PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance

Crosson, Sean M.; Khan, Ahmir H.; Printen, John A.; Pessin, Jeffrey E.; Saltiel, Alan R.

doi:10.1172/jci200317975

Cited by 44 publications

(53 citation statements)

References 56 publications

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“…The latter study depended on a single embryonic stem cell line. Disruption of the gene encoding the ubiquitously expressed protein targeting to glycogen type 1 phosphatase glycogen-targeting subunit (34) was lethal, but heterozygotes for the null mutation had less active glycogen synthase and reduced glycogen stores in several tissues (35). These animals acquire insulin resistance and glucose intolerance with aging.…”

Section: Discussionmentioning

confidence: 99%

Glucose Metabolism in Mice Lacking Muscle Glycogen Synthase

et al. 2005

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Glycogen is an important component of whole-body glucose metabolism. MGSKO mice lack skeletal muscle glycogen due to disruption of the GYS1 gene, which encodes muscle glycogen synthase. MGSKO mice were 5-10% smaller than wild-type littermates with less body fat. They have more oxidative muscle fibers and, based on the activation state of AMP-activated protein kinase, more capacity to oxidize fatty acids. Blood glucose in fed and fasted MGSKO mice was comparable to wild-type littermates. Serum insulin was lower in fed but not in fasted MGSKO animals. In a glucose tolerance test, MGSKO mice disposed of glucose more effectively than wild-type animals and had a more sustained elevation of serum insulin. This result was not explained by increased conversion to serum lactate or by enhanced storage of glucose in the liver. However, glucose infusion rate in a euglycemic-hyperinsulinemic clamp was normal in MGSKO mice despite diminished muscle glucose uptake. During the clamp, MGSKO animals accumulated significantly higher levels of liver glycogen as compared with wild-type littermates. Although disruption of the GYS1 gene negatively affects muscle glucose uptake, overall glucose tolerance is actually improved, possibly because of a role for GYS1 in tissues other than muscle. Diabetes 54: 3466 -3473, 2005 A fter a meal, glucose is distributed into various tissues of the body where it can be utilized as an energy source or stored as glycogen (1). Glycogen is a branched polymer of glucose residues connected by ␣-1,4-glycosidic linkages formed by the enzyme glycogen synthase (EC 2.4.1.11) and branchpoints formed via ␣-1,6-glycosidic linkages, introduced by the branching enzyme (EC 2.4.1.18). There are two mammalian isoforms of glycogen synthase. One, encoded by the GYS2 gene, appears to be expressed only in liver (2) while a second gene, GYS1, is expressed in skeletal and cardiac muscle as well as adipose tissue, kidney, and brain (3).Estimates of the contribution of skeletal muscle glycogen to glucose disposal after ingestion of carbohydrate vary. In humans, reports of ingested glucose conversion to muscle glycogen range from ϳ40% (4) up to 90% (5). It is widely accepted that muscle is an important site for glucose disposal and one might hypothesize that, in the absence of muscle glycogen, glucose clearance would be impaired. Consistent with this hypothesis, mutations in the GYS1 gene in humans have been implicated in certain diabetic populations with, for example, the Pro442Ala mutation resulting in decreased muscle glycogen synthase activity (6).We recently described the MGSKO mouse, in which the GYS1 gene is disrupted (7). Analysis of MGSKO mice confirmed the long-held supposition that glycogen synthase is required for glycogen synthesis since these animals were devoid of glycogen in cardiac and skeletal muscle (7). In the present study, we analyzed a number of metabolic parameters in the MGSKO mouse, including whole-body glucose metabolism, with an initial hypothesis that mice lacking the ability to synthesize muscl...

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Section: Discussionmentioning

confidence: 99%

Glucose Metabolism in Mice Lacking Muscle Glycogen Synthase

et al. 2005

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“…Combined intraperitoneal glucose tolerance test (IPGTT) and 2-deoxyglucose tracer uptake. A 7.4 MBq/ml solution of 2-deoxy-D- [1-14 C] glucose (Amersham Biosciences) in 50% glucose/0.9% saline was prepared and injected at 2 g/kg body weight, ϳ0.37 MBq into overnight-starved mice (24). Blood was collected from the tail tip at 0, 15, 30, 45, 60, and 90 min postinjection and blood glucose measured immediately using an Accu-Check Advantage meter (Roche Diagnostics, New South Wales, Australia).…”

