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Biomedical subjects

B E Dunning

Publications and source records attributed to B E Dunning.

At least 37 records · Page 2Linked to original sources
PubMed1997

New non-sulfonylurea insulin secretagogues.

Current treatments for non-insulin dependent diabetes mellitus (NIDDM) remain far from ideal. The universal finding of islet dysfunction characterised by the absence of first phase insulin secretion, even prior to the level of hyperglycaemia diagnostic of NIDDM, challenges the rationale for treatments that only enhance insulin action. To date, however, the sulfonylureas are the only insulin secretagogues available and even the most rapid acting of these fail to restore early insulin release in response to meals. Four novel non-sulfonylurea insulin secretagogues are in advanced clinical development: A-4166, KAD-1229, BTS 67 582 and repaglinide. These promising new agents control prandial hyperglycaemia by augmenting the early insulin response to meals. Preclinical and early clinical data suggest that their potencies vary considerably, as do their pharmacokinetics and, importantly, their pharmacodynamics. The two shortest-acting compounds, A-4166 and KAD-1229, will be developed to be taken prior to each main meal, while the slower, longer duration agents, repaglinide and BTS 67 582, may be developed to be taken twice daily. With a sufficiently rapid onset and short duration of action, the new non-sulfonylurea insulin secretagogues may improve or even restore the impairment of early insulin secretion without inducing the prolonged hyperinsulinaemia characteristic of sulfonylureas. Treatment with these new agents will immediately improve prandial glucose control and with continued treatment these agents are expected to improve the overall metabolic state. Furthermore, a short-acting secretagogue will have minimal propensity to elicit prolonged or delayed hypoglycaemia and it is expected that by minimising chronic hyperinsulinaemia the weight gain that accompanies sulfonylurea treatment will be avoided. In summary, the new non-sulfonylurea insulin secretagogues will make an important contribution to the limited and inadequate armamentarium currently available for the treatment of NIDDM, and their use in combination with insulin sensitising agents may provide, for the first time, an approximation to ideal metabolic control in NIDDM.

Journal Article↗
PubMed1995

Muscarinic stimulation maintains in vivo insulin secretion in response to glucose after prolonged hyperglycemia.

Prolonged hyperglycemia impairs the in vitro insulin release by islets of Langerhans in response to glucose but exaggerates the in vivo insulin response. We hypothesized that this discrepancy results from increased vagal stimulation of the islets. Conscious chronically cannulated rats were infused with glucose (15 mg/min) or saline for 48 h. Three hours thereafter, an intravenous glucose tolerance test was performed with or without prior injection of atropine (0.2 mg). Atropine markedly (> 70%) reduced the insulin response in glucose-infused, but not in saline-infused, rats. Glucose-infused rats displayed basal hypoglycemia but normal glucose excursions during an intravenous glucose tolerance test. It is concluded that prolonged hyperglycemia produces exaggerated muscarinic activation of the beta-cells that will persist > or = 3 h after the termination of the glucose infusion and normalizes in vivo insulin secretion. It is possible that increased parasympathetic activation of the pancreas might constitute a general mechanism to maintain insulin output when the demand for insulin exceeds the inherent beta-cell responsiveness.

Animals↗
PubMed1994

Glucosamine inhibits glucokinase in vitro and produces a glucose-specific impairment of in vivo insulin secretion in rats.

A characteristic feature of non-insulin-dependent diabetes mellitus (NIDDM) is the lack of an acute insulin response to intravenous glucose with maintenance of the response to other secretagogues. It has been hypothesized that impaired glucose sensing stems from defective beta-cell glucokinase. It remains unclear whether decreased pancreatic glucokinase activity will produce defects of insulin secretion similar to those observed in NIDDM. In this study, the effects of glucosamine on glucokinase activity and on islet function were assessed in vitro and in vivo. Glucosamine (5 mmol/l) reduced glucokinase activity in islet homogenate and diminished the insulin response to glucose (200 mg/dl) by isolated islets, whereas the response to arginine (20 mmol/l at 100 mg/dl glucose) was unaffected. In conscious normal rats, glucosamine lowered plasma insulin, followed by an increase in blood glucose. Administration of glucosamine 10 min before an infusion of glucose (10 mg.min-1. 15 min) reduced the insulin response. The primary effect was an attenuation of the first-phase insulin response relative to the decreased basal insulin levels. Arginine (10 mg.min-1.15 min) induced biphasic insulin release in both groups. Although glucosamine slightly reduced the absolute insulin response, it was normal relative to preinfusion levels. In all experiments, glucagon secretion was unaffected by glucosamine. The results indicate that glucosamine inhibits beta-cell glucokinase activity in vitro. In addition, glucosamine impairs glucose- but not arginine-induced insulin secretion. We conclude that glucosamine, probably via a reduction of glucokinase activity, impairs insulin secretion in a manner comparable to that seen in NIDDM.

