Efficient hepatic glycogen synthesis in refeeding rats requires continued carbon flow through the gluconeogenic pathway.

Newgard, Christopher B.; Moore, S. V.; Foster, Daniel W.; McGarry, Julie

doi:10.1016/s0021-9258(17)39822-8

Cited by 188 publications

(5 citation statements)

References 23 publications

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“…In addition, we found that the liver glycogen concentrations markedly increased in pentobarbital-treated rats (Ta'le' 5), and that specific radioactivity of [14C]glycogen was lower in the anaesthetized group than in the control group (Table 5), suggesting that the net accumulation of liver glycogen caused by pentobarbital treatment was not entirely due to gluconeogenesis, but also a consequence of an accelerated glycogen synthesis via the direct pathway, i.e. glucose-- keeping with the report [8] of enhanced glycogen repletion after intravenous glucose infusion in the pentobarbital-anaesthesized rat, probably owing to activation of the direct pathway for hepatic glycogen synthesis. Certainly this condition represents an interesting model in which to investigate the possible regulating mechanisms of the direct and indirect pathways for glycogen synthesis in the liver, and deserves further study.…”

Section: Non-esterified Fattysupporting

confidence: 80%

“…However, gluconeogenesis also accomplishes other metabolic functions. It is the source of intermediates, such as glucose 6-phosphate, that can be used for glycogen synthesis [3][4][5][6], actively contributing to the repletion of liver glycogen stores during refeeding [7,8]. Furthermore, the conversion of pyruvate into hepatic acylglycerol glycerol during fasting has also been shown [9], suggesting that gluconeogenesis might also provide ac-glycerol phosphate for fatty acid esterification.…”

Section: Introductionmentioning

confidence: 99%

“…In the fasted late-pregnant rat there is a complex array of metabolic adaptations that include the appearance of hypoglycaemia, activated gluconeogenesis and accelerated catabolism of adiposetissue stores [10][11][12][13]. On the other hand, pentobarbital anaesthesia in fasted rats accelerates gluconeogenic activity and glycogen repletion after intravenous glucose infusion [8,14].…”

Section: Introductionmentioning

confidence: 99%

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Pregnancy and pentobarbital anaesthesia modify hepatic synthesis of acylglycerol glycerol and glycogen from gluconeogenic precursors during fasting in rats

Zorzano

Herrera

1988

Biochemical Journal

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1. Incorporation of gluconeogenic precursors into blood glucose and hepatic glycogen and acylglycerol glycerol was examined in 24 h-fasted virgin rats by using a flooding procedure for substrate administration. At 10 min after their intravenous injection, the conversion of alanine or glycerol into liver glycogen or acylglycerol glycerol was proportional to glucose synthesis. 2. In 24 h-fasted 21-day-pregnant rats, the incorporation of alanine and glycerol into hepatic acylglycerol glycerol was markedly enhanced compared with the control group. In addition, during fasting at late pregnancy, the proportion of substrates directed to acylglycerol glycerol as compared with the fraction incorporated into glucose was augmented. 3. In pentobarbital-treated fasted rats, the incorporation of both alanine and pyruvate into circulating glucose and into hepatic glycogen and acylglycerol glycerol was increased. Pentobarbital treatment increased the proportion of substrates incorporated into liver glycogen, compared with the fraction appearing in circulating glucose. These changes were concomitant with a marked accumulation of glycogen. 4. The data indicate that, during fasting, gluconeogenesis provides glucose as well as hepatic glycogen and acylglycerol glycerol, independently of whether the substrates enter gluconeogenesis at the level of pyruvate or dihydroxyacetone phosphate.

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Section: Non-esterified Fattysupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pregnancy and pentobarbital anaesthesia modify hepatic synthesis of acylglycerol glycerol and glycogen from gluconeogenic precursors during fasting in rats

Zorzano

Herrera

1988

Biochemical Journal

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“…7 Most of the work has focused on enzymes in the gluconeogenesis (GNG) pathway, 8 since this pathway is responsible for the excessive glucose production found in T2DM. 9 Phosphoenolpyruvate carboxykinase (PEPCK) 10 and glucose 6-phosphatase (G6Pase) 11 were the primary targets in the 1970s and 1980s. In contrast, we targeted fructose-1,6-bisphosphatase (FBPase), 12 an enzyme whose expression is regulated by the hormones insulin and glucagon and whose activity is endogenously inhibited by fructose-2,6-bisphosphate and AMP through their interactions with the substrate and allosteric binding sites, respectively.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Potent and Specific Fructose-1,6-Bisphosphatase Inhibitors and a Series of Orally-Bioavailable Phosphoramidase-Sensitive Prodrugs for the Treatment of Type 2 Diabetes

