Download PDF
Horm Metab Res 2012; 44(06): 442-450
DOI: 10.1055/s-0032-1306335
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

GLUT4 in the Endocrine Pancreas – Indicating an Impact in Pancreatic Islet Cell Physiology?

I. Bähr
1    Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
,
I. Bazwinsky-Wutschke
1    Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
,
S. Wolgast
2    Saxon Academy of Sciences Leipzig, Leipzig, Germany
,
K. Hofmann
1    Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
,
S. Streck
1    Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
,
E. Mühlbauer
2    Saxon Academy of Sciences Leipzig, Leipzig, Germany
,
D. Wedekind
3    Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany
,
E. Peschke
1    Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
› Author Affiliations
Further Information

Publication History

received 16 September 2011

accepted 16 February 2012

Publication Date:
05 April 2012 (online)

Also available at
    Permissions and Reprints

Abstract

The glucose transporter GLUT4 is well known to facilitate the transport of blood glucose into insulin-sensitive muscle and adipose tissue. In this study, molecular, immunohistochemical, and Western blot investigations revealed evidence that GLUT4 is also located in the mouse, rat, and human endocrine pancreas. In addition, high glucose decreased and insulin elevated the GLUT4 expression in pancreatic α-cells. In contrast, high glucose increased GLUT4 expression, whereas insulin led to a reduced expression level of the glucose transporter in pancreatic β-cells. In vivo experiments showed that in pancreatic tissue of type 2 diabetic rats as well as type 2 diabetic patients, the GLUT4 expression is significantly increased compared to the nondiabetic control group. Furthermore, type 1 diabetic rats exhibited reduced GLUT4 transcript levels in pancreatic tissue, whereas insulin treatment of type 1 diabetic animals enhanced the GLUT4 expression back to control levels. These data provide evidence for the existence of GLUT4 in the endocrine pancreas and indicate a physiological relevance of this glucose transporter as well as characteristic changes in diabetic disease.

