Effects of cadmium on hepatic gluconeogenesis in vivo and in vitro

1984 ◽  
Vol 12 (5) ◽  
pp. 794-795 ◽  
Author(s):  
IAN N. ROBINSON ◽  
KEITH SNELL
Keyword(s):  
Hepatic Gluconeogenesis

scholarly journals Evidence that the stimulation of lipogenesis in the mammary glands of starved lactating rats re-fed with a chow diet is dependent on continued hepatic gluconeogenesis during the absorptive period. Effects of a gluconeogenic inhibitory, mercaptopicolinic acid, in vivo

1985 ◽  
Vol 228 (3) ◽  
pp. 727-733 ◽  
Author(s):  
D H Williamson ◽  
V Ilic ◽  
R G Jones
Keyword(s):  
Mammary Gland ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Mammary Glands ◽  
Hepatic Glycogen ◽  
Chow Diet ◽  
Hepatic Gluconeogenesis ◽  
Rapid Stimulation ◽  
Stimulation Of

The rapid stimulation of lipogenesis in mammary gland that occurs on re-feeding starved lactating rats with a chow diet was decreased (60%) by injection of mercaptopicolinic acid, an inhibitor of hepatic gluconeogenesis at the phosphoenolpyruvate carboxykinase step. Mercaptopicolinate had no effect on lipogenesis in mammary glands of fed lactating rats. The inhibition of lipogenesis persisted in vitro when acini from mammary glands of re-fed rats treated with mercaptopicolinate were incubated with [1-14C]glucose. Mercaptopicolinate added in vitro had no significant effect on lipogenesis in acini from starved-re-fed lactating rats. Mercaptopicolinate prevented the deposition of glycogen and increased the rate of lipogenesis in livers of starved-re-fed lactating rats, whereas it had no significant effect on livers of fed lactating rats. Administration of intraperitoneal glucose restored the rate of mammary-gland lipogenesis in re-fed rats treated with mercaptopicolinate to the values for re-fed rats. Hepatic glycogen deposition was also restored, and the rate of hepatic lipogenesis was stimulated 5-fold. It is concluded that stimulation of mammary-gland lipogenesis on re-feeding with a chow diet after a period of starvation is in part dependent on continued hepatic gluconeogenesis during the absorptive period. Possible sources of the glucose precursors are discussed.

scholarly journals The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis

2012 ◽  
Vol 303 (9) ◽  
pp. E1166-E1176 ◽  
Author(s):  
Wilfred Ip ◽  
Weijuan Shao ◽  
Yu-ting Alex Chiang ◽  
Tianru Jin
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Wnt Signaling ◽  
Wnt Signaling Pathway ◽  
Glucose Production ◽  
Hepatic Gluconeogenesis

Certain single nucleotide polymorphisms (SNPs) in transcription factor 7-like 2 (TCF7L2) are strongly associated with the risk of type 2 diabetes. TCF7L2 and β-catenin (β-cat) form the bipartite transcription factor cat/TCF in stimulating Wnt target gene expression. cat/TCF may also mediate the effect of other signaling cascades, including that of cAMP and insulin in cell-type specific manners. As carriers of TCF7L2 type 2 diabetes risk SNPs demonstrated increased hepatic glucose production, we aimed to determine whether TCF7L2 expression is regulated by nutrient availability and whether TCF7L2 and Wnt regulate hepatic gluconeogenesis. We examined hepatic Wnt activity in the TOPGAL transgenic mouse, assessed hepatic TCF7L2 expression in mice upon feeding, determined the effect of insulin on TCF7L2 expression and β-cat Ser675 phosphorylation, and investigated the effect of Wnt activation and TCF7L2 knockdown on gluconeogenic gene expression and glucose production in hepatocytes. Wnt activity was observed in pericentral hepatocytes in the TOPGAL mouse, whereas TCF7L2 expression was detected in human and mouse hepatocytes. Insulin and feeding stimulated hepatic TCF7L2 expression in vitro and in vivo, respectively. In addition, insulin activated β-cat Ser675 phosphorylation. Wnt activation by intraperitoneal lithium injection repressed hepatic gluconeogenic gene expression in vivo, whereas lithium or Wnt-3a reduced gluconeogenic gene expression and glucose production in hepatic cells in vitro. Small interfering RNA-mediated TCF7L2 knockdown increased glucose production and gluconeogenic gene expression in cultured hepatocytes. These observations suggest that Wnt signaling and TCF7L2 are negative regulators of hepatic gluconeogenesis, and TCF7L2 is among the downstream effectors of insulin in hepatocytes.

