Biomedical subjects

B E Dunning

Publications and source records attributed to B E Dunning.

49 records · Page 3Linked to original sources

PubMed1989

Galanin release during pancreatic nerve stimulation is sufficient to influence islet function.

To determine if galanin is released during pancreatic neural activation, we measured galanin-like immunoreactivity (GLIR) in pancreatic venous and peripheral arterial plasma during 10 min of electrical stimulation of the mixed autonomic pancreatic nerves in halothane-anesthetized dogs, using a sensitive and specific radioimmunoassay. During mixed pancreatic nerve stimulation (MPNS), pancreatic venous GLIR increased by 174 +/- 20 fmol/ml, whereas arterial GLIR did not change. By use of the arteriovenous concentration difference and measurements of pancreatic venous blood flow, pancreatic spillover of GLIR was calculated and found to increase by 640 +/- 90 fmol/min during MPNS. This MPNS inhibited the output of immunoreactive insulin (IRI; delta = -53 +/- 9%) and somatostatin-like immunoreactivity (SLI, delta = -49 +/- 13%) and stimulated that of immunoreactive glucagon (IRG, delta = +600 +/- 200%). To determine if the amount of GLIR released during MPNS was sufficient to elicit these changes of pancreatic hormone secretion, we compared the effect of MPNS on IRI, SLI, and IRG output with the effect of synthetic galanin infused directly into the pancreatic artery at a rate that reproduced the MPNS-induced spillover of GLIR. Exogenous infusion of synthetic galanin (2.7 pmol/min) increased pancreatic venous levels of GLIR by 169 +/- 38 fmol/ml, did not change arterial GLIR levels, and thus increased calculated spillover (appearance) by 550 +/- 160 fmol/min, which was nearly identical to the increment produced by MPNS. This matched infusion of galanin inhibited IRI (delta = -58 +/- 3%) and SLI output (delta = -35 +/- 3%) and modestly stimulated IRG output (delta = +62 +/- 10%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Extraction of epinephrine and norepinephrine by the dog pancreas in vivo.

This study determined the fractional extraction of epinephrine and norepinephrine by the in situ dog pancreas. Plasma samples for epinephrine measurements were taken simultaneously from the femoral artery and the superior pancreaticoduodenal vein. Pancreatic extraction of epinephrine was 73 +/- 5% when basal arterial epinephrine levels were 380 +/- 93 pg/mL, 76 +/- 4% when arterial levels were 896 +/- 123 pg/mL (epinephrine infused intravenously at 20 ng/kg/min), and 84 +/- 1% when arterial levels were 2,956 +/- 414 pg/mL (epinephrine infused intravenously at 80 ng/kg/min) suggesting that the process of epinephrine extraction by the pancreas is not saturable over this range. During a similar sampling protocol, norepinephrine was infused intravenously at 4 micrograms/kg/min; pancreatic extraction of norepinephrine was then 65 +/- 7% when arterial norepinephrine levels were 107,000 +/- 28,000 pg/mL. In separate experiments, lower rates of norepinephrine (12 to 1,200 ng/min) were infused directly into the pancreatic artery and pancreatic norepinephrine extraction was calculated; it ranged between 66% and 75%. Because the pancreas produces as well as extracts norepinephrine, a third technique was required to determine pancreatic norepinephrine extraction at the lower endogenous levels of norepinephrine; 3H-norepinephrine was infused intravenously and the arteriovenous difference of 3H-norepinephrine was measured. Fractional extraction of 3H-norepinephrine was 74 +/- 4% both in the basal state (arterial norepinephrine level = 202 +/- 44 pg/mL) and during systemic, glucopenic, stress induced by 2-deoxy-glucose (arterial norepinephrine level = 636 +/- 70 pg/mL). These data suggest that also the norepinephrine extraction process by the pancreas is not saturable.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Nonadrenergic sympathetic neural influences on basal pancreatic hormone secretion.

