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Published in: Diabetology & Metabolic Syndrome 1/2016

Open Access 01-12-2016 | Research

NK cell count and glucotransporter 4 (GLUT4) expression in subjects with type 2 diabetes and colon cancer

Authors: Paweł Piątkiewicz, Małgorzata Bernat-Karpińska, Tomasz Miłek, Michał Rabijewski, Elżbieta Rosiak

Published in: Diabetology & Metabolic Syndrome | Issue 1/2016

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Abstract

Background

Type 2 diabetes (T2D) and colon cancer (CC) are numbered among the most common diseases in the world. The decreased activity of natural killer (NK) cells previously revealed in both mentioned pathological states may be correlated with impaired expression of GLUT4 as the major insulin-dependent glucose transporter in these cells.

Methods

The aim of this study was to evaluate GLUT4 expression and NK cells number in subjects with T2D and/or CC in comparison with control group. We evaluated 78 individuals divided into four groups: (1) patients with CC and T2DM, (2) patients with CC, (3) patients with T2DM (4) healthy control. GLUT4 expression on the surface of NK cells was measured using flow cytometry and phenotyping of NK cell was performed by immunofluorescent method.

Results

Subjects with diabetes had the highest GLUT4 expression (21.35 ± 7.2 %) in comparison with other groups (P < 0.01). The mean values of GLUT4 expression in group with CC and in patients with both T2D and CC were similar (1.4 ± 0.4 % vs 1.5 ± 1.0 %; respectively). These values were significantly lower than in control group (12.6 ± 2.9 %; P < 0.01). In patients with T2D and CC the number of NK cells (20.15 ± 6.6 %) was significantly higher than in other groups, i.e. in group with T2D (14.08 ± 5.7 %), in group with CC (9.21 ± 3.6 %) and in control group (9.48 ± 4.7 %), respectively (P < 0.01).

