Changes in lateral hypothalamic neuronal activity accompanying hyper- and hypoglycemias

Himmi, T.; Boyer, A.; Orsini, J.C.

doi:10.1016/0031-9384(88)90036-4

Cited by 52 publications

(24 citation statements)

References 35 publications

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“…Again, in the absence of GLUT2, there is a lack of glucose sensing and therefore a lack of inhibition of the autonomic tone. Although this interpretation requires direct experimental verification, we believe that it is compatible with the glucose sensitivity of neurons found in the hypothalamus, which can respond to low-or high-glucose concentrations by increasing or decreasing their firing rates (17)(18)(19)(20)(21). For example, the majority of glucose-sensitive neurons of the lateral hypothalamic area decreased their firing rates in response to small increases in local glucose concentrations.…”

Section: Glut2 and Regulated Glucacon Secretionsupporting

confidence: 68%

“…The mechanisms by which these centers become activated by changes in glycemic levels are not completely understood at the molecular level. It has however been described that glucose-sensitive neurons are present in these different parts of the hypothalamus (17)(18)(19)(20)(21). These neurons respond to low-or high-glucose concentrations either by increasing or decreasing their firing rates.…”

mentioning

confidence: 99%

“…These neurons respond to low-or high-glucose concentrations either by increasing or decreasing their firing rates. Their activity may also be influenced by glucose-sensitive neurons of the nucleus of the tractus solitarius, which are directly sensitive to glycemic variations and send projections toward the lateral hypothalamus and paraventricular nucleus (20,(22)(23)(24)(25). It has been demonstrated that glucose-sensitive neurons of the brainstem participate in the response of the ANS to hypoglycemia in the dog by showing that counterregulation could be partially suppressed by maintaining normoglycemia specifically in the brainstem (26).…”

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confidence: 99%

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Evidence That Extrapancreatic GLUT2-Dependent Glucose Sensors Control Glucagon Secretion

Burcelin

Thorens

2001

Diabetes

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GLUT2؊/؊ mice reexpressing GLUT1 or GLUT2 in their ␤-cells (RIPGLUT1 ؋ GLUT2 ؊/؊ or RIPGLUT2 ؋ GLUT2 ؊/؊ mice) have nearly normal glucose-stimulated insulin secretion but show high glucagonemia in the fed state. Because this suggested impaired control of glucagon secretion, we set out to directly evaluate the control of glucagonemia by variations in blood glucose concentrations. Using fasted RIPGLUT1 ؋ GLUT2 ؊/؊ mice, we showed that glucagonemia was no longer increased by hypoglycemic (2.5 mmol/l glucose) clamps or suppressed by hyperglycemic (10 and 20 mmol/l glucose) clamps. However, an increase in plasma glucagon levels was detected when glycemia was decreased to <1 mmol/l, indicating preserved glucagon secretory ability, but of reduced sensitivity to glucopenia. To evaluate whether the high-fed glucagonemia could be due to an abnormally increased tone of the autonomic nervous system, fed mutant mice were injected with the ganglionic blockers hexamethonium and chlorisondamine. Both drugs lead to a rapid return of glucagonemia to the levels found in control fed mice. We conclude that 1) in the absence of GLUT2, there is an impaired control of glucagon secretion by low or high glucose; 2) this impaired glucagon secretory activity cannot be due to absence of GLUT2 from ␣-cells because these cells do not normally express this transporter; 3) this dysregulation may be due to inactivation of GLUT2-dependent glucose sensors located outside the endocrine pancreas and controlling glucagon secretion; and 4) because fed hyperglucagonemia is rapidly reversed by ganglionic blockers, this suggests that in the absence of GLUT2, there is an increased activity of the autonomic nervous system stimulating glucagon secretion during the fed state.

