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.     

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.     

Glucoregulatory effects of intrahypothalamic injections of bombesin and other peptides

The influence of neuropeptides on hypothalamic regulation of plasma glucose and pancreatic hormone secretion was studied in anesthetized rats. Neuropeptides were injected directly into the ventromedial hypothalamus (VMH) and the lateral hypothalamic area (LHA) and changes in hepatic venous plasma glucose, insulin, and glucagon concentrations were studied. Injection of bombesin into the VMH resulted in a marked and sustained hyperglycemia in the hepatic venous plasma, which was also observed after injection into the LHA. Microinjection of SRIF into the VMH or LHA caused a decrease in hepatic venous plasma glucose concentration. Injection of neurotensin into the VMH or LHA resulted in a transient release of insulin in the 10-min postinjection samples. In 30- and 60-min postinjection samples, significant increases in glucagon concentrations were observed after substance P injection into the VMH or LHA. No major difference in the plasma glucose, insulin, or glucagon concentrations was observed when VMH and LHA stimulation was compared. These data suggest that glucoregulatory neuropeptides may act on the VMH and LHA, which do not necessarily follow the currently recognized anatomical boundaries.     

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.     

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.     

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.     

Hypothalamic involvement in the hyperglycemia and satiety actions of somatostatin in rats

To determine whether the anorexic and the hyperglycemia actions of somatostatin were mediated through the hypothalamic nuclei, rats were infused with somatostatin and normal saline through previously implanted hypothalamic cannulae. Administration of somatostatin (0.5-1.5 microgram in 1.0 microliter) into the lateral hypothalamus, but not the ventromedial or the anterior hypothalamus, caused a reduction in food consumption without affecting relative water intake (or water-to-food ratio) in conscious rats in a freely moving state. On the other hand, administration of somatostatin into the lateral hypothalamus, but not the anterior or the ventromedial hypothalamus, caused an increase in blood glucose level in rats. This hyperglycemia was antagonized by vagotomy, but not by spinal transection or adrenalectomy. The data indicate that the lateral hypothalamus is the most sensitive site of the somatostatin-induced anorexia and the action of somatostatin on the lateral hypothalamus-vagus efferent activity is also a possible mechanism mediating hyperglycemia in rats.     

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.     

Central nervous system action of bombesin: mechanism to induce hyperglycemia.

Bombesin acts within the brain to produce a prompt and sustained hyperglycemia, hyperglucagonemia, and relative or absolute hypoinsulinemia. Bombesin does not decrease plasma glucose turnover. Acute adrenalectomy but not hypophysectomy prevents hyperglycemia and hyperglucagonemia after intracisternal administration of bombesin. Administration of bombesin into the lateral ventricle of awake, unrestrained animals results in elevation of plasma glucose, preceded by a significant increase in plasma epinephrine and no increase in plasma norepinephrine or dopamine. Systemic administration of somatostatin prevents bombesin-induced hyperglycemia and hyperglucagonemia. These data support the conclusion that bombesin acts within the brain to increase sympathetic outflow resulting in increased adrenalmedullary epinephrine secretion, followed by depression of plasma insulin and elevation of plasma glucagon and glucose.     

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.     

The glucoregulatory response to intravenous glucose infusion in normal man: Roles of insulin and glucose

