Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs

Ramnanan, Christopher J.; Saraswathi, Viswanathan; Smith, Marta S.; Donahue, E. Patrick; Farmer, Ben; Farmer, Tiffany D.; Neal, Doss W.; Williams, P. E. V.; Lautz, Margaret; Mari, Andrea; Cherrington, Alan D.; Edgerton, Dale S.

doi:10.1172/jci45472

Cited by 85 publications

(121 citation statements)

References 43 publications

Supporting

Mentioning

112

Contrasting

Order By: Relevance

“…Short duration pancreatic clamp studies in conscious dogs failed to show an acute impact on EGP when insulin delivery to the head was increased 4-fold (39). Further work in dogs confirmed the ability of ICV insulin infusion to increase hepatic STAT3 phosphorylation and suppress hepatic gluconeogenic enzyme expression (40). Although glucose production was not affected in this acute setting, net hepatic glucose output did slowly decrease over the course of these clamps.…”

Section: Evidence For Cns Nutrient and Hormone Sensing In Animalsmentioning

confidence: 82%

Evidence for Central Regulation of Glucose Metabolism

Carey

Kehlenbrink

Hawkins

2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Evidence for central regulation of glucose homeostasis is accumulating from both animal and human studies. Central nutrient and hormone sensing in the hypothalamus appears to coordinate regulation of whole body metabolism. Central signals activate ATP-sensitive potassium (K ATP ) channels, thereby down-regulating glucose production, likely through vagal efferent signals. Recent human studies are consistent with this hypothesis. The contributions of direct and central inputs to metabolic regulation are likely of comparable magnitude, with somewhat delayed central effects and more rapid peripheral effects. Understanding central regulation of glucose metabolism could promote the development of novel therapeutic approaches for such metabolic conditions as diabetes mellitus.The estimated global prevalence of Type 2 diabetes (T2DM) 2 is 347 million (1). Because glycemic control is achieved in only ϳ40% of patients, additional therapeutic strategies are needed (2). Increased endogenous glucose production (EGP) is the main source of fasting hyperglycemia (3, 4), contributing ϳ80% of diurnal hyperglycemia in T2DM (5). Apart from insulin, there is no treatment targeting basal EGP. Better understanding its regulation would have important therapeutic implications. We will examine the evidence for central sensing of nutritional and hormonal signals in animal models and humans, focusing on CNS regulation of glucose metabolism. Evidence for CNS Nutrient and Hormone Sensing in AnimalsUnlike other organs, the brain is an obligate consumer of glucose (6). Central regulation of EGP would therefore be teleologically advantageous. Since the first demonstration by Claude Bernard (7) that lesions in the floor of the fourth ventricle altered blood glucose levels, the ability of central glucose sensing to regulate peripheral glucose homeostasis has been extensively examined in animal models. There are glucosesensing neurons in many areas of the brain (8), particularly the hypothalamus (9). Specifically, the ventromedial hypothalamus (VMH) and arcuate nucleus (10) integrate hormonal and nutrient signals impacting peripheral metabolism (Fig. 1). Central signals appear to activate hypothalamic ATP-sensitive potassium (K ATP ) channels (9,11,12) composed of an inward rectifier potassium ion channel Kir6.2 subunit and a sulfonylurea receptor (SUR) subunit. Pharmacologic compounds including diazoxide activate and thereby close hypothalamic K ATP channels, whereas sulfonylureas inhibit and thereby open them, ultimately modulating EGP (12).Glucose-Elegant studies in rats showed that direct infusion of D-glucose into the VMH inhibited counterregulatory hormonal responses to systemic hypoglycemia during a hypoglycemic clamp, indicating that VMH glucose sensing is needed for the systemic response to peripheral hypoglycemia (13). VMH infusion of L-lactate, a byproduct of glucose metabolism and an alternate fuel source for neurons in conditions of glucose deficiency, produced similar suppression of the counterregulatory hormonal response to systemic...

show abstract

Section: Evidence For Cns Nutrient and Hormone Sensing In Animalsmentioning

confidence: 82%

Evidence for Central Regulation of Glucose Metabolism

Carey

Kehlenbrink

Hawkins

2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…However, it has been reported that while icv insulin activates hepatic STAT3 and suppresses gluconeogenic enzyme gene expression in dogs, their HGP is not reduced [49]. These findings indicate that while central insulin action-mediated mechanism that controls hepatic gluconeogenic enzyme expression is preserved across the species, its importance in whole body glucose metabolism differs greatly among the species.…”

Section: Central Insulin Action-mediated Hgp Control and Type 2 Diabementioning

confidence: 90%

“…As seen with food intake, glucose tolerance test and hyperinsulinemic-euglycemic clamp, STAT3 is activated in the liver following icv insulin administration and diazoxide administration [9,48,49]. On the other hand, STAT3 activation in the liver following glucose tolerance test is attenuated in NIRKO mice [9].…”

Section: Central Insulin Action Regulates Hgpmentioning

confidence: 99%

Central insulin-mediated regulation of hepatic glucose production [Review]

