Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes

被引:177
作者
Friedman, JE
Ishizuka, T
Shao, JH
Huston, L
Highman, T
Catalano, P
机构
[1] Case Western Reserve Univ, Sch Med, Dept Nutr, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Sch Med, Dept Reprod Biol, Cleveland, OH 44106 USA
[3] Metrohlth Med Ctr, Cleveland, OH 44109 USA
关键词
D O I
10.2337/diabetes.48.9.1807
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Women who develop gestational diabetes mellitus (GDM) have severe insulin resistance and markedly increased risk to develop subsequent type 2 diabetes. We investigated the effects of pregnancy and GDM on glucose transport activity and the expression and phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1 in human skeletal muscle fiber strips in vitro, Rectus abdominis muscle biopsies were obtained at the time of cesarean section from 11 pregnant women with normal glucose tolerance (pregnant control), 7 pregnant women with GDM, and 11 non-pregnant women undergoing elective surgery (nonpregnant control), Subjects were matched for age and similar degree of obesity. The rate of maximal insulin (10(-7) mol/l)-stimulated 2-deoxyglucose transport was reduced by 32% (P < 0.05) in muscle strips from the pregnant control group and even further in GDM subjects by 54% (P < 0.05 vs, pregnant control). The maximal effect of insulin on tyrosine phosphorylation of the insulin receptor was 37% lower (P < 0.05) in GDM subjects than in pregnant control subjects and was not related to changes in the abundance of the insulin receptor, Compared with nonpregnant control subjects, maximal insulin-stimulated IRS-1 tyrosine phosphorylation was significantly lower by 59 +/- 24% (mean +/- SD) (P < 0.05) and 62 +/- 28% (P < 0.05) in pregnant control and GDM subjects, respectively. This was reflected by a 23% (P < 0.05) and 44% (P < 0.002) reduction in IRS-1 protein levels in muscle from pregnant control and GDM subjects. Both pregnant control and GDM subjects exhibited a 1.5- to 2-fold increase in the levels of IRS-2 (P < 0.01) and p85 alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase (P < 0,05), despite reduced glucose transport activity. These data indicate that insulin resistance to glucose transport during pregnancy is uniquely associated with a decrease in IRS-1 tyrosine phosphorylation, primarily due to decreased expression of IRS-I protein. However, in GDM subjects, a decrease in tyrosine phosphorylation of the insulin receptor P-subunit is associated with further decreases in glucose transport activity. Thus, impaired insulin receptor autophosphorylation is an important early distinction underlying muscle insulin resistance in young women with GDM, and it may underlie future risk for the development of type 2 diabetes.
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页码:1807 / 1814
页数:8
相关论文
共 54 条
[1]   ALTERNATIVE PATHWAY OF INSULIN SIGNALING IN MICE WITH TARGETED DISRUPTION OF THE IRS-1 GENE [J].
ARAKI, E ;
LIPES, MA ;
PATTI, ME ;
BRUNING, JC ;
HAAG, B ;
JOHNSON, RS ;
KAHN, CR .
NATURE, 1994, 372 (6502) :186-190
[2]   PHOSPHATIDYLINOSITOL 3'-KINASE IS ACTIVATED BY ASSOCIATION WITH IRS-1 DURING INSULIN STIMULATION [J].
BACKER, JM ;
MYERS, MG ;
SHOELSON, SE ;
CHIN, DJ ;
SUN, XJ ;
MIRALPEIX, M ;
HU, P ;
MARGOLIS, B ;
SKOLNIK, EY ;
SCHLESSINGER, J ;
WHITE, MF .
EMBO JOURNAL, 1992, 11 (09) :3469-3479
[3]  
BARDEN T P, 1981, Clinical Obstetrics and Gynecology, V24, P3, DOI 10.1097/00003081-198103000-00005
[4]   Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation [J].
Bjornholm, M ;
Kawano, Y ;
Lehtihet, M ;
Zierath, JR .
DIABETES, 1997, 46 (03) :524-527
[5]   RELATIONSHIP BETWEEN OBESITY AND MAXIMAL INSULIN-STIMULATED GLUCOSE-UPTAKE INVIVO AND INVITRO IN PIMA-INDIANS [J].
BOGARDUS, C ;
LILLIOJA, S ;
MOTT, D ;
REAVEN, GR ;
KASHIWAGI, A ;
FOLEY, JE .
JOURNAL OF CLINICAL INVESTIGATION, 1984, 73 (03) :800-805
[6]   TRANSMEMBRANE GLUCOSE-TRANSPORT IN SKELETAL-MUSCLE OF PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES [J].
BONADONNA, RC ;
DELPRATO, S ;
SACCOMANI, MP ;
BONORA, E ;
GULLI, G ;
FERRANNINI, E ;
BIER, D ;
COBELLI, C ;
DEFRONZO, RA .
JOURNAL OF CLINICAL INVESTIGATION, 1993, 92 (01) :486-494
[7]   GLUCOSE-TRANSPORT IN HUMAN SKELETAL-MUSCLE - THE INVIVO RESPONSE TO INSULIN [J].
BONADONNA, RC ;
SACCOMANI, MP ;
SEELY, L ;
ZYCH, KS ;
FERRANNINI, E ;
COBELLI, C ;
DEFRONZO, RA .
DIABETES, 1993, 42 (01) :191-198
[8]   INSULIN SENSITIVITY AND B-CELL RESPONSIVENESS TO GLUCOSE DURING LATE PREGNANCY IN LEAN AND MODERATELY OBESE WOMEN WITH NORMAL GLUCOSE-TOLERANCE OR MILD GESTATIONAL DIABETES [J].
BUCHANAN, TA ;
METZGER, BE ;
FREINKEL, N ;
BERGMAN, RN .
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 1990, 162 (04) :1008-1014
[9]   INSULIN-RECEPTOR KINASE IN HUMAN SKELETAL-MUSCLE FROM OBESE SUBJECTS WITH AND WITHOUT NONINSULIN DEPENDENT DIABETES [J].
CARO, JF ;
SINHA, MK ;
RAJU, SM ;
ITTOOP, O ;
PORIES, WJ ;
FLICKINGER, EG ;
MEELHEIM, D ;
DOHM, GL .
JOURNAL OF CLINICAL INVESTIGATION, 1987, 79 (05) :1330-1337
[10]   SUBCLINICAL ABNORMALITIES OF GLUCOSE-METABOLISM IN SUBJECTS WITH PREVIOUS GESTATIONAL DIABETES [J].
CATALANO, PM ;
BERNSTEIN, IM ;
WOLFE, RR ;
SRIKANTA, S ;
TYZBIR, E ;
SIMS, EAH .
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 1986, 155 (06) :1255-1262