Evidence for peptidergic innervation of the islets of Langerhans is increasing, yet the role of neuropeptides in mediating neurally induced changes of islet function is not clear. To determine if nonadrenergic transmitters make an important contribution to sympathetic neural effects on basal pancreatic hormone secretion, we examined the effect of local sympathetic nerve stimulation (SNS) on the output of immunoreactive insulin (IRI), immunoreactive glucagon (IRG), and somatostatin (SLI) from the duodenal lobe of the pancreas in situ in halothane-anesthetized dogs, under conditions where the actions of the classical transmitter norepinephrine (NE) should be blocked by propranolol (PROP) and yohimbine (YO). In the absence of adrenergic antagonists, SNS rapidly reduced the output of IRI (delta = -1.34 +/- 0.91 mU/min) and SLI (delta = -600 +/- 350 fmol/min) and stimulated that of IRG (delta = +1.39 +/- 0.57 ng/min). In the presence of PROP and YO, SNS induced similar changes of hormone secretion: delta IRI, -1.30 +/- 0.53 mU/min; delta SLI, -480 +/- 180 fmol/min; delta IRG = +1.89 +/- 0.63 ng/min. Because PROP and YO abolished the pancreatic effects of high dose infusions of NE (1 microgram.kg-1.min-1 iv), we suggest that the antagonists produced sufficient, combined adrenergic blockade at the level of the islet, and we conclude that a nonadrenergic neurotransmitter or modulator plays a major role in mediating sympathetic neural effects on basal islet hormone secretion.

Animals↗

PubMed1988

Pancreatic noradrenergic nerves are activated by neuroglucopenia but not by hypotension or hypoxia in the dog. Evidence for stress-specific and regionally selective activation of the sympathetic nervous system.

To determine if acute stress activates pancreatic noradrenergic nerves, pancreatic norepinephrine (NE) output (spillover) was measured in halothane-anesthetized dogs. Central neuroglucopenia, induced by intravenous 2-deoxy-D-glucose [( 2-DG] 600 mg/kg + 13.5 mg/kg-1 per min-1) increased pancreatic NE output from a baseline of 380 +/- 100 to 1,490 +/- 340 pg/min (delta = +1,110 +/- 290 pg/min, P less than 0.01). Surgical denervation of the pancreas reduced this response by 90% (delta = +120 +/- 50 pg/min, P less than 0.01 vs. intact innervation), suggesting that 2-DG activated pancreatic nerves by increasing the central sympathetic outflow to the pancreas rather than by acting directly on nerves within the pancreas itself. These experiments provide the first direct evidence of stress-induced activation of pancreatic noradrenergic nerves in vivo. In contrast, neither hemorrhagic hypotension (50 mmHg) nor hypoxia (6-8% O2) increased pancreatic NE output (delta = +80 +/- 110 and -20 +/- 60 pg/min, respectively, P less than 0.01 vs. neuroglucopenia) despite both producing increases of arterial plasma NE and epinephrine similar to glucopenia. The activation of pancreatic noradrenergic nerves is thus stress specific. Furthermore, because both glucopenia and hypotension increased arterial NE, yet only glucopenia activated pancreatic nerves, it is suggested that a regionally selective pattern of sympathetic activation can be elicited by acute stress, a condition in which sympathetic activation has traditionally been thought to be generalized and nondiscrete.

Adrenalectomy↗

PubMed1988

Somatostatin-28 does not regulate islet function in the dog.

