At low glucose arginine stimulates and sulfonylureas or K+ depolarization inhibit glucagon secretion by perifused mouse islets

2017 ◽  
Vol 12 (S 01) ◽  
pp. S1-S84
Author(s):  
EH Früh ◽  
I Rustenbeck
Keyword(s):  
Glucagon Secretion ◽  
Low Glucose ◽  
Mouse Islets

scholarly journals Reducing Glucokinase Activity Restores Endogenous Pulsatility and Enhances Insulin Secretion in Islets From db/db Mice

Endocrinology ◽  
2018 ◽  
Vol 159 (11) ◽  
pp. 3747-3760 ◽  
Author(s):  
Ishrat Jahan ◽  
Kathryn L Corbin ◽  
Avery M Bogart ◽  
Nicholas B Whitticar ◽  
Christopher D Waters ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Opposite Effect ◽  
Glucose Sensing ◽  
Β Cell ◽  
Left Shift ◽  
Low Glucose ◽  
Mouse Islets ◽  
Secretion Rates

Abstract An early sign of islet failure in type 2 diabetes (T2D) is the loss of normal patterns of pulsatile insulin release. Disruptions in pulsatility are associated with a left shift in glucose sensing that can cause excessive insulin release in low glucose (relative hyperinsulinemia, a hallmark of early T2D) and β-cell exhaustion, leading to inadequate insulin release during hyperglycemia. Our hypothesis was that reducing excessive glucokinase activity in diabetic islets would improve their function. Isolated mouse islets were exposed to glucose and varying concentrations of the glucokinase inhibitor d-mannoheptulose (MH) to examine changes in intracellular calcium ([Ca2+]i) and insulin secretion. Acutely exposing islets from control CD-1 mice to MH in high glucose (20 mM) dose dependently reduced the size of [Ca2+]i oscillations detected by fura-2 acetoxymethyl. Glucokinase activation in low glucose (3 mM) had the opposite effect. We then treated islets from male and female db/db mice (age, 4 to 8 weeks) and heterozygous controls overnight with 0 to 10 mM MH to determine that 1 mM MH produced optimal oscillations. We then used 1 mM MH overnight to measure [Ca2+]i and insulin simultaneously in db/db islets. MH restored oscillations and increased insulin secretion. Insulin secretion rates correlated with MH-induced increases in amplitude of [Ca2+]i oscillations (R2 = 0.57, P < 0.01, n = 10) but not with mean [Ca2+]i levels in islets (R2 = 0.05, not significant). Our findings show that correcting glucose sensing can restore proper pulsatility to diabetic islets and improved pulsatility correlates with enhanced insulin secretion.

Glucagonotropic and Glucagonostatic Effects of KATP Channel Closure and Potassium Depolarization

Endocrinology ◽  
2020 ◽  
Vol 162 (1) ◽  
Author(s):  
Eike Früh ◽  
Christin Elgert ◽  
Frank Eggert ◽  
Stephan Scherneck ◽  
Ingo Rustenbeck
Keyword(s):  
Insulin Secretion ◽  
Beta Cells ◽  
Katp Channel ◽  
Glucagon Secretion ◽  
Alpha Cells ◽  
High Potassium ◽  
Intrinsic Signal ◽  
Mouse Islets ◽  
Glucagon And Insulin

Abstract The role of depolarization in the inverse glucose-dependence of glucagon secretion was investigated by comparing the effects of KATP channel block and of high potassium. The secretion of glucagon and insulin by perifused mouse islets was simultaneously measured. Lowering glucose raised glucagon secretion before it decreased insulin secretion, suggesting an alpha cell–intrinsic signal recognition. Raising glucose affected glucagon and insulin secretion at the same time. However, depolarization by tolbutamide, gliclazide, or 15 mM KCl increased insulin secretion before the glucagon secretion receded. In contrast to the robust depolarizing effect of arginine and KCl (15 and 40 mM) on single alpha cells, tolbutamide was of variable efficacy. Only when applied before other depolarizing agents had tolbutamide a consistent depolarizing effect and regularly increased the cytosolic Ca2+ concentration. When tested on inside-out patches tolbutamide was as effective on alpha cells as on beta cells. In the presence of 1 µM clonidine, to separate insulinotropic from glucagonotropic effects, both 500 µM tolbutamide and 30 µM gliclazide increased glucagon secretion significantly, but transiently. The additional presence of 15 or 40 mM KCl in contrast led to a marked and lasting increase of the glucagon secretion. The glucagon secretion by SUR1 knockout islets was not increased by tolbutamide, whereas 40 mM KCl was of unchanged efficiency. In conclusion a strong and sustained depolarization is compatible with a marked and lasting glucagon secretion. KATP channel closure in alpha cells is less readily achieved than in beta cells, which may explain the moderate and transient glucagonotropic effect.

