Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1

Protein deacetylase Sirt1 has been implicated in the regulation of hepatic gluconeogenesis; however, the mechanisms are not fully understood. To further elucidate how Sirt1 regulates gluconeogenesis, we took a loss-of-function approach by deleting the coding DNA sequence for the catalytic domain of the Sirt1 gene in the liver of a wild-type mouse (LKOSirt1) or a genetic diabetic mouse in which hepatic insulin receptor substrates 1 and 2 are deleted (DKOIrs1/2). Whereas LKOSirt1 mice exhibited normal levels of fasting and fed blood glucose, inactivation of Sirt1 in DKOIrs1/2 mice (TKOIrs1/2:Sirt1) reduced blood glucose levels and moderately improved systemic glucose tolerance. Pyruvate tolerance was also significantly improved in TKOIrs1/2:Sirt1 mice, suggesting that Sirt1 promotes hepatic gluconeogenesis in this diabetic mouse model. To understand why inactivation of hepatic Sirt1 does not alter blood glucose levels in the wild-type background, we searched for a potential cause and found that expression of small heterodimer partner (SHP, encoded by the Nr0b2 gene), an orphan nuclear receptor, which has been shown to suppress the activity of forkhead transcription factor FoxO1, was decreased in the liver of LKOSirt1 mice. Furthermore, our luciferase reporter assays and chromatin immunoprecipitation analysis revealed that the Nr0b2 gene is a target of FoxO1, which is also regulated by Sirt1. After the gene is upregulated, Nr0b2 can feed back and repress FoxO1- and Sirt1-activated G6pc and Pdk4 gene expression. Thus, our results suggest that Sirt1 can both positively and negatively regulate hepatic gluconeogenesis through FoxO1 and Nr0b2 and keep this physiological process in control.

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

Journal of Diabetes Research ◽

10.1155/2014/961732 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 4

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.

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Sam68 promotes hepatic gluconeogenesis via CRTC2

Nature Communications ◽

10.1038/s41467-021-23624-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Aijun Qiao ◽

Junlan Zhou ◽

Shiyue Xu ◽

Wenxia Ma ◽

Chan Boriboun ◽

...

Keyword(s):

Blood Glucose ◽

Therapeutic Target ◽

Rna Binding ◽

Adaptor Protein ◽

Diabetic Mouse ◽

Mrna Levels ◽

Hepatic Gluconeogenesis ◽

Kinase Substrate ◽

Glucose Levels ◽

Patients With Diabetes

AbstractHepatic gluconeogenesis is essential for glucose homeostasis and also a therapeutic target for type 2 diabetes, but its mechanism is incompletely understood. Here, we report that Sam68, an RNA-binding adaptor protein and Src kinase substrate, is a novel regulator of hepatic gluconeogenesis. Both global and hepatic deletions of Sam68 significantly reduce blood glucose levels and the glucagon-induced expression of gluconeogenic genes. Protein, but not mRNA, levels of CRTC2, a crucial transcriptional regulator of gluconeogenesis, are >50% lower in Sam68-deficient hepatocytes than in wild-type hepatocytes. Sam68 interacts with CRTC2 and reduces CRTC2 ubiquitination. However, truncated mutants of Sam68 that lack the C- (Sam68ΔC) or N-terminal (Sam68ΔN) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68ΔN mice recapitulate the blood-glucose and gluconeogenesis profile of Sam68-deficient mice. Hepatic Sam68 expression is also upregulated in patients with diabetes and in two diabetic mouse models, while hepatocyte-specific Sam68 deficiencies alleviate diabetic hyperglycemia and improves insulin sensitivity in mice. Thus, our results identify a role for Sam68 in hepatic gluconeogenesis, and Sam68 may represent a therapeutic target for diabetes.

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MON-613 The Expression of TBC1 Domain Family, Member 4 (TBC1D4) in Skeletal Muscles of Insulin-Resistant Mice in Response to Sulforaphane

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.554 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Nasser M Rizk ◽

