Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Metabolism and Signal Transduction

Differential Effects of Rosiglitazone on Skeletal Muscle and Liver Insulin Resistance in A-ZIP/F-1 Fatless Mice

  1. Jason K. Kim1,
  2. Jonathan J. Fillmore1,
  3. Oksana Gavrilova2,
  4. Lily Chao2,
  5. Takamasa Higashimori1,
  6. Hyejeong Choi1,
  7. Hyo-Jeong Kim1,
  8. Chunli Yu1,
  9. Yan Chen3,
  10. Xianqin Qu4,
  11. Martin Haluzik2,
  12. Marc L. Reitman2 and
  13. Gerald I. Shulman135
  1. 1Department of Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
  2. 2Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
  3. 3Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
  4. 4Department of Health Sciences, University of Technology, Sydney, New South Wales, Australia
  5. 5Department of Cellular and Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
    Diabetes 2003 Jun; 52(6): 1311-1318. https://doi.org/10.2337/diabetes.52.6.1311
    PreviousNext
    • Article
    • Figures & Tables
    • Info & Metrics
    • PDF
    Loading

    Abstract

    To determine the role of adipocytes and the tissue-specific nature in the insulin sensitizing action of rosiglitazone, we examined the effects of 3 weeks of rosiglitazone treatment on insulin signaling and action during hyperinsulinemic-euglycemic clamps in awake A-ZIP/F-1 (fatless), fat-transplanted fatless, and wild-type littermate mice. We found that 53 and 66% decreases in insulin-stimulated glucose uptake and insulin receptor substrate (IRS)-1–associated phosphatidylinositol (PI) 3-kinase activity in skeletal muscle of fatless mice were normalized after rosiglitazone treatment. These effects of rosiglitazone treatment were associated with 50% decreases in triglyceride and fatty acyl-CoA contents in the skeletal muscle of rosiglitazone-treated fatless mice. In contrast, rosiglitazone treatment exacerbated hepatic insulin resistance in the fatless mice and did not affect already reduced IRS-2–associated PI 3-kinase activity in liver. The worsening of insulin action in liver was associated with 30% increases in triglyceride and fatty acyl-CoA contents in the liver of rosiglitazone-treated fatless mice. In conclusion, these data support the hypothesis that rosiglitazone treatment enhanced insulin action in skeletal muscle mostly by its ability to repartition fat away from skeletal muscle.

    Thiazolidinediones (TZDs) are antidiabetic agents that improve glucose tolerance in patients with type 2 diabetes mostly through enhancing insulin sensitivity in skeletal muscle (1–6). Despite its widespread use, the mechanism by which TZDs increase insulin sensitivity in muscle is much debated. Because TZDs are high-affinity ligands for the transcription factor peroxisome proliferator–activated receptor-γ (PPAR-γ), which is expressed at high levels in adipose tissue (7,8), some investigators have hypothesized that the insulin-sensitizing action of TZDs may involve activation of PPAR-γ in adipocytes resulting in adipocyte differentiation/hyperplasia and partitioning of fat away from skeletal muscle and into adipocytes (9–14). In contrast, others have argued that TZDs may directly affect skeletal muscle insulin sensitivity by binding to PPAR-γ present in this tissue (15) and altering expression of genes involved in fat and glucose metabolism (8,16–18). Recently, Burant et al. (19) demonstrated that troglitazone altered glucose metabolism in ap2/DTA mice that partially lack white and brown adipose tissues and suggested that the insulin-sensitizing action of TZDs may be independent of adipose tissue, therefore supporting the latter hypothesis. In contrast, Chao et al. (20) recently demonstrated that rosiglitazone failed to improve hyperglycemia and glucose intolerance of A-ZIP/F-1 “fatless” mice, which virtually lack white adipose tissue, suggesting that adipose tissue is required for PPAR-γ’s insulin sensitizing action. One possible explanation for these different results may be due to the differences in the severity of lipodystrophy, whereby A-ZIP/F-1 mice are more devoid of fat than ap2/DTA mice (19,21). Furthermore, neither of these previous studies examined the effect of rosiglitazone on insulin action in specific tissues (e.g., liver, skeletal muscle, adipocytes). Therefore, to determine the mechanism of TZDs’ insulin-sensitizing action, we examined the effects of rosiglitazone treatment in A-ZIP/F-1, fat-transplanted A-ZIP/F-1, and wild-type littermate mice on insulin action and signaling in skeletal muscle, liver, and adipose tissue during hyperinsulinemic-euglycemic clamps and combined these measurements with liquid chromatography tandem mass spectrometry (LC/MS/MS) measurements of fatty acyl-CoA and ceramide content in these tissues.

    RESEARCH DESIGN AND METHODS

    Animals.

