Hepatic Venous Plasma Glucose Concentrations Research Articles

Effects of adrenergic blockers on central nervous system-mediated hyperglycemia in fed rats

We studied the effect of adrenergic blockade on hepatic venous hyperglycemia and the activation of a hepatic glycogenolytic enzyme, phosphorylase-a, in response to cerebral cholinergic activation. Neostigmine was injected into the third cerebral ventricle of bilaterally adrenodemedullectomized (ADMX) rats, while somatostatin and insulin were administered intravenously. Hepatic venous plasma glucose concentrations and hepatic phosphorylase-a activity were measured. Intracerebroventricular injection of neostigmine (5 × 10 −8 mol) caused increases in hepatic venous glucose concentrations and hepatic phosphorylase-a activity. Both of these changes were prevented by intraperitoneal (IB) pretreatment with phentolamine (5 × 10 −7, 1 × 10 −6 mol) without the intervention of insulin secretion, but not by pretreatment with the α-antagonists antagonist phenoxybenzamine (1 × 10 −6 mol), the β-adrenoreceptor antagonist propranolol (1 × 10 −6 mol), the α 1-antagonists prazosin or bunazosin (1 × 10 −6 mol), the α 2-antagonist yohimbine (1 × 10 −6 mol), or prazosin (5 × 10 −7 mol) plus yohimbine (5 × 10 −7 mol). These results suggest that phentolamine prevented brain-mediated hepatic glycogenolysis by a mechanism that may not be classified pharmacologically as involving either α 1- or α 2-receptors.

CNS stimulation does not affect hepatic venous glucose concentration in severely diabetic rats

To assess the role of the central nervous system (CNS) in carbohydrate metabolism in diabetes, neostigmine was injected into the third cerebral ventricle in fed rats with streptozotocin (STZ; 80 mg/kg)-induced diabetes under pentobarbital sodium anesthesia. Changes in hepatic venous plasma glucose concentrations were monitored. Neostigmine injection caused no significant changes in the hepatic venous plasma glucose concentration in untreated diabetic rats, whereas the glucose level increased significantly in insulin-treated diabetic rats similarly to the changes in normal control animals. In diabetic rats, the plasma levels of glucagon, epinephrine, and norepinephrine were increased significantly by neostigmine. After various doses (35-80 mg/kg) were given to rats, it was found that the higher the STZ dose, the lower was the hepatic glycogen content and the smaller was the glycemic response to neostigmine. Our results indicate that, in severe diabetes, CNS stimulation with neostigmine fails to increase hepatic glucose output, because glycogen stores are nearly exhausted and gluconeogenesis is already maximal.

Involvement of the Hippocampus in Central Nervous System-Mediated Glucoregulation in Rats

To find out whether the hippocampus is involved in central nervous system-mediated glucoregulation, we injected saline, neostigmine, dopamine, norepinephrine, bombesin, beta-endorphin, somatostatin, and prostaglandin F2 alpha into the dorsal hippocampus in anesthetized fed rats. After injection of dopamine, norepinephrine, bombesin, beta-endorphin, somatostatin, or prostaglandin F2 alpha, the level of hepatic venous plasma glucose did not differ from that in saline-treated control rats. However, neostigmine, an inhibitor of acetylcholine esterase, caused a dose-dependent increase in the hepatic venous plasma glucose concentration. This neostigmine-induced hyperglycemia was dose-dependently suppressed by coadministration of atropine, but not by hexamethonium. Injection of neostigmine (5 X 10(-8) mol) resulted in an increase not only in glucose but also in glucagon, epinephrine, and norepinephrine in hepatic venous plasma. In bilateral adrenalectomized rats, neostigmine-induced hyperglycemia was suppressed, but the hepatic venous plasma glucose concentration still increased significantly. These results indicate that the hippocampus is involved in central nervous system-mediated glucoregulation through cholinergic muscarinic activation, partly via epinephrine secretion.

Central versus peripheral effect of clonidine on hepatic venous plasma glucose concentrations in fasted rats

Central versus peripheral effect of clonidine on hepatic venous plasma glucose concentrations in fasted rats

Effects of naloxone on glucose level in the hepatic venous plasma in the rat.

1. The effect of opioid receptor blockade by naloxone in vivo on hepatic venous plasma glucose concentration in rats was investigated. 2. The plasma glucose levels in naloxone-injected animals (10 mg/kg) were higher than in the control animals (P less than 0.05). 3. At the lower dose of naloxone (2 mg/kg) the resulting plasma glucose concentration did not differ significantly from control (P greater than 0.1). 4. It is concluded that endogenous opioids may moderate the regulation of basal glucose levels in the rat.