Conclusions

It seems that there is a need to pay more attention to the high incidence of colon cancer among patients with type 2 diabetes. Decreased GLUT4 expression observed on NK cells in patients with colon cancer may be responsible for dysfunction of these cells and the higher carcinogenic risk in type 2 diabetic subjects.
Literature
3.
go back to reference Hjartåker A, Langseth H, Weiderpass E. Obesity and diabetes epidemics: cancer repercussions. Adv Exp Med Biol. 2008;630:72–93.CrossRefPubMed Hjartåker A, Langseth H, Weiderpass E. Obesity and diabetes epidemics: cancer repercussions. Adv Exp Med Biol. 2008;630:72–93.CrossRefPubMed
4.
go back to reference Gallagher EJ, LeRoith D. Diabetes, cancer and metformin: connections of metabolism and cell proliferation. Ann NY Acad Sci. 2011;1243:54–68.CrossRefPubMed Gallagher EJ, LeRoith D. Diabetes, cancer and metformin: connections of metabolism and cell proliferation. Ann NY Acad Sci. 2011;1243:54–68.CrossRefPubMed
5.
go back to reference LeRoith D, Novosyadlyy R, Gallagher EJ, Lann D, Vijayakumar A, Yakar S. Obesity and type 2 diabetes are associated with an increased risk of developing cancer and a worse prognosis; epidemiological and mechanistic evidence. Exp Clin Endocrinol Diabetes. 2008;116(Suppl 1):S1–3. LeRoith D, Novosyadlyy R, Gallagher EJ, Lann D, Vijayakumar A, Yakar S. Obesity and type 2 diabetes are associated with an increased risk of developing cancer and a worse prognosis; epidemiological and mechanistic evidence. Exp Clin Endocrinol Diabetes. 2008;116(Suppl 1):S1–3.
6.
go back to reference Feng YH, Velazquez-Torres G, Gully C, Chen J, Lee MH, Yeung SC. The impact of type 2 diabetes and antidiabetic drugs on cancer cell growth. J Cell Mol Med. 2011;15:825–36.CrossRefPubMed Feng YH, Velazquez-Torres G, Gully C, Chen J, Lee MH, Yeung SC. The impact of type 2 diabetes and antidiabetic drugs on cancer cell growth. J Cell Mol Med. 2011;15:825–36.CrossRefPubMed
7.
go back to reference Piątkiewicz P, Czech A. Glucose metabolism disorders and the risk of cancer. Arch Immunol Ther Exp (Warsz). 2011;59:215–30.CrossRef Piątkiewicz P, Czech A. Glucose metabolism disorders and the risk of cancer. Arch Immunol Ther Exp (Warsz). 2011;59:215–30.CrossRef
8.
go back to reference Kendall BJ, Wilson LF, Olsen CM, Webb PM, Neale RE, Bain CJ, Whiteman DC. Cancers in Australia in 2010 attributable to overweight and obesity. Aust NZ J Public Health. 2015;39(5):452–7.CrossRef Kendall BJ, Wilson LF, Olsen CM, Webb PM, Neale RE, Bain CJ, Whiteman DC. Cancers in Australia in 2010 attributable to overweight and obesity. Aust NZ J Public Health. 2015;39(5):452–7.CrossRef
9.
go back to reference Olsen CM, Wilson LF, Nagle CM, Kendall BJ, Bain CJ, Pandeya N, Webb PM, Whiteman DC. Cancers in Australia in 2010 attributable to insufficient physical activity. Aust NZ J Public Health. 2015;39(5):458–63.CrossRef Olsen CM, Wilson LF, Nagle CM, Kendall BJ, Bain CJ, Pandeya N, Webb PM, Whiteman DC. Cancers in Australia in 2010 attributable to insufficient physical activity. Aust NZ J Public Health. 2015;39(5):458–63.CrossRef
10.
go back to reference Wood IS, Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr. 2003;89:3–9.CrossRefPubMed Wood IS, Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr. 2003;89:3–9.CrossRefPubMed
11.
12.
go back to reference Joost HG, Thorens B. The extended GLUT family of sugar/polyol transport facilitators: nomenclature, sequence characteristics and potential function of its novel members. Mol Membr Biol. 2001;18:247–56.CrossRefPubMed Joost HG, Thorens B. The extended GLUT family of sugar/polyol transport facilitators: nomenclature, sequence characteristics and potential function of its novel members. Mol Membr Biol. 2001;18:247–56.CrossRefPubMed
13.
14.
go back to reference Shikman AR, Brinson DC, Valbracht J, Lotz MK. Cytokine regulation of facilitated glucose transport in human articular chondrocytes. J Immunol. 2001;167:7001–8.CrossRef Shikman AR, Brinson DC, Valbracht J, Lotz MK. Cytokine regulation of facilitated glucose transport in human articular chondrocytes. J Immunol. 2001;167:7001–8.CrossRef