Somatostatin-28 (S-28) is a naturally occurring N-terminally extended form of the tetradecapeptide somatostatin (S-14). The concept has arisen that S-28 is a gut hormone that regulates insulin secretion. This concept is based on 1) reports that S-28 is a more potent inhibitor of insulin secretion than S-14; 2) the finding that S-28 is present in D-cells of the intestine and is released after a meal; and 3) the demonstration of selective binding of S-28 to B-cells of the rat islet. To critically test this hypothesis we have 1) measured the circulating levels of somatostatin-like immunoreactivity (SLI) during infusions of S-28 and S-14 to accurately compare their potencies to inhibit insulin and glucagon secretion from the in vivo dog pancreas, and 2) measured the circulating levels of endogenous SLI released after a meal and compared these to the circulating levels of infused S-28 needed to inhibit insulin secretion. Infusion of S-28 at rates of 170 and 500 pmol/min raised arterial SLI levels by 282 +/- 26 and 885 +/- 98 fmol/ml, respectively. Immunoreactive insulin (IRI) output was inhibited by 20 +/- 11% (P less than 0.05) and 52 +/- 7% (P less than 0.0005), respectively. Immunoreactive glucagon (IRG) output was not significantly altered by either dose. Pancreatic SLI output was inhibited by 32 +/- 5% (P less than 0.0005) by the 500 pmol/min infusion. Infusion of S-28 at 50 pmol/min increased arterial SLI by 108 +/- 17 fmol/ml, but did not alter IRI output (+4 +/- 20%). In comparison, infusion of S-14 (100 pmol/min) raised arterial SLI levels by a similar amount (110 +/- 21 fmol/ml), but, unlike S-28, inhibited both IRI (-50 +/- 6%, P less than 0.0005) and IRG output (-17 +/- 8%; P less than 0.05). Thus, comparable increments in arterial S-28 failed to reproduce the inhibition of IRI secretion seen during the S-14 infusion, while similar inhibition was seen with an 8-fold increment. This suggests that S-28 is significantly less potent than S-14 in the dog. After a mixed meal, endogenous SLI levels increased by 35 +/- 3 fmol/ml in arterial plasma.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1988

Galanin--sympathetic neurotransmitter in endocrine pancreas?

The effects of sympathetic neural activation on basal pancreatic hormone secretion cannot be explained solely by the actions of the classic sympathetic neurotransmitter norepinephrine. The nonadrenergic component may be mediated by the 29-amino acid peptide galanin in that this neuropeptide meets several of the criteria necessary to be considered a sympathetic neurotransmitter in the endocrine pancreas. 1) Galanin administration inhibits basal insulin and somatostatin secretion and stimulates basal glucagon secretion from the pancreas, qualitatively reproducing the effects of sympathetic nerve stimulation. These sympathomimetic effects appear to be mediated by direct actions of galanin on the islet. 2) Galanin-like immunoreactivity exists in fibers that innervate pancreatic islets. 3) Galanin is released during electrical stimulation of pancreatic nerves. The quantity released is sufficient to reproduce sympathetic nerve stimulation-induced effects on insulin secretion and to contribute to the neural effects on somatostatin and glucagon release. 4) Whether interference with galanin action or release reduces the islet response to sympathetic nerve stimulation remains to be determined. We hypothesize that galanin and norepinephrine act together to mediate the islet response to sympathetic neural activation. If galanin is a sympathetic neurotransmitter in the endocrine pancreas, it may contribute to the inhibition of insulin secretion that occurs during stress and thereby to the hyperglycemic response. Moreover, the local presence of this potent beta-cell inhibitor in the islet leads to speculation on galanin's contribution to the impairment of insulin secretion that occurs in non-insulin-dependent diabetes mellitus and therefore on the potential utility of a galanin antagonist in the treatment of this disease.

Animals↗

PubMed1987

The presence and actions of NPY in the canine endocrine pancreas.

Immunofluorescent staining for neuropeptide Y (NPY) in canine pancreatic tissue was performed together with an evaluation of the effects of synthetic NPY on the release of insulin (IRI), glucagon (IRG) and somatostatin (SLI) from the duodenal lobe of the canine pancreas in situ. NPY-like immunoreactivity was localized in perivascular nerve fibers throughout the acinar tissue. NPY-immunoreactive fibers were also demonstrated in the islets, usually surrounding blood vessels but also occasionally in fibers associated with endocrine cells, primarily at the periphery of islets. In addition, the ganglia dispersed in the pancreatic parenchyma were densely innervated by NPY-immunoreactive fibers, and these ganglia regularly contained cell bodies staining for NPY. Direct infusion of NPY into the pancreatic artery (p.a.) produced a dose-dependent decrease of pancreatic SLI output and of pancreatic venous blood flow. Low-dose p.a. infusion of NPY (50 pmol/min) had no effect on basal IRI or IRG output or on the islet response to glucose (5-g bolus, i.v.). High-dose p.a. infusion of NPY (500 pmol/min) transiently stimulated IRI output and modestly increased IRG output. However, the comparatively sparse innervation of canine islets with NPY-like immunoreactive fibers and the relatively minor effects of large doses of synthetic NPY on pancreatic hormone release lead us to conclude that this peptide is not an important neuromodulator of islet function in the dog.