Animals↗
PubMed1993

Tissue-specific reduction of galanin content in the pancreas in alloxan diabetes in the mouse.

Galanin inhibits insulin secretion and has been proposed to function as a sympathetic neurotransmitter in the endocrine pancreas in some species, for example in the dog. In this study, pancreatic and adrenal gland galanin content were measured following experimental diabetes induced by alloxan in mice. Three days after administration of alloxan (70 mg kg-1, i.p.) in normal mice, pancreatic content of galanin-like immunoreactivity (GLIR) was reduced to 65 +/- 11% of that in untreated controls (P < 0.01), whereas adrenal gland GLIR was unchanged. Similarly, 8 days after alloxan administration, pancreatic GLIR was reduced (P < 0.002), whereas adrenal gland GLIR was unaffected. Pancreatic GLIR also inversely correlated with plasma glucose levels (r = -0.5055, P < 0.005). To distinguish between the direct effects of alloxan vs. indirect metabolic effects induced by the drug, alloxan-diabetic mice were treated with insulin twice daily, which normalized the plasma glucose levels (7.6 +/- 0.3 mmol l-1). Pancreatic GLIR was then not significantly different from controls. Thus pancreatic but not adrenal gland GLIR content is reduced in alloxan-induced diabetes in mice. The data support a role for galanin as a pancreatic sympathetic neurotransmitter which may participate in the metabolic alterations seen in alloxan diabetes in mice.

Adrenal Glands↗
PubMed1992

Reduced pancreatic content of the inhibitory neurotransmitter galanin in genetically obese, hyperinsulinemic mice.

Because abnormalities of the autonomic nervous system have been described in several animal models of obesity, and because galanin has been proposed to be a sympathetic neurotransmitter in the endocrine pancreas, we hypothesized that the hyperinsulinemia observed in genetically obese (ob/ob) mice may result either from defective ability of galanin to inhibit insulin release or from a reduced degree of pancreatic galaninergic innervation. To address these possibilities, we examined the effect of exogenous galanin on immunoreactive insulin (IRI) levels in ob/ob mice and compared the pancreatic content of galaninlike immunoreactivity (GLIR) in ob/ob mice with that in lean littermates. Intravenous administration of synthetic porcine galanin significantly reduced basal IRI levels in ob/ob mice, suggesting that a defect in galanin action is unlikely to account for the hyperinsulinemia in this model. In contrast, reduced pancreatic galaninergic innervation was supported by findings that pancreatic content of GLIR in ob/ob mice was less than 10% of that in age- and sex-matched lean littermates. The reduction of pancreatic GLIR in ob/ob mice appeared organ specific; no such reduction was observed in adrenal GLIR content when comparing obese and lean mice. In addition, the relationship between pancreatic GLIR content and plasma IRI levels was examined in groups of obese and lean mice. It was found in young females, young males, and older mice of mixed sex that there was a significant negative correlation between pancreatic GLIR and plasma IRI in lean mice, whereas no such correlation was observed in obese mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1992

Corelease of galanin and NE from pancreatic sympathetic nerves during severe hypoglycemia in dogs.

