Skip to main content
SpringerLink
Log in

Role of the voltage-gated proton channel Hv1 in insulin secretion, glucose homeostasis, and obesity

  • Review
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

Diabetes is characterized by an absolutely inadequate insulin secretion (type 1 diabetes mellitus) or a relative deficit in insulin secretion due to insulin resistance (type 2 diabetes mellitus), both of which result in elevated blood glucose. Understanding the molecular mechanisms underlying the pathophysiology of diabetes could lead to the development of new therapeutic approaches. The voltage-gated proton channel Hv1 is an ion channel with specific selectivity for protons, which is regulated by membrane potential and intracellular pH. Recently, our studies showed that Hv1 is expressed in β cells of the endocrine pancreas. Knockout of Hv1 reduces insulin secretion and results in hyperglycemia and glucose intolerance, but not insulin resistance. Furthermore, knockout of Hv1 leads to diet-induced obesity due to inflammation and hepatic steatosis. Increasing evidence suggests that Hv1 plays a pivotal role in glucose homeostasis and lipid metabolism. This review aims to summarize advances made so far in our understanding of the roles of Hv1 in the regulation of insulin secretion in β cells, glucose homeostasis, and obesity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. American Diabetes Association (2011) Diagnosis and classification of diabetes mellitus. Diabetes Care 34:S62-69

    Article  PubMed Central  CAS  Google Scholar 

  2. American Diabetes Association (2018) Classification and diagnosis of diabetes: standards of medical care in diabetes. Diabetes Care 41:S13–S27

    Article  Google Scholar 

  3. Armann B, Hanson MS, Hatch E, Steffen A, Fernandez LA (2007) Quantification of basal and stimulated ROS levels as predictors of islet potency and function. Am J Transplant 7:38–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Aspinwall CA, Brooks SA, Kennedy RT, Lakey JR (1997) Effects of intravesicular H+ and extracellular H+ and Zn2+ on insulin secretion in pancreatic beta cells. J Biol Chem 272:31308–31314

    Article  CAS  PubMed  Google Scholar 

  5. Barg S, Ma X, Eliasson L, Galvanovskis J, Göpel SO, Obermüller S, Platzer J, Renström E, Trus M, Atlas D, Striessnig J, Rorsman P (2001) Fast exocytosis with few Ca2+ channels in insulin-secreting mouse pancreatic B cells. Biophys J 81:3308–3323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Barg S, Huang P, Eliasson L, Nelson DJ, Obermüller S, Rorsman P, Thévenod F, Renström E (2001) Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification. J Cell Sci 114:2145–2154

    Article  CAS  PubMed  Google Scholar 

  7. Bernheim L, Krause RM, Baroffio A, Hamann M, Kaelin A, Bader CR (1993) A voltage-dependent proton current in cultured human skeletal muscle myotubes. J Physiol 470:313–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bindokas VP, Kuznetsov A, Sreenan S, Polonsky KS, Roe MW, Philipson LH (2003) Visualizing superoxide production in normal and diabetic rat islets of Langerhans. J Biol Chem 278:9796–9801

    Article  CAS  PubMed  Google Scholar 

  9. Brito CY, Melián C, Wgner AM (2016) Study of the pathogenesis and treatment of diabetes mellitus through animal models. Endocrinol Nutr 63:345–353

    Article  Google Scholar 

  10. Burhans MG, Hagman DK, Kuzma JN, Schmidt KA, Kratz M (2018) Contribution of adipose tissue inflammation to the development of type 2 diabetes mellitus. Compr Physiol 9:1–58

    PubMed  PubMed Central  Google Scholar 

  11. Capasso M (2014) Regulation of immune responses by proton channels. Immunology 143:131–137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chatzigeorgiou A, Halapas A, Kalafatakis K, Kamper E (2009) The use of animal models in the study of diabetes mellitus. In Vivo 23:245–258

    CAS  PubMed  Google Scholar 

  13. Chawla A, Nguyen KD, Goh YP (2011) Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 11:738–749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen D, Wang MW (2005) Development and application of rodent models for type 2 diabetes. Diabetes Obes Metab 7:307–317