    Male wild-type (n = 10), fatless (A-ZIP/F-1; n = 13), and female fat-transplanted fatless (n = 19) mice were studied at 13 weeks of age (22–24 g of body weight) with or without 3 weeks of rosiglitazone treatment (3 mg/kg rosiglitazone mixed with an AIN-93G diet [20]). All of the mice were generated with FVB as the background strain. For the fat-transplantation, ∼500 mg of parametrial fat from wild-type littermates was transplanted into dorsal subcutaneous tissue of fatless mice at 5 weeks of age (22). Fatless mice received a sham operation at the same age. Animals were housed under controlled temperature (23°C) and lighting (12-h light; 0600–1800, 12-h dark; 1800–0600) with free access to water and mouse diet. All procedures were approved by the Yale University and National Institute of Diabetes and Digestive and Kidney Diseases Animal Care and Use Committees.

    Surgery and animal handling.

    At least 4 days before hyperinsulinemic-euglycemic clamp experiments, mice were anesthetized with an intraperitoneal injection of ketamine (100 mg/kg body wt) and xylazine (10 mg/kg body wt), and an indwelling catheter was inserted in the left internal jugular vein. The catheters were externalized through an incision in the skin flap behind the head, and the mice were returned to individual cages after the surgery. Mice had fully recuperated from the surgery before the in vivo experiments as reflected by their reaching preoperative weight. For conducting experiments in awake mice with minimal stress, a tail restraint method was used (23).

    Hyperinsulinemic-euglycemic clamp to assess in vivo insulin action in awake mice.

    After an overnight fast, high-performance liquid chromatography–purified [3-3H]glucose (0.05 μCi/min; NEN Life Science, Boston, MA) was infused during the 2-h basal period, and blood samples (∼40 μl) were collected at the end to estimate the rate of basal hepatic glucose production. After the basal period, a 120-min hyperinsulinemic-euglycemic clamp was conducted with a primed-continuous infusion of human insulin (Humulin; Eli Lilly, Indianapolis, IN) at a rate of 15 pmol · kg−1 · min−1 to raise plasma insulin within a physiological range (∼650 pmol/l). Blood samples (∼20 μl) were collected at 20-min intervals for the immediate measurement of plasma glucose concentration, and 20% glucose was infused at variable rates to maintain plasma glucose at basal concentrations. Insulin-stimulated whole-body glucose uptake and metabolism were estimated using a primed-continuous infusion of [3-3H]glucose (10 μCi bolus, 0.1 μCi/min) throughout the clamps. All infusions were done using microdialysis pumps (CMA/Micro-dialysis; North Chelmsford, MA). For estimating insulin-stimulated glucose uptake in individual tissues, 2-deoxy-d-[1-14C]glucose (2-[14C]DG; NEN) was administered as a bolus (10 μCi) at 75 min after the start of clamps. Because 2-deoxyglucose is a glucose analog that is phosphorylated but not metabolized, insulin-stimulated glucose uptake in individual tissues can be estimated by determining the tissue content of 2-deoxyglucose-6-phosphate. Blood samples (20 μl) were taken at 80, 85, 90, 100, 110, and 120 min after the start of clamps for the determination of plasma [3H]glucose, 3H2O, and 2-[14C]DG concentrations. Additional blood samples (20 μl) were collected at the end of clamps for measurement of plasma insulin concentrations. At the end of clamp experiments, mice were anesthetized with sodium pentobarbital injection. Within 5 min, three muscles (gastrocnemius, tibialis anterior, and quadriceps) from both hindlimbs, epididymal white adipose tissue, intrascapular brown adipose tissue, liver, and heart were taken. Each tissue, once exposed, was dissected out within 2 s, frozen immediately using liquid N2-cooled aluminum blocks, and stored at −70°C for later analysis.

    In vivo glucose flux analysis and calculations.

    Plasma glucose concentration during the clamp study was analyzed using 10 μl of plasma by a glucose oxidase method on a Beckman Glucose Analyzer 2 (Beckman, Fullerton, CA). Plasma insulin concentration was measured by radioimmunoassay using kits from Linco Research (St. Charles, MO). Tissue triglyceride concentrations were determined using Triglyceride Diagnostic Kit (Sigma Chemicals, St. Louis, MO) after tissue homogenization using chloroform/methanol. For the determination of plasma [3-3H]glucose and 2-[14C]DG concentrations, plasma was deproteinized with ZnSO4 and Ba(OH)2, dried to remove 3H2O, resuspended in water, and counted in scintillation fluid (Ultima Gold; Packard, Meridien, CT) on dual channels for separation of 3H and 14C. The plasma concentration of 3H2O was determined by the difference between 3H counts without and with drying. The radioactivity of 3H in tissue glycogen was determined by digesting tissue samples in KOH and precipitating glycogen with ethanol (23). For the determination of tissue 2-[14C]DG-6-phosphate (2-DG-6-P) content, tissue samples were homogenized, and the supernatants were subjected to an ion-exchange column to separate 2-DG-6-P from 2-DG (23). Rates of basal hepatic glucose production and insulin-stimulated whole-body glucose uptake were determined as the ratio of the [3H]glucose infusion rate (disintegrations per minute [dpm]/min) to the specific activity of plasma glucose (dpm/μmol) at the end of basal period and during the final 30 min of clamps, respectively. Hepatic glucose production during the hyperinsulinemic-euglycemic clamps was determined by subtracting the glucose infusion rate from the whole-body glucose uptake. Whole-body glycolysis was calculated from the rate of increase in plasma 3H2O concentration, determined by linear regression of the measurements at 80, 90, 100, 110, and 120 min. Whole-body glycogen and lipid synthesis were estimated by subtracting whole-body glycolysis from whole-body glucose uptake, assuming that glycolysis and glycogen/lipid synthesis account for the majority of insulin-stimulated glucose uptake (24). Glucose uptake in individual tissues was calculated from plasma 2-[14C]DG profile, which was fitted with a double exponential curve using MLAB (Civilized Software, Bethesda, MD) and tissue 2-DG-6-P content (23). Skeletal muscle glycogen synthesis was calculated from 3H incorporation to muscle glycogen (23). Skeletal muscle glycolysis was then estimated as the difference between muscle glucose uptake and glycogen synthesis.

