Possible role of L-carnosine in the regulation of blood glucose through controlling autonomic nerves

Mammalian muscles synthesize L-carnosine, but its roles were unknown. Previously, we found in rats that the administration of a certain amount of L-carnosine elicited an inhibition of the hyperglycemia induced by the injection of 2-deoxy-D-glucose (2DG) into the lateral cerebral ventricle (LCV), and that intravenous injection of L-carnosine inhibited sympathetic nerves and facilitated the parasympathetic nerve. Moreover, the suppressive effect of L-carnosine on the hyperglycemia induced by 2DG was eliminated by thioperamide, a histaminergic H3 receptor. These findings suggested that L-carnosine might control the blood glucose level through regulating autonomic nerves via H3 receptor. To further clarify the function of L-carnosine, we examined its role in the control of the blood glucose. In this experiment, the following results were observed in rats: (i) A certain amount (0.01% or 0.001%) but not a larger amount (0.1%) of L-carnosine given as a diet suppressed the hyperglycemia induced by LCV-injection of 2DG (2DG-hyperglycemia); (ii) LCV-injection but not the injection into the intraperitoneal space (IP) of a certain amount of L-histidine suppressed the 2DG-hyperglycemia; (iii) treatments of diphenhydramine, an H1 antagonist, and alpha-fluoromethylhistidine, an inhibitor of histamine-synthesizing enzyme, reduced the 2DG-hyperglycemia; (iv) the plasma L-carnosine concentration and carnosinase activity showed daily changes; (v) the plasma L-carnosine concentration was significantly lower in the streptozotocin-diabetic rats; (vi) exercise by a running wheel tended to increase carnosine synthase activity in the gastrocnemius muscle and elevated the plasma L-carnosine concentration in the dark (active) period, and enhanced the plasma carnosinase activity in the light period; (vii) IP-injection of certain amount of L-carnosine stimulated the feeding response to IP-injection of 2DG. These findings suggest a possibility that L-carnosine released from muscles due to exercise functions to reduce the blood glucose level through the regulation of the autonomic nerves.     

Proinsulin C-peptide activates vagus efferent output in rats

The aim of this study was to examine the effect of proinsulin C-peptide on the autonomic nervous systems in rats. Intravenous administration of C-peptide gradually increased electrophysiological activity of the vagus nerves into the stomach and pancreas for at least 90 min. It also slightly increased gastric acid secretion that was suppressed by the treatment with atropine. Intraperitoneal injection of C-peptide did not affect the basal and stress-induced norepinephrine (NE) turnover rate, a biochemical index of sympathetic nerve activity. These results indicate that C-peptide increases parasympathetic nerve activity without affecting sympathetic nerve activity. This could explain, at least in part, the ameliorating effects of C-peptide on impaired cardiac autonomic nerve functions in patients with type 1 diabetes.     

Opposite excitatory and inhibitory effects of central administration of glucagon and of insulin upon the sympathetic cervical and adrenal nerve activities in the rat

The central effects of pancreatic glucagon and insulin given intracerebroventriculary (i.c.v.) upon sympathetic activity in the cervical trunk and adrenal nerve were examined in Wistar Kyoto rats. Glucagon i.c.v. administration led to an increase in sympathetic nerve activity in both nerves. Insulin injected into lateral ventricle caused opposite to glucagon inhibitory influence on sympathetic discharge in the cervical trunk and adrenal nerve. This two different central effects of glucagon and insulin on sympatho-adrenal system may contribute to glycemia homesthasis.     

Sympathoadrenal system in neuroendocrine control of glucose: mechanisms involved in the liver, pancreas, and adrenal gland under hemorrhagic and hypoglycemic stress.