    Article  PubMed  Google Scholar 

  15. Choi CHJ, Cohen P (2017) How does obesity lead to IR? eLife 6:e33298

    Article  PubMed  PubMed Central  Google Scholar 

  16. Civelek VN, Deeney JT, Kubik K, Schultz V, Tornheim K, Corkey BE (1996) Temporal sequence of metabolic and ionic events in glucose-stimulated clonal pancreatic beta-cells (HIT). Biochem J 315:1015–1019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Daniel S, Noda M, Straub SG, Sharp GW (1999) Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion. Diabetes 48:1686–1690

    Article  CAS  PubMed  Google Scholar 

  18. Decoursey TE (2003) Voltage-gated proton channels and other proton transfer pathways. Physiol Rev 83:475–579

    Article  CAS  PubMed  Google Scholar 

  19. DeFronzo RA (2010) Current issues in the treatment of type 2 diabetes. Overview of newer agents: where treatment is going. Am J Med 123:S38–S48

    Article  CAS  PubMed  Google Scholar 

  20. Demaurex N, Furuya W, D’Souza S, Bonifacino JS, Grinstein S (1998) Mechanism of acidification of the trans-Golginetwork (TGN). In situ measurements of pH using retrieval of TGN38 and furin from the cell surface. J Biol Chem 273:2044–2051

    Article  CAS  PubMed  Google Scholar 

  21. Dula SB, Jecmenica M, Wu R, Jahanshahi P, Verrilli GM, Carter JD, Brayman KL, Nunemaker CS (2010) Evidence that low-grade systemic inflammation can induce islet dysfunction as measured by impaired calcium handling. Cell Calcium 48:133–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ebelt H, Peschke D, Bromme HJ, Morke W, Blume R, Peschke E (2000) Influence of melatonin on free radical-induced changes in rat pancreatic beta-cells in vitro. J Pineal Res 28:65–72

    Article  CAS  PubMed  Google Scholar 

  23. El Chemaly A, Okochi Y, Sasaki M, Arnaudeau S, Okamura Y, Demaurex N (2010) VSOP/Hv1 proton channels sustain calcium entry, neutrophil migration, and superoxide production by limiting cell depolarization and acidification. J Exp Med 207:129–139

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Fu Z, Gilbert ER, Liu D (2013) Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes. Curr Diabetes Rev 9:25–53

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gembal M, Gilon P, Henquin JC (1992) Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells. J Clin Investig 89:1288–1295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Han CY, Umemoto T, Omer M et al (2012) NADPH oxidase-derived reactive oxygen species increases expression of monocyte chemotactic factor genes in cultured adipocytes. J Biol Chem 287:10379–10393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Henderson LM, Chappell JB, Jones OT (1987) The superoxide-generating NADPH oxidase of human neutrophils is electrogenic and associated with an H+ channel. Biochem J 246:325–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Henderson LM, Chappell JB, Jones OT (1988) Superoxide generation by the electrogenic NADPH oxidase of human neutrophils is limited by the movement of a compensating charge. Biochem J 255:285–290

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Henderson LM, Chappell JB, Jones OT (1988) Internal pH changes associated with the activity of NADPH oxidase of human neutrophils. Further evidence for the presence of an H+ conducting channel. Biochem J 251:563–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Henquin JC (2000) Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49:1751–1760

    Article  CAS  PubMed  Google Scholar 

  31. Henquin JC (2011) The dual control of insulin secretion by glucose involves triggering and amplifying pathways in β-cells. Diabetes Res Clin Pract 93:S27–S31

    Article  CAS  PubMed  Google Scholar 

  32. Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked IR. Science 259:87–91

    Article  CAS  PubMed  Google Scholar 

  33. Hutton JC (1989) The insulin secretory granule. Diabetologia 32:271–281

    Article  CAS  PubMed  Google Scholar 

  34. Janjic D, Maechler P, Sekine N, Bartley C, Annen AS, Wolheim CB (1999) Free radical modulation of insulin release in INS-1 cells exposed to alloxan. Biochem Pharmacol 57:639–648

