STIM1/Orai1 Inhibition Reduces Store-Operated Ca2+Entry and Modulates a-Cell Glucagon Secretion

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 2174-P
Author(s):  
MOLLY K. ALTMAN ◽  
PRASANNA DADI ◽  
DAVID JACOBSON
Keyword(s):  
Glucagon Secretion ◽  
A Cell

scholarly journals Glucagon resistance and decreased susceptibility to diabetes in a model of chronic hyperglucagonemia

2020 ◽  
Author(s):  
Ada Admin ◽  
Nadejda Bozadjieva Kramer ◽  
Camila Lubaczeuski ◽  
Manuel Blandino-Rosano ◽  
Grant Barker ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Cell Mass ◽  
Glucagon Secretion ◽  
Glucagon Receptor ◽  
Glucose Levels ◽  
Conditional Deletion ◽  
Mtorc1 Signaling ◽  
Nutrient Signaling ◽  
A Cell

Elevation of glucagon levels and increase in a-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR Complex 1 (mTORC1) regulation that controls glucagon secretion and a-cell mass. The current studies investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in a-cells (aTSC2<sup>KO</sup>). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of a-cell proliferation, cell size and mass expansion. Hyperglucagonemia in aTSC2<sup>KO</sup> was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in aTSC2<sup>KO</sup> mice were characterized by reduced expression of the glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and genes involved in amino acid metabolism and urea production. Glucagon resistance in aTSC2<sup>KO</sup> mice was associated with improved glucose levels in Streptozotocin (STZ)-induced β-cell destruction and HFD-induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.

scholarly journals Glucagon resistance and decreased susceptibility to diabetes in a model of chronic hyperglucagonemia

2020 ◽  
Author(s):  
Nadejda Bozadjieva Kramer ◽  
Camila Lubaczeuski ◽  
Manuel Blandino-Rosano ◽  
Grant Barker ◽  
George K. Gittes ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Cell Mass ◽  
Glucagon Secretion ◽  
Glucagon Receptor ◽  
Glucose Levels ◽  
Conditional Deletion ◽  
Mtorc1 Signaling ◽  
Nutrient Signaling ◽  
A Cell

Elevation of glucagon levels and increase in a-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR Complex 1 (mTORC1) regulation that controls glucagon secretion and a-cell mass. The current studies investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in a-cells (aTSC2<sup>KO</sup>). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of a-cell proliferation, cell size and mass expansion. Hyperglucagonemia in aTSC2<sup>KO</sup> was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in aTSC2<sup>KO</sup> mice were characterized by reduced expression of the glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and genes involved in amino acid metabolism and urea production. Glucagon resistance in aTSC2<sup>KO</sup> mice was associated with improved glucose levels in Streptozotocin (STZ)-induced β-cell destruction and HFD-induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.

scholarly journals Glucagon resistance and decreased susceptibility to diabetes in a model of chronic hyperglucagonemia

2020 ◽  
Author(s):  
Nadejda Bozadjieva Kramer ◽  
Camila Lubaczeuski ◽  
Manuel Blandino-Rosano ◽  
Grant Barker ◽  
George K. Gittes ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Cell Mass ◽  
Glucagon Secretion ◽  
Glucagon Receptor ◽  
Glucose Levels ◽  
Conditional Deletion ◽  
Mtorc1 Signaling ◽  
Nutrient Signaling ◽  
A Cell

Elevation of glucagon levels and increase in a-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR Complex 1 (mTORC1) regulation that controls glucagon secretion and a-cell mass. The current studies investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in a-cells (aTSC2<sup>KO</sup>). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of a-cell proliferation, cell size and mass expansion. Hyperglucagonemia in aTSC2<sup>KO</sup> was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in aTSC2<sup>KO</sup> mice were characterized by reduced expression of the glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and genes involved in amino acid metabolism and urea production. Glucagon resistance in aTSC2<sup>KO</sup> mice was associated with improved glucose levels in Streptozotocin (STZ)-induced β-cell destruction and HFD-induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.