Key words

GLUT4 - pancreatic islet - diabetes - insulin - glucose
 

  • References

  • 1 McCarthy AM, Elmendorf JS. GLUT4’s itinerary in health & disease. Indian J Med Res 2007; 125: 373-388
    PubMedGoogle Scholar
  • 2 Ndisang JF, Lane N, Jadhav A. The heme oxygenase system abates hyperglycemia in Zucker diabetic fatty rats by potentiating insulin-sensitizing pathways. Endocrinology 2009; 150: 2098-2108
    CrossrefPubMedGoogle Scholar
  • 3 Desrois M, Sidell RJ, Gauguier D, King LM, Radda GK, Clarke K. Initial steps of insulin signaling and glucose transport are defective in the type 2 diabetic rat heart. Cardiovasc Res 2004; 61: 288-296
    CrossrefPubMedGoogle Scholar
  • 4 Sivitz WI, DeSautel SL, Kayano T, Bell GI, Pessin JE. Regulation of glucose transporter messenger RNA in insulin-deficient states. Nature 1989; 340: 72-74
    CrossrefPubMedGoogle Scholar
  • 5 Wallberg-Henriksson H, Zierath JR. GLUT4: a key player regulating glucose homeostasis? Insights from transgenic and knockout mice (review). Mol Membr Biol 2001; 18: 205-211
    CrossrefPubMedGoogle Scholar
  • 6 Gaster M, Staehr P, Beck-Nielsen H, Schroder HD, Handberg A. GLUT4 is reduced in slow muscle fibers of type 2 diabetic patients: is insulin resistance in type 2 diabetes a slow, type 1 fiber disease?. Diabetes 2001; 50: 1324-1329
    CrossrefPubMedGoogle Scholar
  • 7 Armoni M, Harel C, Bar-Yoseph F, Milo S, Karnieli E. Free fatty acids repress the GLUT4 gene expression in cardiac muscle via novel response elements. J Biol Chem 2005; 280: 34786-34795
    CrossrefPubMedGoogle Scholar
  • 8 Zisman A, Peroni OD, Abel ED, Michael MD, Mauvais-Jarvis F, Lowell BB, Wojtaszewski JF, Hirshman MF, Virkamaki A, Goodyear LJ, Kahn CR, Kahn BB. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med 2000; 6: 924-928
    CrossrefPubMedGoogle Scholar
  • 9 Pattaranit R, van den Berg HA, Spanswick D. The development of insulin resistance in Type 2 diabetes: insights from knockout studies. Sci Prog 2008; 91: 285-316
    CrossrefPubMedGoogle Scholar
  • 10 Carvalho E, Kotani K, Peroni OD, Kahn BB. Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle. Am J Physiol Endocrinol Metab 2005; 289: E551-E561
    CrossrefPubMedGoogle Scholar
  • 11 Tsao TS, Stenbit AE, Factor SM, Chen W, Rossetti L, Charron MJ. Prevention of insulin resistance and diabetes in mice heterozygous for GLUT4 ablation by transgenic complementation of GLUT4 in skeletal muscle. Diabetes 1999; 48: 775-782
    CrossrefPubMedGoogle Scholar
  • 12 Bjornholm M, Al-Khalili L, Dicker A, Naslund E, Rossner S, Zierath JR, Arner P. Insulin signal transduction and glucose transport in human adipocytes: effects of obesity and low calorie diet. Diabetologia 2002; 45: 1128-1135
    CrossrefPubMedGoogle Scholar
  • 13 Krook A, Bjornholm M, Galuska D, Jiang XJ, Fahlman R, Myers Jr MG, Wallberg-Henriksson H, Zierath JR. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 2000; 49: 284-292
    CrossrefPubMedGoogle Scholar
  • 14 Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL. Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest 1995; 95: 2195-2204
    CrossrefPubMedGoogle Scholar
  • 15 Condorelli G, Vigliotta G, Iavarone C, Caruso M, Tocchetti CG, Andreozzi F, Cafieri A, Tecce MF, Formisano P, Beguinot L, Beguinot F. PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus. Embo J 1998; 17: 3858-3866
    CrossrefPubMedGoogle Scholar
  • 16 Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW, Liu ZX, Soos TJ, Cline GW, O'Brien WR, Littman DR, Shulman GI. PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest 2004; 114: 823-827
    CrossrefPubMedGoogle Scholar
  • 17 Pilch PF, Thompson PA, Czech MP. Coordinate modulation of D-glucose transport activity and bilayer fluidity in plasma membranes derived from control and insulin-treated adipocytes. Proc Natl Acad Sci USA 1980; 77: 915-918
