Insulin-mediated hemodynamic changes are impaired in muscle of Zucker obese rats.

Insulin-mediated hemodynamic effects in muscle were assessed in relation to insulin resistance in obese and lean Zucker rats. Whole-body glucose infusion rate (GIR), femoral blood flow (FBF), hindleg glucose extraction (HGE), hindleg glucose uptake (HGU), 2-deoxyglucose (DG) uptake into muscles of the lower leg (R(g)), and metabolism of infused 1-methylxanthine (1-MX) to measure capillary recruitment were determined for isogylcemic (4.8 +/- 0.2 mmol/l, lean; 11.7 +/- 0.6 mmol/l, obese) insulin-clamped (20 mU. min(-1). kg(-1) x 2 h) and saline-infused control anesthetized age-matched (20 weeks) lean and obese animals. Obese rats (445 +/- 5 g) were less responsive to insulin than lean animals (322 +/- 4 g) for GIR (7.7 +/- 1.4 vs. 22.2 +/- 1.1 mg. min(-1). kg(-1), respectively), and when compared with saline-infused controls there was no increase due to insulin by obese rats in FBF, HGE, HGU, and R(g) of soleus, plantaris, red gastrocnemius, white gastrocnemius, extensor digitorum longus (EDL), or tibialis muscles. In contrast, lean animals showed marked increases due to insulin in FBF (5.3-fold), HGE (5-fold), HGU (8-fold), and R(g) ( approximately 5.6-fold). Basal (saline) hindleg 1-MX metabolism was 1.5-fold higher in lean than in obese Zucker rats, and insulin increased in only that of the lean. Hindleg 1-MX metabolism in the obese decreased slightly in response to insulin, thus postinsulin lean was 2.6-fold that of the postinsulin obese. We conclude that muscle insulin resistance of obese Zucker rats is accompanied by impaired hemodynamic responses to insulin, including capillary recruitment and FBF.

[1]  M. Clark,et al.  Lipid infusion impairs physiologic insulin-mediated capillary recruitment and muscle glucose uptake in vivo. , 2002, Diabetes.

[2]  S. Matsukura,et al.  Early events involved in the development of insulin resistance in Zucker fatty rat , 2002, International Journal of Obesity.

[3]  M. Clark,et al.  Contraction-mediated capillary recruitment is not impaired in muscle of insulin-resistant obese Zucker rats , 2002 .

[4]  M. Clark,et al.  Exercise training improves insulin-mediated capillary recruitment in association with glucose uptake in rat hindlimb. , 2001, Diabetes.

[5]  L. Mandarino,et al.  Exercise training increases ERK2 activity in skeletal muscle of obese Zucker rats. , 2001, Journal of applied physiology.

[6]  M. Clark,et al.  Inhibition of nitric oxide synthase prevents insulin-stimulated capillary recruitment and glucose uptake in skeletal muscle in vivo , 2001 .

[7]  M. Clark,et al.  Acute impairment of insulin-mediated capillary recruitment and glucose uptake in rat skeletal muscle in vivo by TNF-alpha. , 2000, Diabetes.

[8]  T. Franke,et al.  Divergent regulation of Akt1 and Akt2 isoforms in insulin target tissues of obese Zucker rats. , 2000, Diabetes.

[9]  M. White,et al.  Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. , 1999, The Journal of clinical investigation.

[10]  E. Barrett,et al.  Acute vasoconstriction-induced insulin resistance in rat muscle in vivo. , 1999, Diabetes.

[11]  C. Lang,et al.  Tissue‐specific effects of in vivo adenosine receptor blockade on glucose uptake in Zucker rats , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  H. Sekihara,et al.  Dehydroepiandrosterone Decreases Serum Tumor Necrosis Factor-α and Restores Insulin Sensitivity: Independent Effect from Secondary Weight Reduction in Genetically Obese Zucker Fatty Rats. , 1998, Endocrinology.

[13]  Y. Yazaki,et al.  Altered Expression Levels and Impaired Steps in the Pathway to Phosphatidylinositol 3-Kinase Activation via Insulin Receptor Substrates 1 and 2 in Zucker Fatty Rats , 1998, Diabetes.

[14]  J. Kolls,et al.  An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance: evidence for differential regulation of insulin signaling by TNF-alpha. , 1998, Endocrinology.

