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.     

Failure of indomethacin to affect arginine-induced C-peptide and glucagon release in insulin-treated diabetics

Summary Fourteen insulin-treated diabetics were submitted to an arginine infusion test performed with either 11.7 or 5.85mg kg^-1 min^-1 arginine monohydrochloride infused during 40 min with or without previous oral administration of a low (75+50 mg) or a high (75 mg + 3 mg/kg) dose of indomethacin. Blood glucose, plasma non-esterified fatty acids, insulin, C-peptide and glucagon were determined at regular intervals before, during and after the arginine infusion. These parameters were totally unaffected by the two doses of indomethacin both in the basal state and during the arginine infusions at the two loads tested. Eight subjects had a basal C-peptide level above 0.07 pmol/ml and a mean (± SEM) maximal rise of 0.21±0.04 pmol/ml during the arginine infusion, whereas the remaining six patients had virtually zero values throughout the tests. The arginine-induced plasma glucagon rise was similar for the two rates of arginine infusion; the sum of the increments in plasma glucagon averaged 877±120 and 647±92 pg/ml (p>0.1) for the high and low rates of arginine infusion, respectively. The magnitude of the blood glucose rise appeared independent of the amount of arginine infused. Confirming previous reports, we found that the blood glucose rise after arginine was three to four times higher in subjects without C-peptide than in subjects with C-peptide. The mean glucagon response did not differ significantly between subjects with or without C-peptide. Thus, residual B cell function determines the magnitude of the blood glucose rise but not the glucagon response after intravenous arginine.     

Somatostatin infusion in liver cirrhosis: Glucagon control of glucose homeostasis

Summary In order to evaluate the role of glucagon in blood glucose homeostasis in liver cirrhosis, ten normal subjects and ten cirrhotic patients were infused with somatostatin (500 g/h for 5 h) with and without glucagon (3 mg/kg/h) administration. Somatostatin infusion brought about a fall in plasma glucose both in normal (37%) and cirrhotic (41%) subjects in the first 90 minutes. In normal subjects, this was followed by a rise in plasma glucose (147±2 mg/dl at 5 h), while in cirrhotics no rise in plasma glucose was observed (50±1 mg/dl at 5 h). Plasma insulin and glucagon levels were suppressed in both normal and cirrhotic subjects. Addition of glucagon to the somatostatin infusion caused a two fold rise in plasma glucose level to 183±12 mg/dl at 4 h in normal subjects; a much smaller increase was found in the cirrhotic group (105±3 mg/dl at 4 h). When the infusion was stopped, plasma glucose fell both in normal and cirrhotic subjects (102±14 and 87±2 mg/dl at 6 h respectively). Subsequently, hyperglucagonaemia recurred in the cirrhotic patients (319 ±31 pg/ml). A rebound of plasma insulin was observed in normal subjects (47±8 U/ml) which did not occur in the cirrhotics (16±2 U/ml). Thus when both insulin and glucagon were suppressed by somatostatin infusion, euglycaemia occurred in cirrhotic subjects only when glucagon concentration was restored exogenously. We conclude that glucagon is important in glucose homeostasis in patients with liver cirrhosis.     

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.     

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.     

Effects of galanin on insulin and glucagon secretion in the rat

Galanin-like immunoreactivity has been visualized in nerve fibers in the islets of Langerhans, suggesting an involvement of galanin in the neural regulation of islet function. In this study, we investigated the effects of galanin on basal and stimulated insulin and glucagon secretion by infusing the peptide at three different dose rates in rats. We also studied the direct effect of galanin on insulin secretion from freshly isolated rat islets. At 320 pmol/kg/min, but not at 20 or 80 pmol/kg/min, galanin lowered basal plasma insulin levels. In contrast, basal plasma glucagon levels were lowered by galanin already at 20 and 80 pmol/kg/min. Furthermore, galanin inhibited both glucose- and arginine-induced insulin release at all three dose levels, whereas arginine-induced glucagon release was not affected by galanin. Glucose-stimulated insulin secretion from isolated rat islets was dose-dependently suppressed by galanin (10^-6-10^-8M). Therefore, it is concluded that galanin in rats inhibits insulin secretion, both in vivo and in vitro, and that at lower dose levels, the peptide also inhibits basal glucagon release.     

