Glucagon in Spontaneously Diabetic KK Mice

Ohneda, Akira; Kobayashi, Takashi; Nihei, Jiro; Nishida, Kohei

doi:10.1055/s-2007-1019222

Cited by 6 publications

(6 citation statements)

References 12 publications

(16 reference statements)

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“…Hyperglucagonaemia has been noted in human type I and type II diabetes mellitus (Unger & Orci,198le) and in spontaneously diabetic rodents, including fatty (fa/fa) rats (Seino, Seino, Takemura, Tsuda, Kuzuya, Ishikawa, Shimazu & Imura, 1981), KK mice (Ohneda, Kobayashi, Nihei & Nishikawa, 1981), db/db mice (Herberg, Berger, Buchanan, Gries & Kern, 1976;Leiter, Coleman, Eisenstein & Strack, 1980), BB rats (Nakhooda, Like, Chappel, Murray & Marliss, 1976) and djungarian hamsters (Herberg, Buchanan, Herbertz, Kern & Kley, 1980). The present study demonstrates that basal plasma glucagon concentrations were inappropriately raised in Aston ob/ob mice, as reported for this mutation on other genetic backgrounds (Lavine et al 1975;Mahler et al 1976;Dubuc et al 1977;Dunbar & Walsh, 1980).…”

Section: Discussionmentioning

confidence: 99%

Regulation of plasma immunoreactive glucagon in obese hyperglycaemic (ob/ob) mice

Flatt¹,

Bailey²,

Buchanan³

1982

Journal of Endocrinology

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This study examines the role of glucagon in the pathogenesis of the obese hyperglycaemic (ob/ob) syndrome in mice. Plasma C-terminal immunoreactive glucagon concentrations were measured in fed and fasted ob/ob mice at different ages between 5-40 weeks, and in 20-week-old mice after the administration of established stimulators and inhibitors of glucagon secretion. Plasma glucagon concentrations were inappropriately raised irrespective of age, nutritional status and the accompanying prominent changes in plasma glucose and insulin concentrations. Glucose suppressed plasma glucagon in the fed but not the fasted state, suggesting a dependence on the marked hyperinsulinaemia associated with feeding. Administration of 0.25 units insulin/kg to fasted mice failed to affect plasma glucagon and glucose concentrations. Increasing the dose to 100 units/kg restored the normal suppressive actions of insulin. Fasted mice showed an exaggerated glucagon response to arginine but not to the parasympathomimetic agent pilocarpine. Fed mice displayed normal plasma glucagon responses to the sympathomimetic agents noradrenaline and adrenaline. Administration of insulin antiserum or 2-deoxy-D-glucose raised plasma glucagon concentrations of fed mice. Contrary to the lack of suppression by glucose in the fasted state, heparin-induced increase in free fatty acids reduced plasma glucagon concentrations. This study demonstrates inappropriate hyperglucagonaemia and defective A-cell function in ob/ob mice. The extent of the abnormality is exacerbated by fasting and appears to result from insensitivity of the A-cell to the normal suppressive action of insulin.

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Section: Discussionmentioning

confidence: 99%

Regulation of plasma immunoreactive glucagon in obese hyperglycaemic (ob/ob) mice

Flatt¹,

Bailey²,

Buchanan³

1982

Journal of Endocrinology

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“…Since there have been many difficulties in studying changing A-cell function of the pancreatic islets over a long period of time in human diabetes, spontaneously diabetic animals have been investigated. Most authors deal with glucagon secretion in animals which are characterized by obesity, hyperglycaemia and hyperinsulinaemia [2][3][4][5]. In contrast, a few studies report the presence ofglucagon in plasma and the pancreas of diabetic animals with ketosis [6][7][8][9].…”

