Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

Velasco, Manuel; Díaz‐García, Carlos Manlio; Larqué, Carlos; Hiriart, Marcia

doi:10.1124/mol.116.103861

Cited by 33 publications

(24 citation statements)

References 192 publications

(259 reference statements)

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“…Inhibition of the insulin secreting process by activation of the sympathetic nervous system has been reported [18,19]. Our findings are consistent with this notion.…”

Section: Page 5 Ofsupporting

confidence: 93%

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Sympathetic Voltage-Independent Regulation of Voltage- Gated Calcium Channels in Pancreatic β-Cells

Cruz¹,

Reyes-Vaca²,

Garduño³

et al. 2018

JED

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Voltage-gated calcium (Ca V ) channels are regulated by G proteins via voltage-dependent and independent pathways. Voltage-independent regulation of calcium channels is important for intracellular calcium concentration and insulin secretion. Voltage dependence of each pathway can be elucidated by a prepulse facilitation protocol. Using this experimental approach, we compared Ca V regulation by GTPγS and noradrenaline (NA) in rat pancreatic β-cells and rat superior cervical ganglion (SCG) neurons. The SCG neuron is a model in which the bases of Ca V channel regulation by G proteins have been established. Ca V channel regulation through activation of the sympathetic nervous system has been poorly studied in native insulin-secreting cells. We recorded Ca V channel currents by means of the patch-clamp technique in the whole-cell configuration. We found that application of both GTPγS (a nonspecific activator of G proteins) by cell dialysis and noradrenaline (NA)-exposure reduced Ca V current amplitude in pancreatic β-cells and in SCG neurons. However, the inhibition of Ca V channel currents in GTPγS-dialyzed SCG neurons was relieved by a strong depolarizing pulse. By contrast, in pancreatic β-cells, the inhibition was maintained after a strong depolarizing pulse. In SCG neurons, the Ca V channel inhibition by NA is predominantly voltage-dependent, whereas in pancreatic β-cells it is only 40%. Thus, it appears that Ca V channels in rat pancreatic β-cells are regulated mainly through a voltage-independent pathway. The signaling pathway for Ca V channel regulation by NA in pancreatic β-cells appears to differ from the classic signaling pathway described in SCG neurons. Therefore, voltage-independent regulation of Ca 2+ entry through Ca V channels is a critical step in understanding the pathophysiology of type 2 diabetes.

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“…Inhibition of the insulin secreting process by activation of the sympathetic nervous system has been reported [18,19]. Our findings are consistent with this notion.…”

Section: Page 5 Ofsupporting

confidence: 93%

“…This signaling pathway is voltage-dependent and requires the action of Gβγ subunits [9,10]. Similarly, α 2 -adrenergic receptor activation by NA reduces insulin release in rat pancreatic β-cells [18,19].…”

Section: Discussionmentioning

confidence: 99%

Sympathetic Voltage-Independent Regulation of Voltage- Gated Calcium Channels in Pancreatic β-Cells

Cruz¹,

Reyes-Vaca²,

Garduño³

et al. 2018

JED

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show abstract

“…As expected, TTX (0.1 µg/mL, 0.31 µM) reduced the activity of VGSC in β-cells; however, insulin secretion was impaired when the islets were applied with 6 and 20 mM glucose [27]. Velasco et al also confirmed that TTX (0.1 µg/mL, 0.31 µM) decreases the amplitude of voltage spikes in pancreatic β-cells cells and the I Na [28]. However, partial inhibition in VGSC will not suppress the action potential but will decrease its amplitude, prolong the duration, increase the excitation threshold, and delay the appearance of the next action potential [25].…”

Section: Discussionsupporting

confidence: 61%

Voltage-Gated Na+ Channels are Modulated by Glucose and Involved in Regulating Cellular Insulin Content of INS-1 Cells

