scholarly journals Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

2020 ◽  
Author(s):  
Ada Admin ◽  
Adam R. Wende ◽  
John C. Schell ◽  
Chae-Myeong Ha ◽  
Mark E. Pepin ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Glucose Uptake ◽  
Diabetic Cardiomyopathy ◽  
Transcriptional Repression ◽  
Glucose Transporter ◽  
Glucose Utilization ◽  
Specific Expression ◽  
Transport Chain ◽  
Atp Generation ◽  
Glucose Transporter Glut4

Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear if these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we generated transgenic mice with inducible cardiomyocyte-specific expression of the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by <i>O</i>-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct <i>O</i>-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins.<b> </b>These findings identify mitochondria as a major target of glucotoxicity. They also suggest reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

scholarly journals Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

2020 ◽  
Author(s):  
Ada Admin ◽  
Adam R. Wende ◽  
John C. Schell ◽  
Chae-Myeong Ha ◽  
Mark E. Pepin ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Glucose Uptake ◽  
Diabetic Cardiomyopathy ◽  
Transcriptional Repression ◽  
Glucose Transporter ◽  
Glucose Utilization ◽  
Specific Expression ◽  
Transport Chain ◽  
Atp Generation ◽  
Glucose Transporter Glut4

Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear if these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we generated transgenic mice with inducible cardiomyocyte-specific expression of the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by <i>O</i>-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct <i>O</i>-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins.<b> </b>These findings identify mitochondria as a major target of glucotoxicity. They also suggest reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

scholarly journals Transcriptional repression of the mouse insulin-responsive glucose transporter (GLUT4) gene by cAMP.

1991 ◽  
Vol 88 (5) ◽  
pp. 1933-1937 ◽  
Author(s):  
K. H. Kaestner ◽  
J. R. Flores-Riveros ◽  
J. C. McLenithan ◽  
M. Janicot ◽  
M. D. Lane
Keyword(s):  
Transcriptional Repression ◽  
Glucose Transporter ◽  
Glucose Transporter Glut4

scholarly journals RalA controls glucose homeostasis by regulating glucose uptake in brown fat

2018 ◽  
Vol 115 (30) ◽  
pp. 7819-7824 ◽  
Author(s):  
Yuliya Skorobogatko ◽  
Morgan Dragan ◽  
Claudia Cordon ◽  
Shannon M. Reilly ◽  
Chao-Wei Hung ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Brown Fat ◽  
Specific Chemical ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Chemical Inhibitors ◽  
Glucose Transporter Glut4

Insulin increases glucose uptake into adipose tissue and muscle by increasing trafficking of the glucose transporter Glut4. In cultured adipocytes, the exocytosis of Glut4 relies on activation of the small G protein RalA by insulin, via inhibition of its GTPase activating complex RalGAP. Here, we evaluate the role of RalA in glucose uptake in vivo with specific chemical inhibitors and by generation of mice with adipocyte-specific knockout of RalGAPB. RalA was profoundly activated in brown adipose tissue after feeding, and its inhibition prevented Glut4 exocytosis. RalGAPB knockout mice with diet-induced obesity were protected from the development of metabolic disease due to increased glucose uptake into brown fat. Thus, RalA plays a crucial role in glucose transport in adipose tissue in vivo.

Abstract 235: Sarcolemmal Membrane Associated Protein Isoform 1: a Unique Regulator of Glucose Uptake and Metabolism in the Myocardium

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Aaraf Dewan ◽  
Maysoon Salih ◽  
Christopher Triggle ◽  
Hong Ding ◽  
Balwant Tuana
Keyword(s):  
Glucose Uptake ◽  
Glucose Transporter ◽  
Glucose Transporter 4 ◽  
Specific Expression ◽  
Western Blots ◽  
Sarcolemmal Membrane ◽  
Neonatal Cardiomyocytes ◽  
Early Endosomes ◽  
Protein Isoform ◽  
Uptake And Metabolism