Section: Methodsmentioning

confidence: 99%

Acute Bidirectional Manipulation of Muscle Glucose Uptake by In Vivo Electrotransfer of Constructs Targeting Glucose Transporter Genes

Cleasby

Davey²,

Reinten³

et al. 2005

Diabetes

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Analysis of conventional germ-line or tissue-specific gene manipulation in vivo is potentially confounded by developmental adaptation of animal physiology. We aimed to adapt the technique of in vivo electrotransfer (IVE) to alter local gene expression in skeletal muscle of rodents as a means of investigating the role of specific proteins in glucose metabolism in vivo. We utilized a square-wave electroporator to induce intracellular electrotransfer of DNA constructs injected into rat or mouse muscles and investigated the downstream effects. In initial studies, expression of green fluorescent protein reporter was induced in 53 ؎ 10% of muscle fibers peaking at 7 days, and importantly, the electrotransfer procedure itself did not impact upon the expression of stress proteins or our ability to detect a reduction in 2-deoxyglucose tracer uptake by electroporated muscle of high-fat-fed rats during hyperinsulinemic-euglycemic clamp. To demonstrate functional effects of electrotransfer of constructs targeting glucose transporters, we administered vectors encoding GLUT-1 cDNA and GLUT-4 short hairpin RNAs (shRNAs) to rodent muscles. IVE of the GLUT-1 gene resulted in a 57% increase in GLUT-1 protein, accompanied by a proportionate increase in basal 2-deoxyglucose tracer uptake into muscles of starved rats. IVE of vectors expressing two shRNAs for GLUT-4 demonstrated to reduce specific protein expression and 2-deoxyglucose tracer uptake in 3T3-L1 adipocytes into mouse muscle caused a 51% reduction in GLUT-4 protein, associated with attenuated clearance of tracer to muscle after a glucose load. These results confirm that glucose transporter expression is largely rate limiting for glucose uptake in vivo and highlight the utility of IVE for the acute manipulation of muscle gene expression in the study of the role of specific proteins in glucose metabolism. Diabetes 54:2702-2711, 2005

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“…19 In brief, 50 --150 mg frozen tissue samples were digested in a suitable volume of 30% KOH for 10 min at 100 1C. Digestion was completed by the addition of 1/5 volume of 20% NaSO 4 .…”

Section: Histology and Morphometric Measurementsmentioning

confidence: 99%

Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity

Mouche

Sajic

et al. 2012

Int J Obes

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OBJECTIVE: NADPH oxidase 4 (NOX4) is a reactive oxygen species (ROS) producing NADPH oxidase that regulates redox homeostasis in diverse insulin-sensitive cell types. In particular, NOX4-derived ROS is a key modulator of adipocyte differentiation and mediates insulin receptor signaling in mature adipocytes in vitro. Our study was aimed at investigating the role of NOX4 in adipose tissue differentiation, whole body metabolic homeostasis and insulin sensitivity in vivo. DESIGN: Mice with genetic ablation of NOX4 (NOX4-deficient mice) were subjected to chow or high-fat-containing diet for 12 weeks. Body weight gain, adiposity, insulin sensitivity, and adipose tissue and liver gene and protein expression were analyzed and compared with similarly treated wild-type mice. RESULTS: Here, we report that NOX4-deficient mice display latent adipose tissue accumulation and are susceptible to diet-induced obesity and early onset insulin resistance. Obesity results from accelerated adipocyte differentiation and hypertrophy, and an increase in whole body energy efficiency. Insulin resistance is associated with increased adipose tissue hypoxia, inflammation and adipocyte apoptosis. In the liver, more severe diet-induced steatosis was observed due to the lack of proper upregulation of mitochondrial fatty acid b-oxidation. CONCLUSION: These findings identify NOX4 as a regulator of metabolic homeostasis. Moreover, they indicate an anti-adipogenic role for NOX4 in vivo and reveal its function as a protector against the development of diet-induced obesity, insulin resistance and hepatosteatosis.

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PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance

Cited by 44 publications

References 56 publications

Glucose Metabolism in Mice Lacking Muscle Glycogen Synthase

Glucose Metabolism in Mice Lacking Muscle Glycogen Synthase

Acute Bidirectional Manipulation of Muscle Glucose Uptake by In Vivo Electrotransfer of Constructs Targeting Glucose Transporter Genes

Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity

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