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Section: Glut2 and Regulated Glucacon Secretionsupporting

confidence: 68%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Evidence That Extrapancreatic GLUT2-Dependent Glucose Sensors Control Glucagon Secretion

Burcelin

Thorens

2001

Diabetes

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“…Glucose sensors detect glycemic variations and produce signals accordingly that trigger different functions in target cells (15,(17)(18)(19)(20) through the ANS (7,(21)(22)(23). Such regulation is involved in a glucoregulatory reflex loop.…”

Section: Introductionmentioning

confidence: 99%

Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage

Knauf¹

2005

Journal of Clinical Investigation

275

242

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Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled wholebody glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.

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“…Electrophysiological studies have shown that the LHA contains glucose-sensing neurons that are activated by hypoglycemia and suppressed by hyperglycemia (Bernardis and Bellinger 1996; Himmi et al 1988;Liu et al 2001). Numerous neuroanatomical and neurophysiological experiments have established that the LHA modulates the efferent output of pancreatic nerves (Bernardis and Bellinger 1996;Buijs et al 2001;Palkovits et al 1980;Williams et al 2001;Yoshimatsu et al 1984).…”

mentioning

confidence: 99%

Hypothalamus–Brain Stem Circuitry Responsible for Vagal Efferent Signaling to the Pancreas Evoked By Hypoglycemia in Rat

Gao

Jin

et al. 2004

Journal of Neurophysiology

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. Hypothalamus-brain stem circuitry responsible for vagal efferent signaling to the pancreas evoked by hypoglycemia in rat. J Neurophysiol 91: 1734 -1747, 2004. First published November 26, 2003 10.1152/jn.00791.2003. Circulating glucose levels significantly affect vagal neural activity, which is important in the regulation of pancreatic functions. Little is known about the mechanisms involved. This study investigates the neural pathways responsible for hypoglycemiainduced vagal efferent signaling to the pancreas and identifies the neurotransmitters involved. Vagal pancreatic efferent nerve activities were recorded in anesthetized rats. Insulin-induced hypoglycemia, a decrease of blood glucose levels from 114 Ϯ 5 to 74 Ϯ 6 mg dl Ϫ1 , stimulated an increase in pancreatic efferent nerve firing from a basal rate of 1.1 Ϯ 0.3 to 19 Ϯ 3 impulses 30 s Ϫ1 . In contrast, vagal primary afferent neuronal discharges recorded in the nodose ganglia were unaltered by systemic hypoglycemia. Vagal afferent rootlet section plus splanchnicotomy had no effect on hypoglycemia-induced vagal efferent firing, suggesting a central site of action. Decerebration reduced the increase in nerve firing stimulated by hypoglycemia from 21 Ϯ 4 to 9.6 Ϯ 2 impulses 30 s Ϫ1 . Chemical ablation of the lateral hypothalamic area, but not the arcuate nucleus, inhibited pancreatic nerve firing evoked by hypoglycemia. Microinjection of the orexin-A receptor antagonist SB-334867 into the dorsal motor nucleus of the vagus (DMV) inhibited pancreatic nerve firing evoked by insulininduced hypoglycemia by 56%. In contrast, injection of orexin-A (20 pmol) into the DMV elicited a 30-fold increase in pancreatic nerve firing. We concluded that systemic hypoglycemia stimulates pancreatic efferent nerve firing through a central mechanism. Full expression of pancreatic nerve activities during hypoglycemia requires both the forebrain and the brain stem. In addition to activating neurons in the brain stem, central neuroglucopenia activates subpopulations of neurons in the lateral hypothalamic area that contain orexin. The released orexin acts on DMV neurons to stimulate pancreatic efferent nerve activities and thus regulate pancreatic functions.

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Changes in lateral hypothalamic neuronal activity accompanying hyper- and hypoglycemias

Cited by 52 publications

References 35 publications

Evidence That Extrapancreatic GLUT2-Dependent Glucose Sensors Control Glucagon Secretion

Evidence That Extrapancreatic GLUT2-Dependent Glucose Sensors Control Glucagon Secretion

Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage

Hypothalamus–Brain Stem Circuitry Responsible for Vagal Efferent Signaling to the Pancreas Evoked By Hypoglycemia in Rat

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