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

1982 ◽  
Vol 95 (2) ◽  
pp. 215-227 ◽  
Author(s):  
P. R. Flatt ◽  
C. J. Bailey ◽  
K. D. Buchanan
Keyword(s):  
Cell Function ◽  
Glucagon Secretion ◽  
Plasma Glucagon ◽  
Fasted State ◽  
A Cell ◽  
Old Mice ◽  
Noradrenaline And Adrenaline ◽  
Adrenaline Administration ◽  
Suppressive Action

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-l-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.

scholarly journals Deleterious mutation V369M in the mouse GCGR gene causes abnormal plasma amino acid levels indicative of a possible liver-α-cell axis

2021 ◽  
Author(s):  
Qiaofeng Liu ◽  
Guangyao Lin ◽  
Yan Chen ◽  
Wenbo Feng ◽  
Yingna Xu ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Glucagon Secretion ◽  
Plasma Amino Acid ◽  
Cell Hyperplasia ◽  
Cell Axis ◽  
Glucagon Receptor ◽  
A Cell ◽  
Amino Acid Levels

Glucagon plays an important role in glucose homeostasis and amino acid metabolism. It regulates plasma amino acid levels which in turn modulate glucagon secretion from the pancreatic a-cell, thereby establishing a liver-α-cell axis described recently. We reported previously that the knock-in mice bearing homozygous V369M substitution (equivalent to a naturally occurring mutation V368M in the human glucagon receptor, GCGR) led to hypoglycemia with improved glucose tolerance. They also exhibited hyperglucagonemia, pancreas enlargement and α-cell hyperplasia. Here, we investigated the effect of V369M/V368M mutation on glucagon-mediated amino acid metabolism. It was found that GcgrV369M+/+ mice displayed increased plasma amino acid levels in general, but significant accumulation of the ketogenic/glucogenic amino acids was observed in animals fed with a high fat diet, resulting in deleterious metabolic consequence characteristic of α-cell proliferation and hyperglucagonemia.

Evidence that a 'memory' for glucose metabolism desensitizes A-cell responsiveness in the perfused pancreas of the rat

1985 ◽  
Vol 110 (1) ◽  
pp. 114-119
Author(s):  
V. Grill ◽  
M. Rundfeldt ◽  
S. Efendić
Keyword(s):  
Glucose Concentration ◽  
Glucagon Secretion ◽  
Energy Availability ◽  
High Glucose Concentration ◽  
Perfused Pancreas ◽  
Total Response ◽  
Cell Sensitivity ◽  
Elevated Glucose ◽  
Cell Energy ◽  
A Cell

Abstract. The effects of prior exposure to glucose or an inhibitor of glycolysis (iodoacetate) on A-cell sensitivity to glucose in the perfused pancreas of the rat was investigated. Inhibition of glucagon secretion by a high glucose concentration (22 mm) was attenuated and delayed when tested 20 min after a previous infusion with the same glucose concentration. Previously elevated glucose also delayed for 2 min a glucagon response to glucose omission whereas the total response was not significantly affected. During a 20 min perfusion with 1 mm iodoacetate, glucagon secretion increased and rates of secretion were further augmented after withdrawal of iodoacetate. When introduced 10 min after cessation of the iodoacetate pulse, 22 mm glucose failed to affect insulin or somatostatin release but, conversely, induced a profound decrease in glucagon secretion which was more marked than during control conditions. Conclusions: A-cell sensitivity to glucose is diminished and enhanced by prior fuel abundance and deprivation, respectively. Such effects could be due to persisting changes in A-cell energy availability rather than to pertubations in insulin or somatostatin secretion.

Evidence for metabolic regulation of pancreatic glucagon secretion by l-glutamine

1985 ◽  
Vol 108 (3) ◽  
pp. 386-391 ◽  
Author(s):  
Claes-Göran Östenson ◽  
Carin Grebing
Keyword(s):  
Metabolic Regulation ◽  
Glucose Oxidation ◽  
Glucagon Secretion ◽  
Porcine Insulin ◽  
Glucagon Release ◽  
Atp Content ◽  
Cell Secretion ◽  
Isolated Pancreatic Islets ◽  
Factors Affecting ◽  
A Cell