    Article  CAS  PubMed  Google Scholar 

  35. Kaneto H, Miyatsuka T, Shiraiwa T, Yamamoto K, Kato K, Fujitani Y, Matsuoka TA (2007) Crucial role of PDX-1 in pancreas development, beta-cell differentiation, and induction of surrogate beta-cells. Curr Med Chem 14:1745–1752

    Article  CAS  PubMed  Google Scholar 

  36. Maechler P, Jornot L, Wollheim CB (1999) Hydrogen peroxide alters mitochondrial activation and insulin secretion in pancreatic beta cells. J Biol Chem 274:27905–27913

    Article  CAS  PubMed  Google Scholar 

  37. Maksymets T, Karpyshyn N, Gutor T, Sklyarova H, Sklyarov E (2018) Influence of risk factors on insulin resistance in patients with overweight and obesity. Wiad Lek 71:558–560

    PubMed  Google Scholar 

  38. Martens GA, Cai Y, Hinke S, Stangé G, Van de Casteele M, Pipeleers D (2005) Glucose suppresses superoxide generation in metabolically responsive pancreatic beta cells. J Biol Chem 280:20389–20396

    Article  CAS  PubMed  Google Scholar 

  39. Morgan D, Oliveira-Emilio HR, Keane D, Hirata AE, Santos da Rocha M, Bordin S, Curi R, Newsholme P, Carpinelli AR (2007) Glucose, palmitate and pro-inflammatory cytokines modulate production and activity of a phagocyte-like NADPH oxidase in rat pancreatic islets and a clonal beta cell line. Diabetologia 50:359–369

    Article  CAS  PubMed  Google Scholar 

  40. Morgan D, Capasso M, Musset B et al (2009) Voltage-gated proton channels maintain pH in human neutrophils during phagocytosis. Proc Natl Acad Sci USA 106:18022–18027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Morgan D, Rebelato E, Abdulkader F, Graciano MF, Oliveira-Emilio HR, Hirata AE, Rocha MS, Bordin S, Curi R, Carpinelli AR (2009) Association of NAD(P)H oxidase with glucose-induced insulin secretion by pancreatic beta-cells. Endocrinology 150:2197–2201

    Article  CAS  PubMed  Google Scholar 

  42. Nesher R, Cerasi E (2002) Modeling phasic insulin release: immediate and time-dependent effects of glucose. Diabetes 51:S53–S59

    Article  CAS  PubMed  Google Scholar 

  43. Newsholme P, Cruzat V, Arfuso F, Keane K (2014) Nutrient regulation of insulin secretion and action. J Endocrinol 221:R105-120

    Article  CAS  PubMed  Google Scholar 

  44. Orci L, Ravazzola M, Amherdt M, Madsen O, Perrelet A, Vassalli JD, Anderson RG (1986) Conversion of proinsulin to insulin occurs coordinately with acidification of maturing secretory vesicles. J Cell Biol 103:2273–2281

    Article  CAS  PubMed  Google Scholar 

  45. Pang H, Wang X, Zhao S, Xi W, Lv J, Qin J, Zhao Q, Che Y, Chen L, Li SJ (2020) Loss of voltage-gated proton channel Hv1 decreases insulin secretion and leads to hyperglycemia and glucose intolerance in mice. J Biol Chem 295:3601–3613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pang H, Li J, Du H, Gao Y, Lv J, Liu Y, Li SJ (2020) Loss of voltage-gated proton channel Hv1 leads to diet-induced obesity in mice. BMJ Open Diabetes Res Care 8:e000951

    Article  PubMed  PubMed Central  Google Scholar 

  47. Paroutis P, Touret N, Grinstein S (2004) The pH of the secretory pathway: measurement, determinants, and regulation. Physiology 19:207–215

