Mechanism of intrahippocampal neostigmine-induced hyperglycemia in fed rats.

We previously reported that the injection of neostigmine, an acetylcholine esterase inhibitor, into the dorsal hippocampus produced hepatic venous plasma hyperglycemia associated with an increase of epinephrine and glucagon in anesthetized fed rats. To evaluate the relative contribution of these glucoregulatory hormones and the nervous system to the net hyperglycemic response, we unilaterally injected neostigmine (5 x 10(-8) mol) into the dorsal hippocampus in the following groups of rats: intact rats with bilateral adrenalectomy to eliminate the action of epinephrine, and rats receiving a constant infusion of somatostatin and insulin to prevent the glucagon response and to maintain the basal insulin level. Hepatic venous plasma levels of glucose, immunoreactive glucagon, immunoreactive insulin, epinephrine, and norepinephrine were determined. The area under the glucose curve during the 120-min period following the injection of neostigmine was compared between groups. The areas under the glucose curve for rats receiving somatostatin and insulin, adrenalectomy rats, and adrenalectomy rats receiving somatostatin and insulin were, respectively, 82, 31, and 61% of that for intact rats. The fashion of hippocampal stimulated hyperglycemia with neostigmine was similar to that after injection of neostigmine into the third cerebral ventricle. Therefore, we investigated hyperglycemia in rats with lesions of ventromedial hypothalamus and found that the response to hippocampal neostigmine was significantly inhibited by the hypothalamic lesion. These findings suggest that the glucoregulatory hippocampal activity evoked by neostigmine may be transmitted to peripheral organs via the ventromedial hypothalamus.     

Relative contribution of nervous system and hormones to hyperglycemia induced by thyrotropin-releasing hormone in fed rats.

In a continuation of our studies on the mechanism of central nervous system induced hyperglycemia in the rat, we evaluated the relative contribution of a direct neural effect on the liver and of certain hormones to the hyperglycemia induced by administration of thyrotropin-releasing hormone (TRH). The findings were compared with those of a previous investigation using neostigmine or 2-deoxy-D-glucose. In the present study TRH was injected into the third cerebral ventricle of rats, and the concentrations of hepatic venous plasma glucose, immunoreactive glucagon, immunoreactive insulin, epinephrine, and norepinephrine, were measured. Four groups of animals were evaluated: (1) intact rats; (2) rats receiving an infusion of somatostatin with insulin via the femoral vein to inhibit glucagon secretion and to maintain the basal insulin level; (3) rats bilaterally adrenalectomized (ADX) to prevent epinephrine secretion, and (4) ADX rats administered an infusion of somatostatin and insulin. Evaluation of the areas under the glucose curves for the rats receiving somatostatin with insulin, ADX rats, and ADX rats receiving somatostatin with insulin showed values 202, 50, and 79% of those observed in intact animals. These observations suggest that TRH-induced hyperglycemia results from at least two effects: a direct neural effect on the liver including a suppressive effect of epinephrine on insulin secretion (contributing about 79% to the total hyperglycemic effect) and a direct effect of epinephrine on the liver (contributing about 21% to the total hyperglycemic effect).(ABSTRACT TRUNCATED AT 250 WORDS)     

The relative importance of nervous system and hormones to the 2-deoxy-D-glucose-induced hyperglycemia in fed rats

We examined the relative contributions of hormones and nervous system to the total 2-deoxy-D-glucose (2-DG)-induced central nervous system-mediated hyperglycemia. 2-DG was injected into the third cerebral ventricle in the following four groups of rats, and hepatic venous plasma glucose, immunoreactive glucagon, immunoreactive insulin, epinephrine, and norepinephrine were measured: 1) intact rats; 2) intact rats receiving somatostatin with insulin infusion through the femoral vein to inhibit glucagon secretion and maintain the basal insulin level; 3) bilateral adrenalectomized (ADX) rats to prevent epinephrine secretion; and 4) ADX rats receiving somatostatin with insulin infusion. Comparing areas under glucose curves among the intact rats, those receiving somatostatin with insulin infusion, ADX rats, and ADX rats receiving somatostatin with insulin infusion, the area under the glucose curve was intact rats greater than intact rats receiving somatostatin with insulin infusion greater than ADX rats receiving somatostatin with insulin infusion greater than ADX rats. These results suggest that there are three distinct sympathetic nervous system responses to 2-DG-induced central nervous system-mediated hyperglycemia. 2-DG-induced hyperglycemia is not dependent on only one of those three systems, it is dependent on all of them. The relative potency of the factors to 2-DG-induced hyperglycemia increases in the following order: direct neural innervation of liver (including suppressive epinephrine action on insulin secretion), glucagon, and direct epinephrine action on liver.     

