Skip to main content
Log in

Effects of exendin-4 and selenium on the expression of GLP-1R, IRS-1, and preproinsulin in the pancreas of diabetic rats

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

An Erratum to this article was published on 05 October 2017

This article has been updated

Abstract

The mechanisms by which exendin-4 and selenium exert their antidiabetic actions are still unclear. Here, we investigated the effects of exendin-4 or selenium administration on the expression of glucagon-like peptide-1 receptor (GLP-1R), insulin receptor substrate-1 (IRS-1), and preproinsulin in the pancreas of diabetic rats. Diabetes was induced by streptozotocin administration. Diabetic rats were injected intraperitoneally with 0.03 μg exendin-4/kg body weight/daily or treated with 5 ppm selenium in drinking water for a period of 4 weeks. GLP-1R and IRS-1 levels were decreased while the level of preproinsulin messenger RNA (mRNA) was increased in the pancreas of diabetic untreated rats, as compared to that in control rats. Treatment of diabetic rats with exendin-4 increased protein and mRNA levels of GLP-1R, and IRS-1, and the mRNA level of preproinsulin in the pancreas, as compared to their levels in diabetic untreated rats. Selenium treatment of diabetic rats increased the pancreatic mRNA levels of GLP-1R, IRS-1, and preproinsulin. Exendin-4 or selenium treatment of diabetic rats also increased the numbers of pancreatic islets and GLP-1R molecules in the pancreas. Therefore, exendin-4 and selenium may exert their antidiabetic effects by increasing GLP-1R, IRS-1, and preproinsulin expression in the pancreas and by increasing the number of pancreatic islets.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Change history

  • 05 October 2017

    Volume 73 issue 3 was published with an incorrect cover date. Correct is August 2017. The Publisher apologizes for this mistake and all related inconveniences caused by this.

References

  1. Barakat GM, Moustafa ME, Bikhazi AB (2012) Effects of selenium and exendin-4 on glucagon-like peptide receptor, IRS-1, and Raf-1 in the liver of diabetic rats. Biochem Genet 50(11–12):922–935

    Article  CAS  PubMed  Google Scholar 

  2. Becker DJ, Reul B, Ozcelikay AT, Buchet JP, Henquin JC, Brichard SM (1996) Oral selenate improves glucose homeostasis and partly reverses abnormal expression of liver glycolytic and gluconeogenic enzymes in diabetic rats. Diabetologia 39:3–11

    Article  CAS  PubMed  Google Scholar 

  3. Bleys J, Navas-Acien A, Guallar E (2007) Serum selenium and diabetes in U.S. adults. Diabetes Care 30:829–834

    Article  CAS  PubMed  Google Scholar 

  4. Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH et al (2006) Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab 8:436–447

    Article  CAS  PubMed  Google Scholar 

  5. Colagiuri S (2010) Diabesity: therapeutic options. Diabetes Obes Metab 12:463–473

    Article  CAS  PubMed  Google Scholar 

  6. Doyle ME, Egan JM (2007) Mechanisms of action of GLP-1 in the pancreas. Pharmacol Ther 113:546–593

    Article  CAS  PubMed  Google Scholar 

  7. Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF (1987) Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci U S a 84:3434–3438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fehmann HC, Habener JF (1992) Insulinotropic hormone glucagon-like peptide-I [7-37] stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma beta TC-1 cells. Endocrinol 130:159–166

    Article  CAS  Google Scholar 

  9. Forstermann U (2008) Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat Clin Pract Card 5:338–349

    Article  Google Scholar 

  10. Gebhard B, Holst JJ, Biegelmayer C, Miholic J (2001) Postprandial GLP-1, norepinephrine, and reactive hypoglycemia in dumping syndrome. Dig Dis Sci 46:1915–1923

    Article  CAS  PubMed  Google Scholar 

  11. Gutniak M, Ørkov C, Holst JJ, Ahrén B, Efendić S (1992) Antidiabetogenic effect of glucagon-like peptide-1[7-36] amide in normal subjects and patients with diabetes mellitus. N Engl J Med 326:1316–1322