    Insulin signaling analysis.

    Tyrosine phosphorylation of insulin receptor substrate (IRS)-1/IRS-2 and IRS-1/IRS-2–associated phosphatidylinositol (PI) 3-kinase activity in skeletal muscle (gastrocnemius) and liver were measured by immunoprecipitating IRS-1/IRS-2 using antibodies to IRS-1/IRS-2 (provided by Dr. Morris White, Joslin Diabetes Center, Boston, MA) and assessing the incorporation of 32P into PI to yield PI-3-monophosphate. Tyrosine phosphorylation of insulin receptor in skeletal muscle was measured using antiphosphotyrosine antibody (Upstate Biotechnology, Lake Placid, NY).

    Mass spectrometry.

    For determining the tissue-specific concentrations of fatty acid–derived metabolites (i.e., fatty acyl-CoA and ceramide) using LC/MS/MS, skeletal muscle (quadriceps) and liver (∼100 mg) were homogenized and prepared using a modified method of Bligh et al. (25). PE sciex API 3000 tandem mass spectrometer interfaced with TurboIonSpray ionization source was used for the analysis. The concentrations of long-chain fatty acyl-CoAs (C16, C16:1, C18, C18:1, and C18:2) were detected in negative electrospray mode, and C17 CoA ester was used as an internal standard. The doubly charged ions of these compounds were transmitted, and singly charged product ions were quantified in MRM mode. For the concentrations of ceramide, the transition pairs [M+H-H2O]+/264.4 (common product ion for all ceramides) were monitored in positive MRM mode for individual ceramide species, and C6 sphingosine was used as an internal standard.

    Statistical analysis.

    Data are expressed as means ± SE. The statistical significance of the difference in mean values among wild-type, fatless, and fat-transplanted fatless mice with or without rosiglitazone treatment was evaluated using the Duncan’s multiple range test.

    RESULTS

    Insulin action on glucose uptake and metabolism was examined during a 2-h hyperinsulinemic-euglycemic clamp in awake wild-type, fatless, and fat-transplanted fatless mice with or without 3 weeks of rosiglitazone treatment. Overnight fasted plasma glucose concentration was significantly increased in the fatless mice as compared with the wild-type mice (Table 1). After rosiglitazone treatment, plasma glucose concentration was significantly decreased when compared with the untreated fatless mice but remained elevated as compared with the wild-type mice (Table 1). In contrast, fat transplantation, with or without rosiglitazone treatment, normalized plasma glucose concentration in the fatless mice. Overnight fasted plasma insulin concentrations did not differ among the groups (Table 1). During the clamps, plasma insulin concentration was raised to ∼650 pmol/l, whereas the plasma glucose concentration was maintained at ∼7 mmol/l by a variable infusion of glucose in all groups (Table 1). The glucose infusion rate required to maintain euglycemia increased rapidly in the wild-type and rosiglitazone-treated wild-type mice and reached a steady state within 90 min. In contrast, there was a markedly blunted insulin response during the hyperinsulinemic-euglycemic clamp studies in the fatless and rosiglitazone-treated fatless mice, as reflected by a much lower steady-state glucose infusion rate in the fatless and rosiglitazone-treated fatless mice (78 ± 25 and 40 ± 12 μmol · kg−1 · min−1, respectively, vs. 296 ± 33 μmol · kg−1 · min−1 in the wild-type mice; P < 0.001). Fat transplantation with or without rosiglitazone treatment increased steady-state glucose infusion rate to the level similar to the wild-type mice (231 ± 17 or 199 ± 31 μmol · kg−1 · min−1, respectively).