15.
go back to reference Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202:654–62.CrossRefPubMed Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202:654–62.CrossRefPubMed
16.
go back to reference Calvo MB, Figueroa A, Pulido EG, Campelo RG, Aparicio LA. Potential role of sugar transporters in cancer and their relationship with anticancer therapy. Inter J Endocrinol. 2010;. doi:10.1155/2010/205357. Calvo MB, Figueroa A, Pulido EG, Campelo RG, Aparicio LA. Potential role of sugar transporters in cancer and their relationship with anticancer therapy. Inter J Endocrinol. 2010;. doi:10.​1155/​2010/​205357.
17.
go back to reference Zorzano A, Wilkinson W, Kotliar N, Thoidis G, Wadzinkski BE, Ruoho AE, Pilch PF. Insulin regulated glucose uptake in rat adipocytes is mediated by two transporter isoforms present in at least two vesicle populations. J Biol Chem. 1989;264:12358–63.PubMed Zorzano A, Wilkinson W, Kotliar N, Thoidis G, Wadzinkski BE, Ruoho AE, Pilch PF. Insulin regulated glucose uptake in rat adipocytes is mediated by two transporter isoforms present in at least two vesicle populations. J Biol Chem. 1989;264:12358–63.PubMed
18.
go back to reference Schwartzenberg-Bar YF, Armoni M, Karnieli E. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res. 2004;64:2627–33.CrossRef Schwartzenberg-Bar YF, Armoni M, Karnieli E. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res. 2004;64:2627–33.CrossRef
20.
go back to reference Dutta A, Banerjee A, Saikia N, Phookan J, Baruah MN, Baruah S. Negative regulation of natural killer cell in tumor tissue and peripheral blood of oral squamous cell carcinoma. Cytokine. 2015;76(2):123–30.CrossRefPubMed Dutta A, Banerjee A, Saikia N, Phookan J, Baruah MN, Baruah S. Negative regulation of natural killer cell in tumor tissue and peripheral blood of oral squamous cell carcinoma. Cytokine. 2015;76(2):123–30.CrossRefPubMed
21.
go back to reference Held W, Kijima M, Angelov G, Bessoles S. The function of natural killer cells: education, reminders and some good memories. Curr Opin Immunol. 2011;23:228–33.CrossRefPubMed Held W, Kijima M, Angelov G, Bessoles S. The function of natural killer cells: education, reminders and some good memories. Curr Opin Immunol. 2011;23:228–33.CrossRefPubMed
23.
go back to reference Piątkiewicz P, Miłek T, Bernat-Karpińska M, Ohams M, Czech A, Ciostek P. The dysfunction of NK cells in patients with type 2 diabetes and colon cancer. Arch Immunol Ther Exp (Warsz). 2013;61(3):245–53. doi:10.1007/s00005-013-0222-5.CrossRef Piątkiewicz P, Miłek T, Bernat-Karpińska M, Ohams M, Czech A, Ciostek P. The dysfunction of NK cells in patients with type 2 diabetes and colon cancer. Arch Immunol Ther Exp (Warsz). 2013;61(3):245–53. doi:10.​1007/​s00005-013-0222-5.CrossRef
24.
go back to reference Spooren PF, Vermes I, Soons JW. Similar alterations of lymphocyte subpopulations in type I and type II diabetes. Neth J Med. 2007;42:163–7. Spooren PF, Vermes I, Soons JW. Similar alterations of lymphocyte subpopulations in type I and type II diabetes. Neth J Med. 2007;42:163–7.
25.
go back to reference Piątkiewicz P, Czech A, Tatoń J. Glucose transport in human peripheral blood lymphocytes influence by type 2 diabetes mellitus. Arch Immunol Ther Exp (Warsz). 2007;55:119–26.CrossRef Piątkiewicz P, Czech A, Tatoń J. Glucose transport in human peripheral blood lymphocytes influence by type 2 diabetes mellitus. Arch Immunol Ther Exp (Warsz). 2007;55:119–26.CrossRef
26.
go back to reference Estrada DE, Elliott E, Zinman B, Poon I, Liu Z, Klip A, Daneman D. Regulation of glucose transport and expression of GLUT3 transporters in human circulating mononuclear cells: studies in cells from insulin-dependent diabetic and nondiabetic individuals. Metabolism. 1994;43:591–8.CrossRefPubMed Estrada DE, Elliott E, Zinman B, Poon I, Liu Z, Klip A, Daneman D. Regulation of glucose transport and expression of GLUT3 transporters in human circulating mononuclear cells: studies in cells from insulin-dependent diabetic and nondiabetic individuals. Metabolism. 1994;43:591–8.CrossRefPubMed