[15]  H. Sekihara,et al.  Dehydroepiandrosterone decreases serum tumor necrosis factor-alpha and restores insulin sensitivity: independent effect from secondary weight reduction in genetically obese Zucker fatty rats. , 1998, Endocrinology.

[16]  P. Björntorp,et al.  Interstitial Muscle Insulin and Glucose Levels in Normal and Insulin-Resistant Zucker Rats , 1997, Diabetes.

[17]  E. Barrett,et al.  Hemodynamic Actions of Insulin in Rat Skeletal Muscle: Evidence for Capillary Recruitment , 1997, Diabetes.

[18]  G. Williams,et al.  Impaired insulin-induced attenuation of noradrenaline-mediated vasoconstriction in insulin-resistant obese Zucker rats. , 1997, Clinical science.

[19]  G. Williams,et al.  Insulin-induced attenuation of noradrenaline-mediated vasoconstriction in resistance arteries from Wistar rats is nitric oxide dependent. , 1997, Clinical science.

[20]  M. Phillips,et al.  Leptin receptor missense mutation in the fatty Zucker rat , 1996, Nature Genetics.

[21]  B. Spiegelman,et al.  Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. , 1995, The Journal of clinical investigation.

[22]  P. Vollenweider,et al.  Nitric oxide release accounts for insulin's vascular effects in humans. , 1994, The Journal of clinical investigation.

[23]  M. Cawthorne,et al.  Potential defect in the vascular control of nonshivering thermogenesis in the obese Zucker rat hind limb. , 1994, Canadian journal of physiology and pharmacology.

[24]  N. Fineberg,et al.  Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. , 1994, The Journal of clinical investigation.

[25]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[26]  M. Zemel,et al.  Insulin attenuation of vasoconstrictor responses to phenylephrine in Zucker lean and obese rats. , 1991, American journal of hypertension.

[27]  H. Imura,et al.  Liver and muscle-fat type glucose transporter gene expression in obese and diabetic rats. , 1991, Biochemical and biophysical research communications.

[28]  W. M. Sherman,et al.  Exercise training increases glucose transporter protein GLUT‐4 in skeletal muscle of obese Zucker (fa/fa) rats , 1990, FEBS letters.

[29]  J. Ivy,et al.  Muscle morphological and biochemical adaptations to training in obese Zucker rats. , 1989, Journal of applied physiology.

[30]  R. Hamlin,et al.  Capillary Basement Membrane Thickness and Capillary Density in Sedentary and Trained Obese Zucker Rats , 1989, Diabetes.

[31]  T. Kurtz,et al.  The Zucker Fatty Rat as a Genetic Model of Obesity and Hypertension , 1989, Hypertension.

[32]  R. Withers,et al.  Glucose transport: locus of muscle insulin resistance in obese Zucker rats. , 1988, The American journal of physiology.

[33]  P. Ferré,et al.  Development of Obesity in Zucker Rats: Early Insulin Resistance in Muscles But Normal Sensitivity in White Adipose Tissue , 1987, Diabetes.

[34]  D. James,et al.  Heterogeneity of insulin action in individual muscles in vivo: euglycemic clamp studies in rats. , 1985, The American journal of physiology.

[35]  D. James,et al.  Dose-response curves for in vivo insulin sensitivity in individual tissues in rats. , 1985, The American journal of physiology.

[36]  J. Stern,et al.  Dynamics of pancreatic insulin release in young Zucker rats: a heterozygote effect. , 1985, The American journal of physiology.

[37]  B. Jeanrenaud,et al.  In vivo hepatic and peripheral insulin resistance in genetically obese (fa/fa) rats. , 1983, Endocrinology.

[38]  M. Prentki,et al.  Insulin resistance in soleus muscle from obese Zucker rats. Involvement of several defective sites. , 1980, The Biochemical journal.

[39]  M. Berger,et al.  Glucose metabolism in perfused skeletal muscle. Demonstration of insulin resistance in the obese Zucker rat. , 1979, The Biochemical journal.

[40]  H. Antoniades,et al.  Insulin and obesity in the Zucker genetically obese rat "fatty". , 1972, Endocrinology.

[41]  L. Zucker.  HEREDITARY OBESITY IN THE RAT ASSOCIATED WITH HYPERLIPEMIA * , 1965, Annals of the New York Academy of Sciences.