immunofluorescence microscopy. Temporal analysis using cells expressing an Akt biosensor demonstrated that ALY688 enhanced insulin sensitivity. This effect was associated with increased insulin-stimulated Akt and IRS-1 phosphorylation. The functional metabolic significance of these signaling effects was examined by measuring glucose uptake in myoblasts stably overexpressing the glucose transporter GLUT4. ALY688 treatment both increased glucose uptake itself and enhanced insulin-stimulated glucose uptake. In the model of high glucose/high insulin (HGHI)-induced insulin resistant cells, both temporal studies using the Akt biosensor as well as immunoblotting assessing Akt and IRS-1 phosphorylation indicated that ALY688 significantly reduced insulin resistance. Importantly, we observed that ALY688 administration to high-fat high sucrose fed mice also improve glucose handling, validating its efficacy in vivo. In summary, these data indicate that ALY688 activates adiponectin signaling pathways in skeletal muscle, leading to improved insulin sensitivity and beneficial metabolic effects.

scholarly journals Prep1 Deficiency Induces Protection from Diabetes and Increased Insulin Sensitivity through a p160-Mediated Mechanism

2008 ◽  
Vol 28 (18) ◽  
pp. 5634-5645 ◽  
Author(s):  
Francesco Oriente ◽  
Luis Cesar Fernandez Diaz ◽  
Claudia Miele ◽  
Salvatore Iovino ◽  
Silvia Mori ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Normal Glucose Tolerance ◽  
Glucose Disposal ◽  
Protein Levels ◽  
Normal Glucose ◽  
Enhanced Expression ◽  
The Stability

ABSTRACT We have examined glucose homeostasis in mice hypomorphic for the homeotic transcription factor gene Prep1. Prep1-hypomorphic (Prep1 i / i ) mice exhibit an absolute reduction in circulating insulin levels but normal glucose tolerance. In addition, these mice exhibit protection from streptozotocin-induced diabetes and enhanced insulin sensitivity with improved glucose uptake and insulin-dependent glucose disposal by skeletal muscle. This muscle phenotype does not depend on reduced expression of the known Prep1 transcription partner, Pbx1. Instead, in Prep1 i / i muscle, we find normal Pbx1 but reduced levels of the recently identified novel Prep1 interactor p160. Consistent with this reduction, we find a muscle-selective increase in mRNA and protein levels of PGC-1α, accompanied by enhanced expression of the GLUT4 transporter, responsible for insulin-stimulated glucose uptake in muscle. Indeed, using L6 skeletal muscle cells, we induced the opposite effects by overexpressing Prep1 or p160, but not Pbx1. In vivo skeletal muscle delivery of p160 cDNA in Prep1 i / i mice also reverses the molecular phenotype. Finally, we show that Prep1 controls the stability of the p160 protein. We conclude that Prep1 controls insulin sensitivity through the p160-GLUT4 pathway.

Abstract 158: A Tether Containing a UBX Domain (TUG) Mediates Glucose Transporter Translocation in the Ischemic Heart

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Ji Li ◽  
Yina Ma ◽  
Jonathan Bogan
Keyword(s):  
Cell Surface ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Ex Vivo ◽  
Ischemia And Reperfusion ◽  
Ampk Activation ◽  
Glut4 Translocation ◽  
Heart Perfusion ◽  
Intracellular Vesicles