Amina Saleh ◽

Abdelrahman ElGamal ◽

Dina Elsayegh ◽

Isin Cakir ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Blood Glucose ◽

Insulin Sensitivity ◽

Skeletal Muscles ◽

Glucose Disposal ◽

Domain Family ◽

Insulin Resistant ◽

Glucose Levels ◽

Blood Glucose Levels

Abstract The Expression of TBC1 Domain Family, member 4 (TBC1D4) in Skeletal Muscles of Insulin-Resistant Mice in Response to Sulforaphane. Background: Obesity is commonly accompanied by impaired glucose homeostasis. Decreased glucose transport to the peripheral tissues, mainly skeletal muscle, leads to reduced total glucose disposal and hyperglycemia. TBC1D4 gene is involved in the trafficking of GLUT4 to the outer cell membrane in skeletal muscle. Sulforaphane (SFN) has been suggested as a new potential anti-diabetic compound acting by reducing blood glucose levels through mechanisms not fully understood (1). The aim of this study is to investigate the effects SFN on TBC1D4 and GLUT4 gene expression in skeletal muscles of DIO mice, in order to elucidate the mechanism(s) through which SFN improves glucose homeostasis. Methodology: C57BL/6 mice (n=20) were fed with a high fat diet (60%) for 16 weeks to generate diet induced obese (DIO) mice with body weights between 45–50 gm. Thereafter, DIO mice received either SFN (5mg/kg BW) (n=10) or vehicle (n=10) as controls daily by intraperitoneal injections for four weeks. Glucose tolerance test (1g/kg BW, IP) and insulin sensitivity test (ITT) were conducted (1 IU insulin/ g BW, IP route) at the beginning and end of the third week of the injection. At the end of 4 weeks of the injection, samples of blood and skeletal muscles of both hindlimbs were collected. The expression levels of GLUT4 and TBC1D4 genes were analyzed by qRT-PCR. Blood was also used for glucose, adiponectin and insulin measurements. Results: SFN-treated DIO mice had significantly lower non-fasting blood glucose levels than vehicle-treated mice (194.16 ± 14.12 vs. 147.44 ± 20.31 mg/dL, vehicle vs. SFN, p value=0.0003). Furthermore, GTT results indicate that the blood glucose levels at 120 minutes after glucose infusion in was (199.83±34.53 mg/dl vs. 138.55±221.78 mg/dl) for vehicle vs. SFN with p=0.0011 respectively. ITT showed that SFN treatment did not enhance insulin sensitivity in DIO mice. Additionally, SFN treatment did not significantly change the expression of TBC1D4, and GLUT4 genes in skeletal muscles compared to vehicle treatment (p values >0.05). Furthermore, SFN treatment did not significantly affect the systemic insulin (1.84±0.74 vs 1.54±0.55 ng/ml, p=0.436), or adiponectin (11.96 ±2.29 vs 14.4±3.33 ug/ml, p=0.551) levels in SFN vs. vehicle-treated DIO mice, respectively. Conclusion: SFN treatment improves glucose disposal in DIO mice, which is not linked to the gene expression of GLUT4 and TBC1D4 and its mechanism of glucose disposal in skeletal muscles. Furthermore, SFN treatment did not improve insulin level, and the insulin sensitizer hormone adiponectin as potential players for enhancing insulin sensitivity. 1. Axelsson AS, Tubbs E, Mecham B, Chacko S, Nenonen HA, Tang Y, et al. Sci Transl Med. 2017;9(394).

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Metformin suppresses hepatic gluconeogenesis and lowers fasting blood glucose levels through reactive nitrogen species in mice

Diabetologia ◽

10.1007/s00125-010-1729-5 ◽

2010 ◽

Vol 53 (7) ◽

pp. 1472-1481 ◽

Cited By ~ 22

Author(s):

Y. Fujita ◽

M. Hosokawa ◽

S. Fujimoto ◽

E. Mukai ◽

A. Abudukadier ◽

...

Keyword(s):

Blood Glucose ◽

Reactive Nitrogen Species ◽

Fasting Blood Glucose ◽

Reactive Nitrogen ◽

Nitrogen Species ◽

Hepatic Gluconeogenesis ◽

Glucose Levels ◽

Blood Glucose Levels

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Effect of reduced dietary zinc intake on carbohydrate and Zn metabolism in the genetically diabetic mouse (C57BL/KsJ db+/db+)

British Journal Of Nutrition ◽

10.1079/bjn19880122 ◽

1988 ◽

Vol 60 (3) ◽

pp. 499-507 ◽

Cited By ~ 9

Author(s):

Susan Southon ◽

Z. Kechrid ◽

A. J. A. Wright ◽

Susan J. Fairweather-Tait

Keyword(s):