Glucose homeostasis is maintained by complex neuroendocrine control mechanisms, involving three peripheral organs: the liver, pancreas, and adrenal gland, all of which are under control of the autonomic nervous system. During the past decade, abundant results from various studies on neuroendocrine control of glucose have been accumulated. The principal objective of this review is to provide overviews of basic adrenergic mechanisms closely related to glucose control in the three peripheral organs, and then to discuss the integrated glucoregulatory mechanisms in hemorrhage-induced hypotension and insulin-induced hypoglycemia with special reference to sympathoadrenal control mechanisms. The liver is richly innervated by sympathetic and parasympathetic nerves. The functional implication in glucoregulation of sympathetic nerves has been well-documented, while that of parasympathetic nerves remains less understood. More recently, hepatic glucoreceptors have been postulated to be coupled with capsaicin-sensitive afferent nerves, conveying sensory signals of blood glucose concentration to the central nervous system. The pancreas is also richly supplied by the autonomic nervous system. Besides the well documented adrenergic and cholinergic mechanisms, the potential implication of peptidergic neurotransmission by neuropeptide Y and neuromodulation by galanin has recently been postulated in the endocrine secretory function. Presynaptic interactions of these putative peptidergic neurotransmitters with the classic transmitters, noradrenaline and acetylcholine, in the pancreas remain to be clarified. It may be of particular interest that it was vagus nerve stimulation that caused a dominant release of neuropeptide Y over that caused by sympathetic nerve stimulation in the pig pancreas. The adrenal medulla receives its main nerve supply from the greater and lesser splanchnic nerves. Adrenal medullary catecholamine secretion appears to be regulated by three distinct local mechanisms: adrenoceptor-mediated, dihydropyridine-sensitive Ca2+ channel-mediated, and capsaicin-sensitive sensory nerve-mediated mechanisms. In response to hemorrhagic hypotension and insulin-induced hypoglycemia, the sympathoadrenal system is activated resulting in increases of adrenal catecholamine and pancreatic glucagon secretions, both of which are significantly implicated in glucoregulatory mechanisms. An increase in sympathetic nerve activity occurs in the liver during hemorrhagic hypotension and is also likely to occur in the pancreas in response to insulin-induced hypoglycemia. The functional implication of hepatic and central glucoreceptors has been suggested in the increased secretion of glucose counterregulatory hormones, particularly catecholamines and glucagon.     

Effect of DG5128 on epinephrine and glucagon induced glucose output from the isolated perfused rat liver

The effect of a specific alpha 2-adrenergic antagonist 2-[2-(4,5-dihydro-1.H-imidazol-2-yl)-1-phenyl-ethyl] pyridine dihydrochloride sesquihydrate (DG5128), on the glucose output by epinephrine and/or glucagon was studied using the perfused rat liver. The administration of DG5128 alone did not affect the glucose output. However, DG5128 produced a significant inhibition of the increased glucose output when induced by 10(-6) M epinephrine alone or 10(-6) M epinephrine plus 1.4 x 10(-10) M glucagon. There were no significant changes of the glucose output by 1.4 x 10(-10) M or 7.0 x 10(-11) M glucagon alone. On the other hand, addition of 1 mU/ml insulin to the perfusate suppressed the 7.0 x 10(-11) M glucagon-induced glucose output, but failed to decrease the 1.4 x 10(-10) M glucagon effect. DG5128 suppressed further the glucagon (7.0 x 10(-11) M)-induced increase of glucose output in the presence of insulin. These results suggest that DG5128 produces a hypoglycemic effect partly through an inhibition of the increased hepatic glucose output elicited by epinephrine and glucagon.     

Insulin and glucagon relationships during aging in rats.

Oral glucose tolerance tests were performed under pentobarbital anesthesia in 43 male Wistar rats 2 to 18 months of age in order to determine if insulin and glucagon secretion are altered with aging. Although any linear correlation was not demonstrated between aging and blood glucose, plasma insulin or glucagon levels, post-glucose levels of blood glucose were significantly suppressed and those of plasma glucagon were significantly elevated at 4 to 6 months of age. No significant difference was found between young (2 months of age) and aged rats (12 to 14 and 17 to 18 months of age) in either blood glucose or plasma insulin levels during oral glucose load. On the other hand, post-glucose plasma glucagon levels of the aged rats were significantly higher than those of the young ones. Furthermore, comparisons of various kinds of indices among the different age groups, such as insulinogenic index, insulin/glucagon and so forth during oral glucose tolerance tests also indicate the significant alteration of glucagon secretion during aging process. It is concluded from the present data that glucose tolerance does not apparently deteriorate during aging process in rats but that glucagon responses to oral glucose administration are elevated with aging.     