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 hyperglycaemic effect of adrenaline and carbachol

The effect of chemical stimulation of the brain on glucoregulation was studied in anaesthetized rats. Adrenaline, noradrenaline, acetylcholine, dopamine and carbachol (5 X 10(-8) mol/microliter saline) were injected directly into the third cerebral ventricle and changes in hepatic venous plasma glucose, immunoreactive glucagon and insulin concentrations were studied. The injection of adrenaline and carbachol into the third cerebral ventricle resulted in a marked hyperglycaemia associated with increased immunoreactive glucagon. Adrenaline-induced hyperglycaemia was not affected by bilateral adrenalectomy, while carbachol-induced hyperglycaemia was completely inhibited by adrenalectomy. The injection of somatostatin (1 X 10(-9) mol) with adrenaline into the third cerebral ventricle did not influence adrenaline-induced hyperglycaemia, while carbachol-induced hyperglycaemia was inhibited by co-administration with somatostatin. These results suggest that adrenergic and cholinergic neurons in the central nervous system may increase hepatic glucose output by different mechanism.     

Altered mechanism of glucagon-mediated hepatic glycogenolysis during long-term starvation in the rat.

The effect of long-term starvation on glucagon-mediated hepatic glycogenolysis was investigated in the rat in vivo. Following glucagon (50 microgram/kg i.v.) fed rats showed rapid phosphorylase activation but no change in synthase-I activities. In contrast, rats fasted 72 hr (long-term fasting) showed rapid synthase inactivation but no significant phosphorylase activation. Rats fasted 24 hr (short-term fasting) demonstrated coordinated inactivation of synthase and activation of phosphorylase. Hepatic cyclic AMP responses were greater in fasted rats. Hepatic glycogen concentrations in rats fasted 72 hr were approximately 30% of fed levels. After glucagon, comparable decrements in hepatic glycogen and increments in plasma glucose concentrations were seen in fed and 72-hr groups. The diminished responsiveness of the hepatic phosphorylase system in rats fasted 72 hr was not attributable to altered cyclic AMP-dependent protein kinase or phosphorylase kinase activities. However, the diminished responsiveness could be ascribed to diminished total phosphorylase with nearly complete activation in the basal state. In fed and fasted rats, synthase decrements after glucagon correlated closely with basal levels of synthase-I. Thus, it is proposed that the enzymatic mechanism of glucagon-mediated hepatic glycogenolysis differs in fed and fasted rats. It is also proposed that partial hepatic glycogen reaccumulation during long-term fasting could be physiologically important for glucose homeostasis.     

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 x 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 x 10(-7), 1 x 10(-6) mol) without the intervention of insulin secretion, but not by pretreatment with the alpha-adrenoreceptor antagonist phenoxybenzamine (1 x 10(-6) mol), the beta-adrenoreceptor antagonist propranolol (1 x 10(-6) mol), the alpha 1-antagonists prazosin or bunazosin (1 x 10(-6) mol), the alpha 2-antagonist yohimbine (1 x 10(-6) mol), or prazosin (5 x 10(-7) mol) plus yohimbine (5 x 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 alpha 1- or alpha 2-receptors.     

Effect of intrahypothalamic injection of neostigmine on the secretion of epinephrine and norepinephrine and on plasma glucose level.

We previously reported that the injection of neostigmine, an inhibitor of acetylcholinesterase, into the third cerebral ventricle of fasted rats produced hyperglycemia associated with the secretion of epinephrine and norepinephrine. However, the central nervous system site of action of neostigmine by which the plasma catecholamine and glucose concentrations were increased is not known. In this study we injected neostigmine into the ventromedial hypothalamus, lateral hypothalamus, paraventricular hypothalamus, median site of the lateral-preoptic area, lateral site of the lateral-preoptic area, anterior site of the anterior hypothalamic area, mammillary body (posterior mamillary nucleus), and cortex of anesthetized fasted rats and measured the plasma levels of glucose, epinephrine, and norepinephrine. It was found that the ventromedial hypothalamus, lateral hypothalamus, paraventricular hypothalamus, and median site of the lateral-preoptic area were involved in increasing the plasma levels of glucose and epinephrine. From this evidence we conclude that neostigmine acts on selected regions known to be involved in glucoregulation in the hypothalamus to increase the plasma levels of epinephrine and glucose.     