Introduction: The adaptive metabolic regulation of glucose and fatty acid in the heart plays a critical role in limiting cardiac damage caused by ischemia and reperfusion (I/R). TUG (tether containing a UBX domain, for GLUT4) can be cleaved to mobilize glucose transporter GLUT4 from intracellular vesicles to the cell surface in skeletal muscle and adipose in response to insulin stimulation. The energy sensor AMP-activated protein kinase (AMPK) plays an important cardioprotective role in response to ischemic insults by modulating GLUT4 translocation. Hypothesis: TUG is one of the downstream targets of AMPK in the heart. TUG could be phosphorylated by ischemic AMPK and cleaved to dissociate with GLUT4 and increase GLUT4 translocation in the ischemic heart. Methods: In vivo regional ischemia by ligation of left anterior coronary artery and ex vivo isolated mouse heart perfusion Langendorff system were used to test the hypothesis. Results: Antithrombin (AT) is an endogenous AMPK agonist in the heart and used to define the role of TUG in regulating GLUT4 trafficking during ischemia and reperfusion in the heart. AT showed its cardioprotective function through recovering cardiac pumping function and activating AMPK. The results showed that AMPK activation by AT treatment was through LKB1 and Sesn2 complex. Furthermore, the ex vivo heart perfusion data demonstrated that AT administration significantly increase GLUT4 translocation, glucose uptake, glycolysis and glucose oxidation during ischemia and reperfusion (p<0.05 vs . vehicle). Moreover, AT treatment increased abundance of a TUG cleavage product (42 KD) in response to I/R. The TUG protein was clearly phosphorylated by activated AMPK in HL-1 cardiomyocytes. The in vivo myocardial ischemia results demonstrated that ischemic AMPK activation triggers TUG cleavage and significantly increases GLUT4 translocation to the cell surface. Moreover, an augmented interaction between AMPK and TUG was observed during ischemia. Conclusions: Cardiac AMPK activation stimulates TUG cleavage and causes the dissociation between TUG and GLUT4 in the intracellular vesicles. TUG is a critical mediator that modulates cardiac GLUT4 translocation to cell surface and enhances glucose uptake by AMPK signaling pathway.

α1-Antitrypsin A treatment attenuates neutrophil elastase accumulation and enhances insulin sensitivity in adipose tissue of mice fed a high-fat diet.

2021 ◽  
Author(s):  
Randall F. D'Souza ◽  
Stewart W.C. Masson ◽  
Jonathan S. T. Woodhead ◽  
Samuel L James ◽  
Caitlin MacRae ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Neutrophil Elastase ◽  
High Fat Diet ◽  
Tolerance Test ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Insulin Tolerance

Neutrophils accumulate in insulin sensitive tissues during obesity and may play a role in impairing insulin sensitivity. The major serine protease expressed by neutrophils is neutrophil elastase (NE), which is inhibited endogenously by α1-antitrypsin A (A1AT). We investigated the effect of exogenous (A1AT) treatment on diet induced metabolic dysfunction. Male C57Bl/6j mice fed a chow or a high fat diet (HFD) were randomized to receive 3x weekly i.p injections of either Prolastin (human A1AT; 2mg) or vehicle (PBS) for 10 weeks. Prolastin treatment did not affect plasma NE concentration, body weight, glucose tolerance or insulin sensitivity in chow fed mice. In contrast, Prolastin treatment attenuated HFD induced increases in plasma and white adipose tissue (WAT) NE without affecting circulatory neutrophil levels or increases in body weight. Prolastin-treated mice fed a HFD had improved insulin sensitivity, as assessed by insulin tolerance test, and this was associated with higher insulin-dependent IRS-1 (insulin receptor substrate) and AktSer473phosphorylation, and reduced inflammation markers in WAT but not liver or muscle. In 3T3-L1 adipocytes, Prolastin reversed recombinant NE-induced impairment of insulin-stimulated glucose uptake and IRS-1 phosphorylation. Furthermore, PDGF mediated p-AktSer473 activation and glucose uptake (which is independent of IRS-1) was not affected by recombinant NE treatment. Collectively, our findings suggest that NE infiltration of WAT during metabolic overload contributes to insulin-resistance by impairing insulin-induced IRS-1 signaling.

