Hypothalamic control of liver glycogen metabolism in adult and aged rats

Shimazu, Takashi; Matsushita, Hiroshi; Ishikawa, Koichi

doi:10.1016/0006-8993(78)90159-2

Cited by 44 publications

(10 citation statements)

References 24 publications

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“…These afferents have been shown to be linked with glucosesensitive neurons within the lateral hypothalamus and nuclear tractus solitarius (14,15). Stimulation of the hypothalamus is in turn associated with increased sympathetic output, including output from the terminal ganglia comprising the adrenal medulla (21)(22)(23). The importance of hepatic glycemia for the hypoglycemic response in vivo was recently shown when we demonstrated that the epinephrine response to hypoglycemia was significantly suppressed by clamping the liver at euglycemia (16).…”

Section: Discussionmentioning

confidence: 78%

Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia.

Donovan

Hamilton-Wessler

Halter

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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The impact of hepatic glucose concentration on the sympathetic response to progressive hypoglycemia was examined in chronically cannulated conscious male dogs (n = 6). Graded hypoglycemia was induced via peripheral insulin infusion (30 pmol kg-1-min-1) with either peripheral (PER) or portal (POR) glucose infusion. Over the 260-min experimental period, arterial glycemia was adjusted from 5.2 ± 0.1 to 2.5 ± 0.1 mM in decrements of %0.5 mM every 40 min. Arterial glycemias were not sigfntly different between PER and POR at any measured level. However, hepatic glycemia was signiicantly elevated at all times during POR (8.4 ± 0.8 to 3.4 ± 0.2 mM) when compared to PER (5.2 ± 0.2 to 2.5 ± 0.1 mM). Plasma epinephrine values were significantly greater during PER vs. POR at all arterial glycemias below 4.0 mM. At the lowest level of arterial glycemia studied (2.5 ± 0.2 mM) the epinephrine response above basal was 3-fold greater for PER (8.7 ± 1.7 nM) when compared to POR (2.6 ± 0.6 nM) (P < 0.01). Plasma norepinephrine results were similar for the two protocols, with PER demonstrating a 3-fold greater response above basal when compared to POR at 2.5 mM arterial glycemia (P < 0.05). While the sympathetic response was markedly different between protocols when expressed as a function of arterial glycemia, when expressed as a function of hepatic glycemia this discrepancy was largely eliminated. This latter observation supports the liver as the primary locus for glycemic detection relevant to the sympathoadrenal response when hypoglycemia develops slowly-i.e., over a period of 2-3 h. A comparison of the current findings with our previous observations suggests that the hepatic glucosensors may play a greater role in hypoglycemic counterregulation as the rate of fall in glycemia is less.In 1924 Walter B. Cannon and coworkers (1) provided the first convincing evidence that insulin-induced hypoglycemia resulted in increased sympathetic output. At that time, they proposed that the enhanced sympathetic activity was likely due to glucopenia "local" to the autonomic nervous system. This position was supported by the earlier work of Claude Bernard (2) and others (3, 4), demonstrating that lesions to specific aspects ofthe brain had a profound impact on glucose metabolism. The existence of specific "glucoreceptors" within the hypothalamus was later proposed by Mayer and Marshall (5). Subsequent studies in which direct microinjections were used have now clearly identified glucosensitive neurons within the ventromedial and lateral hypothalamus (6). In addition, substantial evidence has accumulated over the years delineating the efferent capacity of the central nervous system (CNS) to impact upon glucoregulation (6,7). This has led to the prevailing concept that the brain "senses" ambient glycemia and effects the requisite glucoregulatory mechanisms.Evidence for the role of the CNS in glycemic detection has relied largely on nonphysiological stimuli, such as brain lesions, electrical stimulation, glucose analogues, and direct (in th...

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Section: Discussionmentioning

confidence: 78%

Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia.

Donovan

Hamilton-Wessler

Halter

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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“…This has been shown to be associated with the depletion of liver glycogen and the concomitant increases in the activities of glycogen phosphorylase and glucose-6-phosphatase (17,45,46). Furthermore, both electrical (14,47,48) and chemical (49,50) stimulation of the ventromedial hypothalamus results in hyperglycemia. These effects were shown to be caused by increases in glycogenolysis (14,47,48) and gluconeogenesis (15) and are partially mediated via the nerve supply to the liver (47).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, both electrical (14,47,48) and chemical (49,50) stimulation of the ventromedial hypothalamus results in hyperglycemia. These effects were shown to be caused by increases in glycogenolysis (14,47,48) and gluconeogenesis (15) and are partially mediated via the nerve supply to the liver (47). Although it appears that cerebral mechanisms can regulate glucose metabolism, it is not known if such mechanisms are active during insulin-induced hypoglycemia.…”