Comparative effects of intraduodenal fat and glucose on the gut-incretin axis in healthy males

BackgroundThe interaction of nutrients with the small intestine stimulates the secretion of numerous enteroendocrine hormones that regulate postprandial metabolism. However, differences in gastrointestinal hormonal responses between the macronutrients are incompletely understood. In the present study, we compared blood glucose and plasma hormone concentrations in response to standardised intraduodenal (ID) fat and glucose infusions in healthy humans.MethodsIn a parallel study design, 16 healthy males who received an intraduodenal fat infusion were compared with 12 healthy males who received intraduodenal glucose, both at a rate of 2 kcal/min over 120 min. Venous blood was sampled at frequent intervals for measurements of blood glucose, and plasma total and active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon.ResultsPlasma concentrations of the incretin hormones (both total and active GLP-1 and GIP) and glucagon were higher, and plasma insulin and blood glucose concentrations lower, during intraduodenal fat, when compared with intraduodenal glucose, infusion (treatment by time interaction: P < 0.001 for each).ConclusionsCompared with glucose, intraduodenal fat elicits substantially greater GLP-1, GIP and glucagon secretion, with minimal effects on blood glucose or plasma insulin in healthy humans. These observations are consistent with the concept that fat is a more potent stimulus of the ‘gut-incretin’ axis than carbohydrate.     

Hepatic Branch Vagus Nerve Plays a Critical Role in the Recovery of Post-Ischemic Glucose Intolerance and Mediates a Neuroprotective Effect by Hypothalamic Orexin-A

Orexin-A (a neuropeptide in the hypothalamus) plays an important role in many physiological functions, including the regulation of glucose metabolism. We have previously found that the development of post-ischemic glucose intolerance is one of the triggers of ischemic neuronal damage, which is suppressed by hypothalamic orexin-A. Other reports have shown that the communication system between brain and peripheral tissues through the autonomic nervous system (sympathetic, parasympathetic and vagus nerve) is important for maintaining glucose and energy metabolism. The aim of this study was to determine the involvement of the hepatic vagus nerve on hypothalamic orexin-A-mediated suppression of post-ischemic glucose intolerance development and ischemic neuronal damage. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Intrahypothalamic orexin-A (5 pmol/mouse) administration significantly suppressed the development of post-ischemic glucose intolerance and neuronal damage on day 1 and 3, respectively after MCAO. MCAO-induced decrease of hepatic insulin receptors and increase of hepatic gluconeogenic enzymes on day 1 after was reversed to control levels by orexin-A. This effect was reversed by intramedullary administration of the orexin-1 receptor antagonist, SB334867, or hepatic vagotomy. In the medulla oblongata, orexin-A induced the co-localization of cholin acetyltransferase (cholinergic neuronal marker used for the vagus nerve) with orexin-1 receptor and c-Fos (activated neural cells marker). These results suggest that the hepatic branch vagus nerve projecting from the medulla oblongata plays an important role in the recovery of post-ischemic glucose intolerance and mediates a neuroprotective effect by hypothalamic orexin-A.     

Insulin-mediated increase in sympathetic nerve activity is attenuated by C-peptide in diabetic rats

