Hexokinase II Overexpression Improves Exercise-Stimulated But Not Insulin-Stimulated Muscle Glucose Uptake in High-Fat-Fed C57BL/6J Mice

Fueger, Patrick T.; Bracy, Deanna P.; Malabanan, Carlo M.; Pencek, Richard; Granner, Daryl K.; Wasserman, David H.

doi:10.2337/diabetes.53.2.306

Cited by 63 publications

(89 citation statements)

References 49 publications

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“…As HK2 is involved in the process of anabolism (Sebastian et al, 2000;Southworth et al, 2007), the above results suggest that HK2 may play an important role in milk synthesis in the lactating bovine mammary gland. The expression of HK2 is closely associated with glucose transport (Ong et al, 2008;Chehtane and Khaled, 2010), and over-expression of HK2 usually induced increase of glucose uptake (Fueger et al, 2004). Therefore, it is possible that HK2 plays an important role in the regulation of glucose uptake by the BMEC.…”

Section: Discussionmentioning

confidence: 99%

Effect of glucose availability on glucose transport in bovine mammary epithelial cells

Zhao

Liu

Wang

et al. 2012

Animal

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Primary bovine mammary epithelial cells (BMEC) were cultured in media containing varying concentrations of glucose, to determine the effects of glucose availability on glucose transport and its mechanism in bovine mammary gland. The BMEC incubated with 10 and 20 mM glucose had twofold greater glucose uptake than that with 2.5 mM glucose (P , 0.05). Increased glucose availability enhanced the cell proliferation (P , 0.05). As the glucose uptake is mediated by facilitative glucose transporters (GLUTs), the expression of GLUT mRNA was investigated. Compared with the control (2.5 mM), 5 and 10 mM glucose did not influence the abundance of GLUT1 mRNA (P , 0.05), whereas 20 mM glucose decreased the GLUT1 mRNA expression in the BMEC (P , 0.05). The expression of GLUT8 mRNA was not affected by any concentration of glucose (P . 0.05). As GLUTs are coupled with hexokinases (HKs) in regulating glucose uptake, the expression of HKs and their activities were also studied. The HK activity was greater in 5, 10 and 20 mM glucose than that in 2.5 mM glucose (P , 0.05). The expression of HK2 mRNA rather than HK1 mRNA was detected in the BMEC; however, the abundance of HK2 mRNA was not elevated by any concentrations of glucose compared with control (P . 0.05). Furthermore, addition of 3-bromopyruvate (30, 50 or 70 mM), an inhibitor of HK2, resulted in the decrease of glucose uptake and cell proliferation at both 2.5 and 10 mM glucose (P , 0.05). Therefore, the glucose concentrations may affect glucose uptake partly by altering the activity of HKs, and HK2 may play an important role in the regulation of glucose uptake in the BMEC.

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Section: Discussionmentioning

confidence: 99%

Effect of glucose availability on glucose transport in bovine mammary epithelial cells

Zhao

Liu

Wang

et al. 2012

Animal

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“…** p=0.01, † p=0.007 as determined by paired Student's t test NA, not applicable of glycolytic enzymes (e.g. hexokinase and phosphofructokinase), which can be rate limiting for glucose uptake under insulin-stimulated conditions or during exercise [24,25]. Measurement of hexokinase activity revealed a significant increase in response to Nur77 expression in chow-fed animals.…”

Section: Downstream Targets Of Nur77mentioning

confidence: 99%

Overexpression of the orphan receptor Nur77 alters glucose metabolism in rat muscle cells and rat muscle in vivo

et al. 2010

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Aims/hypothesis A hallmark feature of the metabolic syndrome is abnormal glucose metabolism which can be improved by exercise. Recently the orphan nuclear receptor subfamily 4, group A, member 1 (NUR77) was found to be induced by exercise in muscle and was linked to transcriptional control of genes involved in lipid and glucose metabolism. Here we investigated if overexpression of Nur77 (also known as Nr4a1) in skeletal muscle has functional consequences for lipid and/or glucose metabolism. Methods L6 rat skeletal muscle myotubes were infected with a Nur77-coding adenovirus and lipid and glucose oxidation was measured. Nur77 was also overexpressed in skeletal muscle of chow-and fat-fed rats and the effects on glucose and lipid metabolism evaluated. Results Nur77 overexpression had no effect on lipid oxidation in L6 cells or rat muscle, but did increase glucose oxidation and glycogen synthesis in L6 cells. In chow-and high-fat-fed rats, Nur77 overexpression by electrotransfer significantly increased basal glucose uptake and glycogen synthesis, but no increase in insulin-stimulated glucose metabolism was observed. Nur77 electrotransfer was associated with increased production of GLUT4 and glycogenin and increased hexokinase and phosphofructokinase activity. Interestingly, Nur77 expression in muscle biopsies from obese men was significantly lower than in those from lean men and was closely correlated with bodyfat content and insulin sensitivity. Conclusions/interpretation Our data provide compelling evidence that NUR77 is a functional regulator of glucose metabolism in skeletal muscle in vivo. Importantly, the diminished content in muscle of obese insulin-resistant men suggests that it might be a potential therapeutic target for the treatment of dysregulated glucose metabolism.