To determine whether norepinephrine (NE) and galanin are coreleased during reflex activation of the sympathetic nervous system by hypoglycemia, we administered insulin to halothane-anesthetized (0.8%) dogs and measured the spillover of NE and galanin-like immunoreactivity (GLIR) into pancreatic venous plasma. Insulin injection produced hypoglycemia [plasma glucose (PG) = 34 +/- 3 mg/dl] but did not activate pancreatic noradrenergic (delta pancreatic NE output = +20 +/- 130 pg/min) or galaninergic nerves (delta GLIR output = +40 +/- 50 fmol/min). To determine whether more severe hypoglycemia would activate these nerves, insulin was administered to dogs infused with somatostatin (SS; 2.5 micrograms/min) to block the counterregulatory increase of glucagon secretion. SS reduced the glucagon response to hypoglycemia by greater than 90%, which allowed PG to decrease to 14 +/- 1 mg/dl. Pancreatic NE output increased by 470 +/- 140 pg/min (P less than 0.005); however, pancreatic GLIR output did not increase significantly (delta = +70 +/- 50 fmol/min). When SS was discontinued, pancreatic NE output increased by 490 +/- 200 pg/min (P less than 0.025), and GLIR output increased by an additional +160 +/- 70 fmol/min (P less than 0.025; total delta from baseline = +230 +/- 90 fmol/min, P less than 0.025), suggesting that SS may restrain pancreatic NE and galanin release. Pancreatic NE and GLIR spillover were also increased during severe hypoglycemia when ganglionic neurotransmission was partially impaired with hexamethonium but not when the neural pathway was interrupted by spinal cord transection. We conclude that NE and galanin are coreleased from pancreatic sympathetic nerves when these nerves are centrally activated during severe hypoglycemia in halothane-anesthetized dogs.

Animals↗
PubMed1992

Alpha 2-adrenergic regulation of galanin and norepinephrine release from canine pancreas.

We found previously that electrical stimulation of the mixed autonomic pancreatic nerves (MPNS) is anesthesized dogs elicits marked and rapid increases of pancreatic output of both norepinephrine (NE) and galanin, and on that basis hypothesized a role for galanin as a sympathetic cotransmitter in the endocrine pancreas. In the present study, direct evidence was sought for the co-release of galanin and NE from canine pancreas by determining whether pancreatic galanin output is subject to modulation by presynaptic alpha 2-adrenergic mechanisms as has been established for NE. During MPNS (8 Hz, 1 ms, 10 mA, 10 min) in anesthesized dogs, both pancreatic NE and galanin outflow were increased with similar temporal patterns during consecutive stimulations. Blockade of presynaptic alpha 2-adrenoceptors with yohimbine increased and stimulation of presynaptic alpha 2-adrenoceptors with clonidine reduced NE and galanin outflow. Over all experiments, pancreatic spillover of galanin was highly correlated with that of NE. It is concluded that presynaptic alpha 2-adrenergic mechanisms modulate not only NE but also pancreatic galanin release, suggesting that galanin is co-released with NE from noradrenergic nerves in the endocrine pancreas.

Adrenergic alpha-Agonists↗
PubMed1991

Human galanin: primary structure and identification of two molecular forms.

From acid/ethanol extracts of surgical specimens of human large intestine we isolated two peptides, in approximately equal amounts, that reacted with an antiserum against porcine galanin. By amino acid analysis, sequence analysis and mass spectrometry, the larger of the two peptides was found to consist of 30 amino acid residues, the sequence of which was identical to that of porcine galanin except for the following substitutions: Val16, Asn17, Asn26, Thr29 and Ser30. Unlike porcine galanin, the carboxy-terminus was not amidated. The smaller peptide corresponded to the first 19 amino acid residues counted from the N-terminus of the 30 residue peptide (again without amidation). The structural analysis was repeated on another batch of tissue with identical results. By HPLC analysis of extracts of specimens from a further 4 patients, the same peptides were identified. Thus, human galanin includes two peptides of 19 and 30 amino acids that share the sequence of the N-terminal 15 residues with other mammalian galanins, but exhibit characteristic differences in the remaining part of the molecules.

Amino Acid Sequence↗
PubMed1991

Neural control of islet function by norepinephrine and sympathetic neuropeptides.

