scholarly journals Leptin-induced Trafficking of KATP Channels: A Mechanism to Regulate Pancreatic β-cell Excitability and Insulin Secretion

2019 ◽  
Vol 20 (11) ◽  
pp. 2660 ◽  
Author(s):  
Veronica Cochrane ◽  
Show-Ling Shyng
Keyword(s):  
Insulin Secretion ◽  
Katp Channel ◽  
Energy Homeostasis ◽  
Katp Channels ◽  
Channel Conductance ◽  
Β Cells ◽  
Β Cell ◽  
Peripheral Tissues ◽  
Membrane Hyperpolarization ◽  
Channel Trafficking

The adipocyte hormone leptin was first recognized for its actions in the central nervous system to regulate energy homeostasis but has since been shown to have direct actions on peripheral tissues. In pancreatic β-cells leptin suppresses insulin secretion by increasing KATP channel conductance, which causes membrane hyperpolarization and renders β-cells electrically silent. However, the mechanism by which leptin increases KATP channel conductance had remained unresolved for many years following the initial observation. Recent studies have revealed that leptin increases surface abundance of KATP channels by promoting channel trafficking to the β-cell membrane. Thus, KATP channel trafficking regulation has emerged as a mechanism by which leptin increases KATP channel conductance to regulate β-cell electrical activity and insulin secretion. This review will discuss the leptin signaling pathway that underlies KATP channel trafficking regulation in β-cells.

scholarly journals Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel

2016 ◽  
Vol 149 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Maria S. Remedi ◽  
Jonathan B. Friedman ◽  
Colin G. Nichols
Keyword(s):  
Insulin Secretion ◽  
Katp Channel ◽  
Vascular System ◽  
Wild Type Mouse ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Gain Of Function ◽  
Insulin Promoter

Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of KATP channels have been identified as the most common cause of human neonatal diabetes mellitus. The critical effect of these mutations is confirmed in mice expressing Kir6.2-GOF mutations in pancreatic β cells. A second KATP channel pore-forming subunit, Kir6.1, was originally cloned from the pancreas. Although the prominence of this subunit in the vascular system is well documented, a potential role in pancreatic β cells has not been considered. Here, we show that mice expressing Kir6.1-GOF mutations (Kir6.1[G343D] or Kir6.1[G343D,Q53R]) in pancreatic β cells (under rat-insulin-promoter [Rip] control) develop glucose intolerance and diabetes caused by reduced insulin secretion. We also generated transgenic mice in which a bacterial artificial chromosome (BAC) containing Kir6.1[G343D] is incorporated such that the transgene is only expressed in tissues where Kir6.1 is normally present. Strikingly, BAC-Kir6.1[G343D] mice also show impaired glucose tolerance, as well as reduced glucose- and sulfonylurea-dependent insulin secretion. However, the response to K+ depolarization is intact in Kir6.1-GOF mice compared with control islets. The presence of native Kir6.1 transcripts was demonstrated in both human and wild-type mouse islets using quantitative real-time PCR. Together, these results implicate the incorporation of native Kir6.1 subunits into pancreatic KATP channels and a contributory role for these subunits in the control of insulin secretion.

scholarly journals Chloride transporters and channels in β-cell physiology: revisiting a 40-year-old model

2019 ◽  
Vol 47 (6) ◽  
pp. 1843-1855 ◽  
Author(s):  
Mauricio Di Fulvio ◽  
Lydia Aguilar-Bryan
Keyword(s):  
Insulin Secretion ◽  
Electrical Activity ◽  
Katp Channels ◽  
Cell Physiology ◽  
Consensus Model ◽  
Β Cells ◽  
Β Cell ◽  
Complex Hypothesis ◽  
Cl Channels ◽  
Major Shortcoming

