Decreased fasting blood glucose is associated with impaired hepatic glucose production in thyroid-stimulating hormone receptor knockout mice

Abstract Fasting blood glucose (FBG) and hepatic glucose production are regulated according to a circadian rhythm. An early morning increase in FBG levels, which is pronounced among diabetic patients, is known as the dawn phenomenon. Although the intracellular circadian clock generates various molecular rhythms, whether the hepatic clock is involved in FBG rhythm remains unclear. To address this issue, we investigated the effects of phase shift and disruption of the hepatic clock on the FBG rhythm. In both C57BL/6J and diabetic ob/ob mice, FBG exhibited significant daily rhythms with a peak at the beginning of the dark phase. Light-phase restricted feeding altered the phase of FBG rhythm mildly in C57BL/6J mice and greatly in ob/ob mice, in concert with the phase shifts of mRNA expression rhythms of the clock and glucose production–related genes in the liver. Moreover, the rhythmicity of FBG and Glut2 expression was not detected in liver-specific Bmal1-deficient mice. Furthermore, treatment with octreotide suppressed the plasma growth hormone concentration but did not affect the hepatic mRNA expression of the clock genes or the rise in FBG during the latter half of the resting phase in C57BL/6J mice. These results suggest that the hepatic circadian clock plays a critical role in regulating the daily FBG rhythm, including the dawn phenomenon.

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P0950EFFECT OF THYROID HORMONE TREATMENT ON RENAL REABSORPTION OF GLUCOSE IN ALLOXAN-INDUCED DIABETIC RATS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0950 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Gireesh Dayma

Keyword(s):

Blood Glucose ◽

Thyroid Hormone ◽

Glucose Homeostasis ◽

Hepatic Glucose Production ◽

Liver Perfusion ◽

Glucose Production ◽

Diabetic Rats ◽

Hepatic Glucose ◽

Glucose Output ◽

Renal Expression

Abstract Background and Aims The thyroid hormone (TH) plays an important role in glucose metabolism. Recently, we showed that the TH improves glycemia control by decreasing cytokines expression in the adipose tissue and skeletal muscle of alloxan-induced diabetic rats, which were also shown to present primary hypothyroidism. In this context, this study aims to investigate whether the chronic treatment of diabetic rats with T3 could affect other tissues that are involved in the control of glucose homeostasis, as the liver and kidney. Method Adult male Wistar rats were divided into nondiabetic, diabetic, and diabetic treated with T3 (1.5 ?g/100 g BW for 4 weeks). Diabetes was induced by alloxan monohydrate (150 mg/kg, BW, i.p.). Animals showing fasting blood glucose levels greater than 250 mg/dL were selected for the study. Results After treatment, we measured the blood glucose, serum T3, T4, TSH, and insulin concentration, hepatic glucose production by liver perfusion, liver PEPCK, GAPDH, and pAKT expression, as well as urine glucose concentration and renal expression of SGLT2 and GLUT2. T3 reduced blood glucose, hepatic glucose production, liver PEPCK, GAPDH, and pAKT content and the renal expression of SGLT2 and increased glycosuria. Conclusion Results suggest that the decreased hepatic glucose output and increased glucose excretion induced by T3 treatment are important mechanisms that contribute to reduce serum concentration of glucose, accounting for the improvement of glucose homeostasis control in diabetic rats.

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Regulation of blood glucose concentration: response of liver to glucose administration

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1961.201.1.41 ◽

1961 ◽

Vol 201 (1) ◽

pp. 41-46 ◽

Cited By ~ 24

Author(s):

Bernard R. Landau ◽

Jack R. Leonards ◽

Frank M. Barry

Keyword(s):

Blood Glucose ◽

Glucose Concentration ◽

Blood Glucose Concentration ◽

Dominant Role ◽

Hepatic Glucose Production ◽

High Protein Diet ◽

Glucose Production ◽

Hepatic Veins ◽

Hepatic Glucose ◽

Glucose Output

Hepatic glucose output has been determined during the infusion of glucose in gradually increasing quantities into unanesthetized dogs with cannulas inserted in their aortas, hepatic veins and portal veins. Profound changes in hepatic response to the infusions were consequent to differences in the composition of the diets ingested by the dogs in the days prior to these experiments. Infusion of glucose into dogs maintained on a high protein diet resulted in a rise in blood glucose concentration, with a cessation of net hepatic glucose production only at hyperglycemic levels. In contrast, in carbohydrate-fed dogs the blood glucose concentration increased very little on glucose infusion, and there was a net uptake of glucose by the liver. Under these conditions the liver appears to play a dominant role in the regulation of the constancy of the blood glucose concentration, and the regulating mechanism appears to be particularly sensitive to small changes in glucose concentration.