It is clear that the sympathoadrenal system has a role in the regulation of endocrine pancreatic function and that the sympathetic nerves of the pancreas can change pancreatic hormone secretion to increase the availability of metabolic fuels. It seems likely that the classical sympathetic neurotransmitter, NE, acts in concert with peptide co-transmitters, such as galanin and NPY. Each is released during the stimulation of pancreatic sympathetic nerves and each is capable of influencing either islet function or pancreatic blood flow. There is considerable indirect evidence that the sympathetic innervation of the pancreas is activated during acute stress and influences the endocrine pancreas. However, proving such a physiologic role is difficult because of redundant mechanisms that influence the secretion of the metabolically-crucial hormones, insulin and glucagon. Such definitive proof therefore awaits the development of new techniques to dissect and dissociate these mechanisms.

Animals↗
PubMed1991

Presence of galanin in human pancreatic nerves and inhibition of insulin secretion from isolated human islets.

In several animal species, galanin occurs in pancreatic nerves and inhibits insulin secretion. However, the presence and action of galanin in the human pancreas have not been established. Therefore, we examined the presence and nature of human pancreatic galanin-like immunoreactive material (GLIR) and the effects of galanin on glucose-stimulated insulin secretion from isolated human islets. Immunofluorescent staining of human pancreas revealed GLIR in fine varicose fibers in both islets and exocrine parenchyma. Furthermore, acid extracts of pancreas (n = 3) and isolated islets (n = 3) contained 0.17 +/- 0.06 and 0.23 +/- 0.11 pmol GLIR/mg protein. Human pancreatic GLIR coeluted with synthetic porcine galanin from Sephadex G-50. Moreover, synthetic porcine galanin inhibited glucose-stimulated insulin secretion from collagenase-isolated human islets at dose rates greater than 10(-8) M. Thus, (1) human pancreas is innervated by galanin-containing nerves, (2) human pancreatic GLIR is of similar size as synthetic porcine galanin, and (3) porcine galanin inhibits glucose-stimulated insulin secretion from human islets. Therefore, galanin could be an important local regulator of insulin secretion in man.

Animals↗
PubMed1991

Galanin-immunoreactive nerves in the mouse and rat pancreas.

Galanin-containing nerve fibers have previously been observed in the human, dog, and pig pancreas. Whether the mouse and rat pancreas also contain galanin nerve fibers has been a matter of debate. Therefore, we examined the distribution of galanin in the mouse and the rat pancreas. Further, the possible localization of galanin to adrenergic nerves was studied using sequential immunostaining for galanin and tyrosine hydroxylase (TH). In the mouse pancreas, numerous galanin-immunoreactive (GIR) nerve fibers occurred around blood vessels. They were less numerous in the exocrine parenchyma and in association with the islets. In contrast, in the rat pancreas, only a few GIR nerves were found. They were located around blood vessels and scattered in the exocrine parenchyma. Occasionally, GIR nerves were also observed in the islets. There was a dense distribution of TH-immunoreactive fibers in both the mouse and the rat pancreas. Sequential immunostaining revealed co-localization of galanin and TH immunoreactivity in nerve fibers in both the mouse and the rat pancreas. Following chemical sympathectomy using 6-hydroxydopamine (6-OHDA), not all GIR nerves disappeared. In the mouse pancreas a remaining population of galanin nerves was found around blood vessels, and occasionally in the islets. In the rat pancreas, a few GIR nerves were seen also after chemical sympathectomy. We conclude that intrapancreatic GIR nerves also occur in the mouse and the rat. These findings suggest that many of the GIR nerves are adrenergic but that non-adrenergic, possibly intrinsic or sensory GIR nerves exist as well in both the mouse and the rat pancreas.

Adrenergic Fibers↗
PubMed1991

Neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP), but not galanin, are autonomic cotransmitters in the porcine pancreas.

The neuropeptide galanin has been identified as a potential sympathetic cotransmitter in the canine pancreas. Immunoreactive galanin, also present in nerve fibers of the pig pancreas, was therefore measured in the effluent from isolated perfused pig pancreas with preserved sympathetic (splanchnic) or parasympathetic (vagal) innervation with radioimmunoassays directed against both the N-terminus and the C-terminus of galanin. Electrical vagus stimulation increased the pancreatic exocrine secretion, the secretion of insulin and glucagon, and the release of VIP, but did not influence galanin release. Splanchnic nerve stimulation increased perfusion pressure and glucagon secretion, inhibited insulin secretion, and increased the release of NPY, but galanin release was not affected. We conclude that the pancreatic galanin nerve fibers belong neither to the sympathetic nor to the parasympathetic divisions of the efferent nerve supply to the pig pancreas.

