Low-Dose Oral Glyburide Reduces Fasting Blood Glucose by Decreasing Hepatic Glucose Production in Healthy Volunteers Without Increasing Carbohydrate Oxidation

Hepatic glucose production is autoregulated during infusion of gluconeogenic precursors. In hyperglycemic patients with multiple trauma, hepatic glucose production and gluconeogenesis are increased, suggesting that autoregulation of hepatic glucose production may be defective. To better understand the mechanisms of autoregulation and its possible alterations in metabolic stress, lactate was coinfused with glucose in healthy volunteers and in hyperglycemic patients with multiple trauma or critical illness. In healthy volunteers, infusion of glucose alone nearly abolished endogenous glucose production. Lactate increased gluconeogenesis (as indicated by a decrease in net carbohydrate oxidation with no change in total [13C]carbohydrate oxidation) but did not increase endogenous glucose production. In patients with metabolic stress, endogenous glucose production was not suppressed by exogenous glucose, but lactate did not further increase hepatic glucose production. It is concluded that 1) in healthy humans, autoregulation of hepatic glucose production during infusion of lactate is still present when glycogenolysis is suppressed by exogenous glucose and 2) autoregulation of hepatic glucose production is not abolished in hyperglycemic patients with metabolic stress.

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

Endocrine Journal ◽

10.1507/endocrj.ej12-0462 ◽

2013 ◽

Vol 60 (8) ◽

pp. 941-950 ◽

Cited By ~ 18

Author(s):

Tingting Wang ◽

Jin Xu ◽

Tao Bo ◽

Xiaoming Zhou ◽

Xiuyun Jiang ◽

...

Keyword(s):

Blood Glucose ◽

Knockout Mice ◽

Hormone Receptor ◽

Hepatic Glucose Production ◽

Fasting Blood Glucose ◽

Glucose Production ◽

Thyroid Stimulating Hormone ◽

Hepatic Glucose ◽

Stimulating Hormone

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Daily Fasting Blood Glucose Rhythm in Male Mice: A Role of the Circadian Clock in the Liver

Endocrinology ◽

10.1210/en.2015-1376 ◽

2015 ◽

Vol 157 (2) ◽

pp. 463-469 ◽

Cited By ~ 15

Author(s):

Hitoshi Ando ◽

Kentaro Ushijima ◽

Shigeki Shimba ◽

Akio Fujimura

Keyword(s):

Blood Glucose ◽

Circadian Clock ◽

Mrna Expression ◽

Hepatic Glucose Production ◽

Critical Role ◽

Fasting Blood Glucose ◽

Glucose Production ◽

Diabetic Patients ◽

Dark Phase ◽

Dawn Phenomenon

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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Glucagon and hepatic glucose production: Modulation by low-dose bradykinin infusion

Metabolism ◽

10.1016/0026-0495(89)90235-7 ◽

1989 ◽

Vol 38 (9) ◽

pp. 878-882 ◽

Cited By ~ 7

Author(s):

Wolfgang H. Hartl ◽

Hiroshi Miyoshi ◽

Dariush Elahi ◽

Robert R. Wolfe

Keyword(s):

Low Dose ◽

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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