scholarly journals Glucose-mediated inhibition of calcium-activated potassium channels limits α-cell calcium influx and glucagon secretion

2019 ◽  
Vol 316 (4) ◽  
pp. E646-E659 ◽  
Author(s):  
Matthew T. Dickerson ◽  
Prasanna K. Dadi ◽  
Molly K. Altman ◽  
Kenneth R. Verlage ◽  
Ariel S. Thorson ◽  
...  
Keyword(s):  
Calcium Influx ◽  
Glucagon Secretion ◽  
Bk Channel ◽  
Prolonged Treatment ◽  
Channel Inhibition ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
Calcium Activated Potassium Channels ◽  
Low Glucose ◽  
Ik Channel

Pancreatic α-cells exhibit oscillations in cytosolic Ca2+ (Ca2+c), which control pulsatile glucagon (GCG) secretion. However, the mechanisms that modulate α-cell Ca2+c oscillations have not been elucidated. As β-cell Ca2+c oscillations are regulated in part by Ca2+-activated K+ (Kslow) currents, this work investigated the role of Kslow in α-cell Ca2+ handling and GCG secretion. α-Cells displayed Kslow currents that were dependent on Ca2+ influx through L- and P/Q-type voltage-dependent Ca2+ channels (VDCCs) as well as Ca2+ released from endoplasmic reticulum stores. α-Cell Kslow was decreased by small-conductance Ca2+-activated K+ (SK) channel inhibitors apamin and UCL 1684, large-conductance Ca2+-activated K+ (BK) channel inhibitor iberiotoxin (IbTx), and intermediate-conductance Ca2+-activated K+ (IK) channel inhibitor TRAM 34. Moreover, partial inhibition of α-cell Kslow with apamin depolarized membrane potential ( Vm) (3.8 ± 0.7 mV) and reduced action potential (AP) amplitude (10.4 ± 1.9 mV). Although apamin transiently increased Ca2+ influx into α-cells at low glucose (42.9 ± 10.6%), sustained SK (38.5 ± 10.4%) or BK channel inhibition (31.0 ± 11.7%) decreased α-cell Ca2+ influx. Total α-cell Ca2+c was similarly reduced (28.3 ± 11.1%) following prolonged treatment with high glucose, but it was not decreased further by SK or BK channel inhibition. Consistent with reduced α-cell Ca2+c following prolonged Kslow inhibition, apamin decreased GCG secretion from mouse (20.4 ± 4.2%) and human (27.7 ± 13.1%) islets at low glucose. These data demonstrate that Kslow activation provides a hyperpolarizing influence on α-cell Vm that sustains Ca2+ entry during hypoglycemic conditions, presumably by preventing voltage-dependent inactivation of P/Q-type VDCCs. Thus, when α-cell Ca2+c is elevated during secretagogue stimulation, Kslow activation helps to preserve GCG secretion.

Downstream regulatory element antagonistic modulator regulates islet prodynorphin expression

2006 ◽  
Vol 291 (3) ◽  
pp. E587-E595 ◽  
Author(s):  
David A. Jacobson ◽  
Julie Cho ◽  
Luis R. Landa ◽  
Natalia A. Tamarina ◽  
Michael W. Roe ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Regulatory Element ◽  
Glucagon Secretion ◽  
Dependent Manner ◽  
Β Cells ◽  
Dynorphin A ◽  
Calcium Dependent ◽  
Low Glucose ◽  
Stimulation Of