Abstract. To investigate effects by i-glutamine on pancreatic A-cell secretion and intermediary metabolism, isolated pancreatic islets from normal and streptozotocin treated guinea pigs (A-cell rich islets) were incubated in the presence of glucose (5.5 mm) ± l-glutamine (10 mm). Glutamine significantly enhanced glucagon release from 297 ± 54 to 528 ± 53 pg/μg DNA/h in normal islets and from 553 ±31 to 806 ± 50 pg/μg DNA/h in A-cell rich islets. All results were expressed on the basis of islet DNA concentration, being 66 ± 4 ng DNA per normal islet and 32 ± 2 ng DNA per A-cell rich islet. Simultaneously, glutamine suppressed glucose oxidation to 64 per cent in normal islets and to 47 per cent of basal oxidation in A-cell rich islets. Islet content of ATP was also reduced by glutamine to about 60 per cent in A-cell rich islets, but not significantly changed in normal islets. Glutamine oxidation, at 5.5 mm-glucose, was considerably higher in A-cell rich islets (911 ±65 pmol/μg DNA/h) than in normal islets (313 ± 52 pmol/μg DNA/h). Addition of porcine insulin (25 mU/ml) counteracted these effects by glutamine, i.e. suppressed glucagon release but increased glucose oxidation and ATP content of the A-cell rich islets. The present findings demonstrate that glutamine stimulates glucagon release and is readily metabolized by the A-cells, Furthermore, the regulation of glucagon secretion by glutamine appears to be reciprocally related to factors affecting glucose metabolism and ATP-levels in the A-cell.

340-LB: Optogenetic Control of a-Cell Electrical Activity and Glucagon Secretion in Intact Islets

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 340-LB
Author(s):  
CAROLINE A. MIRANDA ◽  
HAIQIANG DOU ◽  
JOHAN TOLö ◽  
ANDREI I. TARASOV ◽  
PATRIK RORSMAN
Keyword(s):  
Electrical Activity ◽  
Glucagon Secretion ◽  
A Cell ◽  
Optogenetic Control

Effect of Niacin on Mitochondria of Allium Cepa Root Cells

1967 ◽  
Vol 25 ◽  
pp. 78-79
Author(s):  
M. Arif Hayat
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Hydrogen Transfer ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nicotinamide Adenine ◽  
Root Tips ◽  
Root Cells ◽  
Transfer Processes ◽  
Standard Procedures ◽  
A Cell ◽  
Critical Interest

Although it is recognized that niacin (pyridine-3-carboxylic acid), incorporated as the amide in nicotinamide adenine dinucleotide (NAD) or in nicotinamide adenine dinucleotide phosphate (NADP), is a cofactor in hydrogen transfer in numerous enzyme reactions in all organisms studied, virtually no information is available on the effect of this vitamin on a cell at the submicroscopic level. Since mitochondria act as sites for many hydrogen transfer processes, the possible response of mitochondria to niacin treatment is, therefore, of critical interest.Onion bulbs were placed on vials filled with double distilled water in the dark at 25°C. After two days the bulbs and newly developed root system were transferred to vials containing 0.1% niacin. Root tips were collected at ¼, ½, 1, 2, 4, and 8 hr. intervals after treatment. The tissues were fixed in glutaraldehyde-OsO4 as well as in 2% KMnO4 according to standard procedures. In both cases, the tissues were dehydrated in an acetone series and embedded in Reynolds' lead citrate for 3-10 minutes.

Ultrastructure of melanocyte-keratinocyte interactions and pigment transfer in vitro

1978 ◽  
Vol 36 (2) ◽  
pp. 650-651
Author(s):  
Raul I. Garcia ◽  
Evelyn A. Flynn ◽  
George Szabo
Keyword(s):  
Direct Injection ◽  
Skin Pigmentation ◽  
Freeze Fracture ◽  
Pigment Granule ◽  
Time Lapse ◽  
Ultrastructural Level ◽  
Lanthanum Tracer ◽  
A Cell

Skin pigmentation in mammals involves the interaction of epidermal melanocytes and keratinocytes in the structural and functional unit known as the Epidermal Melanin Unit. Melanocytes(M) synthesize melanin within specialized membrane-bound organelles, the melanosome or pigment granule. These are subsequently transferred by way of M dendrites to keratinocytes(K) by a mechanism still to be clearly defined. Three different, though not necessarily mutually exclusive, mechanisms of melanosome transfer have been proposed: cytophagocytosis by K of M dendrite tips containing melanosomes, direct injection of melanosomes into the K cytoplasm through a cell-to-cell pore or communicating channel formed by localized fusion of M and K cell membranes, release of melanosomes into the extracellular space(ECS) by exocytosis followed by K uptake using conventional phagocytosis. Variability in methods of transfer has been noted both in vivo and in vitro and there is evidence in support of each transfer mechanism. We Have previously studied M-K interactions in vitro using time-lapse cinemicrography and in vivo at the ultrastructural level using lanthanum tracer and freeze-fracture.

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