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.     

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.     

Effect of somatostatin and a glucagon-specific analog on glucose homeostasis during arginine infusion

The glucose response to arginine infusion in normal rats was studied during insulin and glucagon deficiency (somatostatin infusion, 1 mg/kg/hr) or selective glucagon deficiency ([D-Cys¹⁴]-somatostain infusion, 1 mg/kg/hr). In control studies, plasma glucose levels rose 14 mg/dl in response to arginine and returned to basal levels at the termination of the infusion. Insulin levels increased 136 ± 12 μU/ml and glucagon increased 76 ± 12 pg/ml during the infusion. Infusion of somatostatin resulted in supression of both arginine-induced insulin and arginine-induced glucagon release, and marked hyperglycemia ensued. The administration of [D-Cys¹⁴]-somatostatin during arginine infusion produced no associated hyperglycemia. It resulted in suppression of glucagon secretion and a modest rise in insulin release. These results demonstrate that the hyperglycemic effects of somatostatin in arginine-treated animals do not arise in animals treated with glucagon-specific somatostatin analogs.     

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.     

The effects of epinephrine on islet hormone secretion in the dog

We investigated the direct effects of physiological levels of epinephrine on the basal and arginine-stimulated secretion of insulin, glucagon, and somatostatin from the in situ pancreas in halothane-anaesthetized dogs. An IV infusion of 20 ng/kg/min of epinephrine increased plasma epinephrine levels to 918 +/- 103 pg/ml (P less than 0.001), and increased the baseline pancreatic output of insulin (P less than 0.05), glucagon (P less than 0.05) and somatostatin (P less than 0.05). The acute insulin response (AIR) to 2.5 g of arginine during this infusion of epinephrine was significantly higher (P less than 0.05) than in controls as were the acute glucagon response (AGR) (P less than 0.05) and the acute somatostatin response (ASLIR) (P less than 0.05). Plasma glucose levels increased slightly and transiently during infusion of epinephrine from 99 +/- 2 mg/dl to a maximum of 110 +/- 3 mg/dl (P less than 0.05). An IV infusion of 80 ng/kg/min of epinephrine produced plasma epinephrine levels of 2,948 +/- 281 pg/ml, and increased the baseline pancreatic output of insulin (P less than 0.05) and glucagon (P less than 0.05). In contrast, baseline somatostatin output decreased transiently during this high dose infusion of epinephrine. The AIR and ASLIR to arginine were both significantly lower (P less than 0.05) than those during the infusion of epinephrine at the low dose. The AGR to arginine remained potentiated (P less than 0.05). Plasma glucose levels increased from 99 +/- 3 mg/dl to 119 +/- 4 mg/dl (P less than 0.01). We conclude that the effect of epinephrine on islet hormone secretion is dependent on the plasma level of epinephrine. At stress levels of 900-1000 pg/ml, both insulin and somatostatin secretion are stimulated; only at near pharmacologic, or extreme stress levels, does epinephrine produce net inhibition.     

Islet secretion of immunoreactive thyrotropin-releasing hormone and the 'paracrine-like' effects of its exogenous administration

In order to know more about the secretory pattern of islet TRH in response to glucose and its possible physiological relevance, the release of this hormone as well as that of insulin, glucagon, and somatostatin was radioimmunologically measured. Whereas the secretion of immunoreactive insulin and somatostatin by incubated rat islets is known to be dose-dependently stimulated by glucose, that of glucagon and TRH was inhibited by glucose. Similarly, palmitate dose-dependently inhibited islet glucagon and TRH release. Exogenous TRH exerted strong and dose-dependent effects on islet secretion of the other hormones at the same concentration range at which its hypophysiotropic effects are produced (10(-10) to 10(-8) mol/l). It inhibited the insulin response to glucose and blocked that of glucagon, whereas it enhanced glucose-induced stimulation of somatostatin. These results are suggestive of a possible paracrine inhibitory role of islet TRH, either directly exerted on the secretion of insulin and glucagon or partially mediated through the stimulation of somatostatin release.     

Glucose homeostasis during prolonged suppression of glucagon and insulin secretion by somatostatin.