Calcium-binding proteins regulate transcription and secretion of pancreatic islet hormones. Here, we demonstrate neuroendocrine expression of the calcium-binding downstream regulatory element antagonistic modulator (DREAM) and its role in glucose-dependent regulation of prodynorphin (PDN) expression. DREAM is distributed throughout β- and α-cells in both the nucleus and cytoplasm. As DREAM regulates neuronal dynorphin expression, we determined whether this pathway is affected in DREAM−/− islets. Under low glucose conditions, with intracellular calcium concentrations of <100 nM, DREAM−/− islets had an 80% increase in PDN message compared with controls. Accordingly, DREAM interacts with the PDN promoter downstream regulatory element (DRE) under low calcium (<100 nM) conditions, inhibiting PDN transcription in β-cells. Furthermore, β-cells treated with high glucose (20 mM) show increased cytoplasmic calcium (∼200 nM), which eliminates DREAM's interaction with the DRE, causing increased PDN promoter activity. As PDN is cleaved into dynorphin peptides, which stimulate κ-opioid receptors expressed predominantly in α-cells of the islet, we determined the role of dynorphin A-(1–17) in glucagon secretion from the α-cell. Stimulation with dynorphin A-(1–17) caused α-cell calcium fluctuations and a significant increase in glucagon release. DREAM−/− islets also show elevated glucagon secretion in low glucose compared with controls. These results demonstrate that PDN transcription is regulated by DREAM in a calcium-dependent manner and suggest a role for dynorphin regulation of α-cell glucagon secretion. The data provide a molecular basis for opiate stimulation of glucagon secretion first observed over 25 years ago.

Cholinergic regulation of fuel-induced hormone secretion and respiration of SUR1−/− mouse islets

2006 ◽  
Vol 291 (3) ◽  
pp. E525-E535 ◽  
Author(s):  
Nicolai M. Doliba ◽  
Wei Qin ◽  
Marko Z. Vatamaniuk ◽  
Carol W. Buettger ◽  
Heather W. Collins ◽  
...  
Keyword(s):  
Insulin Release ◽  
High Glucose ◽  
Hormone Secretion ◽  
Glucagon Secretion ◽  
Insulin And Glucagon Secretion ◽  
Intracellular Ca ◽  
Mouse Islets ◽  
Endocrine Factors ◽  
Glucose Responsiveness

Neural and endocrine factors (i.e., Ach and GLP-1) restore defective glucose-stimulated insulin release in pancreatic islets lacking sulfonylurea type 1 receptors (SUR1−/−) (Doliba NM, Qin W, Vatamaniuk MZ, Li C, Zelent D, Najafi H, Buettger CW, Collins HW, Carr RD, Magnuson MA, and Matschinsky FM. Am J Physiol Endocrinol Metab 286: E834–E843, 2004). The goal of the present study was to assess fuel-induced respiration in SUR1−/− islets and to correlate it with changes in intracellular Ca2+, insulin, and glucagon secretion. By use of a method based on O2 quenching of phosphorescence, the O2 consumption rate (OCR) of isolated islets was measured online in a perifusion system. Basal insulin release (IR) was 7–10 times higher in SUR1−/− compared with control (CON) islets, but the OCR was comparable. The effect of high glucose (16.7 mM) on IR and OCR was markedly reduced in SUR1−/− islets compared with CON. Ach (0.5 μM) in the presence of 16.7 mM glucose caused a large burst of IR in CON and SUR1−/− islets with minor changes in OCR in both groups of islets. In SUR1−/− islets, high glucose failed to inhibit glucagon secretion during stimulation with amino acids or Ach. We conclude that 1) reduced glucose responsiveness of SUR1−/− islets may be in part due to impaired energetics, as evidenced by significant decrease in glucose-stimulated OCR; 2) elevated intracellular Ca2+ levels may contribute to altered insulin and glucagon secretion in SUR1−/− islets; and 3) The amplitudes of the changes in OCR during glucose and Ach stimulation do not correlate with IR in normal and SUR1−/− islets suggesting that the energy requirements for exocytosis are minor compared with other ATP-consuming reactions.