Animals↗

PubMed1987

Calcitonin gene-related peptide: a potent and selective stimulator of gastrointestinal somatostatin secretion.

Calcitonin gene-related peptide (CGRP) exists in nerves throughout the gastrointestinal tract and pancreas, and exogenous CGRP has been reported to inhibit many endocrine and exocrine secretions of the gut and pancreas. Because somatostatin also has widespread inhibitory actions and because both gut and pancreatic somatostatin secretion may be under peptidergic control, we examined the influence of CGRP on circulating levels of somatostatin-like immunoreactivity (SLI) and on hormone output from the duodenal lobe of the dog pancreas in situ. Intravenous infusion of human CGRP in anesthetized dogs increased arterial SLI in a dose-dependent manner. During iv infusion of CGRP at 500 pmol/min, the increment of circulating SLI (change at 20 min, +175 +/- 24 fmol/ml) was composed of nearly equimolar amounts of SLI-14 and SLI-28, suggesting an effect of CGRP on both gastric and intestinal somatostatin secretion. The effect of iv CGRP (500 pmol/min) on arterial SLI exceeded those of iv CCK-8 (440 pmol/min), iv isoproterenol (10 nmol/min), and intragastric administration of acidified liver extract. In contrast, salmon calcitonin (500 pmol/min, iv) was without effect. CGRP did not stimulate pancreatic SLI output when infused iv (500 pmol/min) or when infused directly into a pancreatic artery (5 pmol/min). The pancreatic infusion of CGRP decreased insulin output slightly (change at 20 min, -21 +/- 8%), but did not affect glucagon output. We conclude that CGRP is a most effective yet selective stimulator of gastrointestinal somatostatin release, with little influence on islet function. We suggest that exogenous and possibly endogenous neuronal CGRP could exert inhibitory effects on gastrointestinal function via the release of somatostatin.

Animals↗

PubMed1986

Galanin: a novel pancreatic neuropeptide.

Immunofluorescent staining for galanin in canine pancreatic tissue was performed together with an evaluation of the effects of synthetic galanin on pancreatic output of glucagon, somatostatin, and insulin in pentobarbital-anesthetized dogs. A dense network of galaninlike immunoreactive nerve fibers was visualized in association with the islets of Langerhans and occasional galanin immunoreactive fibers were seen to course through the exocrine parenchyma of dog pancreas. During intravenous infusion of synthetic porcine galanin (25 pmol X kg-1 X min-1) pancreatic glucagon output rapidly doubled, and the output of both somatostatin and insulin decreased by 70%. Because arterial and pancreatic venous catecholamine levels remained unchanged, the effects on hormone secretion were not secondary to activation of the sympathetic nervous system. The direct pancreatic action of galanin was confirmed by infusing a peripherally ineffective dose of galanin (0.25 pmol X kg-1 X min-1) into the pancreatic artery, which also stimulated glucagon (+90%) and suppressed somatostatin (-50%) and insulin (-70%) release. The presence of galaninlike immunoreactive neurons in dog islets, together with the direct action of galanin on pancreatic hormone release, suggest that this recently discovered peptide could serve as an important neuromodulator of endocrine pancreatic function.

Animals↗

PubMed1985

Evidence for participation of the neurohypophysial hormones in the hyperglucagonemic response to hemorrhage in the rat.

Conscious adult male rats bearing jugular cannulae were injected with either normal rabbit serum (NRS) or with serum containing antibodies to both oxytocin (OT) and arginine vasopressin (AVP). In the NRS-treated group, plasma levels of OT, AVP and immunoreactive glucagon (IRG) were significantly elevated 10 min after hemorrhage (2.3 ml/100 g body weight over 5 min) whereas hyperglucagonemia was not detected in the antiserum-treated group until 30 min posthemorrhage. In animals which were deprived of water during the experiment, plasma IRG in the antiserum-treated group reached only 40% of the levels in the NRS-treated controls. These results suggest that hemorrhage-induced elevations in circulating AVP and/or OT contribute to increased release of glucagon by the endocrine pancreas consistent with previous demonstration of glucagonotropic activity of synthetic neurohypophysial peptides.