Somatostatin was infused for 5-8 hr into five normal men and eleven normal, conscious dogs. This infusion resulted in a persistent decline in plasma glucagon (40-60%) and insulin (30-45%). Plasma gluccose fell 15-25% during the initial 1-2 hr, but subsequently rose to hyperglycemic levels (130-155 mg/100ml) by 3-6 hr, despite persistent hypoglucagonemia. Glucose production initially declined by 40-50%, but later rose to levels 15-20% above basal rates while peripheral glucose utilization fell to levels 20-30% below basal, thereby accounting for hyperglycemia. Infusion of exogenous insulin so as to restore plasma insulin to preinfusion values or cessation of the somatostatin infusion with restoration of endogenous insulin secretion resulted in a prompt reduction of plasma glucose to baseline values. Prevention of the initial somatostatin-induced hypoglycemic response by intravenous infusion of glucose failed to prevent the delayed hyperglycemia. We conclude that somatostatin caused only transient hypoglycemia in normal subjects and that hyperglycemia eventually developes as a consequence of insulin deficiency. These data indicate that basal glucagon secretion is not essential for the development of fasting hyperglycemia and support the conclusion that insulin deficiency rather than glucagon excess is the primary factor responsible for abnormal glucose homeostasis in the diabetic.     

Metabolic interactions of glucagon and cortisol in man--studies with somatostatin

The metabolic response to pathophysiologic concentrations of glucagon, induced by glucagon infusion, has been examined in normal man before and after 36-60 hr hypercortisolaemia, induced by administration of tetracosactrin-depot. Glucagon alone increased serum insulin levels twofold but blood glucose was unaltered. Plasma NEFA and blood ketone body concentrations were decreased by glucagon infusion. Tetracosactrin produced a threefold rise in serum cortisol levels and caused mild fasting hyperglycemia and hyperinsulinaemia. Subsequent glucagon infusion had no effect on circulating insulin, glucose, NEFA or ketone body concentrations. Simultaneous infusion of somatostatin, to produce partial insulin-deficiency, unmasked a hyperglycemic action of glucagon (+ 3.8 +/- 0.2 mmol/l at 90 min, p less than 0.02). This glucagon-induced rise in blood glucose was diminished by prior tetracosactrin administration. Tetracosactrin revealed a mild lipolytic action of glucagon in partial insulin deficiency, not apparent in the euadrenal state. Glucagon was equally hyperketonemic during somatostatin infusion before and after tetracosactrin. Thus the hyperglycemic and hyperketonemic actions of glucagon at pathophysiologic levels are restricted to insulin deficiency. Hypercortisolaemia reveals a lipolytic action of glucagon in insulin-deficient man but does not potentiate the hyperglycemic or hyperketonemic effects.     

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.     

Insulin, glucagon, somatostatin, and thyrotropin-releasing hormone content and secretion by perifused fetal rat islets during culture

In the neonatal period of the rat, pancreatic thyrotropin-releasing hormone content decreases and the sensitivity of insulin secretion to glucose increases. In adult rat islets, TRH inhibits glucose-induced insulin release. The aim of this study was to investigate whether a high TRH content and release can be part of the explanation for the functional immaturity of neonatal islets. For that purpose, we have measured the tissue content and the secretion of immunoreactive insulin, glucagon, somatostatin and TRH in islets from 21.5-day-old rat fetuses cultured for up to one week. Insulin, glucagon and somatostatin content increased during one week of culture in the presence of 11.1 mmol/l glucose. The TRH content decreased during culture, but did not equal adult values. Insulin, glucagon and somatostatin responses to glucose were present after one week of culture. Glucose had no effect on TRH release in cultured fetal islets, but inhibited TRH release in adult islets. We conclude that glucose can stimulate insulin secretion without inhibiting TRH release, but that a decrease in islet TRH content and a sensitization of TRH secretion to glucose may be important in the full maturation of fetal pancreatic islets.     

Tachykinins in the porcine pancreas: potent exocrine and endocrine effects via NK-1 receptors

The localization, release, and effects of substance P and neurokinin A were studied in the porcine pancreas and the localization of substance P immunoreactive nerve fibers was examined by immunohistochemistry. The effects of electrical vagus stimulation and capsaicin infusion on tachykinin release and the effects of substance P and neurokinin A infusion on insulin, glucagon, somatostatin, and exocrine secretion were studied using the isolated perfused porcine pancreas with intact vagal innervation. NK-1 and NK-2 receptor antagonists were used to investigate receptor involvement. Substance P immunoreactive nerve fibers were localized to islets of Langerhans, acini, ducts, and blood vessels. Vagus stimulation had no effect on substance P and neurokinin A release, whereas capsaicin infusion stimulated release of both. Substance P and neurokinin A infusion increased release of insulin, glucagon, and exocrine secretion, whereas somatostatin secretion was unaffected. The effect of substance P on insulin, glucagon, and exocrine secretion was blocked by the NK-1 receptor antagonist. The effect of electrical stimulation of vagus nerves on insulin and exocrine secretion was not influenced by tachykinin receptor antagonists. We conclude that tachykinins stimulate both endocrine and exocrine pancreatic functions through NK-1 receptors. Tachykinins are not involved in vagal regulation of pancreatic secretion in pigs but could constitute part of an alternative stimulatory 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.     