Swim training increases glucose output from liver perfused in situ with glucagon in fed and fasted rats

The effect of endurance swim training (3 hours per day, 5 days/week, for 10 weeks) on hepatic glucose production (HGP) in liver perfused in situ for 60 minutes with glucagon and insulin was studied in Sprague-Dawley rats. The experiments were performed in fed rats and in rats fasted for 24 hours, but with lactate (8 mmol/L) added to the perfusion medium. Liver glycogen content was significantly lower in fasted than fed rats (fasted untrained and trained: 14 +/- 4 and 11 +/- 3 micromol glycosyl U/g of liver wet weight (WW); fed untrained and trained: 205 +/- 11 and 231 +/- 11 micromol glycosyl U/g of liver WW; not significantly different in trained and untrained rats). Glucagon increased HGP in the 4 experimental groups, but the increases were more rapid and pronounced in trained than in untrained rats in both fed and fasted states. HGP values (area under the curve [AUC] in micromol/g of liver WW) were significantly higher in trained fed (112.1 +/- 7.1 v 85.9 +/- 12.2 in untrained rats) than in trained fasted rats (50.8 +/- 4.4 v 34.7 +/- 3.6 in untrained rats). When compared with untrained rats, the total amount of glucose released by the liver in response to glucagon in trained rats was approximately 30% higher in the fed state and approximately 45% larger in the fasted state. These results indicate that endurance training increases the response of both glycogenolysis and gluconeogenesis to glucagon.     

Central nervous system-mediated glucagon secretion is enhanced by alpha 2-adrenoreceptor activation

We assessed the response of the adrenergic receptor in pancreatic glucagon secretion to central nervous system stimulation. Injection of neostigmine (5 x 10(-8) mol) into the third cerebral ventricle in intact rats resulted in increased epinephrine and norepinephrine secretion associated with glucagon secretion. This glucagon secretion was still observed in bilateral adrenalectomized (ADX) rats, although its concentration was significantly lower than that in the intact rats. This glucagon rise was significantly inhibited by ip treatment of ganglionic blocker with hexamethonium. Intraperitoneal injection of alpha-adrenergic receptor antagonist phentolamine (5 x 10(-7) mol), but not of beta-adrenergic receptor antagonist propranolol (1 x 10(-6) mol), reduced the hyperglucagonemic effect of a subsequent neostigmine injection in intact and ADX rats, although these antagonists did not influence epinephrine or norepinephrine secretion in intact rats. In addition, ip injection of the selective alpha 2-receptor antagonist yohimbine (5 x 10(-7) mol), but not of the selective alpha 1-receptor antagonist prazosin (1 x 10(-6) mol), inhibited the neostigmine-induced glucagon secretion in intact and ADX rats. From this evidence it is suggested that central nervous system-mediated glucagon release is enhanced by alpha 2-adrenoreceptor stimulation by either catecholamines or the autonomic nervous system.     

Prostaglandins affect the central nervous system to produce hyperglycemia in rats

The influence of prostaglandins (PG) on central nervous system regulation of blood sugar homeostasis was studied in rats. Substances were injected into the third cerebral ventricle of anesthetized rats while rectal temperature and hepatic venous plasma glucose concentration were recorded. Stereotaxic microinjection of PGD2, E1, E2, and F2 alpha produced hyperglycemia and hyperthermia. The relative order of potency in hyperglycemia, PGF2 alpha greater than D2 greater than E1 greater than E2, was not consistent with that of hyperthermia, PGE2 greater than F2 alpha greater than E1 greater than D2, which suggests that hyperglycemia was a primary, not secondary, response to hyperthermia. Injection of PGF2 alpha caused a dose dependent (5-200 micrograms) increase in the hepatic venous plasma glucose level. Neither the injection of PGF2 alpha (50 micrograms) into the cortex nor into the systemic vein caused hyperglycemia. The injection of PGF2 alpha into the ventricle resulted in the increase of not only glucose, but also glucagon, epinephrine, and norephinephrine in the hepatic venous plasma. However, constant infusion of somatostatin through the femoral vein completely prevented the increase of glucagon after administration of PGF2 alpha, although the increase of plasma glucose level was still observed. PGF2 alpha-induced hyperglycemia did not occur in adrenodemedullated rats. Intravenous injection of naloxone or propranolol did not affect the hyperglycemia, but phentolamine significantly prevented the hyperglycemic effect of PGF2 alpha. These results suggest that intraventricular PGF2 alpha affects the central nervous system to produce hyperglycemia by increasing epinephrine secretion from the adrenal medulla.     

