Advertisement
Clinical Studies| Volume 20, ISSUE 1, P125-140, January 1998

Download started.

Ok

Stimulation of glucose and amino acid transport and activation of the insulin signaling pathways by insulin lispro in L6 skeletal muscle cells

      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      The monomeric insulin analogue insulin lispro (Lys B28, Pro B29) is a rapid-acting insulin with a shorter duration of activity than human regular insulin. This compound has the advantage of reducing early postprandial hyperglycemia and the accompanying late hypoglycemia, thereby improving overall blood glucose control. To date, all published studies of the functional properties of insulin lispro have been conducted in whole animals. This study aimed to characterize the cellular actions of insulin lispro and the signals it elicits in an insulin-sensitive muscle cell line, L6 cells. Comparing the cellular actions of insulin lispro with those of human regular insulin, a number of observations were made. (1) Insulin lispro stimulated glucose and amino acid transport into L6 myotubes with a dose dependency and time course virtually identical to those of human regular insulin. (2) Insulin lispro was as effective as human regular insulin in stimulating time-dependent phosphorylation of insulin receptor substrate 1 (IRS-1), p70 ribosomal S6 kinase, and two isoforms of mitogen-activated protein kinase (ERK1 and ERK2). (3) Insulin lispro's ability to induce the association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase was similar to that of human regular insulin. (4) As with human regular insulin, 100 nmol of the fungal metabolite wortmannin completely inhibited insulin lispro stimulation of glucose uptake. We concluded that the cellular actions of insulin lispro are similar to those of human regular insulin with respect to glucose and amino acid uptake and that the biochemical signals elicited are also comparable.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Howey DC
        • Hooper SA
        • Bowsher RR
        [Lys(B28), Pro(B29)]-human insulin: An equipotent analog of human insulin with rapid onset and short duration of action.
        Diabetes. 1991; 40 (Abstract): 423A
        • Brems DN
        The role of insulin's C-terminal B-chain on association, folding and stability.
        Papers Am Chem Soc. 1991; 202 (Abstract): 132
        • Radziuk J
        • Candas B
        • Davies J
        • et al.
        The absorption kinetics of subcutaneously injected insulin and two monomeric analogs.
        Diabetologia. 1992; 35 (Abstract): A3
        • Shaw WN
        • Su KSE
        Biological aspects of a new insulin analog [Lys(B28), Pro (B29)]-human insulin.
        Diabetes. 1991; 40 (Abstract): 464A
        • Slieker LJ
        • Sundell K
        Modifications in the 28–29 positions of the insulin B-chain alter binding to the IGF-1 receptor with minimal effect on the insulin receptor binding.
        Diabetes. 1990; 39 (Abstract): 118A
        • Mitsumoto Y
        • Klip A
        Developmental regulation of the subcellular distribution and glycosylation of GLUT1 and GLUT4 glucose transporters during myogenesis of L6 muscle cells.
        J Biol Chem. 1992; 267: 4957-4962
        • Walker PS
        • Ramlal T
        • Sarabia V
        • et al.
        Glucose transport activity in L6 muscle cells is regulated by the coordinate control of subcellular glucose transporter distribution, biosynthesis, and mRNA transcription.
        J Biol Chem. 1990; 265: 1516-1523
        • Tsakiridis T
        • Vranic M
        • Klip A
        Phosphatidylinositol 3-kinase and the actin network are not required for the stimulation of glucose transport caused by mitochondrial uncoupling: Comparison with insulin action.
        Biochem J. 1995; 309: 1-5
        • Klip A
        • Li G
        • Logan WJ
        Induction of sugar uptake response to insulin by serum depletion in fusing L6 myotubes.
        Am J Physiol. 1984; 247: E494-E499
        • Klip A
        • Logan WJ
        • Lee G
        Hexose transport in L6 muscle cells: Kinetic properties and the number of [3H]cytochalasin B binding sites.
        Biochim Biophys Acta. 1982; 687: 265-280
        • Hundal HS
        • Ramlal T
        • Reyes R
        • et al.
        Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells.
        Endocrinology. 1992; 131: 1165-1173
        • Tsakiridis T
        • McDowell HE
        • Walker T
        • et al.
        Multiple roles of phosphatidylinositol 3-kinase in regulation of glucose transport, amino acid transport and glucose transporters in L6 skeletal muscle cells.
        Endocrinology. 1995; 136: 4315-4322
        • Guma A
        • Castello A
        • Testar X
        • et al.
