Measurement of Glucose Homeostasis In Vivo: Combination of Tracers and Clamp Techniques

Shiota, Masakazu

doi:10.1007/978-1-62703-068-7_15

Cited by 15 publications

(13 citation statements)

References 27 publications

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“…Two weeks before each study (Fig. 1, C and D), surgery was performed to place sterile silicon rubber catheters in the left common carotid artery, the right external jugular vein, and the stomach, as described previously (10,15,16,38). Mixed-meal tolerance (MTT) studies were conducted in 20-h-fasted conscious rats that were treated with either vehicle (5 ml·kg Ϫ1 ·day Ϫ1 ) or SGLT2-I (10 mg·kg Ϫ1 ·day Ϫ1 ) from 14 wk of age for 6 wk (Fig.…”

Section: Methodsmentioning

confidence: 49%

Glucotoxicity targets hepatic glucokinase in Zucker diabetic fatty rats, a model of type 2 diabetes associated with obesity

Ueta¹,

O’Brien²,

McCoy³

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Ueta K, O'Brien TP, McCoy GA, Kim K, Healey EC, Farmer TD, Donahue EP, Condren AB, Printz RL, Shiota M. Glucotoxicity targets hepatic glucokinase in Zucker diabetic fatty rats, a model of type 2 diabetes associated with obesity. Am J Physiol Endocrinol Metab 306: E1225-E1238, 2014. First published April 8, 2014 doi:10.1152/ajpendo.00507.2013.-A loss of glucose effectiveness to suppress hepatic glucose production as well as increase hepatic glucose uptake and storage as glycogen is associated with a defective increase in glucose phosphorylation catalyzed by glucokinase (GK) in Zucker diabetic fatty (ZDF) rats. We extended these observations by investigating the role of persistent hyperglycemia (glucotoxicity) in the development of impaired hepatic GK activity in ZDF rats. We measured expression and localization of GK and GK regulatory protein (GKRP), translocation of GK, and hepatic glucose flux in response to a gastric mixed meal load (MMT) and hyperglycemic hyperinsulinemic clamp after 1 or 6 wk of treatment with the sodiumglucose transporter 2 inhibitor (canaglifrozin) that was used to correct the persistent hyperglycemia of ZDF rats. Defective augmentation of glucose phosphorylation in response to a rise in plasma glucose in ZDF rats was associated with the coresidency of GKRP with GK in the cytoplasm in the midstage of diabetes, which was followed by a decrease in GK protein levels due to impaired posttranscriptional processing in the late stage of diabetes. Correcting hyperglycemia from the middle diabetic stage normalized the rate of glucose phosphorylation by maintaining GK protein levels, restoring normal nuclear residency of GK and GKRP under basal conditions and normalizing translocation of GK from the nucleus to the cytoplasm, with GKRP remaining in the nucleus in response to a rise in plasma glucose. This improved the liver's metabolic ability to respond to hyperglycemic hyperinsulinemia. Glucotoxicity is responsible for loss of glucose effectiveness and is associated with altered GK regulation in the ZDF rat. glucotoxicity; hepatic glucose flux; glucokinase; type 2 diabetes; sodium-glucose cotransporter 2 inhibitor

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Section: Methodsmentioning

confidence: 49%

Glucotoxicity targets hepatic glucokinase in Zucker diabetic fatty rats, a model of type 2 diabetes associated with obesity

Ueta¹,

O’Brien²,

McCoy³

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

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“…Surgery for implanting the catheters was performed 7 days before each experiment as previously described 45 . Rats were anesthetized with isoflurane.…”

Section: Methodsmentioning

confidence: 99%

Metabolic network-based predictions of toxicant-induced metabolite changes in the laboratory rat

Pannala

Wall

Estes

et al. 2018

Sci Rep

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In order to provide timely treatment for organ damage initiated by therapeutic drugs or exposure to environmental toxicants, we first need to identify markers that provide an early diagnosis of potential adverse effects before permanent damage occurs. Specifically, the liver, as a primary organ prone to toxicants-induced injuries, lacks diagnostic markers that are specific and sensitive to the early onset of injury. Here, to identify plasma metabolites as markers of early toxicant-induced injury, we used a constraint-based modeling approach with a genome-scale network reconstruction of rat liver metabolism to incorporate perturbations of gene expression induced by acetaminophen, a known hepatotoxicant. A comparison of the model results against the global metabolic profiling data revealed that our approach satisfactorily predicted altered plasma metabolite levels as early as 5 h after exposure to 2 g/kg of acetaminophen, and that 10 h after treatment the predictions significantly improved when we integrated measured central carbon fluxes. Our approach is solely driven by gene expression and physiological boundary conditions, and does not rely on any toxicant-specific model component. As such, it provides a mechanistic model that serves as a first step in identifying a list of putative plasma metabolites that could change due to toxicant-induced perturbations.

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“…At the end of the clamp, the rats were anesthetized, and tissue samples were frozen in liquid nitrogen and stored at −80 °C for subsequent analysis. Insulin sensitivity was computed with previously described formulas 60 .…”

Section: Methodsmentioning

confidence: 99%

Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery

Wei

Sun

et al. 2018

Cell Discov

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Insulin is critical for glucose homeostasis, and insulin deficiency or resistance leads to the development of diabetes. Recent evidence suggests that diabetes can be remitted independent of insulin. However, the underlying mechanism remains largely elusive. In this study, we utilized metabolic surgery as a tool to identify the non-insulin determinant mechanism. Here, we report that the most common metabolic surgery, Roux-en-Y gastric bypass (RYGB), reduced insulin production but persistently maintained euglycemia in healthy Sprague-Dawley (SD) rats and C57 mice. This reduction in insulin production was associated with RYGB-mediated inhibition of pancreatic preproinsulin and polypyrimidine tract-binding protein 1. In addition, RYGB also weakened insulin sensitivity that was evaluated by hyperinsulinemic-euglycemic clamp test and downregulated signaling pathways in insulin-sensitive tissues. The mechanistic evidence suggests that RYGB predominately shifted the metabolic profile from glucose utilization to fatty acid oxidation, enhanced the energy expenditure and activated multiple metabolic pathways through reducing gut energy uptake. Importantly, the unique effect of RYGB was extended to rats with islet disruption and patients with type 2 diabetes. These results demonstrate that compulsory rearrangement of the gastrointestinal tract can initiate non-insulin determinant pathways to maintain glucose homeostasis. Based on the principle of RYGB action, the development of a noninvasive intervention of the gastrointestinal tract is a promising therapeutic route to combat disorders characterized by energy metabolism dysregulation.

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Measurement of Glucose Homeostasis In Vivo: Combination of Tracers and Clamp Techniques

Cited by 15 publications

References 27 publications

Glucotoxicity targets hepatic glucokinase in Zucker diabetic fatty rats, a model of type 2 diabetes associated with obesity

Glucotoxicity targets hepatic glucokinase in Zucker diabetic fatty rats, a model of type 2 diabetes associated with obesity

Metabolic network-based predictions of toxicant-induced metabolite changes in the laboratory rat

Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery

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