Blood Glucose ◽

Control Diet ◽

Fasting Blood Glucose ◽

Liver Glycogen ◽

Diabetic Mouse ◽

Whole Body ◽

Diabetic Mice ◽

Control Groups ◽

Glucose Levels ◽

Blood Glucose Levels

1. Male, 4–5-week-old, genetically diabetic mice (C57BL/KsJ db/db) and non-diabetic heterozygote litter-mates (C57BL/KsJ db/+)were fed on a diet containing 1 mg zinc/kg (low-Zn groups) or 54 mg Zn/kg (control groups) for 27 d. Food intakes and body-weight gain were recorded regularly. On day 28, after an overnight fast, animals were killed and blood glucose and insulin concentrations, liver glycogen, and femur and pancreatic Zn concentrations were determined.2. The consumption of the low-Zn diet had only a minimal effect on the Zn status of the mice as indicated by growth rate, food intake and femur and pancreatic Zn concentrations. In fact, diabetic mice fed on the low-Zn diet had a higher total food intake than those fed on the control diet. The low-Zn diabetic mice had higher fasting blood glucose and liver glycogen levels than their control counterparts. Fasting blood insulin concentration was unaffected by dietary regimen.3. A second experiment was performed in which the rate of loss of 65Zn, injected subcutaneously, was measured by whole-body counting in the two mouse genotypes over a 28 d period, from 4 to 5 weeks of age. The influence of feeding low-Zn or control diets was also examined. At the end of the study femur and pancreatic Zn and non-fasting blood glucose levels were determined.4. All mice fed on the low-Zn diet showed a marked reduction in whole-body 65Zn loss compared with those animals fed on the control diet. In the low-Zn groups, the loss of 65Zn from the diabetic mice was significantly greater than that from heterozygote mice. This difference was not observed in the control groups. Blood glucose levels were elevated in the low-Zn groups. Possible reasons for these observations are discussed.5. The present study demonstrates an adverse effect of reduced dietary Zn intake on glucose utilization in the genetically diabetic mouse, which occurred before any significant tissue Zn depletion became apparent.

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MicroRNA-185-5p inhibits hepatic gluconeogenesis and reduces fasting blood glucose levels by suppressing G6Pase

Theranostics ◽

10.7150/thno.46882 ◽

2021 ◽

Vol 11 (16) ◽

pp. 7829-7843

Author(s):

Hui Zheng ◽

Jian Wan ◽

Yi Shan ◽

Xi Song ◽

Jie Jin ◽

...

Keyword(s):

Blood Glucose ◽

Fasting Blood Glucose ◽

Hepatic Gluconeogenesis ◽

Glucose Levels ◽

Blood Glucose Levels

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Study of the Mechanism Underlying the Onset of Diabetic Xeroderma Focusing on an Aquaporin-3 in a Streptozotocin-Induced Diabetic Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms20153782 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3782 ◽

Cited By ~ 3

Author(s):

Nobutomo Ikarashi ◽

Nanaho Mizukami ◽

Risako Kon ◽

Miho Kaneko ◽

Ryogo Uchino ◽

...

Keyword(s):

Blood Glucose ◽

Water Transport ◽

Diabetic Mouse ◽

Diabetic Patients ◽

Diabetic Mice ◽

Aquaporin 3 ◽

Expression Levels ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Site Binding

Xeroderma is a frequent complication in diabetic patients. In this study, we investigated the mechanism underlying the onset of diabetic xeroderma, focusing on aquaporin-3 (AQP3), which plays an important role in water transport in the skin. Dermal water content in diabetic mice was significantly lower than that in control mice. The expression level of AQP3 in the skin was significantly lower in diabetic mice than in control mice. One week after streptozotocin (STZ) treatment, despite their increased blood glucose levels, mice showed no changes in the expression levels of AQP3, Bmal1, Clock, and D site-binding protein (Dbp) in the skin and 8-hydroxydeoxyguanosine (8-OHdG) in the urine. In contrast, two weeks after STZ treatment, mice showed increases in the blood glucose level, decreases in AQP3, Bmal1, Clock, and Dbp levels, and increases in the urinary levels of 8-OHdG. The results of this study suggest that skin AQP3 expression decreases in diabetes, which may limit water transport from the vessel side to the corneum side, causing dry skin. In addition, in diabetic mice, increased oxidative stress triggered decreases in the expression levels of Bmal1 and Clock in the skin, thereby inhibiting the transcription of Aqp3 by Dbp, which resulted in decreased AQP3 expression.