    Article  CAS  PubMed  Google Scholar 

  12. Harkavyi A, Whitton PS (2010) Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection. Br J Pharmacol 159:495–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hay CW, Sinclair EM, Bermano G, Durward E, Tadayyon M, Docherty K (2005) Glucagon-like peptide-1stimulates human insulin promoter activity in part through cAMP-responsive elements that lie upstream and downstream of the transcription start site. J Endocrinol 186:353–365

    Article  CAS  PubMed  Google Scholar 

  14. Hwang D, Seo S, Kim Y, Kim C, Shim S, Jee S, Lee S, Jang M, Kim M, Yim S, Lee SK, Kang B, Jang I, Cho J (2007) Selenium acts as an insulin-like molecule for the down-regulation of diabetic symptoms via endoplasmic reticulum stress and insulin signalling proteins in diabetes-induced non-obese diabetic mice. J Biosci 32:723–735

    Article  CAS  PubMed  Google Scholar 

  15. Kelleher AR, Fairchild TJ, Keslacy S (2010) STZ-induced skeletal muscle atrophy is associated with increased p65 content and downregulation of insulin pathway without NF-κB canonical cascade activation. Acta Diabetol 47:315–323

    Article  CAS  PubMed  Google Scholar 

  16. Kornhauser C, Garcia-Ramirez JR, Wrobel K, Pérez-Luque EL, Garay-Sevilla ME, Wrobel K (2008) Serum selenium and glutathione peroxidase concentrations in type 2 diabetes mellitus patients. Primary Care Diabetes 2:81–85

    Article  PubMed  Google Scholar 

  17. Kwon DY, Kim YS, Ahn IS, Kimda S, Kang S, Hong SM, Park S (2009) Exendin-4 potentiates insulinotropic action partly via increasing beta-cell proliferation and neogenesis and decreasing apoptosis in association with the attenuation of endoplasmic reticulum stress in islets of diabetic rats. J Pharmacol Sci 111:361–371

    Article  CAS  PubMed  Google Scholar 

  18. Laybutt DR, Sharma A, Sgroi DC, Gaudet J, Susan Bonner-Weir S, Weir GC (2002) Genetic regulation of metabolic pathways in β-cells disrupted by hyperglycemia. J Biol Chem 277:10912–10921

    Article  CAS  PubMed  Google Scholar 

  19. Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ (2003) Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem 278:471–478

    Article  CAS  PubMed  Google Scholar 

  20. Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL, Minasian LM, Gaziano JM, Hartline JA, Parsons JK, Bearden JD, Crawford ED, Goodman GE, Claudio J, Winquist E, Cook ED, Karp DD, Walther P, Lieber MM, Kristal AR, Darke AK, Arnold KB, Ganz PA, Santella RM, Albanes D, Taylor PR, Probstfield JL, Jagpal TJ, Crowley JJ, Meyskens FL, Baker LH, Coltman CA (2009) Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the selenium and vitamin E cancer prevention trial [SELECT]. Jama 301:39–51

    Article  CAS  PubMed  Google Scholar 

  21. Marcason W (2008) What is the latest research on the connection between selenium and diabetes? J Am Diet Assoc 108:188

    Article  PubMed  Google Scholar 

  22. McNeill JH, Delgatty HL, Battell ML (1991) Insulin like effects of sodium selenate in streptozocin-induced diabetic rats. Diabetes 40:1675–1678

    Article  CAS  PubMed  Google Scholar 

  23. Mojsov S, Heinrich G, Wilson IB, Ravazzola M, Orci L, Habener JF (1986) Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing. J Biol Chem 261:11880–11889

    CAS  PubMed  Google Scholar 

  24. Montrose-Rafizadeh C, Yang H, Rodgers BD, Beday A, Pritchette LA, Eng J (1997) High potency antagonists of the pancreatic glucagon-like peptide-1 receptor. J Biol Chem 272:21201–21206

    Article  CAS  PubMed  Google Scholar 

  25. Ogawa W, Matozaki T, Kasuga M (1998) Role of binding proteins to IRS-1 in insulin signaling. Mol Cell Biochem 182:13–22