Selective effect of some somatostatin analogs on glucagon as opposed to insulin release in rats in vivo

Cyclic somatostatin, at a dose of 700 but not 70 ng/kg/min, inhibited arginine-induced insulin and glucagon release as well as glucose stimulated insulin release in rats in vivo. Three somatostatin (S-S) analogs (D-Cys14-S-S, D-Trp8-D-Cys14-S-S and Ala2-D-Trp8-D-Cys14-S-S), at a dose of 70 ng/kg/min, suppressed arginine-induced glucagon but not insulin release. At the same dose, the first two of these analogs had no effect on glucose-induced insulin release, while the third one. Ala2-D-Trp8-D-Cys14-somatostatin, enhanced insulin release induced by glucose. A fourth analog, D-Trp8-somatostatin, was more potent than somatostatin with regard to arginine stimulated insulin and glucagon release, and equipotent with somatostatin with respect to glucose stimulated insulin release. These studies show, firstly, that the inhibitory effect of somatostatin analogs on arginine induced insulin release may be different from that when glucose is used as a stimulant and, secondly, that Ala2-D-Trp8-D-Cys14-somatostatin inhibits arginine-induced glucagon release while enhancing insulin release on glucose stimulation.     

Importance of glucagon in the control of futile cycling as studied in alloxan-diabetic dogs

Summary In order to determine the role of glucagon in futile or substrate cycling in diabetes, we measured tracer determined glucose kinetics during a combined infusion of 2-³H-glucose (total glucose production) and 6-³H-glucose (glucose production) in six alloxan-diabetic dogs. The animals received either a 420 min infusion of (1) somatostatin alone (0.3 g·kg^–1· min^–1), (2) somatostatin with insulin replacement (100 U·kg^–1min^–1) or (3) glucagon (6 ng·kg^–1· min^–1) together with somatostatin and transient insulin replacement. When somatostatin was given alone, plasma glucagon (p<0.004) and insulin (p<0.0001) were suppressed. Glucose production and disappearance and plasma glucose concentrations fell (p<0.0001), but the metabolic clearance of glucose did not change significantly. In the basal state, futile cycling comprised 29±4%, 33±4% and 33±3% of total glucose production in the three goups of studies, which is high compared to normal dogs. The absolute rate of futile cycling fell slightly but significantly from 10.0±1.7 to 8.3±1.7 mol·kg·^–1min^–1 (p<0.0008). When insulin replacement was given during somatostatin infusion to correct for the small somatostatin-induced insulin suppression, there were similar changes in plasma glucagon, glucose concentrations and glucose kinetics as seen during the infusion of somatostatin alone. Futile cycling decreased to a slightly greater extent from 12.8±2.8 to 9.5±1.7mol·kg^–1·min.^–1 (p<0.02). When glucagon was infused together with somatostatin and insulin replacement, plasma glucagon (p<0.0002) increased and plasma glucose levels rose (p<0.001) due to a transient increase in glucose production. Metabolic clearance of glucose did not change significantly. There was a marked increase in futile cycling from 12.2±1.7 to 21.7±1.7mol· kg^–1·min^–1 (p<0.0001) in response to exogenous glucagon excess. There was a slight (p<0.01) drop in free fatty acid levels with somatostatin. Free fatty acid levels nearly doubled (p<0.025) with the infusion of glucagon together with somatostatin. In conclusion, (a) futile cycling was increased in alloxan-diabetic dogs; (b) glucagon suppression can suppress futile cycling only if total insulin deficiency is prevented; and (3) hyperglucagonaemia increases futile cycling, and this effect is more pronounced during insulin deficiency.     

Possible mechanism by which somatostatin-induced glucagon suppression improves glucose tolerance during insulinopaenia in man

Summary The present study examines the question of whether lowering the basal plasma glucagon concentration alters the response of the liver to an intravenous glucose load under conditions where insulin is present at near-basal concentrations. Acute hyperglycaemia of 220–240 mg/dl was induced by peripheral venous glucose infusion in two groups of normal men who had undergone hepatic vein catheterization. Somatostatin (0.9 mg/h) was infused in both groups together with an infusion of insulin (0.15 mU/kg/min) to maintain arterial insulin levels at 7–12 U/ml. Glucagon (1.5 ng/kg/min) was infused in one group resulting in a rise in plasma glucagon levels from 148±37 to 228±25 pg/ml, thus mimicking basal portal glucagon concentrations, whereas in the second group glucagon was not replaced, resulting in a fall in circulating glucagon levels from 132±21 to 74±15 pg/ml. In the glucagon-deprived group, net splanchnic glucose production (NSGP) fell from 143±31 to –72.5±39 mg/ min (p<0.01), indicating that net splanchnic glucose uptake had occurred. By contrast, NSGP did not change significantly (137±20 vs 151±60 mg/min) in the group in which both insulin and glucagon were replaced during hyperglycaemia. These data thus suggest that during hyperglycaemia, when the insulin concentration is fixed at basal levels, glucagon may play an important role in determining whether or not the liver diminishes its output of glucose and stores glucose in response to a glucose load.     