It is accepted that insulin-secreting β-cells release insulin in response to glucose even in the absence of functional ATP-sensitive K+ (KATP)-channels, which play a central role in a ‘consensus model’ of secretion broadly accepted and widely reproduced in textbooks. A major shortcoming of this consensus model is that it ignores any and all anionic mechanisms, known for more than 40 years, to modulate β-cell electrical activity and therefore insulin secretion. It is now clear that, in addition to metabolically regulated KATP-channels, β-cells are equipped with volume-regulated anion (Cl–) channels (VRAC) responsive to glucose concentrations in the range known to promote electrical activity and insulin secretion. In this context, the electrogenic efflux of Cl– through VRAC and other Cl– channels known to be expressed in β-cells results in depolarization because of an outwardly directed Cl– gradient established, maintained and regulated by the balance between Cl– transporters and channels. This review will provide a succinct historical perspective on the development of a complex hypothesis: Cl– transporters and channels modulate insulin secretion in response to nutrients.

scholarly journals Elevation in Intracellular Long-Chain Acyl-Coenzyme A Esters Lead to Reduced β-Cell Excitability via Activation of Adenosine 5′-Triphosphate-Sensitive Potassium Channels

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3679-3687 ◽  
Author(s):  
Nicola J. Webster ◽  
Gavin J. Searle ◽  
Patrick P. L. Lam ◽  
Ya-Chi Huang ◽  
Michael J. Riedel ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Katp Channel ◽  
Katp Channels ◽  
Channel Activity ◽  
Β Cells ◽  
Β Cell ◽  
Cell Excitability ◽  
Chain Acyl ◽  
Long Chain

Closure of pancreatic β-cell ATP-sensitive potassium (KATP) channels links glucose metabolism to electrical activity and insulin secretion. It is now known that saturated, but not polyunsaturated, long-chain acyl-coenyzme A esters (acyl-CoAs) can potently activate KATP channels when superfused directly across excised membrane patches, suggesting a plausible mechanism to account for reduced β-cell excitability and insulin secretion observed in obesity and type 2 diabetes. However, reduced β-cell excitability due to elevation of endogenous saturated acyl-CoAs has not been confirmed in intact pancreatic β-cells. To test this notion directly, endogenous acyl-CoA levels were elevated within primary mouse β-cells using virally delivered overexpression of long-chain acyl-CoA synthetase-1 (AdACSL-1), and the effects on β-cell KATP channel activity and cell excitability was assessed using the perforated whole-cell and cell-attached patch-clamp technique. Data indicated a significant increase in KATP channel activity in AdACSL-1-infected β-cells cultured in medium supplemented with palmitate/oleate but not with the polyunsaturated fat linoleate. No changes in the ATP/ADP ratio were observed in any of the groups. Furthermore, AdACSL-1-infected β-cells (with palmitate/oleate) showed a significant decrease in electrical responsiveness to glucose and tolbutamide and a hyperpolarized resting membrane potential at 5 mm glucose. These results suggest a direct link between intracellular fatty ester accumulation and KATP channel activation, which may contribute to β-cell dysfunction in type 2 diabetes.

scholarly journals Isoform-specific roles of prolyl hydroxylases in the regulation of pancreatic β-cell function

Endocrinology ◽  
2021 ◽  
Author(s):  
Monica Hoang ◽  
Emelien Jentz ◽  
Sarah M Janssen ◽  
Daniela Nasteska ◽  
Federica Cuozzo ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Katp Channel ◽  
Cell Mass ◽  
Isolated Islets ◽  
Second Phase ◽  
Β Cells ◽  
Β Cell ◽  
Prolyl Hydroxylases ◽  
Glucose Challenge

