α-lipoic acid mitigates insulin resistance in Goto-Kakizaki rats

被引:47
作者
Bitar, MS [1 ]
Wahid, S
Pilcher, CWT
Al-Saleh, E
Al-Mulla, F
机构
[1] Kuwait Univ, Fac Med, Dept Pharmacol & Toxicol, Safat, Kuwait
[2] Kuwait Univ, Fac Med, Dept Pathol, Safat, Kuwait
[3] Kuwait Univ, Fac Med, Dept Obstet & Gynaecol, Safat, Kuwait
关键词
insulin resistance; alpha-lipoic acid; Goto-Kakizaki rats; type II diabetes;
D O I
10.1055/s-2004-825760
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Impaired glucose uptake and metabolism by peripheral tissues is a common feature in both type I and type II diabetes mellitus. This phenomenon was examined in the context of oxidative stress and the early events within the insulin signalling pathway using soleus muscles derived from non-obese, insulin-resistant type II diabetic Goto-Kakizaki (GK) rats, a well-known genetic rat model for human type II diabetes. Insulin-stimulated glucose transport was impaired in soleus muscle from GK rats. Oxidative and non-oxidative glucose disposal pathways represented by glucose oxidation and glycogen synthesis in soleus muscles of GK rats appear to be resistant to the action of insulin when compared to their corresponding control values. These diabetesrelated abnormalities in glucose disposal were associated with a marked diminution in the insulin-mediated enhancement of protein kinase B (Akt/PKB) and insulin receptor substrate-1 (IRS-1)-associated phosphatidylinostol 3-kinase (PI 3-kinase) activities; these two kinases are key elements in the insulin signalling pathway. Moreover, heightened state of oxidative stress, as indicated by protein bound carbonyl content, was evident in soleus muscle of GK diabetic rats. Chronic administration of the hydrophobic/hydrophilic antioxidant alpha-lipoic-acid (ALA, 100 mg/kg, ip) partly ameliorated the diabetes-related deficit in glucose metabolism, protein oxidation as well as the activation by insulin of the various steps of the insulin signalling pathway, including the enzymes Akt/PKB and PI-3 kinase. Overall, the current investigation illuminates the concept that oxidative stress may indeed be involved in the pathogenesis of certain types of insulin resistance. It also harmonizes with the notion of including potent antioxidants such as ALA in the armamentarium of antidiabetic therapy.
引用
收藏
页码:542 / 549
页数:8
相关论文
共 69 条
[1]   Protein kinase C modulates the insulin-stimulated increase in Akt1 and Akt3 activity in 3T3-L1 adipocytes [J].
Barthel, A ;
Nakatani, K ;
Dandekar, AA ;
Roth, RA .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 243 (02) :509-513
[2]   The proto-oncogene product c-Crk associates with insulin receptor substrate-1 and 4PS - Modulation by insulin growth factor-1 (IGF) and enhanced IGF-1 signaling [J].
BeitnerJohnson, D ;
Blakesley, VA ;
ShenOrr, Z ;
Jimenez, M ;
Stannard, B ;
Wang, LM ;
Pierce, J ;
LeRoith, D .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (16) :9287-9290
[3]   Akt activation by growth factors is a multiple-step process: the role of the PH domain [J].
Bellacosa, A ;
Chan, TO ;
Ahmed, NN ;
Datta, K ;
Malstrom, S ;
Stokoe, D ;
McCormick, F ;
Feng, JN ;
Tsichlis, P .
ONCOGENE, 1998, 17 (03) :313-325
[4]   The pharmacology of the antioxidant lipoic acid [J].
Biewenga, GP ;
Haenen, GRMM ;
Bast, A .
GENERAL PHARMACOLOGY, 1997, 29 (03) :315-331
[5]   Regulation of glucose transport and glycogen synthesis in L6 muscle cells during oxidative stress - Evidence for cross-talk between the insulin and SAPK2/p38 mitogen-activated protein kinase signaling pathways [J].
Blair, AS ;
Hajduch, E ;
Litherland, GJ ;
Hundal, HS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (51) :36293-36299
[6]   Biochemistry and molecular cell biology of diabetic complications [J].
Brownlee, M .
NATURE, 2001, 414 (6865) :813-820
[7]   PROTEIN-KINASE-B (C-AKT) IN PHOSPHATIDYLINOSITOL-3-OH INASE SIGNAL-TRANSDUCTION [J].
BURGERING, BMT ;
COFFER, PJ .
NATURE, 1995, 376 (6541) :599-602
[8]  
CABALLERO B, 1993, NUTR REV, V51, P339, DOI 10.1111/j.1753-4887.1993.tb03761.x
[9]   The Tenth Datta Lecture - PDK1, one of the missing links in insulin signal transduction? [J].
Cohen, P ;
Alessi, DR ;
Cross, DAE .
FEBS LETTERS, 1997, 410 (01) :3-10
[10]   INHIBITION OF GLYCOGEN-SYNTHASE KINASE-3 BY INSULIN-MEDIATED BY PROTEIN-KINASE-B [J].
CROSS, DAE ;
ALESSI, DR ;
COHEN, P ;
ANDJELKOVICH, M ;
HEMMINGS, BA .
NATURE, 1995, 378 (6559) :785-789