Download PDF
Horm Metab Res 2008; 40(4): 269-275
DOI: 10.1055/s-2007-1022546
Animals, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

A Novel Insulin Sensitizer (S15511) Enhances Insulin-stimulated Glucose Uptake in Rat Skeletal Muscles

N. Jessen 1 , E. Selmer Buhl 1 , 2 , R. Pold 1 , 2 , O. Schmitz 1 , 2 , S. Lund 1
  • 1Medical Research Laboratory and Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Aarhus C, Denmark
  • 2Institute of Clinical Pharmacology, University of Aarhus, Aarhus C, Denmark
Further Information

Publication History

received 20.04.2007

accepted 24.09.2007

Publication Date:
05 March 2008 (online)

Also available at
    Permissions and Reprints

Abstract

Type 2 diabetes is preceded by the presence of skeletal muscle insulin resistance, and drugs that increase insulin sensitivity in skeletal muscle prevent the disease. S15511 is an original compound with demonstrated effects on insulin sensitivity in animal models of insulin resistance. However, the mechanisms behind the insulin-sensitizing effect of S15511 are unknown. The aim of our study was to explore whether S15511 improves insulin sensitivity in skeletal muscles. Insulin sensitivity was assessed in skeletal muscles from S15511-treated rats by measuring intracellular insulin-signaling activity and insulin-stimulated glucose transport in isolated muscles. In addition, GLUT4 expression and glycogen levels were assessed after treatment. S15511 treatment was associated with an increase in insulin-stimulated glucose transport in type IIb fibers, while type I fibers were unaffected. The enhanced glucose transport was mirrored by a fiber type-specific increase in GLUT4 expression, while no improvement in insulin-signaling activity was observed. S15511 is a novel insulin sensitizer that is capable of improving glucose homeostasis in nondiabetic rats. The compound enhances skeletal muscle insulin sensitivity and specifically targets type IIb muscle fibers by increasing GLUT4 expression. Together these data show S15511 to be a potentially promising new drug in the treatment and prevention of type 2 diabetes.

Key words

insulin sensitivity - type 2 diabetes - skeletal muscle - insulin sensitizer - GLUT4 - Wistar rat - insulin signaling