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Relations between Blood Glucose and Hepatic Glucose Production in Newborn Dogs

BMJ ◽

10.1136/bmj.2.5814.625 ◽

1972 ◽

Vol 2 (5814) ◽

pp. 625-627 ◽

Cited By ~ 6

Author(s):

G. Hetenyi ◽

S. Varma ◽

J. S. Cowan

Keyword(s):

Blood Glucose ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Glucose

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Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00156.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. E718-E728 ◽

Cited By ~ 117

Author(s):

Jennifer Altomonte ◽

Anja Richter ◽

Sonal Harbaran ◽

Jenny Suriawinata ◽

Jun Nakae ◽

...

Keyword(s):

Blood Glucose ◽

Cultured Cells ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Diabetic Mice ◽

Hepatic Expression ◽

Glucose Levels ◽

Fasting Glycemia ◽

Blood Glucose Levels ◽

Hepatic Glucose

Excessive hepatic glucose production is a contributing factor to fasting hyperglycemia in diabetes. Insulin suppresses hepatic glucose production by inhibiting the expression of two gluconeogenic enzymes, phospho enolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase). The forkhead transcription factor Foxo1 has been implicated as a mediator of insulin action in regulating hepatic gluconeogenesis, and a Foxo1 mutant (Foxo1-Δ256), devoid of its carboxyl domain, has been shown to interfere with Foxo1 function and inhibit gluconeogenic gene expression in cultured cells. To study the effect of Foxo1-Δ256 on glucose metabolism in animals, the Foxo1-Δ256 cDNA was delivered to the livers of mice by adenovirus-mediated gene transfer. Hepatic Foxo1-Δ256 production resulted in inhibition of gluconeogenic activity, as evidenced by reduced PEPCK and G-6-Pase expression in the liver. Mice treated with the Foxo1-Δ256 vector exhibited significantly reduced blood glucose levels. In contrast, blood glucose levels in control vector-treated animals remained unchanged, which coincided with the lack of alterations in the expression levels of PEPCK and G-6-Pase. When tested in diabetic db/db mice, hepatic production of Foxo1-Δ256 was shown to reduce fasting hyperglycemia. Furthermore, we showed that hepatic Foxo1 expression was deregulated as a result of insulin resistance in diabetic mice and that Foxo1-Δ256 interfered with Foxo1 function via competitive binding to target promoters. These results demonstrated that functional inhibition of Foxo1, caused by hepatic expression of its mutant, is associated with reduced hepatic gluconeogenic activity and improved fasting glycemia in diabetic mice.

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Cell Autonomous Dysfunction and Insulin Resistance in Pancreatic α Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20153699 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3699 ◽

Cited By ~ 3

Author(s):

Norikiyo Honzawa ◽

Kei Fujimoto ◽

Tadahiro Kitamura

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Blood Glucose ◽

Current Knowledge ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Hepatic Glucose

To date, type 2 diabetes is considered to be a “bi-hormonal disorder” rather than an “insulin-centric disorder,” suggesting that glucagon is as important as insulin. Although glucagon increases hepatic glucose production and blood glucose levels, paradoxical glucagon hypersecretion is observed in diabetes. Recently, insulin resistance in pancreatic α cells has been proposed to be associated with glucagon dysregulation. Moreover, cell autonomous dysfunction of α cells is involved in the etiology of diabetes. In this review, we summarize the current knowledge about the physiological and pathological roles of glucagon.

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Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production

Cell Reports ◽

10.1016/j.celrep.2017.10.034 ◽

2017 ◽

Vol 21 (6) ◽

pp. 1452-1460 ◽

Cited By ~ 11

Author(s):

Nicolai J. Wewer Albrechtsen ◽

Rune E. Kuhre ◽

Daniel Hornburg ◽

Christian Z. Jensen ◽

Mads Hornum ◽

...

