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Biomedical subjects

J I Stagner

Publications and source records attributed to J I Stagner.

36 records · Page 2Linked to original sources
PubMed1990

Islet somatostatin--microvascular, paracrine, and pulsatile regulation.

The possible role of the D cell in the regulation of islet hormone secretion has been controversial for many years. It is known that the D cells characteristically reside in the islet mantle interspaced among A cells. We have shown by the anterograde and retrograde infusion of antibody directed against insulin, glucagon, or somatostatin into the isolated rat and dog pancreas that blood flow within the islet is from the B-cell core outward to the mantle. Despite the apparent randomness of the A and D cell in the mantle, our results indicate a further suborder of cellular perfusion in the mantle with the A cells perfused before the D cells. The D cells are last in line in terms of secretion. Thus the D cell is vascularly neutral and cannot directly effect A- or B-cell secretion through the intra-islet vasculature. Our results demonstrate that the B to A to D cellular order of perfusion is responsible for the regulation of islet hormone secretion, ie, insulin regulates the secretion of glucagon and glucagon (and probably insulin) regulate the secretion of somatostatin. Although each hormone is secreted as pulses, there does not appear to be a consistent phase relationship between insulin, glucagon, or somatostatin. The B to A to D cellular order of perfusion is responsible for net and integrated hormone secretion, but may not be the motive force of pulsatile secretion. Our studies have not documented a role for intra-islet mantle somatostatin. These results strongly suggest that the D cell is not a paracrine regulator of islet hormone secretion, but may be important in the regulation of exocrine function.

Animals↗
PubMed1989

The anterograde and retrograde infusion of glucagon antibodies suggests that A cells are vascularly perfused before D cells within the rat islet.

We have suggested that the order of cellular vascular perfusion within the islet is important in the regulation of islet hormone secretion. Anatomically, the A and D cells appear to be randomly dispersed throughout the mantle. Although islet capillary blood flow is known to be from the B-cell core to the A- and D-cell mantle, it has not yet been established whether the cells of the mantle may influence one another vascularly. Rat pancreata were perfused in vitro anterogradely and retrogradely with or without glucagon antibody in order to determine the order of cellular perfusion and interaction between the A and D cells in the islet mantle. Anterograde infusion of glucagon antibody did not affect insulin secretion, but rapidly decreased somatostatin secretion -46 +/- 8%, (p less than 0.005). Retrograde infusion of glucagon antibody decreased insulin secretion (-27 +/- 8%, p less than 0.005) but had no effect upon somatostatin secretion. This study not only confirms a core to mantle islet perfusion but also establishes that the A cell precedes the D cell in the terms of vascular perfusion. Thus within the islet, vascular borne insulin regulates the release of glucagon, which in turn, regulates the release of somatostatin. Somatostatin is vascularly neutral owing to its downstream position in the sequence (B to A to D) of cellular perfusion.

Animals↗
PubMed1988

Intra-islet regulation.

Intra-islet regulation of islet cells by one another is theoretically possible by two routes: (1) paracrine (i.e., interstitial, which is unproved); and (2) direct cellular perfusion through the islet microvasculature. The latter was tested in in vitro rat pancreases by anterograde and retrograde perfusion with or without anti-insulin or antisomatostatin antibody. Anterograde infusion of insulin antibody increased glucagon and somatostatin secretion (p less than 0.0005), whereas retrograde insulin antibody infusion was without effect. Anterograde infusion of somatostatin antibody had no effect upon insulin or glucagon secretion. In contrast, retrograde infusion of somatostatin antibody increased both insulin and glucagon secretion (p less than 0.0005). In comparison, anterograde infusion of antiglucagon antibody decreased somatostatin secretion without influencing insulin, whereas retrograde antiglucagon antibody infusion decreased insulin without changing somatostatin secretion. These results establish a "directed" functional microvascular circulation with a strict sequence of perfusion, first of B cells, then A cells, then D cells. The B cell microvascularly is the primary glucose sensor and its insulin plays a vital role in inhibiting glucagon secretion. The abnormalities in glucagon secretion in diabetes mellitus can now be explained by a deficiency in intra-islet microvascular insulin.

