Blood glucose levels modulate efferent activity in the vagal supply to the rat liver.

Niijima, Akira

doi:10.1113/jphysiol.1985.sp015733

Cited by 52 publications

(32 citation statements)

References 16 publications

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“…When the hepatic branch of the vagus nerve is excised, icv insulin administration-induced suppression of HGP is attenuated [27]. The vagus nerve is known to maintain constant pacemaker-like activity [33], and it has been reported in an electrophysiological study of the rat under pentobarbital anesthesia that the nerve activity is enhanced by a rise in blood glucose, and inactivated by an increase in plasma insulin concentration [34]. However, the question of how the central insulin action actually controls the vagus nerve activity via hypothalamic neurons and suppresses HGP remains unanswered.…”

Section: Central Insulin Action and The Vagus Nervementioning

confidence: 99%

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

Inoue

2016

Endocr J

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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...

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Section: Central Insulin Action and The Vagus Nervementioning

confidence: 99%

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

Inoue

2016

Endocr J

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“…Electrical stimulation of the lower portion of the cut end of the vagus nerve increased hepatic glycogen synthase activity and deposition of glycogen and decreased net hepatic glucose output in rabbits (15). Niijima (16) demonstrated that intravenous injection of glucose increased the efferent ®ring rate in the hepatic branch of the vagus nerve in rats, and that the ®ring rate was directly related to the arterial blood glucose concentration over a range of physiologic concentrations (3.3±25.0 mmol/l). On the other hand, sympathetic stimulation was shown to activate glycogen phosphorylase and glucose-6-phosphatase (G-6-Pase) in rabbits (17) and to deplete hepatic glycogen reserves and increase net hepatic glucose output in calves (18).…”

Section: Autoregulation In Response To Hyperglycemiamentioning

confidence: 99%

Autoregulation of hepatic glucose production

Moore

Connolly

Cherrington

1998

European Journal of Endocrinology

104

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In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is dif®cult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause signi®cant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60±90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia.A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (#2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role. European Journal of Endocrinology 138 240±248

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“…As hyperglycemia enhances glycogen synthesis in the liver [28], these results also suggest that the glycogen synthesis in the liver might be stimulated via vagi. NIuIMA [46] reported that i.v. injection of glucose increased efferent activity in the hepatic branch of the vagus nerve in the rat, the firing rate of hepatic efferents being linearly related to the arterial blood glucose concentration over a range from 60 mg/100 ml to 450 mg/ 100 ml, which includes the physiological range.…”

Section: Innervation Of the Liver And Its Role In Thementioning

confidence: 99%

“…The effect of 2-deoxy-D-glucose could be accounted for by inhibition of intracellular glucose utilization in the brain [10,66]. These observations indicate that changes in the rate of hepatic glycogenesis, which occur in response to change in blood glucose concentration, are mediated in part by the vagal efferent Innervation of the liver [46]. It is recognized that there are two centers in the hypothalamus regulating food intake, the feeding center in the lateral hypothalamus (LHA) and the satiety center in the ventromedial hypothalamus (VMH) [2,4].…”

Section: Innervation Of the Liver And Its Role In Thementioning

confidence: 99%

Neural control of blood glucose level.

Niijima

1986

Jpn.J.Physiol

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It is well known that blood glucose is a major source of energy for cellular activities and the liver is an important organ for the storage of glucose in the form of glycogen. It is generally recognized that blood glucose level is maintained at a relatively constant level, and catecholamines (epinephrine and norepinephrine) released from the adrenal gland, and insulin and glucagon released from the pancreas play important roles in the regulation of the blood glucose level. Insulin is a key substance in controlling entry of glucose into the cell and utilization of glucose in the cell. Another insulin effect is to increase storage of glycogen in the liver and other tissues. These actions of insulin result in a fall in the blood glucose level. Glucagon, epinephrine, and norepinephrine cause release of glucose from the liver into the circulating blood by stimulating hepatic glycogenolysis. During starvation an increase in the rate of secretion of glucagon, epinephrine, and norepinephrine occurs. This facilitates release of glucose from the liver, thereby contributing to the maintenance of the blood glucose concentration above the lower limit of the physiological range. This is an important factor, guaranteeing reasonable utilization of glucose by the body and brain cells. It can be stated that insulin is an indispensable hormone for the utilization of glucose, and epinephrine, norepinephrine, and glucagon are the hormones which raise and maintain the glucose level in order to support utilization of the blood glucose. It has been reported that stimulation of the sympathetic nerve to the adrenal medulla causes release of epinephrine and norepinephrine into the circulating blood, resulting in release of glucose from the liver. Although it is generally accepted that the glucose concentration in the blood plasma has a direct effect on the islets of Langerhans in the pancreas in controlling the rate of insulin and glucagon secretion, the existence of an autonomic neural control mechanism for regulating the rate of secretion of these substances has been strongly suggested by WooDs and PoRTE [72]. This paper reviews the reports on the visceral afferents, glucose-responsive neurons in the central nervous system and autonomic outflows in relation to the regulation of blood glucose level.

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Blood glucose levels modulate efferent activity in the vagal supply to the rat liver.

Cited by 52 publications

References 16 publications

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

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

Autoregulation of hepatic glucose production

Neural control of blood glucose level.

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