Adropin reduces blood glucose levels in mice by limiting hepatic glucose production

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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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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Effect of a selective rise in sinusoidal norepinephrine on HGP is due to an increase in glycogenolysis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.1.e162 ◽

1998 ◽

Vol 274 (1) ◽

pp. E162-E171 ◽

Cited By ~ 13

Author(s):

Chang An Chu ◽

Dana K. Sindelar ◽

Doss W. Neal ◽

Eric J. Allen ◽

E. Patrick Donahue ◽

...

Keyword(s):

Blood Glucose ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Control Group ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Molar Basis ◽

Hepatic Glucose ◽

The Difference ◽

Over Time

To determine the effect of a selective rise in liver sinusoidal norepinephrine (NE) on hepatic glucose production (HGP), norepinephrine (50 ng ⋅ kg−1 ⋅ min−1) was infused intraportally (Po-NE) for 3 h into five 18-h-fasted conscious dogs with a pancreatic clamp. In the control protocol, NE (0.2 ng ⋅ kg−1 ⋅ min−1) and glucose were infused peripherally to match the arterial NE and blood glucose levels in the Po-NE group. Hepatic sinusoidal NE levels rose ∼30-fold in the Po-NE group but did not change in the control group. The arterial NE levels did not change significantly in either group. During the portal NE infusion, HGP increased from 1.9 ± 0.2 to 3.5 ± 0.4 mg ⋅ kg−1 ⋅ min−1(15 min; P < 0.05) and then gradually fell to 2.4 ± 0.4 mg ⋅ kg−1 ⋅ min−1by 3 h. HGP in the control group did not change (2.0 ± 0.2 to 2.0 ± 0.2 mg ⋅ kg−1 ⋅ min−1) for 15 min but then gradually fell to 1.1 ± 0.2 mg ⋅ kg−1 ⋅ min−1by the end of the study. Because the fall in HGP from 15 min on was parallel in the two groups, the effect of NE on HGP (the difference between HGP in the two groups) did not decline over time. Gluconeogenesis did not change significantly in either group. In conclusion, elevation in hepatic sinusoidal NE significantly increases HGP by selectively stimulating glycogenolysis. Compared with the previously determined effects of epinephrine or glucagon on HGP, the effect of NE is, on a molar basis, less potent but nore sustained over time.

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Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia

Endocrinology ◽

10.1210/en.2010-0890 ◽

2010 ◽

Vol 152 (2) ◽

pp. 394-404 ◽

Cited By ~ 100

Author(s):

Jonathan P. German ◽

Joshua P. Thaler ◽

Brent E. Wisse ◽

Shinsuke Oh-I ◽

David A. Sarruf ◽

...

Keyword(s):

Hepatic Glucose Production ◽

Glucose Production ◽

Underlying Mechanism ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Uncontrolled Diabetes ◽

Urinary Glucose ◽

Hepatic Glucose ◽

Glucose Excretion ◽

The Brain

Abstract The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic β-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.

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A HYPOMETABOLIC DEFENSE STRATEGY AGAINST PLASMODIUM INFECTION

10.1101/2021.09.08.459402 ◽

2021 ◽

Author(s):

Susana Ramos ◽

Temitope W. Ademolue ◽

Elisa Jentho ◽

Qian Wu ◽

Joel Guerra ◽

...

Keyword(s):

Hepatic Glucose Production ◽

Glucose Production ◽

Organ Damage ◽

Defense Strategy ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Immune Mediated ◽

Hepatic Glucose ◽

Reduce Blood Glucose ◽

Hypometabolic State

SUMMARYHypoglycemia is a clinical hallmark of severe malaria, the often-lethal presentation of Plasmodium falciparum infection of humans. Here we report that mice reduce blood glucose levels in response to Plasmodium infection via a coordinated response whereby labile heme, an alarmin produced via hemolysis, induces anorexia and represses hepatic glucose production (HGP). While protective against unfettered immune-mediated inflammation, organ damage and anemia, when sustained over time heme-driven repression of HGP can progress towards hypoglycemia, compromising host energy expenditure and thermoregulation. This hypometabolic state arrests the development of asexual stages of Plasmodium spp., which undergo pyknosis and develop mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program reducing its virulence and inducing sexual differentiation towards the production of transmissible gametocytes. We infer that malaria-associated hypoglycemia represents a trade-off of an evolutionarily conserved defense strategy restricting Plasmodium spp. from accessing host-derived glucose and balancing parasite virulence and transmission.

