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

Pagliara, Anthony S.; Stillings, Susan N; Haymond, Morey W.; Hover, Barbara; Matschinsky, Franz M.

doi:10.1172/jci107928

Cited by 96 publications

(46 citation statements)

References 26 publications

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“…1). We also found an absent A-cell response to glucose, in accordance with previous reports [17][18][19]. Thus there are similarities in the abnormalities of somatostatin and glucagon secretion in experimental diabetes which could both be due to insulin deficiency, as suggested previously for glucagon [20].…”

Section: Discussionsupporting

confidence: 92%

“…There are similarities here to the abnormal A-cell function found in experimental diabetes. Continuous IV insulin administration can reduce hyperglucagonaemia and restore abnormal glucagon responses to various stimuli in man [20] and animals [23,24] in vivo, while in vitro insulin administration has minor or no effect on basal and glucose stimulated glucagon secretion [17,19,25,26], as indeed we have found (Fig. 2).…”

Section: Discussionsupporting

confidence: 81%

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Streptozotocin diabetes: A glucoreceptor dysfunction affecting D cells as well as B and A cells

1979

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Summary. Somatostatin release from the isolated pancreas of 3 normal and 6 streptozotocin diabetic dogs has been measured in response to various stimuli to determine whether abnormalities in somatostatin release are present in the diabetic pancreas. Simultaneous measurement of glucagon secretion was also made. In the pancreas from normal dogs increases in perfusate glucose from 25 to 200mg/100ml induced a 2-3 fold increase in somatostatin release and a two thirds decrease in glucagon secretion. In contrast, in the diabetic pancreas glucose caused no change in the secretion of the two hormones. In the diabetic pancreas addition of insulin to the perfusate (25,000 ~U/ml) for periods from 10 to 75 minutes aimed at restoring normal extracellular insulin levels in the islets failed to restore either somatostatin or glucagon secretion to normal. In contradistinction to the lack of effect of glucose, the somatostatin and glucagon responses to arginine (5 mmol/1), isoproterenol (2 ng/ml) and calcium (5 mmol/1) were normal in the diabetic pancreas. The data suggests the presence of a selective glucoreceptor abnormality of the D as well as of B and A cells in the streptozotocin diabetic dog.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 81%

Streptozotocin diabetes: A glucoreceptor dysfunction affecting D cells as well as B and A cells

1979

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“…It is known that amino acids have stimulatory effects and that FFAs and ketones have inhibitory effects on glucagon secretion from the ␣-cell in the pancreas (22,41,55). As shown in Table 1, blood amino acid concentrations decreased, and plasma NEFA and ketone concentrations increased with the decrement in plasma glucose.…”

Section: Discussionmentioning

confidence: 95%

“…It is possible, therefore, that the decrease in insulin secretion from ␤-cells lowered the level of the insulin concentration to which ␣-cells were exposed and, in turn, caused an increase in glucagon release. The administration of anti-insulin serum to perfused rat pancreas markedly increased glucagon secretion and abolished the ability of an increase in the glucose concentration to decrease glucagon secretion (39)(40)(41). It has also been shown that the destruction of islet ␤-cells prevents the increment in glucagon secretion seen in response to low glucose media in vitro (42).…”

Section: Discussionmentioning

confidence: 99%

α- and β-Cell Responses to Small Changes in Plasma Glucose in the Conscious Dog

et al. 2001

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The responses of the pancreatic ␣-and ␤-cells to small changes in glucose were examined in overnight-fasted conscious dogs. Each study consisted of an equilibration (-140 to -40 min), a control (-40 to 0 min), and a test period (0 to 180 min), during which BAY R3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally, either alone to create mild hypoglycemia or with peripheral glucose infusion to maintain euglycemia or create mild hyperglycemia. Drug administration in the hypoglycemic group decreased net hepatic glucose output (NHGO) from 8.9 ± 1.7 (basal) to 6.0 ± 1.7 and 5.8 ± 1.0 µmol · kg -1 · min -1 by 30 and 90 min. As a result, the arterial plasma glucose level decreased from 5.8 ± 0.2 (basal) to 5.2 ± 0.3 and 4.4 ± 0.3 mmol/l by 30 and 90 min, respectively (P < 0.01). Arterial plasma insulin levels and the hepatic portalarterial difference in plasma insulin decreased (P < 0.01) from 78 ± 18 and 90 ± 24 to 24 ± 6 and 12 ± 12 pmol/l over the first 30 min of the test period and decreased to 18 ± 6 and 0 pmol/l by 90 min, respectively. The arterial glucagon levels and the hepatic portal-arterial difference in plasma glucagon increased from 43 ± 5 and 4 ± 2 to 51 ± 5 and 10 ± 5 ng/l by 30 min (P < 0.05) and to 79 ± 16 and 31 ± 15 ng/l by 90 min (P < 0.05), respectively. In euglycemic dogs, the arterial plasma glucose level remained at 5.9 ± 0.1 mmol/l, and the NHGO decreased from 10 ± 0.6 to -3.3 ± 0.6 µmol · kg -1 · min -1 (180 min). The insulin and glucagon levels and the hepatic portal-arterial differences remained constant. In hyperglycemic dogs, the arterial plasma glucose level increased from 5.9 ± 0.2 to 6.2 ± 0.2 mmol/l by 30 min, and the NHGO decreased from 10 ± 1.7 to 0 µmol · kg -1 · min -1 by 30 min. The arterial plasma insulin levels and the hepatic portal-arterial difference in plasma insulin increased from 60 ± 18 and 78 ± 24 to 126 ± 30 and 192 ± 42 pmol/l by 30 min, after which they averaged 138 ± 24 and 282 ± 30 pmol/l, respectively. The arterial plasma glucagon levels and the hepatic portal-arterial difference in plasma glucagon decreased slightly from 41 ± 7 and 4 ± 3 to 34 ± 7 and 3 ± 2 ng/l during the test period. These data show that the ␣-and ␤-cells of the pancreas respond as a coupled unit to very small decreases in the plasma glucose level. Diabetes 50:367-375, 2001 G lucagon secretion increases in response to a decrease in the plasma glucose concentration and decreases in response to a rise in the plasma glucose level. Furthermore, insulin has been postulated to exert a paracrine influence on glucagon secretion when its release is modified in response to changes in the plasma glucose concentration. To date, studies have not provided a complete understanding of the relationship between a decrement in the plasma glucose level and glucagon or insulin secretion, because the insulin level itself has been elevated to decrease the glucose level, and insulin per se can affect not only its own secretion (1), but also the release of other counterregulatory hormones, inclu...