As one of the leading causes of heart disease, diabetes is a problem which needs a solution. Regulation of glucose uptake and metabolism within skeletal and cardiac muscle has proven capable of altering systemic glucose levels and impacting metabolism to potentially improve patient outcomes. Unfortunately, to date, very few muscle specific metabolic regulators are known which can allow us to achieve blood glucose uptake and metabolism. Sarcolemmal Membrane Associated Protein Isoform 1 (SLMAP1) is a novel protein expressed predominantly within muscle tissue. It has been linked to diabetes through animal models, although its role in metabolism remains to be defined. Here we describe a novel role for SLMAP1 in glucose metabolism within the myocardium. We engineered a transgenic (TG) mouse with cardiac specific expression of SLMAP1. Using neonatal cardiomyocytes (NCMs) collected from these mice we performed glucose uptake assays with 2-deoxy-glucose (2DG), measured glycolytic rate using an Extracellular Flux XF24e Bioanalyzer, and analyzed glucose transporter 4 (GLUT4) trafficking using Western Blots, qPCR, and immunofluorescence imaging. NCMs extracted from TG hearts expressing SLMAP1 displayed increased levels of 2DG uptake (93% ± 25%, n=5, P<0.01), basal glycolysis (glycolysis (92 ± 40%, n=5, P<0.05), and maximal glycolysis (75 ± 31%, n=5, P<0.05) compared with wildtype littermates. Confocal microscopy revealed both increased localization of glucose transporter 4 (GLUT4) at the cell surface as well as an expansion of GLUT4 early endosomes in TG NCMs. The data here indicates SLMAP1 as a novel regulator of glucose uptake and metabolism in the myocardium. The targeted expression of SLMAP1 in a muscle specific manner may enhance systemic glycemic control and serve to limit cardiovascular disease in metabolic disorders such as diabetes.

scholarly journals Reduction of Insulin-Stimulated Glucose Uptake in L6 Myotubes by the Protein Kinase Inhibitor SB203580 Is Independent of p38MAPK Activity

Endocrinology ◽  
2005 ◽  
Vol 146 (9) ◽  
pp. 3773-3781 ◽  
Author(s):  
C. N. Antonescu ◽  
C. Huang ◽  
W. Niu ◽  
Z. Liu ◽  
P. A. Eyers ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Kinase Inhibitor ◽  
Dominant Negative ◽  
Small Interfering Rnas ◽  
Insulin Stimulation ◽  
L6 Myotubes ◽  
Low Levels ◽  
Glucose Transporter Glut4

Abstract Insulin increases glucose uptake through translocation of the glucose transporter GLUT4 to the plasma membrane. We previously showed that insulin activates p38MAPK, and inhibitors of p38MAPKα and p38MAPKβ (e.g. SB203580) reduce insulin-stimulated glucose uptake without affecting GLUT4 translocation. This observation suggested that insulin may increase GLUT4 activity via p38α and/or p38β. Here we further explore the possible participation of p38MAPK through a combination of molecular strategies. SB203580 reduced insulin stimulation of glucose uptake in L6 myotubes overexpressing an SB203580-resistant p38α (drug-resistant p38α) but barely affected phosphorylation of the p38 substrate MAPK-activated protein kinase-2. Expression of dominant-negative p38α or p38β reduced p38MAPK phosphorylation by 70% but had no effect on insulin-stimulated glucose uptake. Gene silencing via isoform-specific small interfering RNAs reduced expression of p38α or p38β by 60–70% without diminishing insulin-stimulated glucose uptake. SB203580 reduced photoaffinity labeling of GLUT4 by bio-LC-ATB-BMPA only in the insulin-stimulated state. Unless low levels of p38MAPK suffice to regulate glucose uptake, these results suggest that the inhibition of insulin-stimulated glucose transport by SB203580 is likely not mediated by p38MAPK. Instead, changes experienced by insulin-stimulated GLUT4 make it susceptible to inhibition by SB203580.