Increase in plasma glucose concentration after intracerebroventricular injection of N,O'-dibutyryl cyclic adenosine 3',5'-monophosphate

The effect of chemical stimulation of the central nervous system was studied in anesthetized rats. (Bu)2 cAMP, cAMP, 5'-adenosine monophosphate (AMP), ATP, and (Bu)2 N6,O2-dibutyryl guanosine-3'5'-cyclic monophosphate sodium salt were injected directly into the third cerebral ventricle, and changes in hepatic venous plasma glucose, immunoreactive glucagon, and insulin concentrations were studied. The injection of (Bu)2cAMP (1 X 10(-8) to 5 X 10(-7) mol/microliter saline) into the third cerebral ventricle caused a dose-dependent hyperglycemia associated with increased immunoreactive glucagon. (Bu)2cAMP-induced hyperglycemia and hyperglucagonemia were inhibited by prior bilateral adrenalectomy. The injection of somatostatin (1 X 10(-9) mol) with (Bu)2cAMP (5 X 10(-7) mol) into the third cerebral ventricle abolished both (Bu)2cAMP-induced hyperglycemia and an increase of glucagon secretion. These results suggest that cAMP may act intracellularly within the central nervous system to increase hepatic glucose output, and this appears to depend on the adrenal gland. Epinephrine secreted from the adrenal gland may directly act on the liver or enhance glucagon secretion, which in turn increases hepatic glucose output.     

Effects of galanin on hormone secretion from the in situ perfused rat pancreas and on glucose production in rat hepatocytes in vitro

Galanin is a novel peptide, widely distributed throughout the central and peripheral nervous system, including nerve endings surrounding the pancreatic islets. In dogs, galanin infusion has been reported to induce hyperglycemia along with a reduction of circulating insulin. In this work, we have studied the effect of galanin (a 200 ng bolus followed by constant infusion at a concentration of 16.8 ng/ml for 22-24 min) on insulin, glucagon, and somatostatin secretion in the perfused rat pancreas. In addition, we have investigated the effect of galanin (10 and 100 nM) on glycogenolysis and gluconeogenesis in isolated rat hepatocytes. In the rat pancreas, galanin infusion marked inhibited unstimulated insulin release as well as the insulin responses to glucose (11 mM), tolbutamide (100 mg/liter) and arginine (5 mM). Galanin failed to alter the glucagon and somatostatin responses to glucose, tolbutamide, and arginine. In isolated rat hepatocytes, galanin did not influence glycogenolysis or glucagon phosphorylase a activity. Gluconeogenesis and the hepatocyte concentration of fructose 2,6-bisphosphate were also unaffected by galanin. In conclusion: in the perfused rat pancreas, galanin inhibited insulin secretion without modifying glucagon and somatostatin output, thus pointing to a direct effect of galanin on the B cell; and in rat hepatocytes, galanin did not affect glycogenolysis or gluconeogenesis; hence, the reported hyperglycemia induced by exogenous galanin does not seem to be accounted for by a direct effect of this peptide on hepatic glucose production.     

Physiologic action of glucagon on liver glucose metabolism

Glucagon is a primary regulator of hepatic glucose production (HGP) in vivo during fasting, exercise and hypoglycaemia. Glucagon also plays a role in limiting hepatic glucose uptake and producing the hyperglycaemic phenotype associated with insulin deficiency and insulin resistance. In response to a physiological rise in glucagon, HGP is rapidly stimulated. This increase in HGP is entirely attributable to an enhancement of glycogenolysis, with little to no acute effect on gluconeogenesis. This dramatic rise in glycogenolysis in response to hyperglucagonemia wanes with time. A component of this waning effect is known to be independent of hyperglycemia, though the molecular basis for this tachyphylaxis is not fully understood. In the overnight fasted state, the presence of basal glucagon secretion is essential in countering the suppressive effects of basal insulin, resulting in the maintenance of appropriate levels of glycogenolysis, fasting HGP and blood glucose. The enhancement of glycogenolysis in response to elevated glucagon is critical in the life-preserving counterregulatory response to hypoglycaemia, as well as a key factor in providing adequate circulating glucose for working muscle during exercise. Finally, glucagon has a key role in promoting the catabolic consequences associated with states of deficient insulin action, which supports the therapeutic potential in developing glucagon receptor antagonists or inhibitors of glucagon secretion.     