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.     

How does glucose regulate the human pancreatic A cell in vivo?

Summary To investigate the mechanism whereby changes in plasma glucose level alter human pancreatic A-cell activity in vivo, A-cell activity was determined during manipulation of plasma glucose and pancreatic B-cell activity by insulin and glucose infusions. A-cell activity (the acute immunoreactive glucagon response to intravenous arginine, 0–10 min) rose from 482±125 to 968±191 pg · ml^-1 · 10 min^-1 (mean±SEM) when the plasma C-peptide level (a measure of B-cell activity) was suppressed from 2164±365 to 872±162 pg/ml by an insulin infusion at euglycaemia (employing the glucose clamp technique) in six normal subjects. Raising plasma glucose to 6.7 mmol/l during the same insulin infusion returned mean C-peptide (2688±581 pg/ml) and the acute glucagon response to arginine (447±146 pg · ml^-1 · 10 min^-1) close to basal levels. Individual changes in the acute glucagon response to arginine followed the C-peptide changes. The mean change in the acute glucagon response to arginine per unit change in plasma glucose (-191±36) was similar to that seen when plasma glucose was raised to twice basal levels in six different subjects without an insulin infusion (-159±45). This suggests that, when plasma glucose is raised to about twice basal level in vivo, the major factor in suppressing A-cell activity is the concurrent change in B-cell activity rather than direct effects of glucose or circulating insulin on the A cell.     

Modulation of arginine-induced glucagon release by epinephrine and glucose levels in man

To assess how physiological epinephrine (EPI) elevations and EPI-induced hyperglycemia interact in the regulation of glucagon secretion, we measured acute glucagon responses (AGR) to arginine at controlled glucose levels during EPI infusions in man. With glucose levels matched at 166 +/- 5 mg/dl using glucose clamp techniques, the AGR (mean change at 2-5 min) to a 5-g iv arginine injection was greater in each subject during the infusion of 15 ng/kg . min EPI (low EPI) than during the control glucose infusion and was still greater during the infusion of 80 ng/kg . min EPI (high EPI; 69 +/- 15, 76 +/- 13, and 142 +/- 22 pg/ml, respectively; n = 8; P less than 0.003). With glucose levels matched at 256 +/- 5 mg/dl, a similar dose-related enhancement of AGR by EPI was seen (control, 53 +/- 12 pg/ml; low EPI, 63 +/- 5 pg/ml; high EPI, 130 +/- 20 pg/ml; P less than 0.008). During control infusions, raising the glucose level from 102 +/- 2 to 166 +/- 5 to 256 +/- 5 mg/dl suppressed AGR from 77 +/- 17 to 69 +/- 15 to 53 +/- 12 pg/ml (P less than 0.002). During low EPI, the same glycemic increments lowered GR from 108 +/- 19 to 76 +/- 13 to 63 +/- 5 pg/ml (P less than 0.02). This suppression of AGR by hyperglycemia was sufficient to obscure stimulation by EPI: at a glucose level of 102 +/- 2 mg/dl during control infusions, AGR was 77 +/- 17 pg/ml, compared to only 76 +/- 13 pg/ml during low EPI with the glucose level higher (166 +/- 5 mg/dl). Multiple linear regression analysis showed a highly significant dependence of AGR on both EPI and glucose levels, accounting for 80% of the within-subject variation in AGR (P less than 0.0001). These data show that 1) EPI is a dose-dependent amplifier of arginine-induced glucagon secretion in man, and 2) hyperglycemia suppresses arginine-induced glucagon secretion, potentially masking the stimulation caused by EPI. The findings suggest that the feedback effect of hyperglycemia on glucagon secretion may help regulate the level of hyperglycemia resulting from adrenergic stimulation.     

Persistent stimulatory effect of glucagon on glucose production despite downregulation.