Antithyrotropin-releasing hormone serum inhibits secretion of glucagon from isolated perfused rat pancreas: an experimental model for positive feedback regulation of glucagon secretion.

TRH is synthesized in the islets of Langerhans and was found in the perfusate of isolated rat pancreas. In the present study, designed to determine the role of endogenous TRH, we first characterized chromatographically the identity of immunoreactive TRH with synthetic pGlu-His-Pro-NH2. Since endogenous TRH secretion may mask the effects of exogenous TRH, we performed, in parallel to dose-response studies, immunoneutralization experiments using anti-TRH serum to neutralize the endogenous TRH secretion from isolated perfused rat pancreas. The data indicate that exogenous TRH enhances basal glucagon secretion; inversely, anti-TRH serum inhibits glucose plus arginine-induced glucagon secretion and produces a concomitant slight inhibition of somatostatin secretion. The present study shows a physiological contribution for endogenous TRH as a local modulator of intraislet hormone regulation; from these observations, we postulate a direct effect of pancreatic TRH on glucagon-containing (alpha) cell secretion, which, in turn, may produce the fluctuation in somatostatin secretion. Local TRH secretion provides a model for positive feedback regulation of glucagon secretion, frequently associated with diabetes.     

The effects of epinephrine on islet hormone secretion in the dog

Summary We investigated the direct effects of physiological levels of epinephrine on the basal and arginine-stimulated secretion of insulin, glucagon, and somatostatin from the in situ pancreas in halothane-anaesthetized dogs. An IV infusion of 20 ng/kg/min of epinephrine increased plasma epinephrine levels to 918±103 pg/ml (P<0.001), and increased the baseline pancreatic output of insulin (P<0.05), glucagon (P<0.05) and somatostatin (P<0.05). The acute insulin response (AIR) to 2.5 g of arginine during this infusion of epinephrine was significantly higher (P<0.05) than in controls as were the acute glucagon response (AGR) (P<0.05) and the acute somatostatin response (ASLIR) (P<0.05). Plasma glucose levels increased slightly and transiently during infusion of epinephrine from 99±2 mg/dl to a maximum of 110±3 mg/dl (P<0.05). An IV infusion of 80 ng/kg/min of epinephrine produced plasma epinephrine levels of 2948±281 pg/ml, and increased the baseline pancreatic output of insulin (P<0.05) and glucagon (P<0.05). In contrast, baseline somatostatin output decreased transiently during this high dose infusion of epinephrine. The AIR and ASLIR to arginine were both significantly lower (P<0.05) than those during the infusion of epinephrine at the low dose. The AGR to arginine remained potentiated (P<0.05). Plasma glucose levels increased from 99±3 mg/dl to 119±4 mg/dl (P<0.01). We conclude that the effect of epinephrine on islet hormone secretion is dependent on the plasma level of epinephrine. At stress levels of 900–1000 pg/ml, both insulin and somatostatin secretion are stimulated; only at near pharmacologic, or extreme stress levels, does epinephrine produce net inhibition.     

Effects of somatostatin analogs on glucose homeostasis in rats

Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for sstr(1,2,3) and sstr(5). The effects of pasireotide and octreotide on blood glucose, insulin, and glucagon levels in rats were evaluated alone and in combination. Single-dose s.c. pasireotide acutely elevated plasma glucose, whereas single-dose s.c. octreotide had no or a small hypoglycemic effect. Glucose elevation with s.c. pasireotide was transient with tachyphylaxis after repeated or continuous administration. Pasireotide and octreotide caused similar inhibitory effects on insulin secretion, whereas pasireotide had a weaker inhibitory effect on glucagon secretion than octreotide. Continuous infusion of pasireotide or injection of pasireotide long-acting release (LAR) resulted in only small and transient elevations of plasma glucose. Based on these results, and differences in the sstr binding affinity of pasireotide vs octreotide, it was hypothesized that the sstr(5) vs sstr(2) receptor activation ratio is the main driver of hyperglycemia after pasireotide. The results also suggest that stronger activation of sstr(2) may counteract the hyperglycemic effect. Indeed, co-administration of octreotide, which has a high affinity for sstr(2), with a hyperglycemic dose of pasireotide did not cause significant changes in plasma glucose levels. In conclusion, although pasireotide and octreotide inhibited insulin to a similar degree, only pasireotide administration was associated with hyperglycemia. The strong glucagon inhibitory effect exhibited by octreotide but not pasireotide may explain this observation. The lack of hyperglycemia during co-administration of pasireotide and octreotide may be explained by the greater activation of sstr(2) compared with pasireotide alone, causing the insulin-glucagon balance to shift within the normoglycemic range. Extrapolation of these data to humans must account for species differences in islet cell sstr expression.     

