Modulation of the JNK Pathway in Liver Affects Insulin Resistance Status

The c-Jun N-terminal kinase (JNK) pathway is known to be activated under diabetic conditions and to possibly be involved in the progression of insulin resistance. In this study, we examined the effects of modulation of the JNK pathway in liver on insulin resistance and glucose tolerance. Overexpression of dominant-negative type JNK in the liver of obese diabetic mice dramatically improved insulin resistance and markedly decreased blood glucose levels. Conversely, expression of wild type JNK in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of crucial molecules for insulin signaling was altered upon modification of the JNK pathway. Furthermore, suppression of the JNK pathway resulted in a dramatic decrease in the expression levels of the key gluconeogenic enzymes, and endogenous hepatic glucose production was also greatly reduced. Similar effects were observed in high fat, high sucrose diet-induced diabetic mice. Taken together, these findings suggest that suppression of the JNK pathway in liver exerts greatly beneficial effects on insulin resistance status and glucose tolerance in both genetic and dietary models of diabetes.

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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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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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Hepatic functions of GLP-1 and its based drugs: current disputes and perspectives

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00069.2016 ◽

2016 ◽

Vol 311 (3) ◽

pp. E620-E627 ◽

Cited By ~ 19

Author(s):

Tianru Jin ◽

Jianping Weng

Keyword(s):

Insulin Resistance ◽

Degradation Products ◽

Hepatic Glucose Production ◽

Wnt Signaling Pathway ◽

Glucose Production ◽

Metabolic Effects ◽

Beneficial Effects ◽

Metabolic Functions ◽

Pathway Activation ◽

Hepatic Glucose

GLP-1 and its based drugs possess extrapancreatic metabolic functions, including that in the liver. These direct hepatic metabolic functions explain their therapeutic efficiency for subjects with insulin resistance. The direct hepatic functions could be mediated by previously assumed “degradation” products of GLP-1 without involving canonic GLP-1R. Although GLP-1 analogs were created as therapeutic incretins, extrapancreatic functions of these drugs, as well as native GLP-1, have been broadly recognized. Among them, the hepatic functions are particularly important. Postprandial GLP-1 release contributes to insulin secretion, which represses hepatic glucose production. This indirect effect of GLP-1 is known as the gut-pancreas-liver axis. Great efforts have been made to determine whether GLP-1 and its analogs possess direct metabolic effects on the liver, as the determination of the existence of direct hepatic effects may advance the therapeutic theory and clinical practice on subjects with insulin resistance. Furthermore, recent investigations on the metabolic beneficial effects of previously assumed “degradation” products of GLP-1 in the liver and elsewhere, including GLP-128–36 and GLP-132–36, have drawn intensive attention. Such investigations may further improve the development and the usage of GLP-1-based drugs. Here, we have reviewed the current advancement and the existing controversies on the exploration of direct hepatic functions of GLP-1 and presented our perspectives that the direct hepatic metabolic effects of GLP-1 could be a GLP-1 receptor-independent event involving Wnt signaling pathway activation.

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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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Leptin contributes to the beneficial effects of insulin treatment in streptozotocin-diabetic male mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00159.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. E1264-E1273

Author(s):

Ursula H. Neumann ◽

Michelle M. Kwon ◽

Robert K. Baker ◽

Timothy J. Kieffer

Keyword(s):

Blood Glucose ◽

Insulin Therapy ◽

Daily Injection ◽

Diabetic Mice ◽

Glucose Lowering ◽

Beneficial Effects ◽

Glucose Levels ◽

Lowering Effect ◽

Blood Glucose Levels ◽

Glucose Lowering Effect

It was long thought that the only hormone capable of reversing the catabolic consequences of diabetes was insulin. However, various studies have demonstrated that the adipocyte-derived hormone leptin can robustly lower blood glucose levels in rodent models of insulin-deficient diabetes. In addition, it has been suggested that some of the metabolic manifestations of insulin-deficient diabetes are due to hypoleptinemia as opposed to hypoinsulinemia. Because insulin therapy increases leptin levels, we sought to investigate the contribution of leptin to the beneficial effects of insulin therapy. To do this, we tested insulin therapy in streptozotocin (STZ) diabetic mice that were either on an ob/ ob background or that were given a leptin antagonist to determine if blocking leptin action would blunt the glucose-lowering effects of insulin therapy. We found that STZ diabetic ob/ ob mice have a diminished blood glucose-lowering effect in response to insulin therapy compared with STZ diabetic controls and exhibited more severe weight loss post-STZ injection. In addition, STZ diabetic mice administered a leptin antagonist through daily injection or plasmid expression respond less robustly to insulin therapy as assessed by both fasting blood glucose levels and blood glucose levels during an oral glucose tolerance test. However, leptin antagonism did not prevent the insulin-induced reduction in β-hydroxybutyrate and triglyceride levels. Therefore, we conclude that elevated leptin levels can contribute to the glucose-lowering effect of insulin therapy in insulin-deficient diabetes.

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MKR mice are resistant to the metabolic actions of both insulin and adiponectin: discordance between insulin resistance and adiponectin responsiveness

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00319.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. E298-E305 ◽

Cited By ~ 29

Author(s):

Chul-Hee Kim ◽

Patricia Pennisi ◽

Hong Zhao ◽

Shoshana Yakar ◽

Jeanne B. Kaufman ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Dominant Negative ◽

Metabolic Phenotype ◽

Dominant Negative Mutant ◽

Acid Oxidation ◽

Mrna Levels ◽

Normal Expression

Most rodent models of insulin resistance are accompanied by decreased circulating adiponectin levels. Adiponectin treatment improves the metabolic phenotype by increasing fatty acid oxidation in skeletal muscle and suppressing hepatic glucose production. Muscle IGF-I receptor (IGF-IR)-lysine-arginine (MKR) mice expressing dominant-negative mutant IGF-IRs in skeletal muscle are diabetic with insulin resistance in muscle, liver, and adipose tissue. Adiponectin levels are elevated in MKR mice, suggesting an unusual discordance between insulin resistance and adiponectin responsiveness. Therefore, we investigated the metabolic actions of adiponectin in MKR mice. MKR and ob/ob mice were treated both acutely (28 μg/g) and chronically (for 2 wk) with full-length adiponectin. Acute hypoglycemic effects of adiponectin were evident only in ob/ob mice but not in MKR mice. Chronic adiponectin treatment significantly improved both insulin sensitivity and glucose tolerance in ob/ob but not in MKR mice. Adiponectin receptor mRNA levels and adiponectin-stimulated phosphorylation of AMPK in skeletal muscle and liver were similar among MKR, wild-type, and ob/ob mice. Thus MKR mice are adiponectin resistant despite normal expression of adiponectin receptors and normal AMPK phosphorylation in muscle and liver. MKR mice may be a useful model for dissecting relationships between insulin resistance and adiponectin action in regulation of glucose homeostasis.

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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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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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