The rise and subsequent return to basal of glucose production (Ra) during a constant glucagon infusion ("downregulation") has suggested to some workers that glucagon's effects are evanescent. To examine whether glucagon displays persistent biological activity even after downregulation, 6 healthy males received an 8 hour infusion of somatostatin and glucagon, with 3H-3-glucose to measure glucose turnover. Ra rose from 2.8 +/- 0.3 to 4.2 +/- 0.3 mg/kg . min at 90 minutes, returned to basal levels at 150 minutes, and remained at this level for the ensuing 330 minutes. Six additional subjects received an 8 hour somatostatin infusion, with glucagon administered concomitantly for the first 5 hours. Glucagon withdrawal at 5 hours produced an immediate decline in Ra from 1.8 +/- 0.2 to 0.9 +/- 0.2 mg/kg . min. Thus, even after downregulation the maintenance of basal Ra is dependent on circulating glucagon.     

Acute effects of alloxan- and streptozotocin-induced insulin deficiency on somatostatin and glucagon secretion by the perfused isolated rat pancreatico-duodenal preparation

Summary The secretion of somatostatin and glucagon by the perfused rat pancreatico-duodenal preparation was examined in situ under control conditions and after the induction of acute insulin deficiency by alloxan or streptozotocin. A 10 min 0.625 mmol/l alloxan perfusion resulted in an immediate and transient increase in basal insulin and glucagon release and a slightly delayed and persistent increase in basal somatostatin secretion. The insulin responses to 16.7 mmol/l glucose, 1 mmol/l theophylline, and 19 mmol/l arginine alone or in combination were virtually eliminated by alloxan treatment, Somatostatin secretion in response to the stimuli was completely inhibited or markedly attenuated. The glucagon-suppressive effect of glucose was unaltered by alloxan and the stimulatory effect of arginine was enhanced. Addition of 1 g/ml porcine insulin to the perfusion medium did not modify the alterations in somatostatin and glucagon responses to arginine. Streptozotocin treatment 90 min prior to the onset of perfusion resulted in changes in somatostatin, glucagon, and insulin responses to glucose and arginine similar to those of alloxan. The present results are consistent with an effect of alloxan and streptozotocin on the D cell similar to that on the B cell, namely, interference with a glucose-mediated effect on hormone secretion.     

Idiopathic reactive hypoglycemia: a role for glucagon?

We previously reported that patients with idiopathic reactive hypoglycemia (plasma glucose concentration lower than 2.5 mmol/L 2-4 h after the ingestion of 75 g of glucose) display reduced or absent counterregulatory response of the glucagon secretion and increased insulin sensitivity. In order to examine the effect of glucagon on the increased insulin sensitivity in these patients, 12 subjects with idiopathic reactive hypoglycemia underwent a two-step hyperinsulinemic (1 mU/kg.min) euglycemic glucose clamp and were compared with 12 normal control subjects matched for age, weight and sex. During the first step of the glucose clamp (only insulin + glucose infusion) the patients with Idiopathic Reactive Hypoglycemia required higher glucose infusion rates to maintain euglycemia than normal subjects (9.09 +/- 0.29 mg/kg. min vs 7.61 mg/kg.min). When basal glucagon secretion was replaced (+ somatostatin and glucagon, second step of the clamp) the glucose infusion rates required to maintain euglycemia in patients with Idiopathic Reactive Hypoglycemia significantly decreased (to 7.17 +/- 0.40 mg/kg.min) and resulted similar to normal subjects (7.64 +/- 0.41 mg/kg.min). Thus, in patients affected by Idiopathic Reactive Hypoglycemia, glucagon secretion may play an important role in the pathogenesis of the increased insulin sensitivity and hypoglycemia.     

Beta-endorphin and islet hormone release in type-2 diabetes mellitus the effects of normoglycemia, enkephalin, naloxone and somatostatin

The present study was aimed at characterizing the effects of beta-endorphin on plasma glucose, insulin and glucagon plasma levels in subjects with type-2 diabetes mellitus. Infusion of 0.5 mg/h human beta-endorphin produced significant and simultaneous increments in both insulin and glucagon concentrations and decreased plasma glucose levels (-18 +/- 4 mg/dl, 60 min level, p less than 0.01). When the same diabetics were rendered euglycemic by an insulin infusion (1 mU/kg/min), beta-endorphin did not produce the expected decrease in plasma glucose concentrations nor raise plasma insulin levels; only the response of glucagon was preserved. Normal subjects were rendered hyperglycemic by an intravenous glucose infusion to match the plasma glucose levels of diabetic subjects. In this condition, beta-endorphin produced a significant increase of insulin concentrations, whereas glucagon remained suppressed. The intravenous administration of the long-acting met-enkephalin analogue DAMME (0.25 mg) blunted the hormonal responses to the subsequent beta-endorphin infusion in diabetic patients, although the inhibition was short-lived (30-40 min). Naloxone (5 mg), an opiate antagonist, did not produce any significant change in the insulin and glucagon responses to beta-endorphin, while somatostatin (0.25 mg/h) completely abolished the hormonal responses to the opioid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of galanin on insulin and glucagon secretion in the rat