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“…Measured islets, SUR1 ϩ/ϩ islets treated with glyburide, and SUR1 Ϫ/Ϫ islets treated with nimodipine given in terms relative to SUR1 ϩ/ϩ (means Ϯ S.E., n ϭ 4). glucagon release rates were about 2 orders of magnitude lower than insulin release rates, and it is doubtful that the apparent differences in glucagon release between conditions are physiologically meaningful in view of the relative rates of insulin and glucagon release that are observed in the perfused pancreas, perifused islets, or the intact organism (7,17,18). Perhaps insulin levels are excessive and result in marked pharmacological inhibition of alpha cells under all conditions.…”

Section: Figure 2 Increased Capacity For Glutaminolysis Of Sur1mentioning

confidence: 99%

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

Nissim

Chen

et al. 2008

Journal of Biological Chemistry

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Pancreatic beta cells are hyper-responsive to amino acids but have decreased glucose sensitivity after deletion of the sulfonylurea receptor 1 (SUR1) both in man and mouse. It was hypothesized that these defects are the consequence of impaired integration of amino acid, glucose, and energy metabolism in beta cells. We used gas chromatography-mass spectrometry methodology to study intermediary metabolism of SUR1 knock-out (SUR1 ؊/؊ ) and control mouse islets with D-[U-13 C]glucose as substrate and related the results to insulin secretion. The levels and isotope labeling of alanine, aspartate, glutamate, glutamine, and ␥-aminobutyric acid (GABA) served as indicators of intermediary metabolism. We found that the GABA shunt of SUR1 ؊/؊ islets is blocked by about 75% and showed that this defect is due to decreased glutamate decarboxylase synthesis, probably caused by elevated free intracellular calcium. Glutaminolysis stimulated by the leucine analogue D,L-␤-2-amino-2-norbornane-carboxylic acid was, however, enhanced in SUR1 ؊/؊ and glyburide-treated SUR1 ؉/؉ islets. Glucose oxidation and pyruvate cycling was increased in SUR1 ؊/؊ islets at low glucose but was the same as in controls at high glucose. Malic enzyme isoforms 1, 2, and 3, involved in pyruvate cycling, were all expressed in islets. High glucose lowered aspartate and stimulated glutamine synthesis similarly in controls and SUR1 ؊/؊ islets. The data suggest that the interruption of the GABA shunt and the lack of glucose regulation of pyruvate cycling may cause the glucose insensitivity of the SUR1 ؊/؊ islets but that enhanced basal pyruvate cycling, lowered GABA shunt flux, and enhanced glutaminolytic capacity may sensitize the beta cells to amino acid stimulation.The pancreatic beta cells function as the predominant sensors and regulators of glucose, amino acid, and fatty acid levels of the mammalian organism, including man, by adjusting the minute to minute rate of insulin secretion such that these fuels are maintained at physiologically optimal blood concentrations under all nutritional conditions including feeding and fasting. This process of fuel-sensing and stimulation of insulin secretion requires that the various stimuli are transported into the beta cells and are metabolized to generate coupling factors that trigger and sustain the secretion of the hormone from large stores of insulin granules (1-4). The diverse specific pathways that allow access to metabolism for glucose, amino acids, and fatty acids converge to a complex network of intermediary metabolism represented by the citric acid cycle, a considerable variety of metabolite and cofactor shuttles including the GABA 2 shunt, and the processes of electron transport and oxidative phosphorylation, to mention just a few outstanding features of the biochemical maze of the beta cell.In the present study we have used uniformly labeled D-[13 C]glucose and GC-MS methods to explore the role of intermediary metabolism of pancreatic islets isolated from normal and sulfonylurea receptor 1 (SUR1) knock-out...

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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.

Cited by 96 publications

References 26 publications

Streptozotocin diabetes: A glucoreceptor dysfunction affecting D cells as well as B and A cells

Streptozotocin diabetes: A glucoreceptor dysfunction affecting D cells as well as B and A cells

α- and β-Cell Responses to Small Changes in Plasma Glucose in the Conscious Dog

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

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