Abstract Pancreatic β-cells can secrete insulin via two pathways characterized as KATP channel-dependent and independent. The KATP channel-independent pathway is characterized by a rise in several potential metabolic signaling molecules, including the NADPH/NADP + ratio and α-ketoglutarate (αKG). Prolyl hydroxylases (PHDs), which belong to the αKG-dependent dioxygenase superfamily, are known to regulate the stability of hypoxia-inducible factor α (HIFα). In the current study, we assess the role of PHDs in vivo using the pharmacological inhibitor dimethyloxalylglycine (DMOG) and generated β-cell specific knockout (KO) mice for all three isoforms of PHD (β-PHD1 KO, β-PHD2 KO, and β-PHD3 KO mice). DMOG inhibited in vivo insulin secretion in response to glucose challenge and inhibited the 1 st phase of insulin secretion but enhanced the second-phase of insulin secretion in isolated islets. None of the β-PHD KO mice showed any significant in vivo defects associated with glucose tolerance and insulin resistance except for β-PHD2 KO mice which had significantly increased plasma insulin during a glucose challenge. Islets from both β-PHD1 KO and β-PHD3 KO had elevated β-cell apoptosis and reduced β-cell mass. Isolated islets from β-PHD1 KO and β-PHD3 KO had impaired glucose-stimulated insulin secretion and glucose-stimulated increases in the ATP/ADP and NADPH/NADP + ratio. All three PHD isoforms are expressed in β-cells, with PHD3 showing the most unique expression pattern. The lack of each PHD protein did not significantly impair in vivo glucose homeostasis. However, β-PHD1 KO and β-PHD3 KO mice had defective β-cell mass and islet insulin secretion, suggesting that these mice may be predisposed to developing diabetes.

Nicotinamide nucleotide transhydrogenase: a link between insulin secretion, glucose metabolism and oxidative stress

2006 ◽  
Vol 34 (5) ◽  
pp. 806-810 ◽  
Author(s):  
H. Freeman ◽  
K. Shimomura ◽  
R.D. Cox ◽  
F.M. Ashcroft
Keyword(s):  
Insulin Secretion ◽  
Katp Channel ◽  
Mitochondrial Protein ◽  
Katp Channels ◽  
Tolerance Test ◽  
Ros Production ◽  
Loss Of Function ◽  
Β Cells ◽  
Atp Production ◽  
Nicotinamide Nucleotide Transhydrogenase

This paper reviews recent studies on the role of Nnt (nicotinamide nucleotide transhydrogenase) in insulin secretion and detoxification of ROS (reactive oxygen species). Glucose-stimulated insulin release from pancreatic β-cells is mediated by increased metabolism. This elevates intracellular [ATP], thereby closing KATP channels (ATP-sensitive potassium channels) and producing membrane depolarization, activation of voltage-gated Ca2+ channels, Ca2+ influx and, consequently, insulin secretion. The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion, which results from a naturally occurring deletion in the Nnt gene. Transgenic expression of the wild-type Nnt gene in C57BL/6J mice rescues the phenotype. Knockdown of Nnt in the insulin-secreting cell line MIN6 with small interfering RNA dramatically reduced Ca2+ influx and insulin secretion. Similarly, mice carrying ENU (N-ethyl-N-nitrosourea)-induced loss-of-function mutations in Nnt were glucose intolerant and secreted less insulin during a glucose tolerance test. Islets isolated from these mice showed impaired insulin secretion in response to glucose, but not to the KATP channel blocker tolbutamide. This is explained by the fact that glucose failed to elevate ATP in Nnt mutant islets. Nnt is a nuclear-encoded mitochondrial protein involved in detoxification of ROS. β-Cells isolated from Nnt mutant mice showed increased ROS production on glucose stimulation. We hypothesize that Nnt mutations enhance glucose-dependent ROS production and thereby impair β-cell mitochondrial metabolism, possibly via activation of uncoupling proteins. This reduces ATP production and lowers KATP channel activity. Consequently, glucose-dependent electrical activity and insulin secretion are impaired.

Decreased KATP channel activity contributes to the low glucose threshold for insulin secretion of rat neonatal islets

Endocrinology ◽  
2021 ◽  
Author(s):  
Juxiang Yang ◽  
Batoul Hammoud ◽  
Changhong Li ◽  
Abigail Ridler ◽  
Daphne Yau ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Katp Channel ◽  
Cultured Cells ◽  
Katp Channels ◽  
Lower Threshold ◽  
Β Cells ◽  
Membrane Area ◽  
Rat Islets ◽  
Glucose Threshold