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.     

Somatostatin,glucagon, and insulin secretion from isolated perfused pancreas of new genetically obese hyperglycemic rats

Insulin, somatostatin, and glucagon release from the perfused pancreas was studied in the newly developed genetically obese hyperglycemic hyperinsulinemic (Wistar fatty) rat. Insulin and somatostatin levels rose significantly compared to those in lean littermate controls during arginine infusion. The glucagon increase, however, was significantly less when total amounts during arginine infusion were calculated. These results show that hypersecretion of insulin and somatostatin in vitro may suppress glucagon release in Wistar fatty rats.     

Somatostatin inhibits urinary cyclic AMP excretion in diabetic rats.

Short term (30 min) infusion of cyclic somatostatin (50 microgram/rat), insulin (1 U/rat) or the two together significantly suppressed urinary cyclic AMP excretion in streptozotocin-diabetic rats. While somatostatin tended to increase cyclic GMP excretion, insulin had an opposite effect in diabetic but not in normal rats. It is suggested that somatostatin suppresses cyclic AMP excretion by inhibiting directly adenylate cyclase in liver and perhaps in other organs. The possibility that suppression of urinary cyclic AMP is due to inhibition of glucagon secretion is also considered.     

Abnormal regulation by glucose of somatostatin secretion in the perfused pancreas of NIDDM rats

We have investigated the influence of non-insulin-dependent diabetes on the regulation of somatostatin secretion from the pancreatic D cell. These results were compared with the concomittantly measured secretory responses from A and B cells. Rats were rendered non-insulin-dependent diabetic by neonatal injection of streptozotocin (STZ). Secretion was studied in perfused pancreas at 6-10 weeks of age. At this age, STZ rats were mildly hyperglycemic, their nonfasting blood glucose being 9.0 +/- 0.8 vs. 5.6 +/- 0.2 mM in control rats. In perfused pancreas from the latter rats, high glucose, i.e., 16.7 mM, stimulated somatostatin secretion but completely failed to do so in STZ rats. Arginine (in the presence of low glucose, i.e., 3.3 mM) moderately stimulated somatostatin secretion in controls but fourfold more in STZ rats. Preperfusion with high glucose markedly potentiated subsequent arginine-induced somatostatin secretion in controls but failed to do so in STZ rats. Basal glucagon release was inhibited by ambient high glucose in control and STZ rats alike. Arginine-induced glucagon release was profoundly inhibited both by ambient and previous exposure to glucose in controls but only slightly and nonsignificantly in STZ rats. The insulin response to high glucose in controls was reduced by 90% in STZ. The insulin response to arginine (in the presence of low glucose) was 3.3-fold enhanced in STZ. Ambient and previous high glucose markedly enhanced arginine-induced insulin secretion in controls but only moderately so in STZ rats. We conclude that already mild hyperglycemia is associated with marked D-cell insensitivity to glucose that is qualitatively similar to A- and B-cell insensitivity.     

Central nervous system control of glycogenolysis and gluconeogenesis in fed and fasted rat liver

The influence of brain cholinergic activation on hepatic glycogenolysis and gluconeogenesis was studied in fed and 48-hour fasted rats. Neostigmine was injected into the third cerebral ventricle and hepatic venous plasma glucose, glucagon, insulin, and epinephrine were measured. The activity of hepatic phosphorylase-a and phosphoenolpyruvate-carboxykinase (PEP-CK) was also measured. Experimental groups: 1, intact rats; 2, rats infused with somatostatin through the femoral vein; 3, bilateral adrenodemedullated (ADMX) rats; 4, somatostatin infused ADMX rats; 5, 5-methoxyindole-2-carboxylic acid (MICA) was injected intraperitoneally 30 minutes before injection of neostigmine into the third cerebral ventricle of intact rats. MICA treatment completely suppressed the increase in hepatic glucose in fasted rats, but had no effect in fed rats. Phosphorylase-a activity was not changed in fasted rats, but increased in fed rats, intact rats, somatostatin-infused rats, somatostatin-infused ADMX rats, and ADMX rats in that order. PEP-CK was not changed in fed rats, but increased at 60 and 120 minutes after neostigmine injection into the third cerebral ventricle in fasted rats. We conclude that, in fed states, brain cholinergic activation causes glycogenolysis by epinephrine, glucagon, and direct neural innervation. In fasted states, on the other hand, gluconeogenesis is dependent on epinephrine alone to increase hepatic glucose output.