Inoue

2016

Endocr J

View full text Add to dashboard Cite

Abstract. Insulin controls hepatic glucose production (HGP) and maintains glucose homeostasis through the direct action of hepatic insulin receptors, as well as the indirect action of insulin receptors in the central nervous system. Insulin acts on insulin receptors in the hypothalamic arcuate nucleus, activates ATP-sensitive potassium channels in a phosphoinositide 3-kinase (PI3K)-dependent manner, induces hyperpolarization of the hypothalamic neurons, and regulates HGP via the vagus nerve. In the liver, central insulin action augments IL-6 expression in Kupffer cells and activates STAT3 transcription factors in hepatocytes. Activated STAT3 suppresses the gene expression of gluconeogenic enzymes, thereby reducing HGP. It has become evident that nutrients such as glucose, fatty acids, and amino acids act upon the hypothalamus together with insulin, affecting HGP. On the other hand, HGP control by central insulin action is impeded in obesity and impeded by insulin resistance due to disturbance of PI3K signaling and inflammation in the hypothalamus or inhibition of STAT3 signaling in the liver. Although the mechanism of control of hepatic gluconeogenic gene expression by central insulin action is conserved across species, its importance in human glucose metabolism has not been made entirely clear and its elucidation is anticipated in the future.Key words: Hypothalamus, Insulin, Liver, Vagus nerve, STAT3 THE LIVER plays a central role in the maintenance of whole-body glucose homeostasis, by adjusting glucose production according to the energy balance. The master regulator of hepatic glucose production (HGP) is insulin, as the liver is exposed to portal blood, which displays high insulin concentrations of approximately three times that in venous blood [1]. Indeed, in diabetes mellitus, the increase of HGP is closely related to the rise of fasting blood level [2]. HGP is strongly controlled by direct actions of insulin on hepatocytes [3]. When bound to its receptor, insulin suppresses HGP via the activation of phosphoinositide 3-kinase (PI3K) signal transduction pathway consisting of insulin receptor substrate (IRS), PI3K, phosphoinositide-dependent kinase 1 (PDK1) and Akt [4]. Thus, liver-specific insulin receptor knockout mice or impaired PI3K signal transduction exhibit hyperinsulinemia and glucose intolerance with impaired insulin-dependent suppression of HGP [5][6][7][8]. Meanwhile, insulin is known to control HGP not only by direct mechanisms via hepatic insulin receptors, but also by indirect mechanisms mediated by insulin actions on other organs (Fig.1). It has been reported that insulin still suppresses HGP partially even in mice with PI3K signal transduction inhibition in the liver [8,9]. Further, in an investigation of the changes in HGP after intravenous and intraportal insulin administration, it was shown that the differences in portal blood insulin level, that is, the direct insulin action on hepatocytes, do not necessarily correlate with the effect of insulin on HGP suppression [10].Indirect suppressio...

show abstract

“…In the fasting state, the liver uses glycogen stores to mobilize glucose and maintain blood glucose levels [1,2] . In addition, the liver obtains glucose through gluconeogenesis.…”

Section: Introductionmentioning

confidence: 99%

Alpha-lipoic acid attenuates insulin resistance and improves glucose metabolism in high fat diet-fed mice

Yang

Liu

et al. 2014

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: To investigate whether alpha-lipoic acid (ALA) could attenuate the insulin resistance and metabolic disorders in high fat diet-fed mice. Methods: Male mice were fed a high fat diet (HFD) plus ALA (100 and 200 mg·kg -1 ·d -1 ) or HFD plus a positive control drug metformin (300 mg·kg ) for 24 weeks. During the treatments, the relevant physiological and metabolic parameters of the mice were measured. After the mice were euthanized, blood samples and livers were collected. The expression of proteins and genes related to glucose metabolism in livers were analyzed by immunoblotting and real time-PCR. Results: HFD induced non-alcoholic fatty liver disease (NAFLD) and abnormal physiological and metabolic parameters in the mice, which were dose-dependently attenuated by ALA. ALA also significantly reduced HFD-induced hyperglycemia and insulin resistance in HFD-fed mice. Furthermore, ALA significantly upregulated the glycolytic enzymes GCK, HK-1 and PK, and the glycogen synthesis enzyme GS, and downregulated the gluconeogenic enzymes PEPCK and G6Pase, thus decreased glucose production, and promoted glycogen synthesis and glucose utilization in livers. Moreover, ALA markedly increased PKB/Akt and GSK3β phosphorylation, and nuclear carbohydrate response element binding protein (ChREBP) expression in livers. Metformin produced similar effects as ALA in HFD-fed mice. Conclusion: ALA is able to sustain glucose homeostasis and prevent the development of NAFLD in HFD-fed mice.

show abstract

Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs

Cited by 85 publications

References 43 publications

Evidence for Central Regulation of Glucose Metabolism

Evidence for Central Regulation of Glucose Metabolism

Central insulin-mediated regulation of hepatic glucose production [Review]

Alpha-lipoic acid attenuates insulin resistance and improves glucose metabolism in high fat diet-fed mice

Contact Info

Product

Resources

About