Connecting peptide (C-peptide) is secreted along with insulin in equimolar amounts into portal circulation in response to beta cell stimulation. The biological function of C-peptide had been mostly limited to establishing the secondary and tertiary structure of proinsulin. Recent studies have suggested that C-peptide can impact several functions, such as autonomic and sensory nerve function, insulin secretion, and microvascular blood flow. In this study we examined the effects of C-peptide in the presence or absence of insulin on cardiovascular and sympathetic nerve activity in both normal and streptozotocin (STZ)-induced diabetic Wistar rats. Animals were made diabetic by a single intravenous injection of STZ (50 mg/kg) and maintained for 6 weeks. The diabetic animals had higher plasma glucose, lower plasma insulin, and C-peptide, compared with the normal animals. To characterize cardiovascular and autonomic nervous responses, the animals were anesthetized with urethane/alpha-chloralose and instrumented for the recording of mean arterial pressure (MAP), heart rate (HR), and lumbar sympathetic nerve activity (LSNA). A bolus administration of C-peptide alone did not alter MAP, HR, or LSNA in normal or diabetic animals. The bolus administration of insulin alone increased HR and LSNA in normal and diabetic animals. However, the administration of insulin plus C-peptide attenuated the increase in HR in normals and the increase in LSNA in diabetic rats. We concluded that the C-peptides play a role in modulating the insulin-stimulated sympathetic nerve response.     

Effects of oral carbohydrate on autonomic nervous system counterregulatory responses during hyperinsulinemic hypoglycemia and euglycemia

The effects of oral carbohydrate on modulating counterregulatory responses in humans remain undecided. This study's specific aim was to determine the effects of oral carbohydrate on autonomic nervous system (ANS) and neuroendocrine responses during hyperinsulinemic hypoglycemia and euglycemia. Nineteen healthy volunteers were studied during paired, single blind experiments. Nine subjects underwent two-step glucose clamps consisting of 60 min of euglycemia (5.0 mmol/l) followed by either 15 g of oral carbohydrate (cal) as orange juice or a noncaloric control (nocal) and subsequent 90 min of clamped hypoglycemia (2.9 mmol/l). Ten other subjects underwent two randomized 150-min hyperinsulinemic-euglycemic clamps with cal or nocal control administered at 60 min. Oral carbohydrate initially blunted (P < 0.05) epinephrine, norepinephrine, cortisol, glucagon, pancreatic polypeptide, muscle sympathetic nerve activity (MSNA), symptom, and systolic blood pressure responses during hypoglycemia. However, by the end of 90 min of hypoglycemia, plasma epinephrine and norepinephrine responses had rebounded and were increased (P < 0.05) compared with control. MSNA and cortisol levels remained suppressed during hypoglycemia (P < 0.05) after cal, whereas pancreatic polypeptide, glucagon, symptom, and blood pressure responses increased similar to control following initial suppression. Oral carbohydrate had no effects on neuroendocrine or ANS responses during hyperinsulinemic euglycemia. These results demonstrate that oral carbohydrate can have differential effects on the time course of ANS and neuroendocrine responses during hypoglycemia. We conclude that gastro-splanchnic-portal sensing of an amount of carbohydrate recommended for use in clinical practice for correction of hypoglycemia can have widespread and significant effects on central nervous system mediated counterregulatory responses in healthy humans.     

Evidence for centers in the central nervous system that selectively regulate fat mobilization in the rat

The blood sugar and plasma free fatty acid responses to administration of 2-deoxyglucose were determined in normal rats and in rats subjected to adrenodemedullation and/or hypothalamic deafferentation, as well as in rats with bilateral hypothalamic lesions. Adrenodemedullation of both intact and deafferentated rats reduced the 2-deoxyglucose-induced increase of blood sugar but did not affect the plasma free fatty acid response to 2-deoxyglucose in normal rats. The increases in blood sugar levels induced by the drug in intact rats were not significantly affected by deafferentation, but, in marked contrast, plasma free fatty acid mobilization after 2-deoxyglucose administration was completely suppressed in deafferentated rats, both in the presence and in the absence of the adrenal medulla. These results confirm previous observations indicating that the sympathetic nervous system and adrenalin release from the adrenal medulla participate in the production of hyperglycemia by 2-deoxyglucose. They provide, in addition, evidence for the existence, in the anterior hypothalamus or in limbic structures, of centers that can specifically influence mobilization of free fatty acids through a direct activation of the sympathetic fibers of adipose tissue without intervening in glucose homeostasis. The experiments in animals with bilateral hypothalamic lesions, although small in number, seem to support the above conclusions.     