Effect of exercise training on in vivo insulin-stimulated glucose uptake in intra-abdominal adipose tissue in rats

2000 ◽  
Vol 278 (1) ◽  
pp. E25-E34 ◽  
Author(s):  
L. H. Enevoldsen ◽  
B. Stallknecht ◽  
J. D. Fluckey ◽  
H. Galbo
Keyword(s):  
Insulin Resistance ◽  
Blood Flow ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Insulin Resistance Syndrome ◽  
Fat Depots ◽  
Lower Glucose ◽  
Interstitial Glucose ◽  
And Training

Intra-abdominal obesity may be crucial in the pathogenesis of the insulin-resistance syndrome, and training may alleviate this condition. We compared insulin-mediated glucose uptake in vivo in three intra-abdominal adipose tissues (ATs; retroperitoneal, parametrial, and mesenteric) and in subcutaneous AT and also studied the effect of training. Rats were either swim trained (15 wk, n = 9) or sedentary ( n = 16). While the rats were under anesthesia, a hyperinsulinemic (∼900 pM), euglycemic clamp was carried out and local glucose uptake was measured by both the 2-deoxy-d-[3H]glucose and microdialysis techniques. Blood flow was measured by microspheres. Upon insulin stimulation, blood flow generally decreased in AT. Flow was higher in mesenteric tissue than in other ATs, whereas insulin-mediated glucose uptake did not differ between ATs. Training doubled the glucose infusion rate during hyperinsulinemia, in part, reflecting an effect in muscle. During hyperinsulinemia, interstitial glucose concentrations were lower, glucose uptake per 100 g of tissue was higher in AT in trained compared with sedentary rats, and training influenced glucose uptake identically in all ATs. In conclusion, differences between ATs in insulin sensitivity with respect to glucose uptake do not explain that insulin resistance is associated with intra-abdominal rather than subcutaneous obesity. Furthermore, training may be beneficial by enhancing insulin sensitivity in intra-abdominal fat depots.

A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats

2014 ◽  
Vol 307 (1) ◽  
pp. E24-E33 ◽  
Author(s):  
Kim V. Andreassen ◽  
Michael Feigh ◽  
Sara T. Hjuler ◽  
Sofie Gydesen ◽  
Jan Erik Henriksen ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Receptor Agonist ◽  
Ex Vivo ◽  
Calcitonin Receptor ◽  
Insulin Tolerance ◽  
Receptor Pharmacology ◽  
Zdf Rats ◽  
Calcitonin Receptors

The present study investigated a novel oral dual amylin and calcitonin receptor agonist (DACRA), KBP-042, in head-to-head comparison with salmon calcitonin (sCT) with regard to in vitro receptor pharmacology, ex vivo pancreatic islet studies, and in vivo proof of concept studies in diet-induced obese (DIO) and Zucker diabetic fatty (ZDF) rats. In vitro, KBP-042 demonstrated superior binding affinity and activation of amylin and calcitonin receptors, and ex vivo, KBP-042 exerted inhibitory action on stimulated insulin and glucagon release from isolated islets. In vivo, KBP-042 induced a superior and pronounced reduction in food intake in conjunction with a sustained pair-fed corrected weight loss in DIO rats. Concomitantly, KBP-042 improved glucose homeostasis and reduced hyperinsulinemia and hyperleptinemia in conjunction with enhanced insulin sensitivity. In ZDF rats, KBP-042 induced a superior attenuation of diabetic hyperglycemia and alleviated impaired glucose and insulin tolerance. Concomitantly, KBP-042 preserved insulinotropic and induced glucagonostatic action, ultimately preserving pancreatic insulin and glucagon content. In conclusion, oral KBP-042 is a novel DACRA, which exerts antiobesity and antidiabetic efficacy by dual modulation of insulin sensitivity and directly decelerating stress on the pancreatic α- and β-cells. These results could provide the basis for oral KBP-042 as a novel therapeutic agent in type 2 diabetes.