Section: Discussionmentioning

confidence: 99%

In the Absence of Counterregulatory Hormones, the Increase in Hepatic Glucose Production During Insulin-Induced Hypoglycemia in the Dog Is Initiated in the Liver Rather Than the Brain

et al. 1996

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We have previously demonstrated that the liver can release glucose in response to insulin-induced hypoglycemia, despite the absence of glucagon, epinephrine, cortisol, and growth hormone. The aim of this study was to determine whether this is activated by liver or brain hypoglycemia. We assessed the response to insulin-induced hypoglycemia in the absence of counterregulatory hormones in overnight-fasted conscious adrenalectomized dogs that were given somatostatin and intraportal insulin (30 pmol x kg(-1) x min(-1)) for 360 min. Glucose was infused to maintain euglycemia for 3 h and then to allow limited peripheral hypoglycemia for the next 3 h. During peripheral hypoglycemia, five dogs received glucose via both carotid and vertebral arteries to maintain cerebral euglycemia (H-EU group) concurrently with peripheral hypoglycemia, while six dogs received saline in these vessels to allow simultaneous cerebral and peripheral hypoglycemia (H-HY group). Throughout the study, arterial insulin was 1,675 +/- 295 and 1,440 +/- 310 pmol/l in the H-HY and H-EU groups, respectively. Glucose fell from 6.2 +/- 0.3 to 2.1 +/- 0.0 mmol/l and from 5.8 +/- 0.3 to 1.9 +/- 0.1 mmol/l in the last hour in the H-HY and H-EU groups, respectively (P < 0.05 for both). Norepinephrine rose from 1.12 +/- 0.35 to 2.44 +/- 0.69 nmol/l and from 1.09 +/- 0.07 to 1.74 +/- 0.16 nmol/l in the last hour in the H-HY and H-EU groups, respectively (P < 0.05 for both; no difference between groups). Glucagon, epinephrine, and cortisol were below the limits of detection. The liver switched from uptake to output of glucose during peripheral hypoglycemia in both the H-HY (-7.1 +/- 2.1 to 5.4 +/- 3.1 micromol x kg(-1) x min(-1)) and H-EU (-7.9 +/- 3.5 to 3.4 +/- 1.7 micromol x kg(-1) x min(-1)) groups (P < 0.05 for both; no difference between groups). Alanine levels and net hepatic alanine uptake fell similarly in both groups. There were increases (P < 0.05) in glycerol (12 +/- 3 to 258 +/- 47 micromol/l) and nonesterified fatty acid (194 +/- 10 to 540 +/- 80 micromol/l) levels and in total ketone production (0.4 +/- 0.1 to 1.1 +/- 0.2 micromol x kg(-1) x min(-1)) in the H-HY group, but these parameters did not change in the H-EU group. These data clearly indicate that the lipolytic and hepatic responses to hypoglycemia are driven by differential sensing mechanisms. Thus, during insulin-induced hypoglycemia, when counterregulatory hormones are absent, liver hypoglycemia triggers the increase in hepatic glucose production, whereas cerebral hypoglycemia causes the increases in lipolysis and ketogenesis.

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“…When the VMH of rats was stimulated electrically, the activity of liver phosphorylase a increased rapidly and markedly, reaching a maximum activity of about 3-fold over unstimulated activity within 30 s [10]. This maximum level of phosphorylase a was then maintained for 5 min of stimulation.…”

Section: Hypothalamo-hepatic Axis In the Control Of Carbohydrate Metamentioning

confidence: 94%

“…This work was later extended by analyzing changes in the activities of key hepatic enzymes involved in glycogen breakdown and synthesis [7,10], i.e., glycogen phosphorylase (EC 2.4.1.1)and glycogen synthetase (EC 2.4.1.11). Phosphorylase and synthetase exist in the liver in two interconvertible forms; phosphorylase a and synthetase I are physiologically active, while phosphorylase b and synthetase D are essentially inactive in vivo.…”

Section: Hypothalamo-hepatic Axis In the Control Of Carbohydrate Metamentioning

confidence: 99%

Central nervous system regulation of liver and adipose tissue metabolism

Shimazu

1981

Diabetologia

253

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Hypothalamic and autonomic nervous regulation of carbohydrate and amino acid metabolism in the liver and of lipid metabolism in adipose tissues is described. The direct neural mechanism underlying this regulation has been evaluated. Electrical stimulation of the ventromedial hypothalamic nucleus (VMH)-splanchnic nerve system causes glycogenolysis in the liver by rapid activation of glycogen phosphorylase, whereas electrical stimulation of the lateral hypothalamic nucleus (LH)-vagus nerve system promotes glycogenesis in the liver by activation of glycogen synthetase, through direct neural and neural-hormonal mechanisms. Studies on chemical coding of the hypothalamic neurones have revealed that norepinephrine-sensitive neurones in the VMH and acetylcholine-sensitive neurones in the LH are specifically involved in the regulation of liver phosphorylase and glycogen synthetase, respectively. Acetylcholine-sensitive neurones of the LH were also found to be concerned in regulation of hepatic tyrosine and aminotransferase activity, through intermediation of the cholinergic system in the LH-vagal pathway. Finally, it has been shown that the VMH acts as a regulatory centre for lipolysis in adipose tissues by modulating activation of the sympathetic nervous system. In addition, stimulation of the VMH enhanced lipogenesis in brown adipose tissue preferentially, probably through a mechanism mediated by sympathetic innervation of this tissue. The latter finding suggests that both the breakdown and resynthesis of triglycerides in brown adipose tissue, but not in white adipose tissue, are accelerated by stimulation of the VMH.

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Hypothalamic control of liver glycogen metabolism in adult and aged rats

Cited by 44 publications

References 24 publications

Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia.

Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia.

In the Absence of Counterregulatory Hormones, the Increase in Hepatic Glucose Production During Insulin-Induced Hypoglycemia in the Dog Is Initiated in the Liver Rather Than the Brain

Central nervous system regulation of liver and adipose tissue metabolism

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