In order to differentiate the roles of hyperinsulinemia and hyperglycemia per se in the homeostatic response to i.v. glucose administration, two groups of normal subjects were given either glucose alone (3.5 mg kg^?1 min^?1) or glucose (3 mg kg^?1 min^?1) in conjunction with somatostatin (500 μg hr^?1), insulin (0.15 mU kg^?1 min^?1) and glucagon (1 ng kg^?1 min^?1). Glucose kinetics were measured by the primed-constant infusion of 3-³H-glucose. During the infusion of glucose alone, plasma glucose stabilized at levels 45–50 mg/dl above the fasting values. Endogenous glucose output was markedly suppressed by 85%–90% while glucose uptake rose to values very close to the infusion rate of exogenous glucose. Glucose clearance remained unchanged. Plasma insulin rose three-fourfold while plasma glucagon fell by 25%–30%. When glucose was infused with somatostatin, insulin, and glucagon, plasma insulin was maintained at levels 50% above baseline while glucagon remained at preinfusion levels. Under these conditions, the infusion of exogenous glucose resulted in a progressive increase of plasma glucose which did not stabilize until the end of the study period (190 mg/dl at 120 min). Endogenous glucose production was consistently suppressed (52%) but significantly less than observed with the infusion of glucose alone (p < 0.01). Glucose uptake increased to the same extent as with glucose alone, despite the more pronounced hyperglycemia. Thus, glucose clearance fell significantly below baseline (25%–30%; p < 0.01). These data demonstrate that hyperglycemia per se (fixed, near basal levels of insulin and glucagon) certainly contributes to the glucoregulatory response to i.v. glucose administration by both inhibiting endogenous glucose output and increasing tissue glucose uptake. However, the extra-insulin evoked by hyperglycemia is necessary for the glucoregulatory system to respond to the glucose load with maximal effectiveness.     

Role of glucagon in hyperglycemic response during a short period of hemorrhage in anesthetized dogs

A role of pancreatic glucagon in hemorrhage induced hyperglycemia was studied in anesthetized dogs with or without functional adrenalectomy (ADRX), surgical hepatic denervation (HNX), and surgical pancreatectomy (PCX). Plasma epinephrine, norepinephrine, and glucose concentrations were determined in both hepatic venous and aortic blood. Plasma glucagon (IRG) and insulin (IRI) levels were determined in aortic blood. All dogs were bled until aortic systolic pressure dropped to approximately 50% (64.8 +/- 1.6 mmHg, n = 25) of its control value (136.7 +/- 4.4 mmHg, n = 25), and the hypotension was maintained for 5 min. In control dogs (n = 10), hemorrhage markedly increased aortic epinephrine and hepatic venous norepinephrine. Similarly, aortic IRG, hepatic venous glucose and aortic glucose rose significantly during hemorrhage. In dogs with HNX combined with ADRX (n = 10), aortic epinephrine and hepatic venous norepinephrine remained unchanged during hemorrhage. Aortic IRG concentration, however, increased to a level similar to that observed in the control group. Aortic glucose increased significantly along with significant increases in hepatic venous glucose. In dogs with PCX combined with HNX and ADRX (n = 5), the increases in aortic IRG, hepatic venous glucose and aortic glucose observed in the first two groups in response to hemorrhage were virtually abolished. The results indicate that the increase in aortic IRG during hemorrhage is of pancreatic origin. We conclude that the pancreatic glucagon may be involved in the hyperglycemic response to hemorrhage, most likely through glucose mobilization by the liver during the early phase of hemorrhagic hypotension.     

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.     

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.     

Role of parasympathetic nervous system in glucagon response to insulin-induced hypoglycemia in normal and diabetic rats

Effects of cholinergic mechanisms on glucagon and epinephrine responses to insulin-induced hypoglycemia were examined in diabetic and age-matched control male rats. Atropine did not affect plasma glucose levels or plasma glucagon concentrations, in the basal state, in normal or short-term diabetic rats (10 to 15 days following streptozotocin injection). However, atropine blocked the glucagon response to insulin hypoglycemia in both normal and short-term diabetic rats. Subcutaneous injection of carbachol also failed to alter basal plasma glucose, glucagon, or epinephrine values in both normal and diabetic rats. The lack of glucagon and epinephrine responses to insulin hypoglycemia in long-term diabetic rats (80 to 100 days after streptozotocin injection) was reversed with a single dose of carbachol. Carbachol exaggerated the glucagon response to insulin hypoglycemia in normal and short-term diabetic rats. These results demonstrate that the parasympathetic nervus system plays an important role in the glucagon release in response to insulin hypoglycemia in rats. The lack of glucagon response to insulin hypoglycemia observed in long-term diabetic rats could be due to deteriorated parasympathetic nervous system and also could be corrected with carbachol.     