Animals↗

PubMed1984

Actions of neurohypophysial peptides on pancreatic hormone release.

The intermittent reports concerning metabolic actions of neurohypophysial extracts or hormones encouraged us to study the effect of these substances on the function of the endocrine pancreas. A surprisingly small amount of neural lobe (NL) extract (0.025 NL eq/ml) stimulated a 425% increase in the release of glucagon from islets isolated from the pancreas of the rat. Gel filtration of the extract produced an elution profile of glucagon-releasing activity that was superimposable on the profiles of oxytocin (OT) and arginine vasopressin (AVP). Synthetic OT and AVP each elicited a concentration-dependent stimulation of glucagon release but failed to influence insulin release in medium 199 containing 5.6 mM glucose. They were effective at 0.2 ng/ml (+55%, +50%) and produced a striking increase (five- to sevenfold) at 20 ng/ml. The response to each peptide was greatly diminished in the presence of a higher concentration of glucose (11 mM). The lysine, desamino-, and 1,6-aminosuberyl analogues of vasopressin, vasotocin, and AVP are equipotent peptides, whereas the desglycinamide analogue, pressinoic acid, and angiotensin II were inactive. Injection of AVP (1 microgram iv) produced a rapid increase in peripheral glucagon (+185% in 5 min). The response to injection of OT was less rapid (+105% in 15 min), but in each case elevation of insulin was also observed. Our results provide evidence that OT and AVP can act directly on the endocrine pancreas and may help explain previous reports of metabolic actions of these peptides.

Animals↗

PubMedDate not supplied

Modulation of insulin and glucagon secretion from the perfused rat pancreas by the neurohypophysial hormones and by desamino-D-arginine vasopressin (DDAVP).

Marked stimulation of glucagon release and modest stimulation of insulin release were observed during in situ perfusion of the rat pancreas with AVP or OT. Glucagon release in response to AVP or OT (200 pg/ml) gradually increased over a 45 min perfusion period reaching maxima of 500% and 300% of the pre-stimulatory levels, respectively. Insulin release transiently increased by 100%. In each case release rates returned to control values immediately after withdrawal of the peptides. Total glucagon release was concentration dependent and linear from 20 pg to 20 ng AVP or OT/ml (r greater than .97). Pancreatic response to DDAVP perfused at 20 ng/ml was virtually indistinguishable from that induced by AVP at 200 pg/ml. This demonstration of a glucagonotrophic action of the neurohypophysial hormones in the in situ perfused rat pancreas confirms earlier studies using isolated islets and bolus IV injection.

Animals↗

PubMedDate not supplied

Nateglinide (Starlix): update on a new antidiabetic agent.

Nateglinide is a new oral antidiabetic agent that stimulates insulin release promptly after its pre-meal administration in a strongly glucose-dependent fashion. Because its insulinotropic effects are short in duration, nateglinide specifically targets postprandial hyperglycaemia with a low potential to elicit hypoglycaemia or sustained hyperinsulinaemia. Nateglinide has an excellent safety and tolerability profile, and its efficacy in reducing HbA1c in monotherapy (120 mg before meals) is comparable to that of metformin, sulphonylureas, thiazolidinediones or acarbose (-0.5 to -1.5%). When combined with metformin, which primarily reduces fasting glucose levels, nateglinide's effects are additive. In our clinical experience, nateglinide is a particularly good therapeutic option in newly diagnosed, treatment-naive patients; elderly patients in whom hypoglycaemia is a concern; patients with kidney failure or mild hepatic impairment; patients taking low-dose sulphonylureas who encounter problems with hypoglycaemia; and patients failing to achieve adequate glycaemic control on metformin or thiazolidinedione monotherapy.

Blood Glucose↗