Mechanism of central hyperglycemic effect of cholinergic agonists in fasted rats.

The influence of cholinergic agonists on central nervous system (CNS) regulation of blood sugar homeostasis was studied in fasted rats. When carbachol, muscarine, bethanechol, methacholine, or neostigmine was injected into the third cerebral ventricle, it caused a dose-dependent increase in the hepatic venous plasma glucose concentration. However, in the case of 1,1-dimethylphenyl-4-piperazinium iodide (DMPP) or nicotine, the level of hepatic venous glucose did not differ from that of the saline-treated control rats. The increase in glucose level caused by neostigmine was dose-dependently suppressed by coadministration of atropine. These facts suggest that cholinergic activation of muscarinic receptors in the CNS plays a role in increasing hepatic glucose output. Injection of neostigmine (5 X 10(-8) mol), an inhibitor of cholinesterase, into the ventricle resulted in the increase of not only glucose, but also glucagon, epinephrine, and norepinephrine in the hepatic venous plasma. However, constant infusion of somatostatin through a femoral vein completely prevented the increase of glucagon after administration of neostigmine, although the increase of hepatic venous glucose and epinephrine levels were still observed. Neostigmine-induced increments in glucose did not occur in adrenalectomized rats. This suggests that the secreted epinephrine acts directly on the liver to increase hepatic glucose output.

Vagotomy or atropine blocks hypoglycemic effect of insulin injected into ventromedial hypothalamic nucleus.

Stereotaxic microinjections of insulin (100 microU) into the ventromedial hypothalamic nucleus (VMN) resulted in rapid decrease, whereas injection of control saline into the same region caused a slight increase of hepatic venous plasma glucose concentration in rats. The hypoglycemic effect of insulin injected into the VMN was eliminated by pretreatment of the animals with atropine but not with propranolol or with phentolamine. Subdiaphragmatic vagotomy also prevented the decrease of hepatic venous plasma glucose concentration seen after microinjection of insulin into the VMN. These results support the hypothesis that the VMN is an insulin-sensitive glucoregulator center or that it is part of one and that the glucoregulatory impulse that originates in the VMN reaches the effector organ, the liver, through the cholinergic fibers of the vagus nerves.

Decrease in plasma glucose concentration after microinjection of insulin into VMN.

The influence of insulin on hypothalamic regulation of blood sugar homeostatis was studied in anesthetized rats. Insulin was injected directly into the ventromedial hypothalamic nucleus (VMN), the lateral hypothalamic area (LHA), the parietal cortex, or the third cerebral ventricle, and changes in hepatic venous plasma glucose concentrations were studied. After injection of 100 microU insulin into the parietal cortex or the third ventricle, hepatic venous plasma glucose concentration did not differ from that of the control rats, which received saline injection into the same CNS regions. Saline injection into the LHA raised the hepatic venous plasma glucose concentration in control rats, where injection of 100 microU insulin into the LHA resulted in a modest but significant decrease of glycemia in the 2-, 5-, and 10-min postinjection samples. As little as 10 microU insulin injected into the VMN eliminated the hyperglycemic response seen in control rats after saline injection into this site. The divergence between insulin-treated rats and their saline-treated controls was further amplified, and an actual fall of plasma glucose was observed in rats given injections of 50 or 100 microU insulin into the VMN. Increasing quantities of insulin (from 10 to 100 microU) injected into the VMN resulted in graded decreases of hepatic venous plasma glucose concentrations, suggestive of a dose-response curve. These observations support the hypothesis that the VMN and the LHA are parts of an insulin-sensitive CNS glucoregulator system that exerts influences on the systemic blood glucose levels by causing rapid alterations in hepatic glucose metabolism.

Hepatic effect of insulin in unanesthetized normal, diabetic, and adrenalectomized dogs.

Measurement of arterial, portal, and hepatic venous plasma glucose concentrations were made in unanesthetized dogs whose hepatic vessels were previously catheterized. Total hepatic blood flow was measured by a modified Bromsulphalein method and hepatic arterial blood flow by a trapezoidal wave electromagnetic blood flowmeter. Serial biopsies of the liver were obtained, also under unanesthetized conditions, for measurement of glycogen and free glucose. Various doses of glucagon-free insulin were given by a single, rapid, intravenous injection or by a constant infusion directly into the liver via portal vein and via femoral vein or vena cava. Insulin was administered in normal, in adrenalectomized, in depancreatized, and in depancreatized-adrenalectomized dogs. Under each of the conditions observed insulin produced no decrease in the hepatic glucose output. Moreover, no increased hepatic glycogen or free glucose concentrations were found in hepatic biopsies after insulin administration.