Animals↗
PubMed1988

The order of islet microvascular cellular perfusion is B----A----D in the perfused rat pancreas.

In order to determine whether microvascular blood flow is important in the regulation of intra-islet cellular interactions, rat pancreata were isolated and perfused in vitro, both anterogradely or retrogradely, with and without anti-insulin or anti-somatostatin gamma-globulin. Expressed as percent change, anterograde infusion of insulin antibody increased efflux concentrations of glucagon (110 +/- 20%, P less than 0.0005) and somatostatin (2,112 +/- 73%, P less than 0.0005) above their respective control. Retrograde infusion of insulin antibody did not affect efflux concentrations of glucagon (P less than 0.50) or somatostatin (P less than 0.50). The anterograde infusion of anti-somatostatin antibody had no effect upon insulin (P less than 0.50) or glucagon (P less than 0.50) efflux concentrations, whereas retrograde anti-somatostatin antibody infusion produced immediate increases in efflux concentrations of both insulin (115 +/- 33%, P less than 0.0005) and glucagon (77 +/- 8%, P less than 0.0005). These results strongly suggest that (a) the vascular compartment is important in the regulation of intra-islet cellular interactions and further suggest that (b) the order of islet cellular perfusion and interaction is from the B cell core outward to the mantle, and (c) the mantle is further subordered with the majority of D cells downstream or distal to the majority of A cells. Thus, in the vascular compartment, B cells inhibit A-cell secretion and A cells stimulate D-cell secretion.

Animals↗
PubMed1988

beta----alpha----delta pancreatic islet cellular perfusion in dogs.

Intraislet communication between alpha-, beta-, and delta-cells and their secretory products may theoretically occur via the paracrine (interstitial) and/or vascular routes. Recently, we have shown that there is a directed microvascular circulation in the rat islet with a cellular order of perfusion of beta----alpha----delta. The direction of microvascular perfusion of cells within the dog islet has been controversial. Anterograde (arterial) perfusion and retrograde (reversed or venous) perfusion of a segment of isolated dog pancreas with potent insulin antibodies yielded results similar to those found in the rat pancreas (anterograde, 158 +/- 44% increase in glucagon and 65 +/- 20% increase in somatostatin; retrograde, no change in glucagon or somatostatin). Anterograde infusion of glucagon antibody (no change in insulin, -33.5 +/- 3% decrease in somatostatin) or somatostatin antibody (no change in insulin or glucagon) also yielded the same results as in the rat pancreas. Anterograde infusion of 500 pg/ml glucagon caused a larger increase in insulin secretion (245 +/- 10%) than retrograde infusion (45 +/- 4%), whereas somatostatin was stimulated more retrogradely (339 +/- 17%) than anterogradely (121 +/- 9%). Anterograde infusion of somatostatin produced a larger decrease in insulin and glucagon than did retrograde perfusion (P less than .0001 for both comparisons). The retrograde infusion of 0.3 mU/ml insulin caused a decrease in glucagon but was without effect anterogradely. The results from the infusion of exogenous hormones suggest that the sensitivity of the alpha-, beta-, and delta-cells to insulin, glucagon, and somatostatin is determined by the beta----alpha----delta order of perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Alpha-adrenergic blockade improves glucose-potentiated insulin secretion in non-insulin-dependent diabetes mellitus.