Abstract Transitional hypoglycemia in normal newborns occurs in the first 3 days of life and has clinical features consistent with hyperinsulinism. We found a lower threshold for glucose-stimulated insulin secretion from freshly isolated embryonic day (E)22 rat islets, which persisted into the first postnatal days. The threshold reached the adult level by postnatal day (P)14. Culturing P14 islets also decreased the glucose threshold. Freshly isolated P1 rat islets had a lower threshold for insulin secretion in response to BCH (2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid), a non-metabolizable leucine analog, and diminished insulin release in response to tolbutamide, an inhibitor of β-cell KATP channels. These findings suggested that decreased KATP channel function could be responsible for the lower glucose threshold for insulin secretion. Single-cell transcriptomic analysis did not reveal a lower expression of KATP subunit genes in E22 compared to P14 β-cells. The investigation of electrophysiological characteristics of dispersed β-cells showed that early neonatal and cultured cells had fewer functional KATP channels per unit membrane area. Our findings suggest that decreased surface density of KATP channels may contribute to the observed differences in glucose threshold for insulin release.

scholarly journals Glucose Controls Cytosolic Ca2+ and Insulin Secretion in Mouse Islets Lacking Adenosine Triphosphate-Sensitive K+ Channels Owing to a Knockout of the Pore-Forming Subunit Kir6.2

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 33-45 ◽  
Author(s):  
Magalie A. Ravier ◽  
Myriam Nenquin ◽  
Takashi Miki ◽  
Susumu Seino ◽  
Jean-Claude Henquin
Keyword(s):  
Insulin Secretion ◽  
High Glucose ◽  
Katp Channel ◽  
Katp Channels ◽  
Metabolic Effects ◽  
Β Cells ◽  
Subsequent Increase ◽  
K Channels ◽  
Channel Dependent ◽  
Amplifying Pathway

Glucose-induced insulin secretion is classically attributed to the cooperation of an ATP-sensitive potassium (KATP) channel-dependent Ca2+ influx with a subsequent increase of the cytosolic free Ca2+ concentration ([Ca2+]c) (triggering pathway) and a KATP channel-independent augmentation of secretion without further increase of [Ca2+]c (amplifying pathway). Here, we characterized the effects of glucose in β-cells lacking KATP channels because of a knockout (KO) of the pore-forming subunit Kir6.2. Islets from 1-yr and 2-wk-old Kir6.2KO mice were used freshly after isolation and after 18 h culture to measure glucose effects on [Ca2+]c and insulin secretion. Kir6.2KO islets were insensitive to diazoxide and tolbutamide. In fresh adult Kir6.2KO islets, basal [Ca2+]c and insulin secretion were marginally elevated, and high glucose increased [Ca2+]c only transiently, so that the secretory response was minimal (10% of controls) despite a functioning amplifying pathway (evidenced in 30 mm KCl). Culture in 10 mm glucose increased basal secretion and considerably improved glucose-induced insulin secretion (200% of controls), unexpectedly because of an increase in [Ca2+]c with modulation of [Ca2+]c oscillations. Similar results were obtained in 2-wk-old Kir6.2KO islets. Under selected conditions, high glucose evoked biphasic increases in [Ca2+]c and insulin secretion, by inducing KATP channel-independent depolarization and Ca2+ influx via voltage-dependent Ca2+ channels. In conclusion, Kir6.2KO β-cells down-regulate insulin secretion by maintaining low [Ca2+]c, but culture reveals a glucose-responsive phenotype mainly by increasing [Ca2+]c. The results support models implicating a KATP channel-independent amplifying pathway in glucose-induced insulin secretion, and show that KATP channels are not the only possible transducers of metabolic effects on the triggering Ca2+ signal. Glucose can stimulate insulin secretion from beta cells by increasing Ca2+ influx, cytosolic Ca2+ concentration, and Ca2+ action independently of ATP-sensitive K channels.

scholarly journals Decreased KATP channel activity contributes to the low glucose threshold for insulin secretion in the early postnatal period

2021 ◽  
Author(s):  
Juxiang Yang ◽  
Batoul Hammoud ◽  
Changhong Li ◽  
Abigail Ridler ◽  
Daphne Yau ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Single Cell ◽  
Insulin Release ◽  
Katp Channel ◽  
Katp Channels ◽  
Postnatal Period ◽  
Β Cells ◽  
Lower Glucose ◽  
Low Glucose ◽  
Glucose Threshold