scholarly journals Transcriptional repression of the gluconeogenic gene PEPCK by the orphan nuclear receptor SHP through inhibitory interaction with C/EBPα

2007 ◽  
Vol 402 (3) ◽  
pp. 567-574 ◽  
Author(s):  
Min Jung Park ◽  
Hee Jeong Kong ◽  
Hye Young Kim ◽  
Hyeong Hoe Kim ◽  
Joon Hong Kim ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Transcriptional Repression ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Regulatory Element ◽  
Direct Interaction ◽  
Orphan Nuclear Receptor ◽  
Hepatic Gluconeogenesis ◽  
Inhibitory Interaction

SHP (short heterodimer partner) is an orphan nuclear receptor that plays an important role in regulating glucose and lipid metabolism. A variety of transcription factors are known to regulate transcription of the PEPCK (phosphoenolpyruvate carboxykinase) gene, which encodes a rate-determining enzyme in hepatic gluconeogenesis. Previous reports identified glucocorticoid receptor and Foxo1 as novel downstream targets regulating SHP inhibition [Borgius, Steffensen, Gustafsson and Treuter (2002) J. Biol. Chem. 277, 49761–49796; Yamagata, Daitoku, Shimamoto, Matsuzaki, Hirota, Ishida and Fukamizu (2004) J. Biol. Chem. 279, 23158–23165]. In the present paper, we show a new molecular mechanism of SHP-mediated inhibition of PEPCK transcription. We also show that the CRE1 (cAMP regulatory element 1; −99 to −76 bp relative to the transcription start site) of the PEPCK promoter is also required for the inhibitory regulation by SHP. SHP repressed C/EBPα (CCAAT/enhancer-binding protein α)-driven transcription of PEPCK through direct interaction with C/EBPα protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPα and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription. Taken together, these results suggest that SHP might regulate a level of hepatic gluconeogenesis driven by C/EBPα activation.

scholarly journals Cellular and Molecular Mechanisms of Metformin Action

2020 ◽  
Author(s):  
Traci E LaMoia ◽  
Gerald I Shulman
Keyword(s):  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Low Cost ◽  
Mechanisms Of Action ◽  
Hepatic Gluconeogenesis ◽  
Glucose Lowering ◽  
Dependent Mechanism

Abstract Metformin is a first-line therapy for the treatment of type 2 diabetes, due to its robust glucose-lowering effects, well-established safety profile, and relatively low cost. While metformin has been shown to have pleotropic effects on glucose metabolism, there is a general consensus that the major glucose-lowering effect in patients with type 2 diabetes is mostly mediated through inhibition of hepatic gluconeogenesis. However, despite decades of research, the mechanism by which metformin inhibits this process is still highly debated. A key reason for these discrepant effects is likely due to the inconsistency in dosage of metformin across studies. Widely studied mechanisms of action, such as complex I inhibition leading to AMPK activation, have only been observed in the context of supra-pharmacological (>1 mM) metformin concentrations, which do not occur in the clinical setting. Thus, these mechanisms have been challenged in recent years and new mechanisms have been proposed. Based on the observation that metformin alters cellular redox balance, a redox-dependent mechanism of action has been described by several groups. Recent studies have shown that clinically relevant (50-100 μM) concentrations of metformin inhibit hepatic gluconeogenesis in a substrate-selective manner both in vitro and in vivo, supporting a redox-dependent mechanism of metformin action. Here, we review the current literature regarding metformin’s cellular and molecular mechanisms of action.