The impairment of glucose-potentiated insulin secretion present in non-insulin-dependent diabetes mellitus (NIDDM) can be approximated in normal subjects by an epinephrine infusion. Therefore, we sought to determine the role of the endogenous sympathetic nervous system in glucose-potentiated insulin secretion in both NIDDM (n = 6) and normal (n = 6) subjects. Glucose-potentiated insulin secretion was calculated as the slope of the curve relating increasing ambient glucose levels to the acute insulin response to an intravenous pulse of 5 g of L-arginine. Glucose-potentiated insulin secretion was determined on separate days during alpha-, beta-, and combined alpha- plus beta-adrenergic blockade and compared with a saline control. In normal subjects, there was no effect of alpha-, beta-, or alpha- plus beta-blockade on the slope of glucose potentiation. In NIDDM, the initially decreased slope of glucose potentiation (0.25 +/- 0.06 microU X ml-1 X mg-1 X dl, mean +/- SE; P less than .01) was not affected by beta-blockade but increased during alpha-blockade (0.91 +/- 0.22 microU X ml-1 X mg-1 X dl; P less than .05). However, this improvement was abolished by combined alpha- plus beta-blockade (0.32 +/- 0.07 microU X ml-1 X mg-1 X dl). Plasma norepinephrine was increased above basal levels in both normal (+260 +/- 89 pg/ml) and NIDDM (+438 +/- 162 pg/ml) subjects during alpha-blockade (P less than .05 for both). This increase in plasma norepinephrine strongly suggests that there is an increase in synaptic cleft norepinephrine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1986

Retrograde perfusion as a model for testing the relative effects of glucose versus insulin on the A cell.

In order to determine whether the A cell may be directly suppressed by glucose in the absence of insulin, canine pancreata were perfused in vitro, both antegrade, through the arterial system and retrograde, through the venous system. Studies of the islet microvasculature have suggested that blood flows from the B cell core to the mantle; thus, the A cell may be tonically inhibited by intra-islet insulin. Retrograde perfusion may then be expected to prevent insulin from reaching the A cell, releasing it from inhibition. Retrograde perfusion with 88 mg/dl glucose markedly increased both insulin and glucagon secretion relative to antegrade levels. In a series of experiments, glucose concentrations were changed from 88 to 200 mg/dl. An antegrade glucose change resulted in increased insulin (134+/-21%; P less than 0.0025) and decreased glucagon (-26+/-9%, P less than 0.025) secretion. A retrograde glucose increase resulted in increased secretion of both insulin (91+/-15%; P less than 0.0005) and glucagon (23+/-9%; P less than 0.0125). To confirm that retrograde perfusion deprived the A cell of endogenous core derived, vascularly delivered insulin, possibly resulting in increased insulin sensitivity, 0.3 mU/ml exogenous porcine insulin was infused. Antegrade, 0.3 mU/ml insulin, had no effect on glucagon secretion (P less than 0.250), while retrograde infusion of 0.3 mU/ml insulin significantly inhibited glucagon secretion (-31 + 8%; P less than 0.0005). The results of our study support the concept that the direction of blood flow and of flow-dependent intra-islet hormone interactions are from the islet B cell core to the mantle. It was further concluded that the normal A cell may not be suppressed by glucose in the absence of insulin.

Animals↗
PubMed1986

Modulation of insulin secretion by pancreatic ganglionic nicotinic receptors.

Autonomic ganglia may be regulated, in part, by nicotinic receptors. To test whether basal insulin secretion may be modulated by an endogenous pancreatic ganglionic mechanism, the effects of ganglionic pre- and postsynaptic nicotinic receptor antagonism were studied in the in vitro canine pancreas. Combined infusion of atropine, phentolamine, and propranolol had no affect on insulin secretion (P less than .30). Presynaptic nicotinic receptor blockade by beta-bungarotoxin (beta-BuTX) in combination with atropine and phentolamine reduced mean insulin secretion (78 +/- 18 U/ml, P less than .0025) from preinfusion concentrations (287 +/- 43 U/ml). The decrease in insulin secretion resulting from BuTX, atropine, and phentolamine was prevented by the addition of either specific postsynaptic nicotinic receptor blockade by alpha-bungarotoxin (P less than .05) or propranolol (P less than .005). Because it is known that postsynaptic nicotinic receptor agonism may stimulate the intraganglionic release of norepinephrine, these results suggest that nicotinic receptors are present at the ganglionic level in the pancreas and modulate insulin secretion by a complex intraganglionic mechanism. The postulated ganglionic nicotinic receptor-mediated mechanism may operate by the interaction of a beta-adrenergic inhibitory component, which may be activated by intraganglionic norepinephrine, and a stimulatory nonmuscarinic nonadrenergic (possibly peptidergic) component, which may be activated in the absence of intraganglionic norepinephrine.