Effects of somatostatin on gastrointestinal hormone-induced glycogenolysis and gluconeogenesis in cultured liver cells

When isolated rat liver cells were incubated for 15 min in the presence of vasoactive intestinal peptide, gastric inhibitory polypeptide, secretin or glucagon at a concentration of 2.0 micrograms/ml, glycogenolysis was stimulated by 30%-67% above the control. Slight but significant increase on gluconeogenesis was also observed by the addition vasoactive intestinal peptide, gastric inhibitory polypeptide or secretin. Somatostatin inhibited both glycogenolysis and gluconeogenesis induced by these hormones, but the degrees of inhibition are clearly much higher in the hormone-induced gluconeogenesis than glycogenolysis, and no significant inhibition of glycogenolysis was observed in case of glucagon and VIP. These results suggest the possibility that the so-called enterohepatic axis may play a part of roles in the regulation of serum glucose levels through gastrointestinal hormones belonging to the secretin family, and that it may be further regulated by somatostatin through gluconeogenesis.     

The metabolism of plasma glucose and catecholamines in Alzheimer's disease

Several lines of evidence suggest that the cholinergic system in the hippocampus plays a pivotal roll in regulating the peripheral metabolism of glucose and catecholamines. The injection of cholinergic stimulators including neostigmine, the acetylcholine esterase inhibitor, into the third ventricle or the hippocampus induces the elevation of glucose or catecholamines in plasma in rats. Under stress conditions, release of acetylcholine in the hippocampus increases, which coincides with the elevation of plasma glucose and catecholamines. Age-related reduction in responsivity of the cholinergic system in the hippocampus has been well documented. The intrahippocampal neostigmine injection induces significantly attenuated responses in plasma glucose and catecholamines in rats, the finding suggested that changes in cholinergic system activity in the hippocampus could result in alteration of the peripheral metabolism of glucose and catecholamines. In Alzheimer's disease (AD), the most common type of dementia, degeneration of the hippocampal cholinergic system is one of the most robust pathological features. Measurement of plasma catecholamines during a fasting state in the groups of AD subjects, vascular dementia subjects, and non-demented control subjects showed significantly lower plasma epinephrine levels in the AD subjects.     

Somatostatin receptor subtype-2-deficient mice with diet-induced obesity have hyperglycemia, nonfasting hyperglucagonemia, and decreased hepatic glycogen deposition

Hypersecretion of glucagon contributes to abnormally increased hepatic glucose output in type 2 diabetes. Somatostatin (SST) inhibits murine glucagon secretion from isolated pancreatic islets via somatostatin receptor subtype-2 (sst2). Here, we characterize the role of sst2 in controlling glucose homeostasis in mice with diet-induced obesity. Sst2-deficient (sst2(-/-)) and control mice were fed high-fat diet for 14 wk, and the parameters of glucose homeostasis were monitored. Hepatic glycogen and lipid contents were quantified enzymatically and visualized histomorphologically. Enzymes regulating glycogen and lipid synthesis and breakdown were measured by real-time PCR and/or Western blot. Gluconeogenesis and glycogenolysis were determined from isolated primary hepatocytes and glucagon or insulin secretion from isolated pancreatic islets. Nonfasting glucose, glucagon, and fasting nonesterified fatty acids of sst2(-/-) mice were increased. Inhibition of glucagon secretion from sst2-deficient pancreatic islets by glucose or somatostatin was impaired. Insulin less potently reduced blood glucose concentration in sst2-deficient mice as compared with wild-type mice. Sst2-deficient mice had decreased nonfasting hepatic glycogen and lipid content. The activity/expression of enzymes controlling hepatic glycogen synthesis of sst2(-/-) mice was decreased, whereas enzymes facilitating glycogenolysis and lipolysis were increased. Somatostatin and an sst2-selective agonist decreased glucagon-induced glycogenolysis, without influencing de novo glucose production using cultured primary hepatocytes. This study demonstrates that ablation of sst2 leads to hyperglucagonemia. Increased glucagon concentration is associated with impaired glucose control in sst2(-/-) mice, resulting from decreased hepatic glucose storage, increased glycogen breakdown, and reduced lipid accumulation. Sst2 may constitute a therapeutic target to lower hyperglucagonemia in type 2 diabetes.     