GdCl3 reduces hyperglycaemia through Akt/FoxO1-induced suppression of hepatic gluconeogenesis in Type 2 diabetic mice

2014 ◽  
Vol 127 (2) ◽  
pp. 91-100 ◽  
Author(s):  
Qian Wang ◽  
Ning Wang ◽  
Mei Dong ◽  
Fang Chen ◽  
Zhong Li ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Diabetic Mice ◽  
Hepatic Gluconeogenesis ◽  
Potential Therapeutic Target ◽  
Hepatocarcinoma Cells ◽  
Type 2 Diabetic

In the present study, we demonstrate that GdCl3 reduces hyperglycaemia via the Akt/FoxO1-induced suppression of hepatic gluconeogenesis, both in Type 2 diabetic mice (in vivo) and in hepatocarcinoma cells (in vitro), suggesting that GdCl3 may be a potential therapeutic target for diabetes.

scholarly journals An in Vitro Model of Post-Exercise Hepatic Gluconeogenesis in the Gulf Toadfish Opsanus Beta

1989 ◽  
Vol 147 (1) ◽  
pp. 393-406 ◽  
Author(s):  
PATRICK J. WALSH
Keyword(s):  
Isolated Hepatocytes ◽  
Blood Parameters ◽  
Strenuous Exercise ◽  
Hepatic Gluconeogenesis ◽  
Post Exercise ◽  
Opsanus Beta ◽  
Stimulation Of ◽  
Gulf Toadfish

During strenuous exercise, fish develop substantial proton and lactate loads. Although acidosis is usually rapidly corrected during recovery (1–2 h), lactate levels often remain elevated for up to 8–12 h. The quantitative role of the liver in clearance of the lactate load during recovery from exercise in fish has received little direct examination. The purposes of this study were (1) to attempt to quantify hepatic contribution to lactate clearance, and (2) to identify factors that regulate hepatic gluconeogenesis during recovery from exercise in fish. Both in vivo and in vitro (isolated hepatocytes) approaches were used. Important blood parameters (pHe, Ccoco2, [lactate], [glucose], [epinephrine] and [norepinephrine]) were measured in the gulf toadfish (Opsanus beta Goode and Bean) during recovery from strenuous exercise, and they conformed to the general patterns for sluggish benthic species noted in earlier studies. When toadfish hepatocytes wereexposed to simulated post-exercise conditions in vitro, gluconeogenesis from lactate was stimulated by over 2.5-fold in ‘0–1 h-’ and ‘l-2h-post-exercise periods’. Variation of the extracellular parameters in controlled combinations indicated that exercise-induced changes in [glucose], [epinephrine], [norepinephrine], Pcoco2 and [HCO3−] had no significant effects on rates of gluconeogenesis.The observed stimulation of gluconeogenesis could be induced independently byeither decreased pH (which lowered Km for lactate) or increased [lactate] (bysimple hyperbolic kinetic effects), but the effects were not additive. Despite thispotentially adaptive stimulation of gluconeogenesis, I estimate, based on observedin vitro rates and in vivo estimates of lactate load, that hepatic gluconeogenesisaccounts for less than 2% of the lactate load clearance in toadfish.

Plasma amino acid levels and development of hepatic gluconeogenesis in the newborn rat

1975 ◽  
Vol 229 (2) ◽  
pp. 466-473 ◽  
Author(s):  
Girard ◽  
I Guillet ◽  
J Marty ◽  
EB Marliss
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Blood Glucose Concentration ◽  
Hepatic Gluconeogenesis ◽  
Substrate Conversion ◽  
Amino Acid Levels ◽  
Gluconeogenic Substrates ◽  
Gluconeogenic Substrate