Animals↗
PubMed1985

Perturbation of insulin oscillations by nerve blockade in the in vitro canine pancreas.

The in vitro canine pancreas produces an oscillatory pattern of insulin secretion during a constant glucose concentration despite the lack of external nervous modulation or recirculating hormone feedback. The normal period of insulin fluctuations (7.4 +/- 0.34 min) is unaffected by combined adrenergic and cholinergic blockade by 5 microM atropine, 4 microM propranolol, and 4 microM phentolamine (8.0 +/- 0.31 min, P less than 0.20). To test the theory that the coordination of islet secretion may be controlled by an intrapancreatic nervous system (nonadrenergic, noncholinergic), nerve blockade was attempted by the infusion of tetrodotoxin (TTX) on a background of combined autonomic blockade. TTX infusion resulted in a change in the oscillatory pattern of insulin release by increasing net insulin release and shifting the period of oscillation to 4.5 +/- 0.29 min (P less than 0.0005) at both 88 and 200 mg/dl glucose. These results suggest that an intrinsic autonomously functioning pancreatic nervous system is responsible for the coordination of islet secretion and the production of periodic fluctuations of insulin secretion.

Animals↗
PubMed1985

Role of intrapancreatic ganglia in regulation of periodic insular secretions.

The regulatory system responsible for insulin oscillations from the in vitro pancreas is unknown. To test the hypothesis that intrapancreatic ganglia are the pacemaker or driver of the oscillations, combined nicotinic, muscarinic, and adrenergic antagonists were infused. Combined muscarinic, alpha- and beta-adrenergic, and presynaptic nicotinic receptor blockade (beta-bungarotoxin) was without effect on oscillations. The infusion of the postsynaptic nicotinic receptor antagonists, hexamethonium, alpha-bungarotoxin (ATX), or curarine, significantly altered the preinfusion oscillatory pattern of insulin release by reducing the period. Nicotine-stimulated insulin release was inhibited by ATX on a background of atropine, phentolamine, and beta-bungarotoxin. Propranolol decreased nicotine-stimulated insulin release, which was further reduced by ATX. These data support the theory that nicotinic receptors may be present pre- and postsynaptically at the ganglionic level and presynaptically on sympathetic nerve axons. We propose that ganglionic nicotinic receptors may be regulatory and that ganglia may serve as the pacemaker to regulate pancreatic hormone oscillations.

Animals↗
PubMed1982

Intraocular penetration of amikacin. Iris binding and bioavailability.

The penetration of amikacin sulfate into the anterior chamber of the human eye was determined by radioimmunoassay. Bactericidal concentrations of amikacin were not achieved by topical or intravenous administration. Subconjunctival injection did not produce consistent bactericidal concentration of amikacin in aqueous humor. Poor corneal penetration and subsequent tight binding to iris pigment are responsible for these observations. Tissue or pigment binding is adsorptive, nonspecific, and readily reversible. Amikacin released after being bound retains its bactericidal potency.

Administration, Topical↗
PubMed1981

Autonomic function and control of pancreatic somatostatin.

In the canine pancreas alpha and beta adrenergic receptors exist on D cells with alpha stimulation inhibiting and beta stimulation increasing somatostatin release. There are no dopaminergic receptors on D cells. Stimulation of muscarinic receptors causes mild inhibition of somatostatin secretion. Autonomic receptors on the D cell may be physiologically stimulated in vivo via local ganglionic and/or central autonomic drivers.

Animals↗
PubMed1980

Reinterpretation of the effect of haloperidol and ethanol on insulin secretion.