Animals↗
PubMed1991

Contribution of galanin to stress-induced impairment of insulin secretion in swimming mice.

This study examines the potential role of the neuropeptide, galanin, in stress-induced inhibition of insulin secretion in swimming mice. Firstly, the pancreatic and adrenal content of galanin-like immunoreactivity was determined in mice after swimming stress. It was found that pancreatic content was significantly lower in stressed mice than in resting controls, both after 2 (P less than 0.05) and 6 (P less than 0.025) minutes of swimming, suggesting partial release of pancreatic galanin during stress. In contrast, the adrenal content of galanin-like immunoreactivity did not change during the swimming stress. Gel filtration of tissue extracts indicated that (1) mouse pancreas contains two forms of galanin-like immunoreactivity; one co-eluting with synthetic porcine galanin (centered on Kav of 0.70) and another with a larger molecular weight (centered on Kav of 0.30), and (2) mouse adrenal contains a small void volume-peak and a larger peak of immunoreactivity, the latter co-eluting with synthetic galanin. Secondly, the effects of swimming stress on plasma glucose and insulin levels were compared in mice that received high titre rabbit anti-galanin serum with those in mice receiving normal rabbit serum. In normal rabbit serum-pretreated swimming mice, glucose-induced insulin levels were only 50% of resting controls (P less than 0.01). Immunoneutralization of galanin with specific antiserum abolished this swimming stress-induced inhibition of glucose-stimulated insulin levels. This was accompanied by a modestly enhanced rate of glucose disappearance. These findings suggest that pancreatic galanin is released during swimming stress in mice and that endogenous galanin makes a major contribution to stress-induced impairment of insulin secretion.

Adrenal Glands↗
PubMed1991

Role for autonomic nervous system to increase pancreatic glucagon secretion during marked insulin-induced hypoglycemia in dogs.

To determine the role of the autonomic nervous system (ANS) in mediating the glucagon response to marked insulin-induced hypoglycemia in dogs, we measured arterial and pancreatic venous glucagon responses to insulin-induced hypoglycemia during acute, terminal experiments in halothane-anesthetized dogs in which the ANS was intact (control; n = 9), pharmacologically blocked by the nicotinic ganglionic antagonist hexamethonium (n = 6), or surgically ablated by cervical vagotomy and cervical spinal cord section (n = 6). In control dogs, insulin injection caused plasma glucose to fall by 4.4 +/- 0.2 mM to a nadir of 1.7 +/- 0.2 mM. Arterial epinephrine (EPI) levels increased by 13,980 +/- 1860 pM (P less than 0.005), confirming marked activation of the ANS. Pancreatic output of glucagon increased from 0.53 +/- 0.12 to 2.04 +/- 0.38 ng/min during hypoglycemia (change [delta] +1.51 +/- 0.33 ng/min, P less than 0.005). This increased arterial plasma glucagon from 27 +/- 3 to 80 +/- 15 ng/L (delta +52 +/- 14 ng/L, P less than 0.025). Hexamethonium markedly reduced the ANS response to insulin injection (delta EPI +2130 +/- 600 pM, P less than 0.025 vs. control) despite a similar fall of plasma glucose (delta -4.1 +/- 0.2 mM) and a lower nadir (0.6 +/- 0.1 mM). Both the pancreatic glucagon response (delta glucagon output +0.45 +/- 0.2 ng/min) and the arterial immunoreactive glucagon response (delta +5 +/- 4 ng/L) were substantially reduced by hexamethonium (P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Galanin is co-localized with noradrenaline and neuropeptide Y in dog pancreas and celiac ganglion.