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Nighttime Administration of Nicotine Improves Hepatic Glucose Metabolism via the Hypothalamic Orexin System in Mice

Endocrinology ◽

10.1210/en.2015-1488 ◽

2016 ◽

Vol 157 (1) ◽

pp. 195-206 ◽

Cited By ~ 10

Author(s):

Hiroshi Tsuneki ◽

Takashi Nagata ◽

Mikio Fujita ◽

Kanta Kon ◽

Naizhen Wu ◽

...

Keyword(s):

Blood Glucose ◽

Glucose Metabolism ◽

Oral Intake ◽

Mrna Levels ◽

Active Period ◽

Wild Type ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Deficient Mice

Abstract Nicotine is known to affect the metabolism of glucose; however, the underlying mechanism remains unclear. Therefore, we here investigated whether nicotine promoted the central regulation of glucose metabolism, which is closely linked to the circadian system. The oral intake of nicotine in drinking water, which mainly occurred during the nighttime active period, enhanced daily hypothalamic prepro-orexin gene expression and reduced hyperglycemia in type 2 diabetic db/db mice without affecting body weight, body fat content, and serum levels of insulin. Nicotine administered at the active period appears to be responsible for the effect on blood glucose, because nighttime but not daytime injections of nicotine lowered blood glucose levels in db/db mice. The chronic oral treatment with nicotine suppressed the mRNA levels of glucose-6-phosphatase, the rate-limiting enzyme of gluconeogenesis, in the liver of db/db and wild-type control mice. In the pyruvate tolerance test to evaluate hepatic gluconeogenic activity, the oral nicotine treatment moderately suppressed glucose elevations in normal mice and mice lacking dopamine receptors, whereas this effect was abolished in orexin-deficient mice and hepatic parasympathectomized mice. Under high-fat diet conditions, the oral intake of nicotine lowered blood glucose levels at the daytime resting period in wild-type, but not orexin-deficient, mice. These results indicated that the chronic daily administration of nicotine suppressed hepatic gluconeogenesis via the hypothalamic orexin-parasympathetic nervous system. Thus, the results of the present study may provide an insight into novel chronotherapy for type 2 diabetes that targets the central cholinergic and orexinergic systems.

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Inflammation but not Glycemic Control is Associated with Neurocognitive Decline After Cardiac Surgery

10.22541/au.162349776.69083213/v1 ◽

2021 ◽

Author(s):

Laura Scrimgeour ◽

Ian Ikeda ◽

Nicholas Sellke ◽

Guangbin Shi ◽

Jun Feng ◽

...

Keyword(s):

Gene Expression ◽

Cardiac Surgery ◽

Blood Glucose ◽

Glycemic Control ◽

Transcriptome Analysis ◽

Neurocognitive Function ◽

Human Transcriptome ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Neurocognitive Decline

Background: Whether perioperative glycemic control or markers of inflammation is associated with neurocognitive decline (NCD) after cardiac surgery was examined. Methods: Thirty patients undergoing cardiac surgery utilizing cardiopulmonary bypass (CPB) were screened for NCD preoperatively and on post-operative day four (POD4). Serum cytokine levels were measured and human transcriptome analysis was performed on blood samples. Neurocognitive data are presented as a change from baseline to POD4 in a score standardized with respect to age and gender. Results: A decline in neurocognitive function was identified in 73% (22/30) of patients on POD4. Patients with postoperative leukocytosis (WBC ≥ 10.5) had more NCD when compared to their baseline function (p=0.03). Patients with elevated IL-8 levels at 6 hours postoperatively had a significant decline in NCD at POD4 (p=0.04). Surprisingly, TNF-α, IL-1β, IL-2, or IL-6 levels were not associated with NCD (p>0.3 for all). There was no difference in neurocognitive function between patients with elevated HbA1c levels preoperatively (p=0.973) or elevated fasting blood glucose levels the morning of surgery (>126mg/dL, p=0.910), or a higher maximum blood glucose levels during CPB (>180mg/dL, p=0.252), or higher average glucose levels during CPB (>160mg/dL, p=0.639). Human transcriptome analysis demonstrated unique and differential patterns of gene expression in patients depending on the presence of DM and NCD. Conclusions: Perioperative glycemic control does not have an effect on NCD soon after cardiac surgery. Postoperative leukocytosis and elevated IL-8 levels are associated with neurocognitive decline. The profile of gene expression was altered in patients with NCD with or without diabetes.

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