Dang¹,

Kasibhatla

Reddy

et al. 2007

J. Am. Chem. Soc.

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Excessive glucose production by the liver coupled with decreased glucose uptake and metabolism by muscle, fat, and liver results in chronically elevated blood glucose levels in patients with type 2 diabetes. Efforts to treat diabetes by reducing glucose production have largely focused on the gluconeogenesis pathway and rate-limiting enzymes within this pathway such as fructose-1,6-bisphosphatase (FBPase). The first potent FBPase inhibitors were identified using a structure-guided drug design strategy (Erion, M. D.; et al. J. Am. Chem. Soc. 2007, 129, 15480-15490) but proved difficult to deliver orally. Herein, we report the synthesis and characterization of a series of orally bioavailable FBPase inhibitors identified following the combined discoveries of a low molecular weight inhibitor series with increased potency and a phosphonate prodrug class suitable for their oral delivery. The lead inhibitor, 10A, was designed with the aid of X-ray crystallography and molecular modeling to bind to the allosteric AMP binding site of FBPase. High potency (IC50 = 16 nM) and FBPase specificity were achieved by linking a 2-aminothiazole with a phosphonic acid. Free-energy perturbation calculations provided insight into the factors that contributed to the high binding affinity. 10A and standard phosphonate prodrugs of 10A exhibited poor oral bioavailability (0.2-11%). Improved oral bioavailability (22-47%) was achieved using phosphonate diamides that convert to the corresponding phosphonic acid by sequential action of an esterase and a phosphoramidase. Oral administration of the lead prodrug, MB06322 (30, CS-917), to Zucker Diabetic Fatty rats led to dose-dependent inhibition of gluconeogenesis and endogenous glucose production and consequently to significant blood glucose reduction.

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“…Physiologic concentration of glucose could not effectively promote glycogen synthesis when glucose was the sole substrate and efficient glycogen synthesis occurred when gluconeogenic precursors were added [ 133 ]. It has been proven that the gluconeogenic pathway contributes for 50–70% of newly synthesized glycogen during the postprandial state [ 134 , 135 , 136 ]. To mimic the phosphorylation site found in CBP, a phosphorylation-competent P300G422S knock-in mouse model was generated.…”

Section: Regulation Of Liver Metabolism By Coactivators and Corepressorsmentioning

confidence: 99%

Regulation of Liver Glucose and Lipid Metabolism by Transcriptional Factors and Coactivators

Ramatchandirin

Pearah

2023

Life

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The prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide is on the rise and NAFLD is becoming the most common cause of chronic liver disease. In the USA, NAFLD affects over 30% of the population, with similar occurrence rates reported from Europe and Asia. This is due to the global increase in obesity and type 2 diabetes mellitus (T2DM) because patients with obesity and T2DM commonly have NAFLD, and patients with NAFLD are often obese and have T2DM with insulin resistance and dyslipidemia as well as hypertriglyceridemia. Excessive accumulation of triglycerides is a hallmark of NAFLD and NAFLD is now recognized as the liver disease component of metabolic syndrome. Liver glucose and lipid metabolisms are intertwined and carbon flux can be used to generate glucose or lipids; therefore, in this review we discuss the important transcription factors and coactivators that regulate glucose and lipid metabolism.

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Efficient hepatic glycogen synthesis in refeeding rats requires continued carbon flow through the gluconeogenic pathway.

Cited by 188 publications

References 23 publications

Pregnancy and pentobarbital anaesthesia modify hepatic synthesis of acylglycerol glycerol and glycogen from gluconeogenic precursors during fasting in rats

Pregnancy and pentobarbital anaesthesia modify hepatic synthesis of acylglycerol glycerol and glycogen from gluconeogenic precursors during fasting in rats

Discovery of Potent and Specific Fructose-1,6-Bisphosphatase Inhibitors and a Series of Orally-Bioavailable Phosphoramidase-Sensitive Prodrugs for the Treatment of Type 2 Diabetes

Regulation of Liver Glucose and Lipid Metabolism by Transcriptional Factors and Coactivators

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