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“…The corollary to these findings is that hexokinase and glycogen synthase activators are probably not very good targets to reverse insulin resistance in skeletal muscle. Indeed, mice with overexpression of hexokinase in skeletal muscle (23) and rats treated with a glycogen synthase kinase-3 inhibitor to activate glycogen synthase (24) were not protected from fat-induced insulin resistance in skeletal muscle.…”

Section: Early Defects In the Pathogenesis Of Type 2 Diabetesmentioning

confidence: 99%

Molecular Mechanisms of Insulin Resistance in Humans and Their Potential Links With Mitochondrial Dysfunction

2006

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Recent studies using magnetic resonance spectroscopy have shown that decreased insulin-stimulated muscle glycogen synthesis due to a defect in insulin-stimulated glucose transport activity is a major factor in the pathogenesis of type 2 diabetes. The molecular mechanism underlying defective insulin-stimulated glucose transport activity can be attributed to increases in intramyocellular lipid metabolites such as fatty acyl CoAs and diacylglycerol, which in turn activate a serine/threonine kinase cascade, thus leading to defects in insulin signaling through Ser/Thr phosphorylation of insulin receptor substrate (IRS)-1. A similar mechanism is also observed in hepatic insulin resistance associated with nonalcoholic fatty liver, which is a common feature of type 2 diabetes, where increases in hepatocellular diacylglycerol content activate protein kinase C-, leading to reduced insulin-stimulated tyrosine phosphorylation of IRS-2. More recently, magnetic resonance spectroscopy studies in healthy lean elderly subjects and healthy lean insulin-resistant offspring of parents with type 2 diabetes have demonstrated that reduced mitochondrial function may predispose these individuals to intramyocellular lipid accumulation and insulin resistance. Further analysis has found that the reduction in mitochondrial function in the insulin-resistant offspring can be mostly attributed to reductions in mitochondrial density. By elucidating the cellular and molecular mechanisms responsible for insulin resistance, these studies provide potential new targets for the treatment and prevention of type 2 diabetes. Diabetes 55 (Suppl. 2):S9 -S15, 2006 T ype 2 diabetes is rapidly emerging as one of the greatest global health challenges of the 21st century. The World Health Organization estimates that by the year 2030, ϳ366 million people will be afflicted with diabetes (1). This looming epidemic is also expected to trigger a steep rise in the complications associated with diabetes, such as ischemic heart disease, stroke, neuropathy, retinopathy, and nephropathy.Developing better treatments and novel prevention strategies for type 2 diabetes is therefore a matter of great urgency. To accomplish this goal, it is necessary to better understand the pathogenesis of type 2 diabetes. Although the underlying cause remains unknown, recent studies have clearly demonstrated that insulin resistance plays a critical role in the development of type 2 diabetes (2-5). This brief review will focus on recent magnetic resonance spectroscopy (MRS) studies that have shed new light on the cellular and molecular mechanisms of insulin resistance in humans. EARLY DEFECTS IN THE PATHOGENESIS OF TYPE 2 DIABETESOver the past 2 decades, our group has extensively used in vivo MRS to noninvasively probe the cellular and molecular mechanisms of insulin resistance in humans. This technique is ideal for human studies, since it is capable of monitoring particular intracellular metabolite concentrations and kinetics noninvasively and in real time (6 -22). Furthermore, in contrast...

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Hexokinase II Overexpression Improves Exercise-Stimulated But Not Insulin-Stimulated Muscle Glucose Uptake in High-Fat-Fed C57BL/6J Mice

Cited by 63 publications

References 49 publications

Effect of glucose availability on glucose transport in bovine mammary epithelial cells

Effect of glucose availability on glucose transport in bovine mammary epithelial cells

Overexpression of the orphan receptor Nur77 alters glucose metabolism in rat muscle cells and rat muscle in vivo

Molecular Mechanisms of Insulin Resistance in Humans and Their Potential Links With Mitochondrial Dysfunction

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