Glucagon and epinephrine effect on blood glucose levels in rats carrying Yoshida solid sarcoma and Walker-256 carcinosarcoma

Changes in blood glucose in response to glucagon and epinephrine administration, in rats bearing Yoshida solid sarcoma and Walker-256 carcinosarcoma have been studied, and in rats carrying Yoshida tumor which had received previously intraperitoneal glucose. The response to glucagon by tumor-bearing rats follows the control pattern but at a lower level of blood glucose. Rats which had received glucose before glucagon administration responded to this hormone as the control animals. These results indicate that glycogen metabolism in the host liver is not diturbed by the presence of the tumor.     

Sinoaortic denervation attenuates vasopressin-induced hypothermia and reduction of sympathetic nerve activity innervating brown adipose tissue in rats

It is well known that sympathetic nerve activity innervating brown adipose tissue (BAT sympathetic nerve activity) plays an important role in BAT thermogenesis. We have found that peripheral administration of arginine vasopressin (AVP) induced hypothermia by reduced thermogenesis in BAT. However, little is known about AVP-induced hypothermic response and its relationship with BAT sympathetic nerve activity. Because increases in baroreceptor inputs inhibit peripheral sympathetic nervous activity, we hypothesized that AVP-induced hypothermia is related to baroreceptor reflex suppression of BAT sympathetic nerve activity. To test this hypothesis, Male Sprague-Dawley rats were subjected to sinoaortic denervation or sham denervation, and implanted with radiotelemetry transmitters to assess the effects of peripheral administration of AVP on BAT sympathetic nerve activity, core and BAT temperatures. In sham-operated rats, an intraperitoneal (i.p.) injection of 10 µg/kg AVP led to a significant decrease in core and BAT temperatures. However, sinoaortic denervation significantly reduced the fall of core and BAT temperatures induced by AVP, compared with levels in sham-operated rats. AVP (10 µg/kg i.p.) rapidly decreased BAT sympathetic nerve activity in control and sham-operated rats, with the greatest levels of suppression occurring at 35 min and these lowest levels attained were with 30.6% and 29.24%, respectively. Furthermore, we found that sinoaortic denervation attenuated the suppressive effects of AVP (10 µg/kg i.p.) on BAT sympathetic nerve activity. The greatest level of suppression was only 20.8% occurring at 35 min after AVP. Therefore, these results indicate that the hypothermic effects of peripheral administration of AVP are partially mediated by the arterial baroreceptor reflex suppression of BAT sympathetic nerve activity and BAT thermogenesis.     

Modulation of A and B cell functions by tolbutamide and arginine in the pancreas of thiamine-deficient rats

The effects of administration of glucose orally and tolbutamide or arginine intravenously on insulin and glucagon secretion and blood glucose level were studied in normal and thiamine-deficient rats. In thiamine deficiency, insulin secretion and glucose tolerance were impaired during glucose ingestion. Tolbutamide decreased the blood glucose level in both control and thiamine-deficient rats but its stimulatory effect on insulin secretion was minimal in thiamine-deficient rats unlike the control animals. Arginine did not alter substantially the blood glucose or insulin in thiamine-deficient rats, whereas it increased the insulin level in control rats. The fasting plasma glucagon level was high in thiamine deficiency. Tolbutamide increased the plasma glucagon in control rats, but did so only marginally in thiamine-deficient rats. Arginine also increased the glucagon secretion throughout the period of study in control rats. In thiamine-deficient rats the glucagon secretion was pronounced only after 20 min of arginine administration. These results suggest that an unimpaired glucose metabolism is a prerequisite to induce proper insulin secretion. Only proper insulin secretion can check the glucagon secretion rather than the increased glucose level. Hypoglycemia can induce glucagon secretion independent of the insulin level.     