    Article  CAS  PubMed  Google Scholar 

  48. Perry RJ, Samuel VT, Petersen KF, Shulman GI (2014) The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510:84–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Qureshi FM, Dejene EA, Corbin KL, Nunemaker CS (2015) Stress-induced dissociations between intracellular calcium signaling and insulin secretion in pancreatic islets. Cell Calcium 57:366–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ramalingam L, Oh E, Yoder SM, Brozinick JT, Kalwat MA, Groffen AJ, Verhage M, Thurmond DC (2012) Doc2b is a key effector of insulin secretion and skeletal muscle insulin sensitivity. Diabetes 61:2424–2432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ramsey IS, Moran MM, Chong JA, Clapham DE (2006) A voltage-gated proton-selective channel lacking the pore domain. Nature 440:1213–1216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ramsey IS, Ruchti E, Kaczmarek JS, Clapham DE (2009) Hv1 proton channels are required for high-level NADPH oxidase-dependent superoxide production during the phagocyte respiratory burst. Proc Natl Acad Sci U S A 106:7642–7647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rorsman P, Renstrom E (2003) Insulin granule dynamics in pancreatic beta cells. Diabetologia 46:1029–1045

    Article  CAS  PubMed  Google Scholar 

  54. Sasaki M, Takagi M, Okamura Y (2006) A voltage sensor-domain protein is a voltage-gated proton channel. Science 312:589–592

    Article  CAS  PubMed  Google Scholar 

  55. Sato Y, Aizawa T, Komatsu M, Okada N, Yamada T (1992) Dual functional role of membrane depolarization/Ca2+ influx in rat pancreatic B-cell. Diabetes 41:438–443

    Article  CAS  PubMed  Google Scholar 

  56. Srinivasan K, Ramarao P (2007) Animal models in type 2 diabetesresearch: an overview. Indian J Med Res 125:451–472

    CAS  PubMed  Google Scholar 

  57. Taylor-Fishwick DA (2013) NOX, NOX Who is there? The contribution of NADPH oxidase one to beta cell dysfunction. Front Endocrinol (Lausanne) 4:40

    Article  Google Scholar 

  58. Thomas RC, Meech RW (1982) Hydrogen ion currents and intracellular pH in depolarized voltage-clamped snail neurones. Nature 299:826–828

    Article  CAS  PubMed  Google Scholar 

  59. Uysal KT, Wiesbrock SM, Hotamisligil GS (1998) Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated IR in genetic obesity. Endocrinology 139:4832–4838

    Article  CAS  PubMed  Google Scholar 

  60. Wellen KE, Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115:1111–1119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wu MM, Grabe M, Adams S, Tsien RY, Moore HP, Machen TE (2001) Mechanisms of pH regulation in the regulated secretory pathway. J Biol Chem 276:33027–33035

    Article  CAS  PubMed  Google Scholar 

  62. Zhao Q, Che Y, Li Q, Zhang S, Gao YT, Wang Y, Wang X, Xi W, Zuo W, Li SJ (2015) The voltage-gated proton channel Hv1 is expressed in pancreatic islet β-cells and regulates insulin secretion. Biochem Biophys Res Commun 468:746–751

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported partly by Tianjin Graduate Research and Innovation Project (No. 2019YJSB031).

Author information

Authors and Affiliations

  1. Department of Biophysics, School of Physics, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, 94 Weijin Road, Nankai District, Tianjin, 300071, People’s Republic of China

    Huimin Pang, Jinwen Li & Shu Jie Li

Authors
  1. Huimin Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinwen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shu Jie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SJL and HMP conceived and reviewed the literature. HMP, SJL, and JWL wrote the manuscript. JWL finished drawing the graph. SJL and HMP reviewed and edited the manuscript. All authors were involved in reading and approving the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Shu Jie Li.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key points

1. The newly discovered role of Hv1 in metabolism homeostasis is summarized.

2. It provides a theoretical basis for Hv1 as new therapeutic strategies for obesity and diabetes in the future.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pang, H., Li, J. & Li, S.J. Role of the voltage-gated proton channel Hv1 in insulin secretion, glucose homeostasis, and obesity. J Physiol Biochem 78, 593–601 (2022). https://doi.org/10.1007/s13105-022-00891-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-022-00891-8

Keywords

Search

Navigation