27.
go back to reference James DK, Brown R, Navarro J, Pilch PF. Insulin regulatable tissues express a unique insulin-sensitive glucose transport protein. Nature. 1988;333:183–5.CrossRefPubMed James DK, Brown R, Navarro J, Pilch PF. Insulin regulatable tissues express a unique insulin-sensitive glucose transport protein. Nature. 1988;333:183–5.CrossRefPubMed
28.
go back to reference Studelska DR, Campbell C, Pang S, Rodnick KJ, James DE. Developmental expression of insulin-regulatable glucose transporter GLUT-4. Am J Physiol. 1992;263:E102–6.PubMed Studelska DR, Campbell C, Pang S, Rodnick KJ, James DE. Developmental expression of insulin-regulatable glucose transporter GLUT-4. Am J Physiol. 1992;263:E102–6.PubMed
29.
go back to reference Flier JS, Mueckler MM, Usher P, Lodish HF. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science. 1987;235:1492–5.CrossRefPubMed Flier JS, Mueckler MM, Usher P, Lodish HF. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science. 1987;235:1492–5.CrossRefPubMed
30.
go back to reference Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, Schmidt K, Willson JK, Markowitz S, Zhou S, Diaz LA Jr, Velculescu VE, Lengauer C, Kinzler KW, Vogelstein B, Papadopoulos N. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009;325:1555–9.CrossRefPubMedPubMedCentral Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, Schmidt K, Willson JK, Markowitz S, Zhou S, Diaz LA Jr, Velculescu VE, Lengauer C, Kinzler KW, Vogelstein B, Papadopoulos N. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009;325:1555–9.CrossRefPubMedPubMedCentral
31.
go back to reference Suganuma N, Segade F, Matsuzu K, Bowden DW. Differential expression of facilitative glucose transporters in normal and tumour kidney tissues. Br J Urol Int. 2007;99:1143–9.CrossRef Suganuma N, Segade F, Matsuzu K, Bowden DW. Differential expression of facilitative glucose transporters in normal and tumour kidney tissues. Br J Urol Int. 2007;99:1143–9.CrossRef
32.
go back to reference Haber RS, Rathan A, Weiser KR, Pritsker A, Itzkowitz SH, Bodian C, Slater G, Weiss A, Burstein DE. GLUT1 glucose transporter expression in colorectal carcinoma: a marker for poor prognosis. Cancer. 1998;83:34–40.CrossRefPubMed Haber RS, Rathan A, Weiser KR, Pritsker A, Itzkowitz SH, Bodian C, Slater G, Weiss A, Burstein DE. GLUT1 glucose transporter expression in colorectal carcinoma: a marker for poor prognosis. Cancer. 1998;83:34–40.CrossRefPubMed
33.
go back to reference Furudoi A, Tanaka S, Haruma K, Yoshihara M, Sumii K, Kajiyama G, Shimamoto F. Clinical significance of human erythrocyte glucose transporter 1 expression at the deepest invasive site of advanced colorectal carcinoma. Oncology. 2001;60:162–9.CrossRefPubMed Furudoi A, Tanaka S, Haruma K, Yoshihara M, Sumii K, Kajiyama G, Shimamoto F. Clinical significance of human erythrocyte glucose transporter 1 expression at the deepest invasive site of advanced colorectal carcinoma. Oncology. 2001;60:162–9.CrossRefPubMed
34.
go back to reference Bernat-Karpińska M, Piątkiewicz P, Czech A, Wierzbicki P. The expression of particular glucose transporters and insulin resistance indicators in the risk groups of type 2 diabetes: a two-year follow-up. Endokrynol Pol. 2012;63:212–9.PubMed Bernat-Karpińska M, Piątkiewicz P, Czech A, Wierzbicki P. The expression of particular glucose transporters and insulin resistance indicators in the risk groups of type 2 diabetes: a two-year follow-up. Endokrynol Pol. 2012;63:212–9.PubMed
35.
go back to reference Tseng CH. Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan. Eur J Endocrinol. 2012;167:409–16.CrossRefPubMed Tseng CH. Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan. Eur J Endocrinol. 2012;167:409–16.CrossRefPubMed
36.