    Basal hepatic glucose production (HGP) showed a tendency to increase in the fatless mice (P = 0.08) and was significantly elevated after rosiglitazone treatment in the fatless mice (Fig. 1A). Insulin suppressed basal HGP by 80% in the wild-type mice with or without rosiglitazone treatment (Fig. 1B). In contrast, insulin suppressed basal HGP by 30% in the fatless mice and failed to suppress basal HGP after rosiglitazone treatment in the fatless mice. Fat transplantation restored insulin’s ability to suppress basal HGP with or without rosiglitazone treatment (Fig. 1B). Insulin-stimulated whole-body glucose turnover was decreased by 40% in the fatless mice but was normalized to the level similar to that of wild-type mice after rosiglitazone treatment (P = 0.05 for fatless mice vs. rosiglitazone-treated fatless mice) and/or fat transplantation in the fatless mice (Fig. 1C). The rate of insulin-stimulated glucose uptake in skeletal muscle in vivo was estimated using 2-deoxy-d-[1-14C]glucose injection during hyperinsulinemic-euglycemic clamps in awake mice. Insulin-stimulated glucose uptake in skeletal muscle (gastrocnemius) was decreased by 53% in the fatless mice but was normalized after rosiglitazone treatment and/or fat transplantation in the fatless mice (Fig. 1D).

    Insulin-stimulated whole-body glycolysis was not significantly different among the groups, although it showed a tendency to decrease in the fatless mice and a tendency to increase after rosiglitazone treatment in the fatless mice (Fig. 2A). Insulin-stimulated whole-body glycogen/lipid synthesis were decreased by 66% in the fatless mice with or without rosiglitazone treatment and showed a tendency to increase after fat transplantation with or without rosiglitazone treatment (Fig. 2B). Similar to the pattern of changes in whole-body glucose metabolism, insulin-stimulated skeletal muscle glycolysis was decreased by 52% in the fatless mice and returned to normal after rosiglitazone treatment and/or fat transplantation (Fig. 2C). Insulin-stimulated muscle glycogen synthesis was decreased by 68% in the fatless mice and was normalized after rosiglitazone treatment and/or fat transplantation (Fig. 2D). These findings suggest that decreases in insulin-stimulated muscle glucose uptake was partly responsible for decreases in muscle glucose metabolism and that normalization of insulin-stimulated muscle glucose uptake also restored muscle glucose metabolism after rosiglitazone treatment and/or fat transplantation.

    Recent studies in IRS-1 and IRS-2 gene–disrupted mice have suggested that IRS-1 is important in insulin activation of muscle glucose metabolism (i.e., insulin-stimulated glucose transport and glycogen synthase activity), whereas IRS-2 is more important in mediating insulin activation of hepatic glucose metabolism (i.e., insulin suppression of basal HGP) (25–27). Insulin-stimulated IRS-1 tyrosine phosphorylation in skeletal muscle (gastrocnemius) was decreased by 65% in the fatless mice and returned to normal after rosiglitazone treatment and/or fat transplantation (Fig. 3A). Similarly, insulin-stimulated IRS-1–associated PI 3-kinase activity in skeletal muscle (gastrocnemius) was decreased by 66% in the fatless mice and was normalized after rosiglitazone treatment and/or fat transplantation (Fig. 3B). Insulin-stimulated IRS-2 tyrosine phosphorylation in liver was decreased by 45% in the fatless mice and showed a tendency to be further reduced after rosiglitazone treatment (Fig. 3C). Similarly, insulin-stimulated IRS-2–associated PI 3-kinase activity in liver was significantly decreased by 66% in the fatless mice and showed a tendency to be further reduced after rosiglitazone treatment (P = 0.09; Fig. 3D).

    To examine whether the changes in insulin signaling and action were associated with changes in tissue-specific fat contents, triglyceride, fatty acyl-CoA, and ceramide concentrations were measured in skeletal muscle and liver using LC/MS/MS. Triglyceride concentration in skeletal muscle (quadriceps) was increased in the fatless mice and returned to normal after rosiglitazone and/or fat transplantation (Fig. 4A). Long-chain fatty acyl-CoA concentration in skeletal muscle (quadriceps) was increased in the fatless mice and returned to normal after rosiglitazone treatment or fat transplantation (Fig. 4B). Rosiglitazone treatment or fat transplantation did not affect ceramide concentration in skeletal muscle (quadriceps) of the fatless mice (18 ± 2, 24 ± 4, 17 ± 3, and 19 ± 2 nmol/g in the wild-type, fatless, rosiglitazone-treated fatless, and fat-transplanted fatless mice, respectively). Furthermore, triglyceride concentration in liver was increased in the fatless mice and showed a tendency to increase further after rosiglitazone treatment in the fatless mice (P = 0.09; Fig. 4C). In contrast, fat transplantation with or without rosiglitazone treatment lowered the liver triglyceride concentration to the level similar to the wild-type mice. Long-chain fatty acyl-CoA concentration in liver was increased in the fatless mice and was further increased after rosiglitazone treatment in the fatless mice (Fig. 4D). In contrast, fat transplantation lowered the liver fatty acyl-CoA concentration in the fatless mice. Rosiglitazone treatment or fat transplantation did not affect ceramide concentration in the liver of fatless mice (375 ± 15, 457 ± 44, 377 ± 43, and 383 ± 15 nmol/g in the wild-type, fatless, rosiglitazone-treated fatless, and fat-transplanted fatless mice, respectively).