Pancreatic hormones in streptozotocin-diabetic rats

Pancreatic polypeptide (PP) levels of plasma and pancreas were studied in the rat after streptozotocin (STZ) injection. In 4 weeks of observation, plasma PP was elevated up to 4 times the control values with marked hyperglycemia and insulinopenia. At 4 weeks, intravenous (i.v.) glucose tolerance tests and i.v. insulin tolerance tests were performed. In the glucose tolerance test, control rats responded with a 10-fold increase in plasma insulin and 15% decrease in plasma PP levels, whereas STZ-diabetic rats produced no increase of plasma insulin and an approximately 50% reduction of plasma PP levels with marked hyperglycemia. In the insulin tolerance test, diabetic rats showed a marked increase in plasma PP levels and less increase in plasma insulin levels than the controls. In diabetic rats, pancreatic insulin levels were reduced to about 3.5% of control, whereas those of somatostatin (SRIF), PP and glucagon were elevated to 8.3, 2.7 and 1.4 times control, respectively. In a morphometric study, islet areas of diabetic rats were seen to be reduced to about 10% of control. With in vitro perfused pancreatic slices, STZ-diabetic pancreas released much more glucagon and PP than control pancreas. Thus, STZ injection in the rat caused marked beta-cell damage as well as hyperplasia of SRIF, PP and glucagon cells, with glucagon and PP hypersecretion.     

Effect of ventromedial hypothalamic lesions on the secretion of somatostatin,insulin, and glucagon by the perfused rat pancreas

Somatostatin, insulin, and glucagon secretion by the perfused pancreas were studied in adult female rats 10 days after ventromedial hypothalamic (VMH) lesions and in sham operated controls to assess the role of their hypothalamic control. Insulin secretion was significantly greater in VMH-lesioned rats both under basal conditions and after stimulation by theophylline and arginine plus theophylline. Basal glucagon secretion was greater in VMH-lesioned rats as was the glucagon response to theophylline alone and in combination with arginine. Basal somatostatin secretion was similar in VMH and control rats but somatostatin secretion induced by theophylline and by arginine plus theophylline was significantly increased in VMH-lesioned rats. Both the pancreatic content and concentration of somatostatin were increased in VMH-lesioned rats. These results indicate the presence of hyperresponsiveness of A, B, and D cells following VMH destruction and provide new evidence for a role of the hypothalamus in the regulation of pancreatic somatostatin secretion.     

Pancreatic hormones in streptozotocin-diabetic rats

Summary Pancreatic polypeptide (PP) levels of plasma and pancreas were studied in the rat after streptozotocin (STZ) injection. In 4 weeks of observation, plasma PP was elevated up to 4 times the control values with marked hyperglycemia and insulinopenia. At 4 weeks, intravenous (i.v.) glucose tolerance tests and i.v. insulin tolerance tests were performed. In the glucose tolerance test, control rats responded with a 10-fold increase in plasma insulin and 15% decrease in plasma PP levels, whereas STZ-diabetic rats produced no increase of plasma insulin and an approximately 50% reduction of plasma PP levels with marked hyperglycemia. In the insulin tolerance test, diabetic rats showed a marked increase in plasma PP levels and less increase in plasma insulin levels than the controls. In diabetic rats, pancreatic insulin levels were reduced to about 3.5% of control, whereas those of somatostatin (SRIF), PP and glucagon were elevated to 8.3, 2.7 and 1.4 times control, respectively. In a morphometric study, islet areas of diabetic rats were seen to be reduced to about 10% of control. With in vitro perfused pancreatic slices, STZ-diabetic pancreas released much more glucagon and PP than control pancreas. Thus, STZ injection in the rat caused marked β-cell damage as well as hyperplasia of SRIF, PP and glucagon cells, with glucagon and PP hypersecretion.     

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.