Objective: Transitional hypoglycemia in normal newborns occurs in the first 3 days of life and has clinical features consistent with hyperinsulinism. We hypothesized that this transitional hyperinsulinism is due to the persistence of a fetal lower glucose threshold for insulin release from β-cells into the first postnatal days. Methods: We tested dynamic insulin secretion from freshly isolated rat islets between late gestation and adult age and from rat islets kept in culture for 1 or 2 days. We used single-cell transcriptomic and electrophysiology approaches to investigate the mechanism for insulin secretion at low glucose concentrations. Results: We found that a lower threshold for glucose-stimulated insulin secretion (GSIS) is present in embryonic day (E)22 islets and persists into the first postnatal days. The glucose threshold increases in the postnatal period and reaches the adult level by postnatal day (P)14. We also demonstrated that culturing P14 islets for 24-48 hrs can also decrease the glucose threshold. Insulin release in response to BCH, a non-metabolizable leucine analog activating glutamate dehydrogenase, had a similar lower threshold in P1 compared to P14 islets. This showed that the low threshold for GSIS is determined at a step downstream of the glycolytic pathway. P1 islets had lower insulin release in response to tolbutamide, an inhibitor of β-cell KATP channels, compared to P14 islets, suggesting that decreased KATP channel expression and/or function could be responsible for the lower glucose threshold for insulin secretion. Single-cell transcriptomic analysis did not reveal differences in transcripts between E22 and P14 β-cells supporting the lower glucose threshold. The investigation of electrophysiological characteristics of dispersed β cells showed that early neonatal cells and cultured islet cells had fewer functional KATP channels per unit membrane area. Conclusion: These findings suggest that decreased surface density of KATP channels may contribute to the observed differences in glucose threshold for insulin release.

scholarly journals Pancreatic Islet Neuropeptide Y Overexpression Has Minimal Effect on Islet Morphology and β-Cell Adaptation to High-Fat Diet

Endocrinology ◽  
2014 ◽  
Vol 155 (12) ◽  
pp. 4634-4640 ◽  
Author(s):  
Yui Machida ◽  
Christine Bruinsma ◽  
Daniel R. Hallinger ◽  
Stephen M. Roper ◽  
Eden Garcia ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Neuropeptide Y ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Cell Area ◽  
High Fat ◽  
Β Cell ◽  
Peripheral Tissues ◽  
Islet Morphology ◽  
Insulin Promoter

Neuropeptide Y (NPY) is highly expressed in the hypothalamus, where it regulates feeding and energy homeostasis. Interestingly, NPY and its receptors are also expressed in peripheral tissues with roles in metabolism, including pancreatic islets. In islets, NPY is known to suppress insulin secretion acutely. In addition, the role of NPY in β-cell de-differentiation has been postulated recently. Therefore, we studied transgenic mice expressing NPY under rat insulin promoter (TG) to determine the effects of chronic up-regulation of NPY on islet morphology and function. NPY levels were 25 times higher in islets of TG mice compared with wild-type (WT) littermates, whereas no differences in NPY expression were noted in the brains of TG and WT mice. Islet NPY secretion was 2.3-fold higher in TG compared with WT mice. There were no significant changes in body weight, glucose tolerance, or insulin sensitivity in TG mice fed regular rodent diet or high-fat diet (HF). Islet β-cell area was comparable between TG and WT mice both on regular rodent and HF diets, indicating that NPY overexpression is insufficient to alter β-cell maturation or the compensatory increase of β-cell area on HF. One abnormality noted was that the glucose-stimulated insulin secretion in islets isolated from TG was reduced compared with those from WT mice on HF diet. Overall, an increase in islet NPY level has little impact on islet function and is insufficient to affect glucose homeostasis in mice.

scholarly journals Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brenda Strutt ◽  
Sandra Szlapinski ◽  
Thineesha Gnaneswaran ◽  
Sarah Donegan ◽  
Jessica Hill ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucose Transporter ◽  
Cell Mass ◽  
Elevated Serum ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

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