    CrossrefPubMedGoogle Scholar
  • 18 McCarthy AM, Spisak KO, Brozinick JT, Elmendorf JS. Loss of cortical actin filaments in insulin-resistant skeletal muscle cells impairs GLUT4 vesicle trafficking and glucose transport. Am J Physiol Cell Physiol 2006; 291: C860-C868
    CrossrefPubMedGoogle Scholar
  • 19 Wolf G. Serum retinol-binding protein: a link between obesity, insulin resistance, and type 2 diabetes. Nutr Rev 2007; 65: 251-256
    CrossrefPubMedGoogle Scholar
  • 20 Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997; 46: 3-10
    CrossrefPubMedGoogle Scholar
  • 21 Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci USA 1994; 91: 4854-4858
    CrossrefPubMedGoogle Scholar
  • 22 El Messari S, Ait-Ikhlef A, Ambroise DH, Penicaud L, Arluison M. Expression of insulin-responsive glucose transporter GLUT4 mRNA in the rat brain and spinal cord: an in situ hybridization study. J Chem Neuroanat 2002; 24: 225-242
    CrossrefPubMedGoogle Scholar
  • 23 Chin E, Zhou J, Bondy C. Anatomical and developmental patterns of facilitative glucose transporter gene expression in the rat kidney. J Clin Invest 1993; 91: 1810-1815
    CrossrefPubMedGoogle Scholar
  • 24 Aschenbach JR, Steglich K, Gabel G, Honscha KU. Expression of mRNA for glucose transport proteins in jejunum, liver, kidney and skeletal muscle of pigs. J Physiol Biochem 2009; 65: 251-266
    CrossrefPubMedGoogle Scholar
  • 25 Peschke E, Stumpf I, Bazwinsky I, Litvak L, Dralle H, Muhlbauer E. Melatonin and type 2 diabetes – a possible link?. J Pineal Res 2007; 42: 350-358
    CrossrefPubMedGoogle Scholar
  • 26 Goto Y, Suzuki K, Ono T, Sasaki M, Toyota T. Development of diabetes in the non-obese NIDDM rat (GK rat). Adv Exp Med Biol 1988; 246: 29-31
    PubMedGoogle Scholar
  • 27 Lenzen S, Tiedge M, Elsner M, Lortz S, Weiss H, Jorns A, Kloppel G, Wedekind D, Prokop CM, Hedrich HJ. The LEW.1AR1/Ztm-iddm rat: a new model of spontaneous insulin-dependent diabetes mellitus. Diabetologia 2001; 44: 1189-1196
    CrossrefPubMedGoogle Scholar
  • 28 Peschke E, Hofmann K, Bahr I, Streck S, Albrecht E, Wedekind D, Muhlbauer E. The insulin-melatonin antagonism: studies in the LEW.1AR1-iddm rat (an animal model of human type 1 diabetes mellitus). Diabetologia 2011; 54: 1831-1840
    CrossrefPubMedGoogle Scholar
  • 29 Peschke E, Fauteck JD, Musshoff U, Schmidt F, Beckmann A, Peschke D. Evidence for a melatonin receptor within pancreatic islets of neonate rats: functional, autoradiographic, and molecular investigations. J Pineal Res 2000; 28: 156-164
    PubMedGoogle Scholar
  • 30 Muhlbauer E, Gross E, Labucay K, Wolgast S, Peschke E. Loss of melatonin signalling and its impact on circadian rhythms in mouse organs regulating blood glucose. Eur J Pharmacol 2009; 606: 61-71
    CrossrefPubMedGoogle Scholar
  • 31 Bazwinsky-Wutschke I, Wolgast S, Muhlbauer E, Peschke E. Distribution patterns of calcium-binding proteins in pancreatic tissue of non-diabetic as well as type 2 diabetic rats and in rat insulinoma beta-cells (INS-1). Histochem Cell Biol 2010; 134: 115-127
    CrossrefPubMedGoogle Scholar
  • 32 Kobayashi H, Mitsui T, Nomura S, Ohno Y, Kadomatsu K, Muramatsu T, Nagasaka T, Mizutani S. Expression of glucose transporter 4 in the human pancreatic islet of Langerhans. Biochem Biophys Res Commun 2004; 314: 1121-1125
    CrossrefPubMedGoogle Scholar
  • 33 Brant AM, McCoid S, Thomas HM, Baldwin SA, Davies A, Parker JC, Gibbs EM, Gould GW. Analysis of the glucose transporter content of islet cell lines: implications for glucose-stimulated insulin release. Cell Signal 1992; 4: 641-650
    CrossrefPubMedGoogle Scholar
  • 34 Kawamori D, Welters HJ, Kulkarni RN. Molecular pathways underlying the pathogenesis of pancreatic alpha-cell dysfunction. Adv Exp Med Biol 2010; 654: 421-445