go back to reference Feng YH, Velazquez-Torres G, Gully C, Chen J, Lee MH, Yeung SC. The impact of type 2 diabetes and antidiabetic drugs on cancer cell growth. J Cell Mol Med. 2011;15:825–36.CrossRefPubMed Feng YH, Velazquez-Torres G, Gully C, Chen J, Lee MH, Yeung SC. The impact of type 2 diabetes and antidiabetic drugs on cancer cell growth. J Cell Mol Med. 2011;15:825–36.CrossRefPubMed
37.
39.
go back to reference Xirasagar S, Li YJ, Hurley TG, Tsai MH, Hardin JW, Hurley DM, Hebert JR, de Groen PC. Colorectal cancer prevention by an optimized colonoscopy protocol in routine practice. Int J Cancer. 2015;136(6):E731–42.CrossRefPubMed Xirasagar S, Li YJ, Hurley TG, Tsai MH, Hardin JW, Hurley DM, Hebert JR, de Groen PC. Colorectal cancer prevention by an optimized colonoscopy protocol in routine practice. Int J Cancer. 2015;136(6):E731–42.CrossRefPubMed
40.
go back to reference Sconocchia G, Eppenberger S, Spagnoli GC, Tornillo L, Droeser R, Caratelli S, Ferrelli F, Coppola A, Arriga R, Lauro D, Iezzi G, Terracciano L, Ferrone S. NK cells and T cells cooperate during the clinical course of colorectal cancer. Oncoimmunology. 2014;3(8):e952197.CrossRefPubMedPubMedCentral Sconocchia G, Eppenberger S, Spagnoli GC, Tornillo L, Droeser R, Caratelli S, Ferrelli F, Coppola A, Arriga R, Lauro D, Iezzi G, Terracciano L, Ferrone S. NK cells and T cells cooperate during the clinical course of colorectal cancer. Oncoimmunology. 2014;3(8):e952197.CrossRefPubMedPubMedCentral
41.
go back to reference Sun C, Sun HY, Xiao WH, Zhang C, Tian ZG. Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy. Acta Pharmacol Sin. 2015;36(10):1191–9.CrossRefPubMedPubMedCentral Sun C, Sun HY, Xiao WH, Zhang C, Tian ZG. Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy. Acta Pharmacol Sin. 2015;36(10):1191–9.CrossRefPubMedPubMedCentral
42.
go back to reference McBrayer SK, Cheng JC, Singhal S, Krett NL, Rosen ST, Shanmugam M. Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy. Blood. 2012;119(20):4686–97.CrossRefPubMedPubMedCentral McBrayer SK, Cheng JC, Singhal S, Krett NL, Rosen ST, Shanmugam M. Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy. Blood. 2012;119(20):4686–97.CrossRefPubMedPubMedCentral
43.
go back to reference Pietra G, Vitale C, Pende D, Bertaina A, Moretta F, Falco M, Vacca P, Montaldo E, Cantoni C, Mingari MC, Moretta A, Locatelli F, Moretta L. Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias. Cancer Immunol Immunother. 2015;65(4):465–76.CrossRefPubMed Pietra G, Vitale C, Pende D, Bertaina A, Moretta F, Falco M, Vacca P, Montaldo E, Cantoni C, Mingari MC, Moretta A, Locatelli F, Moretta L. Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias. Cancer Immunol Immunother. 2015;65(4):465–76.CrossRefPubMed
44.
go back to reference Mishra RK, Wei C, Hresko RC, Bajpai R, Heitmeier M, Matulis SM, Nooka AK, Rosen ST, Hruz PW, Schiltz GE, Shanmugam M. In silico modeling-based identification of glucose transporter 4 (GLUT4)-selective inhibitors for cancer therapy. J Biol Chem. 2015;290(23):1441–53.CrossRef Mishra RK, Wei C, Hresko RC, Bajpai R, Heitmeier M, Matulis SM, Nooka AK, Rosen ST, Hruz PW, Schiltz GE, Shanmugam M. In silico modeling-based identification of glucose transporter 4 (GLUT4)-selective inhibitors for cancer therapy. J Biol Chem. 2015;290(23):1441–53.CrossRef
45.
go back to reference Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75(1):33–59.CrossRefPubMed Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75(1):33–59.CrossRefPubMed
46.
go back to reference Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015. (Epub ahead of print). Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015. (Epub ahead of print).
Metadata
Title
NK cell count and glucotransporter 4 (GLUT4) expression in subjects with type 2 diabetes and colon cancer
Authors
Paweł Piątkiewicz
Małgorzata Bernat-Karpińska
Tomasz Miłek
Michał Rabijewski
Elżbieta Rosiak
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Diabetology & Metabolic Syndrome / Issue 1/2016
Electronic ISSN: 1758-5996
DOI
https://doi.org/10.1186/s13098-016-0152-6

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