Keyword(s):

Insulin Secretion ◽

Blood Glucose ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Glucose

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Phosphorylation of Forkhead Protein FoxO1 at S253 Regulates Glucose Homeostasis in Mice

Endocrinology ◽

10.1210/en.2018-00853 ◽

2019 ◽

Vol 160 (5) ◽

pp. 1333-1347 ◽

Cited By ~ 5

Author(s):

Kebin Zhang ◽

Xiaoqin Guo ◽

Hui Yan ◽

Yuxin Wu ◽

Quan Pan ◽

...

Keyword(s):

Blood Glucose ◽

Glucose Homeostasis ◽

Target Genes ◽

Cell Function ◽

Hepatic Glucose Production ◽

Fasting Blood Glucose ◽

Phosphorylation Site ◽

Glucose Production ◽

Β Cell Function

Abstract The transcription factor forkhead box O1 (FoxO1) is a key mediator in the insulin signaling pathway and controls multiple physiological functions, including hepatic glucose production (HGP) and pancreatic β-cell function. We previously demonstrated that S256 in human FOXO1 (FOXO1-S256), equivalent to S253 in mouse FoxO1 (FoxO1-S253), is a key phosphorylation site mediating the effect of insulin as a target of protein kinase B on suppression of FOXO1 activity and expression of target genes responsible for gluconeogenesis. Here, we investigated the role of FoxO1-S253 phosphorylation in control of glucose homeostasis in vivo by generating global FoxO1-S253A/A knockin mice, in which FoxO1-S253 alleles were replaced with alanine (A substitution) blocking FoxO1-S253 phosphorylation. FoxO1-S253A/A mice displayed mild increases in feeding blood glucose and insulin levels but decreases in fasting blood glucose and glucagon concentrations, as well as a reduction in the ratio of pancreatic α-cells/β-cells per islet. FoxO1-S253A/A mice exhibited a slight increase in energy expenditure but barely altered food intake and glucose uptake among tissues. Further analyses revealed that FoxO1-S253A/A enhances FoxO1 nuclear localization and promotes the effect of glucagon on HGP. We conclude that dephosphorylation of S253 in FoxO1 may reflect a molecular basis of pancreatic plasticity during the development of insulin resistance.

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Berberine Attenuates Hyperglycemia by Inhibiting the Hepatic Glucagon Pathway in Diabetic Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/6210526 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Ying Zhong ◽

Jing Jin ◽

Peiyu Liu ◽

Yu Song ◽

Hui Zhang ◽

...

Keyword(s):

Blood Glucose ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Intracellular Camp ◽

Diabetic Mice ◽

Hepatic Gluconeogenesis ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Hepatic Glucose ◽

Glucose Output

Dysregulated glucagon drives hyperfunction in hepatic glucose output, which is the main cause of persistent hyperglycemia in type 2 diabetes. Berberine (Zhang et al., 2010) has been used as a hypoglycemic agent, yet the mechanism by which BBR inhibits hepatic gluconeogenesis remains incompletely understood. In this study, we treated diabetic mice with BBR, tested blood glucose levels, and then performed insulin, glucose lactate, and glucagon tolerance tests. Intracellular cAMP levels in hepatocytes were determined by ELISA, hepatic gluconeogenetic genes were assayed by RT-qPCR, and the phosphorylation of CREB, which is the transcriptional factor controlling the expression of gluconeogenetic genes, was detected by western blot. BBR reduced blood glucose levels, improved insulin and glucose tolerance, and suppressed lactate- and glucagon-induced hepatic gluconeogenesis in ob/ob and STZ-induced diabetic mice. Importantly, BBR blunted glucagon-induced glucose production and gluconeogenic gene expression in hepatocytes, presumably through reducing cAMP, which resulted in the phosphorylation of CREB. By utilizing a cAMP analogue, adenylate cyclase (AC), to activate cAMP synthetase, and an inhibitor of the cAMP degradative enzyme, phosphodiesterase (PDE), we revealed that BBR accelerates intracellular cAMP degradation. BBR reduces the intracellular cAMP level by activating PDE, thus blocking activation of downstream CREB and eventually downregulating gluconeogenic genes to restrain hepatic glucose production.

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