Galanin-like immunoreactivity has been visualized in nerve fibers in the islets of Langerhans, suggesting an involvement of galanin in the neural regulation of islet function. In this study, we investigated the effects of galanin on basal and stimulated insulin and glucagon secretion by infusing the peptide at three different dose rates in rats. We also studied the direct effect of galanin on insulin secretion from freshly isolated rat islets. At 320 pmol/kg/min, but not at 20 or 80 pmol/kg/min, galanin lowered basal plasma insulin levels. In contrast, basal plasma glucagon levels were lowered by galanin already at 20 and 80 pmol/kg/min. Furthermore, galanin inhibited both glucose- and arginine-induced insulin release at all three dose levels, whereas arginine-induced glucagon release was not affected by galanin. Glucose-stimulated insulin secretion from isolated rat islets was dose-dependently suppressed by galanin (10(-6)-10(-8) M). Therefore, it is concluded that galanin in rats inhibits insulin secretion, both in vivo and in vitro, and that at lower dose levels, the peptide also inhibits basal glucagon 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.     

Changes in glucagon do not play an essential role in the glucoregulatory responses to mild hyperinsulinemia in dogs

To examine whether an increase in the glucagon concentration is essential for restoring hepatic glucose output following moderate decrements in blood glucose, we used isotope dilution techniques in trained conscious dogs (n = 5) to measure glucose production (Ra) and glucose utilization (Rd) during mild hyperinsulinemia (19 +/- 1 mU/l). In Study A, when insulin was infused to raise plasma insulin (IRI) from 13 +/- 2 to 19 +/- 1 mU/l, basal glucose (93 +/- 3 mg/dl) fell at a rate of 0.37 +/- 0.06 mg/dl/min over 30 min. Ra fell from 2.8 +/- 0.4 mg/kg/min by 0.5 +/- 0.1 mg/kg/min at 20 min (P less than 0.05), but recovered to baseline by 30 min; glucagon (IRG) fell transiently but returned to baseline by 45 min. In Study B, endogenous secretion of IRI and IRG was suppressed by infusion of somatostatin (0.2 microgram/kg/min), while peripheral concentrations were maintained constant by replacing glucagon (0.65 ng/kg/min) and insulin (0.225 mU/kg/min). Steady-state baseline plasma IRI, IRG, glucose and glucose turnover rates were similar to Study A; hyperinsulinemia was then induced as in Study A. Glucose fell by 0.78 +/- 0.19 mg/dl/min over 30 min and, as in Study A, Ra decreased transiently, but recovered to baseline by 30 min. The restoration of Ra occurred in study B despite constant IRG, and preceded later increments in cortisol and catecholamines at 60-90 min. Thus, in both studies A and B, Ra recovered to baseline without an increase in IRG and before the onset of significant hypoglycemia (glucose 83 +/- 1 and 70 +/- 1 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of galanin and calcitonin gene-related peptide on insulin and glucagon secretion in man.

To study the influence of the pancreatic neuropeptides, galanin and calcitonin gene-related peptide, on insulin and glucagon secretion in man, synthetic porcine galanin (80 pmol.kg-1.min-1; N = 6) or synthetic human calcitonin gen-related peptide (10 pmol.kg-1.min-1; N = 5) was infused intravenously in human volunteers. Following 5 min of infusion, arginine (5 g bolus + 10 mg.kg-1.min-1) was given. Galanin did not affect basal or arginine-stimulated insulin secretion judged from determinations of plasma insulin and C-peptide. Similarly, galanin did not affect arginine-stimulated glucagon secretion. Calcitonin gene-related peptide did not affect basal or arginine-stimulated insulin or glucagon secretion. However, calcitonin gene-related peptide slightly potentiated the arginine-induced hyperglycemia (p less than 0.01). Thus, in man, galanin has no influence on insulin or glucagon secretion when infused at 80 pmol.kg-1.min-1, whereas CGRP at 10 pmol.kg-1.min-1 induces slight hyperglycemia.