    Insulin-stimulated glucose uptake in tibialis anterior muscle was reduced in the fatless mice but increased after rosiglitazone treatment and/or fat transplantation, consistent with the findings in the gastrocnemius muscles (Fig. 5A). Insulin-stimulated glucose uptake in intrascapular brown adipose tissue was increased with rosiglitazone treatment in the wild-type mice, whereas it was decreased in the fatless and fat-transplanted fatless mice with or without rosiglitazone treatment (Fig. 5B). Last, insulin-stimulated glucose uptake in epididymal white adipose tissue was unaltered in the wild-type and fat-transplanted fatless mice with or without rosiglitazone treatment (Fig. 5C).

    DISCUSSION

    In this study, we used the A-ZIP/F-1 “fatless” mouse as an adipocyte null model to examine the role of adipocytes in the insulin-sensitizing action of rosiglitazone. Insulin-stimulated glucose uptake in skeletal muscle was significantly decreased in the fatless mice, which was associated with decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and decreased activation of IRS-1–associated PI 3-kinase activity. Because tyrosine phosphorylation of IRS-1 and activation of IRS-1–associated PI 3-kinase are important intracellular insulin signaling events (26–28), these defects may be responsible for subsequent decreases in skeletal muscle glucose uptake in the fatless mice. The defects in muscle insulin signaling and action were accompanied by increased concentrations of triglyceride and fatty acyl-CoA in skeletal muscle of the fatless mice and are consistent with previous studies in animals (29–33) and humans (33–40), demonstrating an inverse relationship between intramyocellular lipid content and insulin sensitivity. It has been hypothesized that the mechanism by which increased levels of fatty acyl-CoA impair skeletal muscle insulin signaling and action involves activation of serine kinase cascade, of which protein kinase C and/or IκB kinase-β may play a role (41–44), leading to the serine phosphorylation of IRS-1 at Ser307 (45). Recent studies have shown that serine phosphorylation of IRS-1 prevents tyrosine phosphorylation of IRS-1 and interferes with its ability to recruit and activate PI 3-kinase, as occurs upon treatment with tumor necrosis factor-α (TNF-α) and okadaic acid (46–49). Transplantation of fat from wild-type littermates into the fatless mice normalized insulin-stimulated glucose uptake and IRS-1–associated PI 3-kinase activity in skeletal muscle. These changes were accompanied by decreases in skeletal muscle fatty acyl-CoA levels in the fat-transplanted fatless mice. These findings suggest that fat transplantation caused repartitioning of fat away from skeletal muscle and into transplanted adipocytes, and the resultant lowering of fatty acyl-CoA may be responsible for normalization of skeletal muscle insulin action in the fat-transplanted fatless mice.

    Rosiglitazone treatment similarly normalized insulin-stimulated glucose uptake and metabolism in skeletal muscle of the fatless mice. This was accompanied by increases in insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-1–associated PI 3-kinase activity in skeletal muscle of the rosiglitazone-treated fatless mice. Rosiglitazone treatment also decreased triglyceride and fatty acyl-CoA levels in the skeletal muscle of fatless mice. These findings are remarkably similar to what was observed after fat transplantation in the fatless mice and suggest that repartitioning of fat out of skeletal muscle may also be responsible for rosiglitazone’s effect on skeletal muscle insulin action. To address this issue further, we examined the effect of rosiglitazone treatment in the fat-transplanted fatless mice and found that rosiglitazone treatment did not further enhance the effect of fat transplantation to lower fatty acyl-CoA content and increase skeletal muscle insulin action in the fatless mice. The lack of additive effect of rosiglitazone and fat transplantation supports the notion that a common mechanism (i.e., repartitioning of fat and fatty acid–derived metabolites) may underlie the effects of rosiglitazone and fat transplantation on normalization of insulin action in the fatless mice. In support of this hypothesis, Mayerson et al. (11) recently showed that 3 months of rosiglitazone treatment in patients with type 2 diabetes resulted in lowering of plasma fatty acids and intrahepatic triglyceride content, which was associated with enhanced insulin action in peripheral adipocytes and an increase in extramyocellular lipid content. Moreover, Sreenan et al. (50) showed that 6 weeks of troglitazone treatment lowered muscle triglyceride content in lean and obese Zucker rats. Taken together, these findings support the hypothesis that rosiglitazone normalized skeletal muscle insulin action in the fatless mice by repartitioning fat and fatty acid–derived metabolites away from the skeletal muscle.