References

  • 1 Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, Willett WC. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women.  N Engl J Med. 2001;  345 790-797
    CrossrefPubMedGoogle Scholar
  • 2 Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, Marks JS. Diabetes trends in the U.S.: 1990-1998.  Diabetes Care. 2000;  23 1278-1283
    CrossrefPubMedGoogle Scholar
  • 3 UK Prospective Diabetes Study (UKPDS) Group . Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).  Lancet. 1998;  352 854-865
    CrossrefPubMedGoogle Scholar
  • 4 UK Prospective Diabetes Study (UKPDS) Group . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).  Lancet. 1998;  352 837-853
    CrossrefPubMedGoogle Scholar
  • 5 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.  N Engl J Med. 2002;  346 393-403
    CrossrefPubMedGoogle Scholar
  • 6 Knowler WC, Hamman RF, Edelstein SL, Barrett-Connor E, Ehrmann DA, Walker EA, Fowler SE, Nathan DM, Kahn SE. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program.  Diabetes. 2005;  54 1150-1156
    CrossrefPubMedGoogle Scholar
  • 7 Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial.  Lancet. 2002;  359 2072-2077
    CrossrefPubMedGoogle Scholar
  • 8 Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.  Lancet. 2006;  368 1096-1105
    CrossrefPubMedGoogle Scholar
  • 9 Knowler WC, Narayan KM, Hanson RL, Nelson RG, Bennett PH, Tuomilehto J, Schersten B, Pettitt DJ. Preventing non-insulin-dependent diabetes.  Diabetes. 1995;  44 483-488
    CrossrefPubMedGoogle Scholar
  • 10 Cline GW, Petersen KF, Krssak M, Shen J, Hundal RS, Trajanoski Z, Inzucchi S, Dresner A, Rothman DL, Shulman GI. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes.  N Engl J Med. 1999;  341 240-246
    CrossrefPubMedGoogle Scholar
  • 11 Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents.  Ann Intern Med. 1990;  113 909-915
    PubMedGoogle Scholar
  • 12 Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus.  J Clin Endocrinol Metab. 1996;  81 4059-4067
    PubMedGoogle Scholar
  • 13 Kim YB, Ciaraldi TP, Kong A, Kim D, Chu N, Mohideen P, Mudaliar S, Henry RR, Kahn BB. Troglitazone but not metformin restores insulin-stimulated phosphoinositide 3-kinase activity and increases p110beta protein levels in skeletal muscle of type 2 diabetic subjects.  Diabetes. 2002;  51 443-448
    CrossrefPubMedGoogle Scholar
  • 14 Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B, Hsueh WA, Inzucchi S, Kelley D, Nolan J, Olefsky JM, Polonsky KS, Silver D, Valiquett TR, Shulman GI. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial.  Ann Intern Med. 1998;  128 176-185
    PubMedGoogle Scholar
  • 15 Kubo K, Foley JE. Rate-limiting steps for insulin-mediated glucose uptake into perfused rat hindlimb.  Am J Physiol. 1986;  250 E100-E102
    PubMedGoogle Scholar
  • 16 Lund S, Holman GD, Schmitz O, Pedersen O. Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulin.  Proc Natl Acad Sci USA. 1995;  92 5817-5821
    CrossrefPubMedGoogle Scholar
  • 17 Welsh GI, Hers I, Berwick DC, Dell G, Wherlock M, Birkin R, Leney S, Tavare JM. Role of protein kinase B in insulin-regulated glucose uptake.  Biochem Soc Trans. 2005;  33 346-349
    CrossrefPubMedGoogle Scholar
  • 18 Lund S, Holman GD, Schmitz O, Pedersen O. Glut 4 content in the plasma membrane of rat skeletal muscle: comparative studies of the subcellular fractionation method and the exofacial photolabelling technique using ATB-BMPA.  FEBS Lett. 1993;  330 312-318
    CrossrefPubMedGoogle Scholar
  • 19 Marquie G, El Madani T, Solera ML, Duhault J, Espinal J, Khallayoun S, Bennani N. S15261, a novel agent for the treatment of insulin resistance. Studies on Psammomys obesus.  Life Sci. 1997;  61 1741-1753
    CrossrefPubMedGoogle Scholar
  • 20 Russell JC, Ravel D, Pegorier JP, Delrat P, Jochemsen R, O’Brien SF, Kelly SE, Davidge ST, Brindley DN. Beneficial insulin-sensitizing and vascular effects of S15261 in the insulin-resistant JCR:LA-cp rat.  J Pharmacol Exp Ther. 2000;  295 753-760
    PubMedGoogle Scholar
  • 21 Duhault J, Lacour F, Boulanger M, Della-Zuana O, Ravel D, Wierzbicki M, Espinal J. S15261, a new compound for the treatment of the insulin resistance syndrome.  Diabetologia. 1994;  37 969-975
    CrossrefPubMedGoogle Scholar
  • 22 Henquin JC, Garrino MG, Nenquin M. Stimulation of insulin release by benzoic acid derivatives related to the non-sulphonylurea moiety of glibenclamide: structural requirements and cellular mechanisms.  Eur J Pharmacol. 1987;  141 243-251
    CrossrefPubMedGoogle Scholar
  • 23 DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization.  Diabetes. 1981;  30 1000-1007
    CrossrefPubMedGoogle Scholar
  • 24 Armstrong RB, Phelps RO. Muscle fiber type composition of the rat hindlimb.  Am J Anat. 1984;  171 259-272
    CrossrefPubMedGoogle Scholar
  • 25 Nesher R, Karl IE, Kaiser KE, Kipnis DM. Epitrochlearis muscle. I. Mechanical performance, energetics, and fiber composition.  Am J Physiol. 1980;  239 E454-E460
    PubMedGoogle Scholar
  • 26 Wojtaszewski JF, Hansen BF, Urso B, Richter EA. Wortmannin inhibits both insulin- and contraction-stimulated glucose uptake and transport in rat skeletal muscle.  J Appl Physiol. 1996;  81 1501-1509
    PubMedGoogle Scholar
  • 27 Lund S, Flyvbjerg A, Holman GD, Larsen FS, Pedersen O, Schmitz O. Comparative effects of IGF-I and insulin on the glucose transporter system in rat muscle.  Am J Physiol. 1994;  267 E461-E466
    PubMedGoogle Scholar
  • 28 Tsao TS, Li J, Chang KS, Stenbit AE, Galuska D, Anderson JE, Zierath JR, MacCarter RJ, Charron MJ. Metabolic adaptations in skeletal muscle overexpressing GLUT4: effects on muscle and physical activity.  FASEB J. 2001;  15 958-969
    CrossrefPubMedGoogle Scholar
  • 29 Brozinick Jr JT, MacCoid SC, Reynolds TH, Nardone NA, Hargrove DM, Stevenson RW, Cushman SW, Gibbs EM. GLUT4 overexpression in db/db mice dose-dependently ameliorates diabetes but is not a lifelong cure.  Diabetes. 2001;  50 593-600
    CrossrefPubMedGoogle Scholar
  • 30 Daugaard JR, Richter EA. Relationship between muscle fibre composition, glucose transporter protein 4 and exercise training: possible consequences in non-insulin-dependent diabetes mellitus.  Acta Physiol Scand. 2001;  171 267-276
    CrossrefPubMedGoogle Scholar
  • 31 Cortez MY, Torgan CE, Brozinick Jr JT, Ivy JL. Insulin resistance of obese Zucker rats exercise trained at two different intensities.  Am J Physiol. 1991;  261 E613-E619
    PubMedGoogle Scholar
  • 32 Pruett ED, Oseid S. Effect of exercise on glucose and insulin response to glucose infusion.  Scand J Clin Lab Invest. 1970;  26 277-285
    CrossrefPubMedGoogle Scholar
  • 33 Nyholm B, Qu Z, Kaal A, Pedersen SB, Gravholt CH, Andersen JL, Saltin B, Schmitz O. Evidence of an increased number of type IIb muscle fibers in insulin-resistant first-degree relatives of patients with NIDDM.  Diabetes. 1997;  46 1822-1828
    CrossrefPubMedGoogle Scholar
  • 34 Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action.  J Clin Invest. 2001;  108 1167-1174
    CrossrefPubMedGoogle Scholar
  • 35 Jessen N, Pold R, Buhl ES, Jensen LS, Schmitz O, Lund S. Effects of AICAR and exercise on insulin-stimulated glucose uptake, signaling, and GLUT-4 content in rat muscles.  J Appl Physiol. 2003;  94 1373-1379
    PubMedGoogle Scholar
  • 36 Fujii N, Jessen N, Goodyear LJ. AMP-activated protein kinase and the regulation of glucose transport.  Am J Physiol Endocrinol Metab. 2006;  291 E867-E877
    CrossrefPubMedGoogle Scholar

Correspondence

N. JessenMD, PhD 

Medical Research Laboratory and Medical Department M (Endocrinology and Diabetes)

Aarhus University Hospital

8000 Aarhus C

Denmark

Phone: +45/89/49 16 15

Fax: +45/89/49 21 50

Email: Niels.Jessen@ki.au.dk