scholarly journals Specialized sorting of GLUT4 and its recruitment to the cell surface are independently regulated by distinct Rabs

2013 ◽  
Vol 24 (16) ◽  
pp. 2544-2557 ◽  
Author(s):  
L. Amanda Sadacca ◽  
Joanne Bruno ◽  
Jennifer Wen ◽  
Wenyong Xiong ◽  
Timothy E. McGraw
Keyword(s):  
Plasma Membrane ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Receptor Activation ◽  
Glut4 Translocation ◽  
Insulin Stimulation ◽  
Transport Vesicles ◽  
Glucose Transporter Glut4

Adipocyte glucose uptake in response to insulin is essential for physiological glucose homeostasis: stimulation of adipocytes with insulin results in insertion of the glucose transporter GLUT4 into the plasma membrane and subsequent glucose uptake. Here we establish that RAB10 and RAB14 are key regulators of GLUT4 trafficking that function at independent, sequential steps of GLUT4 translocation. RAB14 functions upstream of RAB10 in the sorting of GLUT4 to the specialized transport vesicles that ferry GLUT4 to the plasma membrane. RAB10 and its GTPase-activating protein (GAP) AS160 comprise the principal signaling module downstream of insulin receptor activation that regulates the accumulation of GLUT4 transport vesicles at the plasma membrane. Although both RAB10 and RAB14 are regulated by the GAP activity of AS160 in vitro, only RAB10 is under the control of AS160 in vivo. Insulin regulation of the pool of RAB10 required for GLUT4 translocation occurs through regulation of AS160, since activation of RAB10 by DENND4C, its GTP exchange factor, does not require insulin stimulation.

scholarly journals Noradrenaline increases glucose transport into brown adipocytes in culture by a mechanism different from that of insulin

1996 ◽  
Vol 314 (2) ◽  
pp. 485-490 ◽  
Author(s):  
Yasutake SHIMIZU ◽  
Danuta KIELAR ◽  
Yasuhiko MINOKOSHI ◽  
Takashi SHIMAZU
Keyword(s):  
Cyclic Amp ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Sympathetic Nerves ◽  
Intrinsic Activity ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Km Value ◽  
Glucose Transporter Glut4

Glucose uptake into brown adipose tissue has been shown to be enhanced directly by noradrenaline (norepinephrine) released from sympathetic nerves. In this study we characterized the glucose transport system in cultured brown adipocytes, which responds to noradrenaline as well as insulin, and analysed the mechanism underlying the noradrenaline-induced increase in glucose transport. Insulin increased 2-deoxyglucose (dGlc) uptake progressively at concentrations from 10-11 to 10-6 M, with maximal stimulation at 10-7 M. Noradrenaline concentrations ranging from 10-8 to 10-6 M also enhanced dGlc uptake, even in the absence of insulin. The effects of noradrenaline and insulin on dGlc uptake were additive. The stimulatory effect of noradrenaline was mimicked by the β3-adrenergic agonist, BRL37344, at concentrations two orders lower than noradrenaline. Dibutyryl cyclic AMP also mimicked the stimulatory effect of noradrenaline, and the antagonist of cyclic AMP, cyclic AMP-S Rp-isomer, blocked the enhancement of glucose uptake due to noradrenaline. Furthermore Western blot analysis with an anti-phosphotyrosine antibody revealed that, in contrast with insulin, noradrenaline apparently does not stimulate intracellular phosphorylation of tyrosine, suggesting that the noradrenaline-induced increase in dGlc uptake depends on elevation of the intracellular cyclic AMP level and not on the signal chain common to insulin. When cells were incubated with insulin, the content of the muscle/adipocyte type of glucose transporter (GLUT4) in the plasma membrane increased, with a corresponding decrease in the amount in the microsomal membrane. In contrast, noradrenaline did not affect the subcellular distribution of GLUT4 or that of the HepG2/erythrocyte type of glucose transporter. Although insulin increased Vmax. and decreased the Km value for glucose uptake, the effect of noradrenaline was restricted to a pronounced decrease in Km. These results suggest that the mechanism by which noradrenaline stimulates glucose transport into brown adipocytes is not due to translocation of GLUT but is probably due to an increase in the intrinsic activity of GLUT, which is mediated by a cyclic AMP-dependent pathway.