The metabolism of endogenous and exogenous amino acids has been characterized during a 16-h fast after birth in the rat. Eighteen of 22 amino acids showed a decrease in plasma concentration up to 16 h, the most profound and sustained changes affecting those quantitatively important in gluconeogenesis. The hepatic accumulation of injected [14C]aminoisobutyric acid showed a progressive rise after birth. The in vivo conversion of 14C-labeled lactate, alanine, serine, and glutamine to [14C]glucose increased for 6 h, but all except glutamine showed a decline by 16 h. The in vitro conversion of several gluconeogenic substrates (10mM), however, increased with time in each instance. These data confirm that the capacity for hepatic gluconeogenesis and maintenance of blood glucose concentration appears immediately after birth. Nevertheless, profound hypoglycemia recurs at 16 h and responds only minimally and transiently to exogenous gluconeogenic substrate loads. In contrast, the fed newborn maintains normoglycemia, higher endogenous amino acid levels, and the capacity for substrate conversion at this time. The mechanism for stimulation of hepatic gluconeogenic pathways thus is present in both fasted and fed neonatal rats. However, owing to insufficient energy sources to sustain gluconeogenesis and to inadequate gluconeogenic substrate, the rat is unable to maintain normoglycemia if fasted 16 h.

scholarly journals Sodium Meta-Arsenite Ameliorates Hyperglycemia in Obese Diabeticdb/dbMice by Inhibition of Hepatic Gluconeogenesis

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Young-Sun Lee ◽  
Eun-Kyu Lee ◽  
Hyun-Hee Oh ◽  
Cheol Soo Choi ◽  
Sujong Kim ◽  
...  
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Glucose Production ◽  
Diabetic Mouse ◽  
Hepatic Gluconeogenesis ◽  
Glucose Levels ◽  
Blood Glucose Levels

Sodium meta-arsenite (SA) is implicated in the regulation of hepatic gluconeogenesis-related genesin vitro; however, the effectsin vivohave not been studied. We investigated whether SA has antidiabetic effects in a type 2 diabetic mouse model. Diabeticdb/dbmice were orally intubated with SA (10 mg kg−1body weight/day) for 8 weeks. We examined hemoglobin A1c (HbA1c), blood glucose levels, food intake, and body weight. We performed glucose, insulin, and pyruvate tolerance tests and analyzed glucose production and the expression of gluconeogenesis-related genes in hepatocytes. We analyzed energy metabolism using a comprehensive animal metabolic monitoring system. SA-treated diabeticdb/dbmice had reduced concentrations of HbA1c and blood glucose levels. Exogenous glucose was quickly cleared in glucose tolerance tests. The mRNA expressions of genes for gluconeogenesis-related enzymes, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK) were significantly reduced in the liver of SA-treated diabeticdb/dbmice. In primary hepatocytes, SA treatment decreased glucose production and the expression of G6Pase, PEPCK, and hepatocyte nuclear factor 4 alpha (HNF-4α) mRNA. Small heterodimer partner (SHP) mRNA expression was increased in hepatocytes dependent upon the SA concentration. The expression of Sirt1 mRNA and protein was reduced, and acetylated forkhead box protein O1 (FoxO1) was induced by SA treatment in hepatocytes. In addition, SA-treated diabeticdb/dbmice showed reduced energy expenditure. Oral intubation of SA ameliorates hyperglycemia indb/dbmice by reducing hepatic gluconeogenesis through the decrease of Sirt1 expression and increase in acetylated FoxO1.

Induction and Differentiation of Dental Epithelium in Vivo and in Vitro

1982 ◽  
Vol 40 ◽  
pp. 142-145
Author(s):  
E. J. Kollar
Keyword(s):  
Connective Tissue ◽  
Oral Mucosa ◽  
Basal Lamina ◽  
Functional Derivatives ◽  
Specific Source ◽  
Dental Epithelium ◽  
Connective Tissue Stroma

The differentiation and maintenance of many specialized epithelial structures are dependent on the underlying connective tissue stroma and on an intact basal lamina. These requirements are especially stringent in the development and maintenance of the skin and oral mucosa. The keratinization patterns of thin or thick cornified layers as well as the appearance of specialized functional derivatives such as hair and teeth can be correlated with the specific source of stroma which supports these differentiated expressions.

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