Origin of glucose released in the regulatory response against hypoglycemia

When the rate of removal of glucose from the plasma is increased by the infusion of 50 μg/kg. min phlorizin (PHL) the rate of hepatic glucose release (Ra) increases, so that the concentration of glucose in plasma falls only marginally. The response is mediated by glucagon. The purpose of the experiments was to establish to what extent glycogenolysis and gluconeogenesis contribute to the increment in Ra mediated by glucagon which is released in response to a physiological stimulus: the increased rate of removal of glucose from the plasma. Two series of experiments were carried out on non-anaesthetized trained dogs. In the first, to dogs in the post-absorptive (p.a.) state ³H-3-glucose and ¹⁴C-U-alanine were infused in trace amounts. The Ra and the clearance of glucose from the plasma (CR) were calculated together with the irreversible rate of removal (Ri) of alanine and the rate of glucose formation from plasma alanine before, during and after the infusion of PHL. When Ra(glucose) was increased during the infusion of PHL, so was the synthesis of glucose from alanine. This was achieved by an increase in the fraction of utilized alanine which was converted to glucose, since Ri(alanine) remained unchanged. The experiment was repeated after 4 day fasting when the rate of gluconeogenesis was twice that in the p.a. state; the Ra(glucose) still increased during the infusion of PHL, but to a lesser degree and somewhat more slowly than in the p.a. state. The concentration of glucose in plasma fell by about 30 mg/dl. The Ri(alanine) was not changed. In the second series hepatic glycogen stores were pre-labelled with ³H-6-glucose three days before the experiment in which ¹⁴C-1-glucose was infused as the tracer. The appearance of ³H-atoms in plasma glucose was taken as a measure of glycogenolysis. During the infusion of PHL the rate of glucogenolysis was doubled. Conclusion: Glucagon released in response to an increased removal of glucose from plasma increases the rate of glucose production by stimulating both gluconeogenesis from alanine and breakdown of hepatic glycogen. In fasted dogs in which the basal rate of gluconeogenesis was twice as high than in the p.a. state, PHL infusion caused a further increase. The increase was achieved by a larger fraction of utilized alanine being converted to plasma glucose.     

The changes of peripheral-central nervous system interaction in Alzheimer's disease

Several lines of evidence suggest that the cholinergic system in the hippocampus plays a pivotal roll in regulating the peripheral metabolism of glucose and catecholamines. The injection of cholinergic stimulators including neostigmine, the acetylcholine esterase inhibitor, into the third ventricle or the hippocampus induces the elevation of glucose or catecholamines in plasma in rats. Under stress conditions, release of acetylcholine in the hippocampus increases, which coincides with the elevation of plasma glucose and catecholamines. Age-related reduction in responsivity of the cholinergic system in the hippocampus has been well-documented. The intrahippocampal neostigmine injection induces significantly attenuated responses in plasma glucose and catecholamines in rats, which finding suggested that changes in cholinergic system activity in the hippocampus could result in alteration of the peripheral metabolism of glucose and catecholamines. In Alzheimer's disease, the most common type of dementia, degeneration of the hippocampal cholinergic system is one of the most robust pathological features. Measurement of plasma catecholamines during a fasting state in groups of Alzheimer's disease subjects, vascular dementia subjects, and non-demented control subjects showed significantly lower plasma epinephrine levels in the Alzheimer's disease subjects.     

Energy metabolism in the perinatal period (author's transl)]

Neonatal hypoglycemia is of frequent occurrence in fasted newborn babies or animals but the origin of this hypoglycemia is not fully understood. Studies performed in newborn rats have shown that liver glycogenolysis and gluconeogenesis occur immediately after birth and that the increase in the activities of key regulatory enzymes (phosphorylase, glycogen synthetase and phosphoenolpyruvate carboxykinase) results probably from the rise of plasma glucagon and the fall of plasma insulin induced by the "stress" of birth. When the liver glycogen stores have been exhausted, i.e. between 6 and 16 hours after birth, a profound hypoglycemia develops in fasting newborn rats. The inability of hepatic gluconeogenesis to produce sufficient glucose to meet the energy requirement of the newborn tissues results from a lack of fat-derived (free fatty acids and ketone bodies) and gluconeogenic (lactate, amino acids) substrates. The stage of appearance and the mechanisms regulating gluconeogenesis in other species including human are discussed.