Adrenergic Modulation of Pancreatic Glucagon Secretion in Man

A B S T R A C T The hyperglucagonemia that occurs in vivo in animals made diabetic with alloxan or streptozotocin is not suppressed by high glucose but is suppressed by exogenous insulin. These observations together with other studies suggested that insulin-dependent glucose transport and metabolism by the a-cells serves as the primary mechanism controlling glucagon secretion. This hypothesis was tested in the present investigation. The possible interactions between glucose, insulin, and a mixture of 20 amino acids at physiological proportions were examined in the isolated-perfused pancreas of normal, alloxan diabetic, and streptozotocin diabetic rats. Release of insulin and glucagon were used as indicators of A-cell and a-cell function. According to rigid criteria the diabetic animals entering the study were severely diabetic. It was found that in vitro: (a) basal glucagon release (measured in the absence of an a-cell stimulus or inhibitor) was extremely low, even lower (i.e. 10%) than the basal rates seen in controls; (b) the a-cells of alloxanized-and streptozotocin-treated rats responded with a biphasic glucagon release to stimulation by an amino acid mixture; (c) this a-cell response was reduced after both streptozotocin and alloxan; (d) glucose at 5 mM was a potent inhibitor of amino acid-induced glucagon secretion in both types of experimental diabetes; (e) in alloxan diabetes a-cell stimulation by amino acids can be curbed by exogenous This work was presented in part at the meetings

Section: Table Vi)mentioning

confidence: 99%

Insulin and glucose as modulators of the amino acid-induced glucagon release in the isolated pancreas of alloxan and streptozotocin diabetic rats.

Pagliara¹,

Stillings²,

Haymond³

et al. 1975

“…For example, it has been proposed that the effects of a-adrenergic agonism on Acell secretion are (a) stimulatory in ducks (5), rats (6), and man (7, preliminary report); (b) inhibitory in man (8), a study not confirmed by others (9); or (c) not evident in dogs (10). It has also been suggested that ,8-adrenergic agonism either inhibits glucagon secretion in man (7) and ducks (5), or stimulates glucagon in man (8), rats (11), or dogs (10).…”

Section: Introductionmentioning

confidence: 99%

Adrenergic Modulation of Pancreatic A, B, and D Cells

Samols¹,

Weir²

1979

172

A B S T R A C T The effects ofadrenergic substances on pancreatic insular secretions were studied in a completely isolated canine pancreas with exclusion of the duodenum from the perfusion circuit. To ensure adequate blockade, blockers were infused before agonists. A dose range of 8-receptor blockade was tested, and putative a-adrenergic effects were confirmed by combined a-and 13-adrenergic receptor blockade.j3-Adrenergic agonism (2 ng/ml isoproterenol) induced a mean integrated increase of 79+20% in somatostatin secretion, whereas glucagon and insulin secretion were increased by 185+45 and 495±146%, respectively. The stimulations of D, A, and B cells were abolished by propranolol. a-Adrenergic agonism (10 ng/ml epinephrine) after ,f-adrenergic blockade) moderately decreased somatostatin (-37±7%) secretion, moderately increased glucagon (91±19%), and markedly decreased insulin (-85±3%) release. Similar effects on D-, A-, and B-cell secretion were induced with 2 ng/ml epinephrine or 10 ng/ml norepinephrine after,8-adrenergic blockade.The a-adrenergic effects on the D and A cell were abolished by either phentolamine or by phenoxybenzamine.This study showed that there are indeed a-adrenergic receptors on A cells and that the secretion of glucagon, a "stress" hormone, was stimulated either by a-or ,3-adrenergic receptor agonism. D-cell secretion, like that of the B cell, was inhibited by a-adrenergic agon-

“…Two lines of evidence suggest that the improvted metabolic state of the hypophysectomized, depancreatized dog might be mediated by a deficiency of glucagon secondary to a reduction in corticosteroids and(or) growth hormone (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). First, it has been reported that glucocorticoids increase both the A-cell response to aminogenic stimulation (5,6) and the sensitivity of the liver to glucagon (7,8), suggesting that the adrenocortical insufficiency secondary to pituitary ablation might reduce the secretion and(or) biologic effectiveness of glucagon.…”

Section: Introductionmentioning

confidence: 99%

“…First, it has been reported that glucocorticoids increase both the A-cell response to aminogenic stimulation (5,6) and the sensitivity of the liver to glucagon (7,8), suggesting that the adrenocortical insufficiency secondary to pituitary ablation might reduce the secretion and(or) biologic effectiveness of glucagon. Second, growth hormone itself may enhance glucagon secretion; growth hormone increases the hyperglycemic activity of the pancreatic venous effluent of cats and dogs (9,10), and the secretion of immunoreactive glucagon (11,12), and glucagon levels are reported to be high in acromegalics (13,14). It would not be surprising, therefore, if glucagon levels were reduced by hypophysectomy, and then further reduced by total pancreatectomy, which would leave the gastric fundus as the major site of glucagon secretion (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

The Role of Glucagon Deficiency in the Houssay Phenomenon of Dogs

Nakabayashi

Dobbs

Unger³

1978

A B S T R A C T Plasma glucose, immunoreactive glucagon (IRG), and insulin were measured in hypophysectomized dogs receiving cortisol and thyroid replacement therapy. 4 wk after hypophysectomy mean fasting plasma glucose levels had declined from 90+2 mg/100 ml to 64+2; fasting and arginine-stimulated insulin and IRG levels were, respectively, -50% lower and unchanged. 12 wk or more after hypophysectomy, despite lower plasma glucose levels, fasting and arginine-stimulated IRG levels were significantly below control dogs. Hypophysectomized and shamhypophysectomized dogs were subjected to total pancreatectomy. Postoperatively, in the sham-hypophysectomized, depancreatized dogs fasting glucose levels ranged from 300-500 mg/100 ml on 8-10 U/day of insulin; IRG levels averaged 215+29 pg/ml. The hypophysectomized, depancreatized dogs required 0-4 U/day and fasting glucose levels under 100 mg/100 ml were not uncommon, even without insulin; fasting IRG levels averaged 63+4 pg/ml (P < 0.001). During arginine infusion in sham-hypophysectomized, depancreatized dogs, IRG levels rose from 215+60 pg/ml to a peak of 404±+112 pg/ml; in hypophysectomized, depancreatized dogs, the base line IRG averaged 44+8 and the peak 110+25 pg/ml (P < 0.05). IRG levels in the venous effluent of the gastric fundus, the major source of nonpancreatic glucagon, reached a peak of 4,898±+-959 pg/ml in the sham-hypophysectomized, depancreatized group during arginine infusion and only 219+128 pg/ml in the hypophysectomized, depancreatized group. In three hypophysectomized, depancreatized dogs, a replacement infusion with glucagon for 10 h promptly increased hyperglycemia by 80-180 mg/100 ml and worsened glycosuria, evidence of a hepatic response to glucagon replacement. It is concluded that hypophysectomy somehow de-