    PubMedGoogle Scholar
  • 35 Leung YM, Ahmed I, Sheu L, Gao X, Hara M, Tsushima RG, Diamant NE, Gaisano HY. Insulin regulates islet alpha-cell function by reducing KATP channel sensitivity to adenosine 5′-triphosphate inhibition. Endocrinology 2006; 147: 2155-2162
    CrossrefPubMedGoogle Scholar
  • 36 MacDonald PE, De Marinis YZ, Ramracheya R, Salehi A, Ma X, Johnson PR, Cox R, Eliasson L, Rorsman P. A K ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans. PLoS Biol 2007; 5: e143
    CrossrefPubMedGoogle Scholar
  • 37 Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, Liu S, Wendt A, Deng S, Ebina Y, Wheeler MB, Braun M, Wang Q. Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metab 2006; 3: 47-58
    CrossrefPubMedGoogle Scholar
  • 38 Kern M, Wells JA, Stephens JM, Elton CW, Friedman JE, Tapscott EB, Pekala PH, Dohm GL. Insulin responsiveness in skeletal muscle is determined by glucose transporter (Glut4) protein level. Biochem J 1990; 270: 397-400
    PubMedGoogle Scholar
  • 39 Flores-Riveros JR, McLenithan JC, Ezaki O, Lane MD. Insulin down-regulates expression of the insulin-responsive glucose transporter (GLUT4) gene: effects on transcription and mRNA turnover. Proc Natl Acad Sci USA 1993; 90: 512-516
    CrossrefPubMedGoogle Scholar
  • 40 Kohn AD, Summers SA, Birnbaum MJ, Roth RA. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem 1996; 271: 31372-31378
    CrossrefPubMedGoogle Scholar
  • 41 Efrat S, Tal M, Lodish HF. The pancreatic beta-cell glucose sensor. Trends Biochem Sci 1994; 19: 535-538
    CrossrefPubMedGoogle Scholar
  • 42 Heimberg H, De Vos A, Pipeleers D, Thorens B, Schuit F. Differences in glucose transporter gene expression between rat pancreatic alpha- and beta-cells are correlated to differences in glucose transport but not in glucose utilization. J Biol Chem 1995; 270: 8971-8975
    CrossrefPubMedGoogle Scholar
  • 43 Pedersen O, Bak JF, Andersen PH, Lund S, Moller DE, Flier JS, Kahn BB. Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity or NIDDM. Diabetes 1990; 39: 865-870
    CrossrefPubMedGoogle Scholar
  • 44 Holten MK, Zacho M, Gaster M, Juel C, Wojtaszewski JF, Dela F. Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes. Diabetes 2004; 53: 294-305
    CrossrefPubMedGoogle Scholar
  • 45 Frese T, Bazwinsky I, Muhlbauer E, Peschke E. Circadian and age-dependent expression patterns of GLUT2 and glucokinase in the pancreatic beta-cell of diabetic and nondiabetic rats. Horm Metab Res 2007; 39: 567-574
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Chankiewitz E, Peschke D, Herberg L, Bazwinsky I, Muhlbauer E, Bromme HJ, Peschke E. Did the gradual loss of GLUT2 cause a shift to diabetic disorders in the New Zealand obese mouse (NZO/Hl)?. Exp Clin Endocrinol Diabetes 2006; 114: 262-269
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Zhang Z, Jiang J, Yu P, Zeng X, Larrick JW, Wang Y. Hypoglycemic and beta cell protective effects of andrographolide analogue for diabetes treatment. J Transl Med 2009; 7: 62
    CrossrefPubMedGoogle Scholar
  • 48 Sato K, Iemitsu M, Aizawa K, Ajisaka R. DHEA improves impaired activation of Akt and PKC zeta/lambda-GLUT4 pathway in skeletal muscle and improves hyperglycaemia in streptozotocin-induced diabetes rats. Acta Physiol (Oxf) 2009; 197: 217-225
    CrossrefPubMedGoogle Scholar
  • 49 Hwang SL, Liu IM, Tzeng TF, Cheng JT. Activation of imidazoline receptors in adrenal gland to lower plasma glucose in streptozotocin-induced diabetic rats. Diabetologia 2005; 48: 767-775
    CrossrefPubMedGoogle Scholar
  • 50 Chan P, Wong KL, Liu IM, Tzeng TF, Yang TL, Cheng JT. Antihyperglycemic action of angiotensin II receptor antagonist, valsartan, in streptozotocin-induced diabetic rats. J Hypertens 2003; 21: 761-769
    CrossrefPubMedGoogle Scholar