The effect of experimental insulin deficiency on glucagon secretion

Müller, W.; Faloona, Gerald R.; Unger, Roger H

doi:10.1172/jci106691

Cited by 238 publications

(112 citation statements)

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“…This has been attributed mainly to the Iaek of insulin. The thesis was put forward that the alpha cell is an insulin requiring cell [17]. Samols, Tyler and Marks [21] even suggested a decreased suppressive effect of insulin upon glueagon secretion as the cause of hyperglucagonemia in diabetes mellitus.…”

Section: Discussionmentioning

confidence: 99%

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Hyperglucagonemia of the isolated perfused pancreas of diabetic mice (db/db)

et al. 1973

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Summary. Diabetes mellitus is held to be accompanied by inappropriately high levels of plasma glueagon relative to blood glucose concentrations. This has been interpreted as indicating lack of insulin. To establish ghcagon release in presence of high levels of endogenous insulin, the effects of both glucose and arginine were studied in the isolated perfused pancreas of genetically diabetic mice (db/db). Stimulation with glucose 2.75 mM or glucose plus arginine 8.25 mM exhibited a pronounced hyperglueagonemia. Following glucose 8.25 raM, however, there was no depression of glucagon secretion. Despite excessive high levels of endogenous insulin, there was a pattern of rather non-suppressible glueagon release. Lack of insulin per se, therefore, is unlikely to be the sole cause of hyperglucagonemia in this type of genetic animal diabetes mellitus.Key words : Diabetic mice, isolated perfused pancreas, high insulin levels, hyperglucagonemia.Patients with inherited diabetes mellitus are said to demonstrate increased pancreatic glueagon release relative to blood sugar levels [25,16]. Extremely high levels of glueagon have also been reported in alloxan treated dogs [17], streptozotoein diabetic rats [13] and in patients with severe ketoacidosis [1]. This has been interpreted as a state of decreased suppressibility of the alpha cell in the diabetics, probably on the base of lack of insulin. Infusion of insulin in animals with artificially achieved diabetes corrected instantly the state of hyperglucagonemia.Recent studies-in diabetic patients, however, exhibited only a slow and modest decline of glueagon after infusion of high insulin dosages. It was, therefore, concluded that mere lack of insulin may not adequately explain the alpha cell abnormality in diabetes mellitus [26]. Most of these patients, however, were receiving tolbutamide, and exhibited a markedly decreased insulin release following a carbohydrate meal compared to non diabetic controls.The present report deals with the alpha cell function in diabetic mice. The isolated perfused mouse pancreas was examined. Due to the hyperinsulinism in these obese animals the effect of high endogenous insulin release on pancreatic glueagon secretion was examined. Material and MethodsFor the present experiments diabetic mutant mice (C 57 BL/Ks-db/db ; Jackson Laboratory, Bar Harbour, Maine, USA), weighing 50--60 g, approximately 2--3 months old, and lean litter controls were used. Each group consisted of 5 animals.The mice were operated on after a 6 h fast. The pancreas was dissected under sodium pentobarbital anesthesia in a way similar to that already described for rats [23]. Arterial flow was achieved by cannulation * Supported by Deutsche Forschungsgemeinsehaft, Bad Godesberg. of the thoracic aorta. The perfusion medium consisted of an Umbreit buffer supplemented with 1% albumin (Fa. Behring Werke, Marburg) and equilibrated with 95% O2: 5% C02. The FFA content of the albumin buffer was < 50/~Lva]/1. A constant flow rate of 1 ml/ min was achieved by a pressure of about 40 m...

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Section: Discussionmentioning

confidence: 99%

“…Extremely high levels of glueagon have also been reported in alloxan treated dogs [17], streptozotoein diabetic rats [13] and in patients with severe ketoacidosis [1]. This has been interpreted as a state of decreased suppressibility of the alpha cell in the diabetics, probably on the base of lack of insulin.…”

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confidence: 99%

Hyperglucagonemia of the isolated perfused pancreas of diabetic mice (db/db)

et al. 1973

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“…It has further been shown that insulin therapy of alloxan diabetic dogs rapidly corrects the hyperglucagonemia (5). From these observations it has been concluded that the hyperglycemic suppression of glucagon release results from enhanced glucose transport and metabolism within the a-cell, and that the glucose metabolism of these cells may be an insulin-requiring process (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

“…Suppression of pancreatic glucagon secretion by hyperglycemia is a characteristic feature of normal a-cell function (1)(2)(3). Recent studies have suggested that in both genetic diabetes in man (2,4) and in alloxan diabetes in animals, the a-cell loses this susceptibility to inhibition by glucose (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

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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

J. Clin. Invest.

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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

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Hormone-Substrate Interrelationships Following Trauma

Meguid¹

1974

Arch Surg

106

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The effect of experimental insulin deficiency on glucagon secretion

Cited by 238 publications

References 16 publications

Hyperglucagonemia of the isolated perfused pancreas of diabetic mice (db/db)

Hyperglucagonemia of the isolated perfused pancreas of diabetic mice (db/db)

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

Hormone-Substrate Interrelationships Following Trauma

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