Effects of galanin on the release of insulin, glucagon and somatostatin from the isolated, perfused dog pancreas

1988 ◽  
Vol 119 (1) ◽  
pp. 91-98 ◽  
Author(s):  
K. Hermansen
Keyword(s):  
Hormone Secretion ◽  
Glucagon Secretion ◽  
Hormonal Control ◽  
Amino Acid Peptide ◽  
Glucose Levels ◽  
Somatostatin Secretion ◽  
Normal Glucose ◽  
Islet Hormone ◽  
Low Glucose ◽  
Dog Pancreas

Abstract. Galanin is a 29 amino acid peptide which has been found in intrapancreatic nerves. The effects of galanin, adrenergic and cholinergic blockade as well as somatostatin on the hormone release from the isolated perfused dog pancreas were studied. It was found that galanin dose-dependently inhibited insulin (P < 0.001) and somatostatin (P < 0.001) but not glucagon secretion at normal glucose levels. The lowest galanin concentration that caused a significant suppression of insulin and somatostatin secretion was 10−11and 10−10 mol/l, respectively. Similar effects were evident during stimulation with 2.5 mmol/l arginine. Galanin (10−9 mol/l) caused a more pronounced inhibition of insulin and somatostatin secretion at high (10 mmol/l) and normal (5 mmol/l) than at low glucose (1.3 mmol/l). In contrast, suppression of the glucagon secretion was only seen at low glucose (1.3 mmol/l). Perfusion of 10−6 mol/l of atropine, phentolamine and propranolol had no effect on the galanin-mediated (10−10 mol/l) inhibition of insulin and somatostatin secretion. Galanin (10−12–10−10 mol/l) and somatostatin (10−12 – 10−10 mol/l) were equipotent in inhibiting insulin secretion whereas only somatostatin exerted a suppression of the glucagon secretion at normal glucose. Thus, galanin exerts a differential effect on islet hormone secretion and may participate in the hormonal control of insulin, glucagon and somatostatin secretion.

scholarly journals γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion

2020 ◽  
Vol 295 (16) ◽  
pp. 5419-5426
Author(s):  
Qian Yu ◽  
Bao Khanh Lai ◽  
Parvin Ahooghalandari ◽  
Anders Helander ◽  
Erik Gylfe ◽  
...  
Keyword(s):  
Glucagon Secretion ◽  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Human Islets ◽  
Glucagon Release ◽  
Paracrine Factors ◽  
Glucose Inhibition ◽  
Mouse Islets ◽  
Blood Glucose Concentrations ◽  
Effect Of Glucose

Hypersecretion of glucagon from pancreatic α-cells strongly contributes to diabetic hyperglycemia. Moreover, failure of α-cells to increase glucagon secretion in response to falling blood glucose concentrations compromises the defense against hypoglycemia, a common complication in diabetes therapy. However, the mechanisms underlying glucose regulation of glucagon secretion are poorly understood and likely involve both α-cell–intrinsic and intraislet paracrine signaling. Among paracrine factors, glucose-stimulated release of the GABA metabolite γ-hydroxybutyric acid (GHB) from pancreatic β-cells might mediate glucose suppression of glucagon release via GHB receptors on α-cells. However, the direct effects of GHB on α-cell signaling and glucagon release have not been investigated. Here, we found that GHB (4–10 μm) lacked effects on the cytoplasmic concentrations of the secretion-regulating messengers Ca2+ and cAMP in mouse α-cells. Glucagon secretion from perifused mouse islets was also unaffected by GHB at both 1 and 7 mm glucose. The GHB receptor agonist 3-chloropropanoic acid and the antagonist NCS-382 had no effects on glucagon secretion and did not affect stimulation of secretion induced by a drop in glucose from 7 to 1 mm. Inhibition of endogenous GHB formation with the GABA transaminase inhibitor vigabatrin also failed to influence glucagon secretion at 1 mm glucose and did not prevent the suppressive effect of 7 mm glucose. In human islets, GHB tended to stimulate glucagon secretion at 1 mm glucose, an effect mimicked by 3-chloropropanoic acid. We conclude that GHB does not mediate the inhibitory effect of glucose on glucagon secretion.

scholarly journals Distinguishing Features of Leucine and α-Ketoisocaproate Sensing in Pancreatic β-Cells