    Rosiglitazone was recently shown to upregulate aP2, fatty acid transporter, and lipoprotein lipase, which are key enzymes involved in fatty acid utilization in white adipose tissue, during adipocyte differentiation (8). Activation of these adipocyte enzymes by rosiglitazone may contribute to its ability to promote redistribution of fat out of skeletal muscle and into adipocytes and indirectly affecting muscle insulin sensitivity. The resultant lowering of intramyocellular fat may improve skeletal muscle insulin action. However, because fatless mice are devoid of adipocytes, one obvious question is, “Where does the fat repartition to?” In this regard, insulin’s ability to suppress basal HGP was significantly impaired in the fatless mice, and this was accompanied by marked decreases in insulin-stimulated tyrosine phosphorylation of IRS-2 and IRS-2–associated PI 3-kinase activity, which is an important intracellular mediator of hepatic insulin signaling (26,27). In contrast to rosiglitazone’s insulin-sensitizing effect on skeletal muscle insulin action, rosiglitazone treatment grossly exacerbated hepatic insulin resistance in the fatless mice. These defects in hepatic insulin signaling and action were associated with increased levels of triglyceride and fatty acyl-CoA in liver of the fatless mice and their sustained levels in the rosiglitazone-treated fatless mice. These data are consistent with the findings of Chao et al. (20) that rosiglitazone treatment caused hepatic steatosis in the A-ZIP/F-1 fatless mice that was due to increased expression of hepatic PPAR-γ. These findings indicate that as a result of an ablation of adipose tissue, rosiglitazone caused a repartitioning of fat away from skeletal muscle and into liver of the fatless mice, thereby improving skeletal muscle insulin sensitivity while exacerbating hepatic insulin resistance in the fatless mice. Thus, rosiglitazone treatment was shown to have a divergent regulation of insulin action in skeletal muscle and liver of the fatless mice. In this regard, this is the first study to demonstrate that rosiglitazone may partition fat into liver in the presence of inadequate fat storage in the adipocytes potentially by stimulating hepatic PPAR-γ. Moreover, because changes in insulin sensitivity were observed in the adipocyte-null A-ZIP/F-1 mice, this study further demonstrates that local accumulation of fat (i.e., fatty acid–derived metabolites) may alter insulin sensitivity in skeletal muscle and liver independent of adipocyte-derived circulating factors (e.g., TNF-α, leptin, resistin, Acrp30) (46,51–53).

    It is also possible that rosiglitazone directly alters skeletal muscle insulin sensitivity independent of its PPAR-γ–mediated changes in adipocyte gene expression (54–56). Hevener et al. (54) recently showed that troglitazone prevented fatty acid–induced insulin resistance in skeletal muscle independent of changes in plasma fatty acid levels, although the concentration of intracellular fatty acid–derived metabolites, which are the likely mediators of fatty acid–induced insulin resistance, was not measured. In addition, Brunmair et al. (55) found that TZDs suppressed lipid oxidation in isolated soleus muscle. Further evidence supporting the direct insulin-sensitizing action of TZDs in skeletal muscle comes from a recent observation that TZDs increase skeletal muscle expression of lipoprotein lipase, fatty acid–binding protein, and muscle carnitine palmitoyl transferase-1, which are genes involved in lipid metabolism (18,56). Furthermore, TNF-α is an adipocyte-derived circulating factor that has been demonstrated to regulate negatively skeletal muscle insulin sensitivity, and TZDs were found to prevent TNF-α–induced insulin resistance in skeletal muscle (17).

    In summary, rosiglitazone treatment increased insulin action in skeletal muscle of the A-ZIP/F-1 fatless mice by repartitioning fat away from skeletal muscle and into liver and thereby lowering fatty acid–derived metabolites in skeletal muscle, resulting in enhanced insulin signaling. These data support the hypothesis that rosiglitazone treatment enhances insulin action in skeletal muscle mostly through an indirect mechanism by repartitioning fat (and fatty acid–derived metabolites) out of skeletal muscle and into other PPAR-γ responsive tissues.

    FIG. 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    FIG. 1.

    Liver, whole-body, and skeletal muscle (gastrocnemius) insulin action during hyperinsulinemic-euglycemic clamps in awake wild-type, fatless, and fat-transplanted fatless mice with (black bars) or without (grey bars) rosiglitazone treatment. A: Basal hepatic glucose production. B: Hepatic glucose production during clamps. C: Insulin-stimulated whole-body glucose turnover. D: Insulin-stimulated skeletal muscle glucose uptake. Values are means ± SE for 4–12 experiments. *P < 0.05 vs. wild-type mice; §P < 0.05 vs. fatless mice.

    FIG. 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    FIG. 2.

    Insulin-stimulated whole-body and skeletal muscle (gastrocnemius) glucose metabolism in wild-type, fatless, and fat-transplanted fatless mice with (black bars) or without (grey bars) rosiglitazone treatment. A: Insulin-stimulated rates of whole-body glycolysis. B: Insulin-stimulated rates of whole-body glycogen/lipid synthesis. C: Insulin-stimulated rates of skeletal muscle glycolysis. D: Insulin-stimulated rates of skeletal muscle glycogen synthesis. Values are means ± SE for 4–12 experiments. *P < 0.05 vs. wild-type mice; §P < 0.05 vs. fatless mice.