mentioning

confidence: 99%

Insulin and glucagon in spontaneously diabetic non-obese mice

et al. 1984

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To investigate the role of glucagon in the development of diabetes mellitus, spontaneously diabetic non-obese mice were studied before (group 1) and after the onset of diabetes mellitus (group 2). In group 1, fasting blood glucose and insulin in plasma and pancreas did not differ significantly, while plasma glucagon was elevated (48.9 +/- 10.4 versus control 18.6 +/- 6.0 pmol/l). In group 2, the insulin content of plasma and the pancreas were markedly reduced, whereas plasma glucagon was elevated (180.9 +/- 59.1 pmol/l). When diabetic mice were treated with insulin for 4 weeks (group 3), plasma glucagon was markedly reduced compared with that of group 2 (30.3 +/- 9.0 pmol/l). In group 1, glucagon and glucagon-like immunoreactivity of the intestine were reduced. The glucagon content of the intestine was elevated in group 2. Group 3 elicited increased contents of gastric glucagon as well as intestinal glucagon-like immunoreactivity. We conclude that, in addition to insulin deficiency, hypersecretion of glucagon might contribute to the development and clinical course of diabetes mellitus in the non-obese diabetic mouse.

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“…Thus, ADORA1 can inhibit exocytosis of glucagon-containing granules in α-cells, and loss or inhibition of ADORA1 may lead to the unrestrained secretion of glucagon. This may explain why NOD mice, T1D patients, and Adora1-KO mice show diminished suppression of glucagon after a glucose challenge ( 3 – 6 , 12 , 13 ).…”

Section: Discussionmentioning

confidence: 99%

“…Glucagon stimulates gluconeogenesis and glycogenolysis and thus plays a critical role in blood glucose homeostasis. Elevated fasting plasma glucagon levels ( 1 ) and reduced suppression of glucagon secretion after hyperglycemia ( 2 , 3 ) occurs in NOD mice and in spontaneously diabetic KK mice. Similarly, early- and late-stage T1D patients exhibit diminished suppression of glucagon secretion after the administration or ingestion of glucose ( 4 – 6 ).…”

mentioning

confidence: 99%

“…Hypersecretion of glucagon is primarily attributed to a deficiency of insulin or somatostatin. However, islets can regulate glucagon over a glucose concentration range that is not associated with changes in insulin or somatostatin ( 7 ), and prediabetic NOD and KK mice show elevated fasting and nonfasting plasma glucagon levels without changes in plasma insulin or blood glucose ( 1 – 3 , 8 ). In addition, increased α-cell function has been demonstrated in diabetic NOD mice ( 9 ) and enlarged glucagon-containing granules in streptozotocin-treated mice ( 10 ), suggesting that an intrinsic α-cell defect may contribute to the early stages of disease pathophysiology.…”

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confidence: 99%

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Diminished Adenosine A1 Receptor Expression in Pancreatic α-Cells May Contribute to the Pathology of Type 1 Diabetes

et al. 2013

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Prediabetic NOD mice exhibit hyperglucagonemia, possibly due to an intrinsic α-cell defect. Here, we show that the expression of a potential glucagon inhibitor, the adenosine A1 receptor (Adora1), is gradually diminished in α-cells of NOD mice, autoantibody-positive (AA+) and overtly type 1 diabetic (T1D) patients during the progression of disease. We demonstrated that islet inflammation was associated with loss of Adora1 expression through the alternative splicing of Adora1. Expression of the spliced variant (Adora1-Var) was upregulated in the pancreas of 12-week-old NOD versus age-matched NOD.B10 (non–diabetes-susceptible) control mice and was detected in the pancreas of AA+ patients but not in control subjects or overtly diabetic patients, suggesting that inflammation drives the splicing of Adora1. We subsequently demonstrated that Adora1-Var expression was upregulated in the islets of NOD.B10 mice after exposure to inflammatory cytokines and in the pancreas of NOD.SCID mice after adoptive transfer of activated autologous splenocytes. Adora1-Var encodes a dominant-negative N-terminal truncated isoform of Adora1. The splicing of Adora1 and loss of Adora1 expression on α-cells may explain the hyperglucagonemia observed in prediabetic NOD mice and may contribute to the pathogenesis of human T1D and NOD disease.

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Glucagon in Spontaneously Diabetic KK Mice

Cited by 6 publications

References 12 publications

Regulation of plasma immunoreactive glucagon in obese hyperglycaemic (ob/ob) mice

Regulation of plasma immunoreactive glucagon in obese hyperglycaemic (ob/ob) mice

Insulin and glucagon in spontaneously diabetic non-obese mice

Diminished Adenosine A1 Receptor Expression in Pancreatic α-Cells May Contribute to the Pathology of Type 1 Diabetes

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