Altered renal expression of the insulin-responsive glucose transporter GLUT4 in experimental diabetes mellitus

1994 ◽  
Vol 267 (5) ◽  
pp. F816-F824 ◽  
Author(s):  
R. G. Marcus ◽  
R. England ◽  
K. Nguyen ◽  
M. J. Charron ◽  
J. P. Briggs ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Experimental Diabetes ◽  
Diabetic Rats ◽  
Experimental Diabetes Mellitus ◽  
Early Diabetes ◽  
Glut4 Expression ◽  
Microvascular Cells ◽  
Glucose Transporter Glut4

Because the insulin-responsive glucose transporter, GLUT4, is expressed in renal vascular and glomerular cells, we determined the effects of experimental diabetes mellitus on GLUT4 expression and glucose uptake by these tissues. Quantitative reverse-transcription polymerase chain reaction studies of microdissected afferent microvessels and renal glomeruli showed that, after 1 wk of diabetes, GLUT4 mRNA was decreased to 26 and 34% of control values, respectively. GLUT4 immunoblots of renal glomerular and microvessel samples showed that GLUT4 polypeptide was decreased to 51% of control values. These results were confirmed by indirect immunofluorescence, which showed decreased GLUT4 expression in glomerular cells and in vascular smooth muscle cells of the afferent microvasculature of diabetic animals. Uptake of the glucose analogue, 2-deoxyglucose, was also depressed in microvessels of diabetic rats to 57% of control values, supporting the conclusion that fewer total glucose transporters were available for glucose uptake into diabetic renal glomerular and microvascular cells. Thus both GLUT4 expression and glucose uptake by glomerular and microvascular cells are decreased in diabetic animals. These results have led us to suggest a mechanism by which decreased renal GLUT4 expression could contribute to glomerular hyperfiltration and hypertension seen in early diabetes.

Insulin, Muscle Glucose Uptake, and Hexokinase: Revisiting the Road Not Taken

Physiology ◽  
2021 ◽  
Author(s):  
David H. Wasserman
Keyword(s):  
Skeletal Muscle ◽  
Cell Membrane ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Hexokinase Ii ◽  
The Road ◽  
Glucose Phosphorylation ◽  
Skeletal Muscle Glucose Uptake ◽  
Cell Membrane Transport ◽  
Glucose Transporter Glut4

Research conducted over the last 50 years has provided insight into the mechanisms by which insulin stimulates glucose transport across the skeletal muscle cell membrane. Transport alone, however, does not result in net glucose uptake as freeglucose equilibrates across the cell membrane and is not metabolized. Glucose uptake requires that glucose is phosphorylated by hexokinases. Phosphorylated glucosecannot leave the cell and is the substrate for metabolism. It is indisputable that glucose phosphorylation is essential for glucose uptake. Major advances have been made in defining the regulation of the insulin-stimulated glucose transporter, GLUT4, in skeletalmuscle. By contrast, the insulin-regulated hexokinase, hexokinase II parallels RobertFrost's Road Not Taken. Here the case is made that an understanding of glucosephosphorylation by hexokinase II is necessary to define the regulation of skeletal muscle glucose uptake in health and insulin resistance. Results of studies from different physiological disciplines that have elegantly described how hexokinase II can beregulated are summarized to provide a framework for potential application to skeletal muscle. Mechanisms by which hexokinase II is regulated in skeletal muscle await rigorous examination.

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