    FIG. 3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    FIG. 3.

    Insulin signaling in skeletal muscle (gastrocnemius) and liver of wild-type, fatless, and fat-transplanted fatless mice with (black bars) or without (grey bars) rosiglitazone treatment. A: Insulin-stimulated IRS-1 tyrosine phosphorylation in skeletal muscle. B: Insulin-stimulated IRS-1–associated PI 3-kinase activity in skeletal muscle. C: Insulin-stimulated IRS-2 tyrosine phosphorylation in liver. D: Insulin-stimulated IRS-2–associated PI 3-kinase activity in liver. Values are means ± SE for 4–12 experiments. *P < 0.05 vs. wild-type mice; §P < 0.05 vs. fatless mice.

    FIG. 4.
    • Download figure
    • Open in new tab
    • Download powerpoint
    FIG. 4.

    Intracellular triglyceride and fatty acyl-CoA concentrations in skeletal muscle (quadriceps) and liver of wild-type, fatless, and fat-transplanted fatless mice with (black bars) or without (grey bars) rosiglitazone treatment. A: Intramuscular triglyceride concentration. B: Intramuscular fatty acyl-CoA concentration. C: Intrahepatic triglyceride concentration. D: Intrahepatic fatty acyl-CoA concentration. Values are means ± SE for 4–12 experiments. *P < 0.05 vs. wild-type mice; §P < 0.05 vs. fatless mice.

    FIG. 5.
    • Download figure
    • Open in new tab
    • Download powerpoint
    FIG. 5.

    Insulin-stimulated glucose uptake in tibialis anterior and adipose tissue during hyperinsulinemic-euglycemic clamps in wild-type, fatless, and fat-transplanted fatless mice with (black bars) or without (grey bars) rosiglitazone treatment. A: Tibialis anterior. B: Intrascapular brown adipose tissue. C: Epididymal white adipose tissue. Values are means ± SE for 4–12 experiments. *P < 0.05 vs. wild-type mice; §P < 0.05 vs. fatless mice.

    View this table:
    • View inline
    • View popup
    TABLE 1

    Metabolic parameters during basal (overnight fasted) and hyperinsulinemic-euglycemic clamp periods in the wild-type, fatless, and fat-transplanted fatless mice with or without 3 weeks of rosiglitazone treatment (Rosi-treated)

    Acknowledgments

    This study was conducted at the Yale Mouse Metabolic Phenotyping Center and supported by grants from the U.S. Public Health Service (U24 DK-59635 [to J.K.K. and G.I.S.], R01 DK-40936 [to G.I.S.], and P30 DK-45735 [to G.I.S.]). This study was also supported by the grant from the American Diabetes Association (7-01-JF-05 [to J.K.K.]).

    Gerald I. Shulman is an investigator of the Howard Hughes Medical Institute. We are grateful to Aida Groszmann, Jianying Dong, and Haihong Zong for technical assistance.

    Footnotes

    • Address correspondence and reprint requests to Jason K. Kim, Yale University School of Medicine, Department of Internal Medicine, Section of Endocrinology, S269C CAB, P.O. Box 208020, New Haven, CT 06520-8020. E-mail: jason.k.kim{at}yale.edu.

      Received for publication 9 July 2002 and accepted in revised form 19 February 2003.

      M.L.R. is employed by Merck. G.I.S. has been on an advisory panel for and has received honoraria and consulting fees from GlaxoSmithKline.

      2-DG-6-P, 2-[14C]DG-6-phosphate; HGP, hepatic glucose production; IRS, insulin receptor substrate; LC/MS/MS, liquid chromatography tandem mass spectrometry; PI, phosphatidylinositol; PPAR-γ; peroxisome proliferator–activated receptor-γ; TNF-α, tumor necrosis factor-α; TZD, thiazolidinedione.