Chen

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Islet beta cells (β-cells) are unique cells that play a critical role in glucose homeostasis by secreting insulin in response to increased glucose levels. Voltage-gated ion channels in β-cells, such as K + and Ca 2+ channels, contribute to insulin secretion. The response of voltage-gated Na + channels (VGSCs) in β-cells to the changes in glucose levels remains unknown. This work aims to determine the role of extracellular glucose on the regulation of VGSC. Methods: The effect of glucose on VGSC currents (I Na ) was investigated in insulinsecreting β-cell line (INS-1) cells of rats using whole-cell patch clamp techniques, and the effects of glucose on insulin content and cell viability were determined using Enzyme-Linked Immunosorbent Assay(ELISA)and Methylthiazolyldiphenyl-tetrazolium Bromide(MTT) assay methods respectively. Results: Our results show that extracellular glucose application can inhibit the peak of I Na in a concentration-dependent manner. Glucose concentration of 18 mM reduced the amplitude of I Na , suppressed the I Na of steady-state activation, shifted the steady-state inactivation curves of I Na to negative potentials, and prolonged the time course of I Na recovery from inactivation. Glucose also enhanced the activity-dependent attenuation of I Na and reduced the fraction of activated channels. Furthermore, 18 mM glucose or low concentration of tetrodotoxin (TTX, a VGSC-specific blocker) partially inhibited the activity of VGSC and also improved insulin synthesis. Conclusion: These results revealed that extracellular glucose application enhances the insulin synthesis in INS-1 cells and the mechanism through the partial inhibition on I Na channel is involved. Our results innovatively suggest that VGSC plays a vital role in modulating glucose homeostasis.

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“…32,35,63 Functional and structural defects in K ATP channels impair insulin secretion leading to the onset of diabetes. 64 Our present study demonstrated an increased KCNJ8 mRNA expression at the end of IHT in both healthy and prediabetic subjects and more pronounced effect at one month after IHT in prediabetic patients. Based on the observed similarity in KCNJ8 mRNA expression among healthy and prediabetes subjects under IHT, we postulate that KCNJ8 channels may be less vulnerable during the development of diabetes.…”

supporting

confidence: 65%

Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression

Serebrovskaya

Portnychenko

Drevytska

et al. 2017

Exp Biol Med (Maywood)

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The present study investigated the beneficial effects of intermittent hypoxia training (IHT) in humans under prediabetic conditions. We found that three-week moderate IHT induced higher HIF-1a mRNA expressions as well as its target genes, which were positively correlated with higher tolerance to acute hypoxia and better glucose homeostasis in both middle-aged healthy and prediabetic subjects. This small clinical trial has provided new data suggesting a potential utility of IHT for management of prediabetes patients. AbstractThe present study aimed at examining beneficial effects of intermittent hypoxia training (IHT) under prediabetic conditions. We investigate the effects of three-week IHT on blood glucose level, tolerance to acute hypoxia, and leukocyte mRNA expression of hypoxia inducible factor 1a (HIF-1a) and its target genes, i.e. insulin receptor, facilitated glucose transporter-solute carrier family-2, and potassium voltage-gated channel subfamily J. Seven healthy and 11 prediabetic men and women (44-70 years of age) were examined before, next day and one month after three-week IHT (3 sessions per week, each session consisting 4 cycles of 5-min 12% O 2 and 5-min room air breathing). We found that IHT afforded beneficial effects on glucose homeostasis in patients with prediabetes reducing fasting glucose and during standard oral glucose tolerance test. The most pronounced positive effects were observed at one month after IHT termination. IHT also significantly increased the tolerance to acute hypoxia (i.e. SaO 2 level at 20th min of breathing with 12% O 2 ) and improved functional parameters of respiratory and cardiovascular systems. IHT stimulated HIF-1a mRNA expression in blood leukocytes in healthy and prediabetic subjects, but in prediabetes patients the maximum increase was lagged. The greatest changes in mRNA expression of HIF-1a target genes occurred a month after IHT and coincided with the largest decrease in blood glucose levels. The higher expression of HIF-1a was positively associated with higher tolerance to hypoxia and better glucose homeostasis. In conclusion, our results suggest that IHT may be useful for preventing the development of type 2 diabetes.

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Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

Cited by 33 publications

References 192 publications

Sympathetic Voltage-Independent Regulation of Voltage- Gated Calcium Channels in Pancreatic β-Cells

Sympathetic Voltage-Independent Regulation of Voltage- Gated Calcium Channels in Pancreatic β-Cells

Voltage-Gated Na+ Channels are Modulated by Glucose and Involved in Regulating Cellular Insulin Content of INS-1 Cells

Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression

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