Neuropeptides as central integrators of autonomic nerve activity: effects of TRH, SRIF, VIP and bombesin on gastric and adrenal nerves

The nerve activity of the gastric ramus of the splanchnic (sympathetic) nerve, gastric ramus of the vagus, adrenal ramus of the splanchnic nerve and the superior laryngeal nerve (laryngeal ramus of vagus) were assessed before and after i.c.v. injection of neuropeptides in the rat. TRH stimulated the vagal branch but attenuated the sympathetic outflow to the stomach. In contrast, the sympathetic outflow to the adrenal was enhanced by TRH. SRIF suppressed the activity of all the nerves studied. VIP did not affect the sympathetic outflow to the stomach while suppressing the gastric branch of the vagus. The adrenal sympathetic branch as well as the superior laryngeal nerve was stimulated by VIP. Bombesin suppressed both vagal and sympathetic outflow to the stomach but markedly stimulated the laryngeal branch of the vagus. The adrenal sympathetic nerve was either stimulated or attenuated slightly by bombesin. These results indicate that centrally administered neuropeptides produce reactions specific for each nerve.     

Effects of adiponectin on the renal sympathetic nerve activity and blood pressure in rats

Adiponectin is an adipocytokine that modulates energy homeostasis and glucose metabolism. Here, we examined the effects of acute intravenous (iv) and lateral cerebral ventricular (LCV) injections of adiponectin on the renal sympathetic nerve activity (RSNA) and blood pressure (b/p) in urethane-anesthetized rats. Both iv and LCV injections of adiponectin induced dose-dependent suppressions of RSNA and b/p. Moreover, we found that bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) abolished the effects of iv injection of adiponectin on RSNA and b/p. These findings suggest that adiponectin decreases the RSNA and b/p in a dose-dependent manner and that the SCN is implicated in mechanism of adiponectin actions on RSNA and b/p. These findings also suggest that the hypotensive-action activity of adiponectin is realized, at least partially, via changes in activities of autonomic nerves activity.     

Hyperglycemia and hyperglucagonemia following neurotensin administration

Neurotensin (NT), a tridecapeptide of bovine hypothalamic origin, was injected into anesthetized rats to clarify the mechanism of its hyperglycemic effects. A dose-related hyperglycemic response was observed at 15 and 30 min after intraarterial injection of 2.5 and 5 μg/kg. Hyperglucagonemia was present with the higher dose and, in some experiments, with the lower dose. Minimal insulin responses were observed. In contrast, injection of NT into the lateral cerebral ventricle did not increase plasma glucose, insulin, or glucagon. Adrenal autotransplantation partially inhibited the hyperglycemia, markedly enhanced the insulin response, and did not affect the hyperglucagonemia. NT effects were unaltered by propranolol (2 mg/kg) whereas the effects of phentolamine (2 mg/kg) were similar to those of adrenal autotransplantation. Somatostatin infusion (1.5 μg/kg/min) blocked the glucagon and insulin responses to NT but only partially suppressed the hyperglycemia. The results suggest that NT hyperglycemia is mediated by effects on the pancreatic islets, the adrenal medulla, and possibly the liver, though effects on the sympathetic nervous system have not been excluded. The physiologic significance of NT in the regulation of carbohydrate metabolism remains to be determined.     

Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis

It is well established that impaired glucose metabolism is a frequent complication in patients with hepatic cirrhosis. We previously showed that leucine, one of the branched-chain amino acids (BCAA), promotes glucose uptake under insulin-free conditions in isolated skeletal muscle from normal rats. The aim of the present study was to evaluate the effects of BCAA on glucose metabolism in a rat model of CCl(4)-induced cirrhosis (CCl(4) rats). Oral glucose tolerance tests were performed on BCAA-treated CCl(4) rats. In the CCl(4) rats, treatment with leucine or isoleucine, but not valine, improved glucose tolerance significantly, with the effect of isoleucine being greater than the effect of leucine. Glucose uptake experiments using isolated soleus muscle from the CCl(4) rats revealed that leucine and isoleucine, but not valine, promoted glucose uptake under insulin-free conditions. To clarify the mechanism of the blood glucose-lowering effects of BCAA, we collected soleus muscles from BCAA-treated CCl(4) rats with or without a glucose load. These samples were used to determine the subcellular location of glucose transporter proteins and glycogen synthase (GS) activity. Oral administration of leucine or isoleucine without a glucose load induced GLUT4 and GLUT1 translocation to the plasma membrane. GS activity was augmented only in leucine-treated rats and was completely inhibited by rapamycin, an inhibitor of mammalian target of rapamycin. In summary, we found that leucine and isoleucine improved glucose metabolism in CCl(4) rats by promoting glucose uptake in skeletal muscle. This effect occurred as a result of upregulation of GLUT4 and GLUT1 and also by mammalian target of rapamycin-dependent activation of GS in skeletal muscle. From these results, we consider that BCAA treatment may have beneficial effects on glucose metabolism in cirrhotic patients.     