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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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Glucagon Deficiency Reduces Hepatic Glucose Production and Improves Glucose Tolerance In Adult Mice

Endocrine Reviews ◽

10.1210/edrv.31.4.9983 ◽

2010 ◽

Vol 31 (4) ◽

pp. 606-606

Author(s):

Aidan S. Hancock ◽

Aiping Du ◽

Jingxuan Liu ◽

Mayumi Miller ◽

Catherine L. May

Keyword(s):

Glucose Homeostasis ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Postprandial Glucose ◽

Glucagon Receptor ◽

Glucose Levels ◽

Adult Mice ◽

Hepatic Glucose ◽

Knockout Animals

Abstract The major role of glucagon is to promote hepatic gluconeogenesis and glycogenolysis to raise blood glucose levels during hypoglycemic conditions. Several animal models have been established to examine the in vivo function of glucagon in the liver through attenuation of glucagon via glucagon receptor knockout animals and pharmacological interventions. To investigate the consequences of glucagon loss to hepatic glucose production and glucose homeostasis, we derived mice with a pancreas specific ablation of the α-cell transcription factor, Arx, resulting in a complete loss of the glucagon-producing pancreatic α-cell. Using this model, we found that glucagon is not required for the general health of mice but is essential for total hepatic glucose production. Our data clarifies the importance of glucagon during the regulation of fasting and postprandial glucose homeostasis.

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Hypoglycemia counterregulation in elderly humans: relationship to glucose levels

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1994.267.4.e497 ◽

1994 ◽

Vol 267 (4) ◽

pp. E497-E506 ◽

Cited By ~ 3

Author(s):

F. J. Ortiz-Alonso ◽

A. Galecki ◽

W. H. Herman ◽

M. J. Smith ◽

J. A. Jacquez ◽

...

Keyword(s):

Glucose Utilization ◽

Hepatic Glucose Production ◽

Severe Hypoglycemia ◽

Glucose Production ◽

Counterregulatory Hormones ◽

Glucose Levels ◽

Hepatic Glucose ◽

Consistent Increase ◽

Step Study ◽

Elderly Humans

This study was designed to define the effect of human aging on hypoglycemia counterregulatory mechanisms. A hyperinsulinemic (2 mU.kg-1.min-1) glucose clamp procedure was used to control glucose and insulin levels during stepwise lowering of plasma glucose. Counterregulatory hormones, hepatic glucose production (HGP), glucose utilization, and symptoms of hypoglycemia were studied in 13 healthy young [age 24 +/- 1 (SE) yr] and 11 healthy old (age 65 +/- 1 yr) nondiabetic volunteers on two occasions: 1) at matched euglycemia and 70 and 60 mg/dl (study 1) and 2) at matched euglycemia and 60 and 50 mg/dl (study 2). The old had consistently lower epinephrine (P < 0.005), glucagon (P < 0.02), cortisol (P < 0.05), and pancreatic polypeptide (P < 0.02) responses at the 60-mg/dl glucose step in study 1. However, these differences were no longer detectable at the more severe hypoglycemic stimulus of 50 mg/dl in study 2. A consistent increase in HGP occurred in both groups only at the 50-mg/dl glucose step (study 2) and was not different between young and old. There were also no differences in symptom responses between young and old. In summary, we found that elderly individuals have a subtle impairment of the glucose counterregulatory response during moderate hypoglycemia, but this impairment is no longer detectable during more severe hypoglycemia.

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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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