Endocrinology ◽  
2003 ◽  
Vol 144 (5) ◽  
pp. 1949-1957 ◽  
Author(s):  
Zhiyong Gao ◽  
Robert A. Young ◽  
Guizhu Li ◽  
Habiba Najafi ◽  
Carol Buettger ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
Aminooxyacetic Acid ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Rat Islets ◽  
Cell Extracts ◽  
Glutamate Dehydrogenase Activity ◽  
Low Glucose ◽  
Mouse Islets ◽  
Stimulation Of

Culturing rat islets in high glucose (HG) increased 1-14C-α-ketoisocaproate (KIC) oxidation compared with culturing them in low glucose. Leucine caused insulin secretion (IS) in low glucose but not in HG rat islets, whereas KIC did so in both. Pretreatment with HG for 40 min abolished leucine stimulation of IS by mouse islets and prevented the cytosolic Ca2+ rise without inhibiting IS and Ca2+ increments caused by KIC. When islets were pretreated without glucose and glutamine, aminooxyacetic acid (AOA) markedly decreased KIC effects. When islets were pretreated without glucose and with glutamine, AOA potentiated leucine effects but attenuated KIC effects. AOA stimulated glutamine oxidation in the presence but not the absence of ±2-amino-2-norbornane-carboxylic acid, a nonmetabolized leucine analog. Pretreatment with HG and glutamine partially reversed AOA inhibition of KIC effects. Glucose increased intracellular ATP and GTP, whereas it decreased ADP and GDP in βHC9 cells. Glutamate dehydrogenase activity of βHC9 cell extracts was increased by leucine and attenuated by GTP, but it was potentiated by ADP. In conclusion, leucine and KIC stimulated β-cells via distinct mechanisms. Glutamate dehydrogenase is the sensor of leucine, whereas transamination plays an important role in KIC stimulation of pancreatic β-cells.

scholarly journals Regulation of Glucagon Secretion at Low Glucose Concentrations: Evidence for Adenosine Triphosphate-Sensitive Potassium Channel Involvement

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5514-5521 ◽  
Author(s):  
Alvaro Muñoz ◽  
Min Hu ◽  
Khalid Hussain ◽  
Joseph Bryan ◽  
Lydia Aguilar-Bryan ◽  
...  
Keyword(s):  
Inverse Correlation ◽  
Glucagon Secretion ◽  
Katp Channels ◽  
Hepatic Glycogen ◽  
Glucagon Release ◽  
Cell Secretion ◽  
Cellular Mechanisms ◽  
Low Glucose

Glucagon is a potent counterregulatory hormone that opposes the action of insulin in controlling glycemia. The cellular mechanisms by which pancreatic α-cell glucagon secretion occurs in response to hypoglycemia are poorly known. SUR1/KIR6.2-type ATP-sensitive K+ (KATP) channels have been implicated in the glucagon counterregulatory response at central and peripheral levels, but their role is not well understood. In this study, we examined hypoglycemia-induced glucagon secretion in vitro in isolated islets and in vivo using Sur1KO mice lacking neuroendocrine-type KATP channels and paired wild-type (WT) controls. Sur1KO mice fed ad libitum have normal glucagon levels and mobilize hepatic glycogen in response to exogenous glucagon but exhibit a blunted glucagon response to insulin-induced hypoglycemia. Glucagon release from Sur1KO and WT islets is increased at 2.8 mmol/liter glucose and suppressed by increasing glucose concentrations. WT islets increase glucagon secretion approximately 20-fold when challenged with 0.1 mmol/liter glucose vs. approximately 2.7-fold for Sur1KO islets. Glucagon release requires Ca2+ and is inhibited by nifedipine. Consistent with a regulatory interaction between KATP channels and intra-islet zinc-insulin, WT islets exhibit an inverse correlation between β-cell secretion and glucagon release. Glibenclamide stimulated insulin secretion and reduced glucagon release in WT islets but was without effect on secretion from Sur1KO islets. The results indicate that loss of α-cell KATP channels uncouples glucagon release from inhibition by β-cells and reveals a role for KATP channels in the regulation of glucagon release by low glucose.

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