Signal propagation via gap junctions, a key step in the regulation of liver metabolism by the sympathetic hepatic nerves.

Cell-to-cell communication via gap junctions has been proposed to be involved in the metabolic actions of sympathetic liver nerves in the rat. The effects of hepatic nerve stimulation and noradrenaline-, PGF2 alpha- and glucagon infusion on glucose metabolism and perfusion flow were studied in perfused rat liver in the absence and presence of the gap junctional inhibitors, heptanol, carbenoxolone and (4 beta)phorbol 12-myristate 13-acetate (4 beta PMA). (i) Stimulation of the hepatic nerve plexus increased glucose output, decreased flow and caused an overflow of noradrenaline into the hepatic vein. (ii) Heptanol completely inhibited not only the nerve stimulation-dependent metabolic and hemodynamic alterations but also the noradrenaline overflow. Thus the heptanol-dependent inhibitions were caused primarily by a strong impairment of transmitter release. (iii) Carbenoxolone inhibited the effects of neurostimulation on glucose metabolism partially by about 50%, whereas it left perfusion flow and noradrenaline overflow essentially unaltered. (iv) 4 beta PMA reduced the nerve stimulation-dependent enhancement of glucose release by about 80% but the noradrenaline-dependent increase in glucose output only by about 30%; the increase in glucose release by PGF2 alpha and by glucagon remained essentially unaltered. 4 beta PMA reduced the nerve stimulation-dependent decrease in portal flow by about 35% but did not affect the noradrenaline-and PGF2 alpha-elicited alterations, nor did it alter noradrenaline overflow. The results allow the conclusion that gap junctional communication plays a major role in the regulation of hepatic carbohydrate metabolism by sympathetic liver nerves, but not by circulating noradrenaline, PGF2 alpha or glucagon.     

Cardiovascular Vagosympathetic Activity in Rats with Ventromedial Hypothalamic Obesity

Objective: Rats with ventromedial hypothalamic lesion (VMH) are massively obese with endogenous hyperinsulinemia, insulin resistance, low sympathetic activity, and high parasympathetic activity, which are likely to induce hypertension. The goal was to follow in this model the long‐term hemodynamic changes and to investigate the role of autonomic nervous system and insulin resistance in these changes. Research Metho ds and Procedures: Heart rate and blood pressure were monitored for 12 weeks after operation using a telemetric system in VMH and sham rats. Plasma catecholamines and heart β‐adrenoceptors were measured. Glucose tolerance was studied after an intravenous glucose injection and insulin sensitivity during a euglycemic hyperinsulinemic clamp test. Results: A marked bradycardia and only a mild increase in blood pressure occurred in VMH rats compared with sham animals. Response to autonomic‐acting drugs showed an increase in heart vagal tone and responsiveness to a β‐agonist drug. Plasma catecholamine levels were markedly increased, and the density and affinity of heart β‐adrenoceptors were similar in VMH, sham, and control rats. Muscle glucose use was reduced by 1 week after operation in VMH animals. Discussion: These results show the following in this model of massively obese rats with sympathetic impairment: 1) adrenal medulla secretion is increased, probably as a result of hyperinsulinemia and increased vagal activity; 2) cardiac responsiveness to β‐agonist stimulation is increased; and 3) despite these changes and suspected resistance to the vasodilative effect of insulin, blood pressure does not increase. We conclude that high vagal activity may be protective against hypertension associated with obesity.