Uncoupling protein 1 expression in murine skeletal muscle increases AMPK activation, glucose turnover, and insulin sensitivity in vivo

2008 ◽  
Vol 33 (3) ◽  
pp. 333-340 ◽  
Author(s):  
Susanne Neschen ◽  
Yvonne Katterle ◽  
Julia Richter ◽  
Robert Augustin ◽  
Stephan Scherneck ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Glucose Uptake ◽  
Insulin Action ◽  
Uncoupling Protein ◽  
Glucose Turnover ◽  
Ampk Activation ◽  
Uncoupling Protein 1 ◽  
Uncoupling Of Oxidative Phosphorylation

Uncoupling of oxidative phosphorylation represents a potential target for the treatment of hyperglycemia and insulin resistance in obesity and type 2 diabetes. The present study investigated whether the expression of uncoupling protein 1 in skeletal muscles of transgenic (mUCP1 TG) mice modulates insulin action in major insulin target tissues in vivo. Euglycemic-hyperinsulinemic clamps (17 pM·kg lean body mass−1·min−1) were performed in 9-mo-old hemizygous male mUCP1 TG mice and wild-type (WT) littermates matched for body composition. mUCP1 TG mice exhibited fasting hypoglycemia and hypoinsulinemia compared with WT mice, whereas fasting hepatic glucose production rates were comparable in both genotypes. mUCP1 TG mice were markedly more sensitive to insulin action compared with WT mice and displayed threefold higher glucose infusion rates, enhanced skeletal muscle and white adipose tissue glucose uptake, and whole body glycolysis rates. In the absence of alterations in plasma adiponectin concentrations, acceleration of insulin-stimulated glucose turnover in skeletal muscle of mUCP1 TG mice was accompanied by increased phosphorylated Akt-to-Akt and phosphorylated AMP-activated protein kinase (AMPK)-to-AMPK ratios compared with WT mice. UCP1-mediated uncoupling of oxidative phosphorylation in skeletal muscle was paralleled by AMPK activation and thereby stimulated insulin-mediated glucose uptake in skeletal muscle.

scholarly journals p50α/p55α Phosphoinositide 3-Kinase Knockout Mice Exhibit Enhanced Insulin Sensitivity

2004 ◽  
Vol 24 (1) ◽  
pp. 320-329 ◽  
Author(s):  
Dong Chen ◽  
Franck Mauvais-Jarvis ◽  
Matthias Bluher ◽  
Simon J. Fisher ◽  
Alison Jozsi ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Knockout Mice ◽  
Splice Variants ◽  
Tolerance Test ◽  
Glucose Levels ◽  
Gold Thioglucose ◽  
Insulin Tolerance ◽  
Altered Glucose ◽  
Phosphoinositide 3 Kinase

ABSTRACT Class Ia phosphoinositide (PI) 3-kinases are heterodimers composed of a regulatory and a catalytic subunit and are essential for the metabolic actions of insulin. In addition to p85α and p85β, insulin-sensitive tissues such as fat, muscle, and liver express the splice variants of the pik3r1 gene, p50α and p55α. Το define the role of these variants, we have created mice with a deletion of p50α and p55α by using homologous recombination. These mice are viable, grow normally, and maintain normal blood glucose levels but have lower fasting insulin levels. Results of an insulin tolerance test indicate that p50α/p55α knockout mice have enhanced insulin sensitivity in vivo, and there is an increase in insulin-stimulated glucose transport in isolated extensor digitorum longus muscle tissues and adipocytes. In muscle, loss of p50α/p55α results in reduced levels of insulin-stimulated insulin receptor substrate 1 (IRS-1) and phosphotyrosine-associated PI 3-kinase but enhanced levels of IRS-2-associated PI 3-kinase and Akt activation, whereas in adipocytes levels of both insulin-stimulated PI 3-kinase and Akt are unchanged. Despite this, adipocytes of the knockout mice are smaller and have increased glucose uptake with altered glucose metabolic pathways. When treated with gold thioglucose, p50α/p55α knockout mice become hyperphagic like their wild-type littermates. However, they accumulate less fat and become mildly less hyperglycemic and markedly less hyperinsulinemic. Taken together, these data indicate that p50α and p55α play an important role in insulin signaling and action, especially in lipid and glucose metabolism.

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