We were unable to confirm the report of haloperidol induced dose-dependent inhibition of insulin and glucagon release from the isolated canine pancreas. The possibility that the inhibition was caused by ethanol, previously used as the solvent for haloperidol, was tested. Infusion of ethanol at increasing concentrations (15.8 to 252 mmol/l) caused a progressive inhibition of insulin (-17 +/- 1 to -69 +/- 2%) and glucagon (-13 +/- 3 to -67 +/- 3%) secretion, using a perfusate containing 200 mg/dl glucose and 2.65 mmol/l calcium. Haloperidol (5 to 20 mumol/l) dissolved in ethanol (252 mmol/l) did not augment the inhibitory effects of ethanol. At a low calcium concentration (1.3 mmol/l) ethanol further inhibited insulin secretion (-83 +/- 2%) with no additional inhibition by 20 mumol/l haloperidol (-80 +/- 3%). At a high calcium concentration (8.8 mmol/l) the inhibitory effect of ethanol on insulin or glucagon secretions was diminished and variable. This strongly suggests that the inhibition of insulin and glucagon secretion previously attributed to haloperidol was caused by the ethanol solvent.

Animals↗
PubMed1980

Sustained oscillations of insulin, glucagon, and somatostatin from the isolated canine pancreas during exposure to a constant glucose concentration.

Canine pancreata were perfused in vitro to examine whether hormone cycles could be demonstrated without hepatic or central nervous influence. Insulin, glucagon, and somatostatin demonstrated regular sustained cyclic secretion from the in vitro canine pancreas. Oscillations were noted for over 200 min during the infusion of a constant glucose concentration. Insulin demonstrated a 10-min period with a range of 8-12 min/cycle. Somatostatin had a 10-min period with a range of 8-11 min. Glucagon had a period of 8.6 min with range of 6-10 min. These periods do not allow glucagon to be consistently 90 degrees out of phase with insulin and somatostatin. When glucose was increased from 88 to 200 mg/dl, insulin cycles persisted but on an elevated base line, demonstrating that cycles react to glucose changes but are not dependent upon them. Cycles were disrupted by infusions of dopamine, apomorphine, epinephrine, and acetylcholine, but were reestablished. Autonomic blockade by both single and combined infusions of atropine (cholinergic), propranolol, and dibenzyline (adrenergic) had no effect on cycles. These results suggest that, in vitro, there is an intrinsic rhythm of hormone secretion by the pancreas despite a constant glucose level. The production of in vitro cycles requires the presence of a driving oscillator or pacemaker within the pancreas and the coordination of islets by pace-maker-islet communication, presumably by a non-adrenergic neural system. In vitro oscillations may Indicate that the pancreas is the driver or Zeitgeber of in vivo glucose-insulin cycles.

Animals↗
PubMed1977

Regulation of lactogenic hormone binding in rat liver by steroid hormones.

We have measured the effects of testosterone propionate, medroxy-progesterone acetate and cortisol on the binding of ovine [125I]iodoprolactin to 100,000 X g particulate fractions from liver of normal and estrogen-treated female rats. In untreated animals 6.7 +/- 1.1% (SD) of the radioactivity added to 0.5 mg of membrane protein was specifically bound to the hormone receptor. Specific binding was significantly (P less than .05) decreased after 7 daily doses of testosterone (1.0 mg) to 2.8 +/- 1.4%, medroxyprogesterone (0.25 mg) to 2.7 +/- 0.2% and cortisol (5.0 mg) to 3.1 +/- 1.3%. The serum prolactin concentration, 4.2 +/- 3.4 ng/ml in normal animals, was not affected by the hormone treatment. Ethinyl estradiol, 10 mug/day for 7 days, increasing the binding of [125I]iodo-prolactin to 16.6 +/- 6.0% and increased serum prolactin to 50.6 +/- 11.5 ng/ml. Simultaneous administration of testosterone, medroxyprogesterone or cortisol with estradiol did not diminish the estradiol-induced increase in serum prolactin, but completely prevented the increase in prolactin binding. Testosterone or cortisol given to animals pretreated with estradiol suppressed prolactin binding from 16.4 +/- 4.2% to less than 2.5% after 48-72 h. Parellel results were obtained with 125I labeled human growth hormone whereas 125I labeled-insulin binding was not affected by these treatments. Scatchard analysis showed that the decrease in lactogenic hormone binding was due to a reduced concentration of receptors with no significant change in affinity. Since serum levels of prolactin were not changed, we conclude that treatment with testosterone, medroxyprogesterone, and cortisol decreased lactogenic hormone binding by a direct action on the liver.

Animals↗