    Article  CAS  PubMed  Google Scholar 

  26. Okerson T, Chilton RJ (2010) The cardiovascular effects of GLP-1 receptor agonists. Cardiovasc Ther 30:e146–e155

    Article  PubMed  PubMed Central  Google Scholar 

  27. Orskov C, Holst JJ, Knuhtsen S, Baldissera FG, Poulsen SS, Nielsen OV (1986) Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas. Endocrinol 119:1467–1475

    Article  CAS  Google Scholar 

  28. Perfetti R, Merkel P (2000) Glucagon-like peptide-1: a major regulator of pancreatic β-cell function. Eur J Endocrinol 143:717–725

    Article  CAS  PubMed  Google Scholar 

  29. Ruíz C, Alegría A, Barberá R, Farré R, Lagarda J (1998) Selenium, zinc and copper in plasma of patients with type 1 diabetes mellitus in different metabolic control states. J Trace Elem Med Biol 12:91–95

    Article  PubMed  Google Scholar 

  30. Scaglia L, Cahill CJ, Finegood DT, Bonner-Weir S (1997) Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinol 138:1736–1741

    Article  CAS  Google Scholar 

  31. Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M, Combs GF, Cappuccio FP, Ceriello A, Reid ME (2007) Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Ann Intern med 147:217–223

    Article  PubMed  Google Scholar 

  32. Wang X, Cahill CM, Pineyro MA, Zhou J, Doyle ME, Egan JM (1999) Glucagon-like peptide-1 regulates the beta cell transcription factor, PDX-1, in insulinoma cells. Endocrinol 140:4904–4907

    Article  CAS  Google Scholar 

  33. Wootten D, Simms J, Koole C, Woodman OL, Summers RJ, Christopoulos A, Sexton PM (2011) Modulation of the glucagon-like peptide-1 receptor signaling by naturally occurring and synthetic flavonoids. J Pharmacol Exp Ther 336:540–550

    Article  CAS  PubMed  Google Scholar 

  34. Xu G, Stoffers DA, Habener JF, Bonner-Weir S (1999) Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats. Diabetes 48:2270–2276

    Article  CAS  PubMed  Google Scholar 

  35. Xu G, Kaneto H, Laybutt DR, Duvivier-Kali VF, Trivedi N, Suzuma K, King GL, Weir GC, Bonner-Weir S (2007) Downregulation of GLP-1 and GIP receptor expression by hyperglycemia. Diabetes 56:1551–1558

    Article  CAS  PubMed  Google Scholar 

  36. Yeo JE, Kang SK (2007) Selenium effectively inhibits ROS-mediated apoptotic neural precursor cell death in vitro and in vivo in traumatic brain injury. Biochim Biophys Acta 1772:1199–1210

    Article  CAS  PubMed  Google Scholar 

  37. Young-Sun L, Seungjin S, Toshikatsu S, Eunsil H, Meng-Ju L, Jaeseok H, Ji-Won Y, Hee-Sook J (2007) Glucagon-like peptide-1 gene therapy in obese diabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. Diabetes 56:1671–1679

    Article  Google Scholar 

  38. Yusta B, Baggio LL, Estall JL, Koehler JA, Holland DP, Li H, Pipeleers D, Ling Z, Drucker DJ (2006) GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab 4:391–406

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

SR, MEM, and AB conceived, designed the study, and oversaw the analysis and interpretation of data. GB performed all animal experiments and drafted the manuscript. GB and MH designed and carried out western blots and PCR experiments. IK performed the immunofluorescence experiments and the hematoxylin/eosin staining. MEM and SR secured the funding for the project. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Sandra Rizk.

Ethics declarations

Funding

This work was supported by the research fund from the National Council for Scientific Research (CNRS), Lebanon to M.E.M. (grant number 01-11-08) and by the School Research and Development Council, Lebanese American University (SRDC-t-2016-4).

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

An erratum to this article is available at https://doi.org/10.1007/s13105-017-0593-x.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barakat, G., Moustafa, M.E., Khalifeh, I. et al. Effects of exendin-4 and selenium on the expression of GLP-1R, IRS-1, and preproinsulin in the pancreas of diabetic rats. J Physiol Biochem 73, 387–394 (2016). https://doi.org/10.1007/s13105-017-0565-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-017-0565-1

Keywords

Navigation