        Differential sensitivity of insulin and adaptive regulation-induced system A activation to microtubular function in skeletal muscle.
        Biochem J. 1992; 281: 407-411
        • White MF
        • Kahn CR
        The insulin signaling system.
        J Biol Chem. 1994; 269: 1-4
        • Kasuga M
        • Karlsson FA
        • Kahn CR
        Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor.
        Science. 1982; 215: 185-187
        • White MF
        • Maron R
        • Kahn CR
        Insulin rapidly stimulates tyrosine phosphorylation of a Mr 185,000 protein in intact cells.
        Nature. 1985; 318: 183-186
        • Yaffe D
        Retention of differentiation potentialities during prolonged cultivation of myogenic cells.
        Proc Natl Acad Sci USA. 1968; 61: 477-483
        • Bilan PJ
        • Mitsumoto Y
        • Maher F
        • et al.
        Detection of the GLUT3 glucose transporter in rat L6 muscle cells: Regulation by cellular differentiation, insulin and insulin-like growth factor I.
        Biochem Biophys Res Commun. 1992; 186: 1129-1137
        • Bradford MM
        A rapid and sensitive method for the quantitation of microgram quantities of proteins utilising the principle of protein-dye binding.
        Ann Biochem. 1976; 72: 247-254
        • Hundal HS
        • Bilan PJ
        • Tsakiridis T
        • et al.
        Structural disruption of the trans-Golgi network does not interfere with the acute stimulation of glucose and amino acid uptake by insulin-like growth factor-1 in muscle cells.
        Biochem J. 1994; 297: 289-295
        • Cowley S
        • Paterson H
        • Kemp P
        • Marshall CJ
        Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells.
        Cell. 1994; 77: 841-852
        • Yano H
        • Nakanishi S
        • Kimura K
        • et al.
        Inhibition of histamine secretion by wortmannin through the blockade of phosphatidylinositol 3-kinase in RBL-2H3 cells.
        J Biol Chem. 1993; 268: 25846-25856
        • Yeh J
        • Gulves EA
        • Rameh L
        • Birnbaum MJ
        The effects of wortmannin on rat skeletal muscle.
        J Biol Chem. 1995; 270: 2107-2111
        • Clarke JF
        • Young PW
        • Yonezawa K
        • et al.
        Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol 3-kinase inhibitor, wortmannin.
        Biochem J. 1994; 300: 631-635
        • Guma A
        • Mora C
        • Santalucia T
        • et al.
        System A transport activity is stimulated in skeletal muscle in response to diabetes.
        FEBS Lett. 1992; 310: 51-54
        • Keller SR
        • Lienhard GE
        Insulin signalling: The role of insulin receptor substrate 1.
        Trends Cell Biol. 1994; 4: 115-118
        • Shepherd PR
        • Nave BT
        • O'Rahilly S
        The role of phosphoinositide 3-kinase in insulin signalling.
        J Mol Endocrinol. 1996; 17: 175-184
        • Saltiel AR
        Diverse signaling pathways in the cellular actions of insulin.
        Am J Physiol. 1996; 270: E375-E385
        • Cobb MH
        • Goldsmith EJ
        How MAP kinases are regulated.
        J Biol Chem. 1995; 270: 14843-14846
        • Proud CG
        P70 S6 kinase: Enigma with variations.
        Trends Biochem Sci. 1996; 21: 181-185
        • Taha C
        • Mitsumoto Y
        • Skolnik EY
        • Klip A
        The insulin-dependent biosynthesis of GLUT1 and GLUT3 glucose transporters of L6 muscle cells is mediated by different pathways: Roles of pp70 S6 kinase and Ras.
        J Biol Chem. 1995; 270: 24678-24681
        • Chung J
        • Kuo CJ
        • Crabtree GR
        • Blenis J
        Rapamycin-FKBP specifically blocks growth-dependent activation of and signalling by the 70 kD S6 protein kinases.
        Cell. 1992; 69: 1227-1236
        • Ferrari S
        • Bannwarth W
        • Morley SJ
        • et al.
        Activation of p70s6k is associated with phosphorylation of four clustered sites displaying Ser/Thr-Pro motifs.
        Proc Natl Acad Sci USA. 1992; 89: 3325-3335
        • Trautman ME
        Effect of the insulin analogue [Lys(B28), Pro(B29)] on blood glucose control.
        Horm Metab Res. 1994; 26: 588-590
        • Zinman B
        • Tildesley H
        • Chiasson J
        • et al.
        Insulin lispro in CSII: Results of a double-blind crossover study.
        Diabetes. 1997; 46: 440-443
        • Lahtela TT
        • Knip M
        • Paul R
        • et al.
        Severe antibody-mediated human insulin resistance: Successful treatment with the insulin analog lispro.
        Diabetes Care. 1997; 20: 71-73
        • Henrichs HR
        • Unger H
        • Trautman ME
        • Pfutzner A
        Severe insulin resistance treated with insulin lispro.
        Lancet. 1996; 348: 1248