To visualize the localization and potential co-localization of noradrenaline and the putative pancreatic sympathetic neurotransmitters, galanin and neuropeptide Y (NPY), immunofluorescent staining for galanin, NPY and tyrosine hydroxylase (TH) was performed on sections of canine pancreas and celiac ganglion. In the pancreas, galanin-immuno-fluorescent nerve fibers were confirmed as densely and preferentially innervating the islets, whereas numerous NPY-positive nerve fibers were found in the exocrine parenchyma, the surrounding of the blood vessels and within the islets. Double-staining for the peptides and TH indicated that most galanin-positive nerve fibers were adrenergic, most NPY-positive nerve fibers were adrenergic, and many islet nerves contained both galanin and NPY, although some galanin-positive nerve fibers appeared to lack NPY. In the celiac ganglion, virtually all cell bodies were positive for both galanin and TH; a large subpopulation of these cells were also positive for NPY. Radioimmunoassay (RIA) of galanin in extracts of dog celiac ganglion revealed a very high content (256 +/- 33 pmol/g wet weight) of galanin-like immunoreactivity (GLIR), consistent with the dense staining observed. This GLIR behaved in a similar manner to synthetic porcine galanin in the RIA. In addition, the majority of the GLIR in ganglion extracts co-eluted with the synthetic peptide upon gel filtration, although a minor peak of a larger apparent molecular weight was also observed, observations consistent with the presence of a precursor peptide. These findings suggest that galanin is a sympathetic post-ganglionic neurotransmitter in the canine endocrine pancreas and that NPY might serve a similar function.

Animals↗
PubMed1990

Galanin of the homologous species inhibits insulin secretion in the rat and in the pig.

It is known that pig galanin inhibits insulin secretion in dogs, rats and mice. The present study examined whether species-specific, homologous, galanin inhibits insulin secretion. Thus, the effects of rat galanin were examined in the rat, and the effects of pig galanin were examined in the pig, both in vivo and in vitro. In conscious rats, synthetic rat galanin (2 nmol kg-1) abolished the glucose- (0.56 mmol kg-1) induced increase in plasma insulin levels. In vitro, rat galanin (10(-9) to 10(-6) mol l-1) inhibited glucose- (8.3 mmol l-1) stimulated insulin release from isolated rat islets. In anaesthetized pigs, 15 min infusion of synthetic pig galanin (207 pmol min-1) into the pancreatic artery decreased the insulin output with a subsequent recovery. In vitro, pig galanin (10(-6) mol l-1) inhibited glucose- (8.3 mmol l-1) stimulated insulin release from isolated pig islets. We conclude that homologous galanin inhibits insulin secretion in both the rat and the pig.

Animals↗
PubMed1990

Pancreatic and extrapancreatic galanin release during sympathetic neural activation.

To address the hypothesis that the neutropeptide, galanin, functions as a sympathetic neurotransmitter in the endocrine pancreas, we sought to determine if galanin is released from pancreatic sympathetic nerves during their direct electrical stimulation in halothane-anesthetized dogs. During bilateral thoracic splanchnic nerve stimulation (BTSNS), both peripheral arterial and pancreatic venous levels of galanin-like immunoreactivity (GLIR) increased (delta at 10 min = +92 +/- 31 and +88 +/- 25 fmol/ml, respectively). Systemic infusions of synthetic galanin demonstrated that 1) the increment of arterial GLIR observed during BTSNS was sufficient to modestly restrain basal insulin secretion and 2) only 25% of any given increment of arterial GLIR appears in the pancreatic vein, suggesting that the pancreas extracts galanin, as it does other neurotransmitters. By use of 75% for pancreatic extraction of circulating galanin, it was calculated that pancreatic galanin spillover (output) increased by 410 +/- 110 fmol/min during BTSNS. To reinforce the conclusion that pancreatic sympathetic nerves release galanin, GLIR spillover was next measured during direct local stimulation of the pancreatic sympathetic input produced by electrical stimulation of the mixed autonomic pancreatic nerves (MPNS) in the presence of the ganglionic blocker, hexamethonium. During this local pancreatic sympathetic nerve stimulation, arterial GLIR remained unchanged, but pancreatic venous GLIR increased by 123 +/- 34 fmol/ml. Thus pancreatic GLIR spillover increased by 420 +/- 110 fmol/min during MPNS in the presence of hexamethonium. We conclude that galanin is released from both pancreatic and extrapancreatic sources during sympathetic neural activation in dogs.

Animals↗