    • DIABETES

    REFERENCES

    1. ↵
      Kahn CR, Chen L, Cohen SE: Unraveling the mechanism of action of thiazolidinediones. J Clin Invest106 :1305 –1307,2000
      OpenUrlPubMedWeb of Science
    2. Olefsky JM: Treatment of insulin resistance with peroxisome proliferators-activated receptor γ agonists. J Clin Invest106 :467 –472,2000
      OpenUrlCrossRefPubMedWeb of Science
    3. Saltiel AR, Olefsky JM: Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes45 :1661 –1669,1996
      OpenUrlAbstract/FREE Full Text
    4. 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 Med128 :176 –185,1999
      OpenUrl
    5. Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton V, Shulman GI: Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med338 :908 –909,1998
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      Olefsky JM, Saltiel AR: PPARgamma and the treatment of insulin resistance. Trends Endocrinol Metab11 :362 –368,2000
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Wilson TM, Kliewer SA: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferators-activated receptor gamma (PPAR gamma). J Biol Chem270 :12953 –12956,1995
      OpenUrlAbstract/FREE Full Text
    8. ↵
      Albrektsen T, Frederiksen KS, Holmes WE, Boel E, Taylor K, Fleckner J: Novel genes regulated by the insulin sensitizer rosiglitazone during adipocyte differentiation. Diabetes51 :1042 –1051,2002
      OpenUrlAbstract/FREE Full Text
    9. ↵
      Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T: Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest101 :1354 –1361,1998
      OpenUrlCrossRefPubMedWeb of Science
    10. Shulman GI: Cellular mechanisms of insulin resistance. J Clin Invest106 :171 –176,2000
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      Mayerson AB, Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, Enocksson S, Inzucchi SE, Shulman GI, Petersen KF: The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes51 :797 –802,2002
      OpenUrlAbstract/FREE Full Text
    12. Berger J, Bailey P, Biswas C, Cullinan CA, Doebber TW, Hayes NS, Saperstein R, Smith RG, Leibowitz MD: Thiazolidinediones produce a conformational change in peroxisomal proliferators-activated receptor-γ: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology137 :4189 –4195,1996
      OpenUrlCrossRefPubMedWeb of Science
    13. Wilson TM, Cobb JE, Cowan DJ, Wiethe RW, Correa ID, Prakash SR, Beck KD, Moore LB, Kliewer SA, Lehmann JM: The structure-activity relationship between peroxisomal proliferators-activated receptor-γ agonism and the antihyperglycemic activity of thiazolidinediones. J Med Chem39 :665 –668,1996
      OpenUrlCrossRefPubMedWeb of Science
    14. ↵
      Berger J, Leibowitz MD, Doebber TW, Elbrecht A, Zhang B, Zhou G, Biswas C, Cullinan CA, Hayes NS, Li Y, Tanen M, Ventre J, Wu MS, Berger GD, Mosley R, Marquis R, Santini C, Sahoo SP, Tolman RL, Smith RG, Moller DE: Novel peroxisome proliferator-activated receptor (PPAR) γ and PPARδ ligands produce distinct biological effects. J Biol Chem274 :6718 –6725,1999
      OpenUrlAbstract/FREE Full Text
    15. ↵
      Loviscach M, Rehman N, Carter L, Mudaliars S, Mohadeen P, Ciaraldi TP, Veerkamp JH, Henry RR: Distribution of peroxisome proliferator-activated receptors (PPARs) in human skeletal muscle and adipose tissue: relation to insulin action. Diabetologia43 :304 –311,2000
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      Wahl HG, Kausch C, Machicao F, Rett K, Stumvoll M, Harling H-U: Troglitazone downregulates Δ-6 desaturase gene expression in human skeletal muscle cell cultures. Diabetes51 :1060 –1065,2002
      OpenUrlAbstract/FREE Full Text
    17. ↵
      Iwata M, Haruta T, Usui I, Takata Y, Takano A, Uno T, Kawahara J, Ueno E, Sasaoka T, Ishibashi O, Kobayashi M: Pioglitazone ameliorates tumor necrosis factor-α-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferators-activated receptor-γ. Diabetes50 :1083 –1092,2001
      OpenUrlAbstract/FREE Full Text
    18. ↵
      Lapsys NM, Kriketos AD, Lim-Fraser M, Poynten AM, Lowy A, Furler SM, Chisholm DJ, Cooney GJ: Expression of genes involved in lipid metabolism correlate with peroxisome proliferators-activated receptor γ expression in human skeletal muscle. J Clin Endocrinol Metab85 :4293 –4297,2000
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      Burant CF, Sreenan S, Hirano K-I, Tai T-AC, Lohmiller J, Lukens J, Davidson NO, Ross S, Graves RA: Troglitazone action is independent of adipose tissue. J Clin Invest100 :2900 –2908,1997
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      Chao L, Marcus-Samuels B, Mason MM, Moitra J, Vinson C, Arioglu E, Gavrilova O, Reitman ML: Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones. J Clin Invest106 :1221 –1228,2000
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, Feigenbaum L, Lee E, Aoyama T, Eckhaus M, Reitman ML, Vinson C: Life without white fat: a transgenic mouse. Genes Dev12 :3168 –3181,1998
      OpenUrlAbstract/FREE Full Text
    22. ↵
      Gavrilova O, Marcus-Samuels B, Graham D, Kim JK, Shulman GI, Castle AL, Vinson C, Eckhaus M, Reitman ML: Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest105 :271 –278,2000
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      Kim JK, Michael MD, Previs SF, Peroni OD, Mauvais-Jarvis F, Neschen S, Kahn BB, Kahn CR, Shulman GI: Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle. J Clin Invest105 :1791 –1797,2000
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      Rossetti L, Giaccari A: Relative contribution of glycogen synthesis and glycolysis to insulin-mediated glucose uptake. A dose-response euglycemic clamp study in normal and diabetic rats. J Clin Invest85 :1785 –1792,1990
    25. ↵
      Bligh EG, Dyer WJ: A rapid method of total lipid extraction and purification. Can J Biochem Physiol37 :911 –917,1959
    26. ↵
      Kahn CR: Insulin action, diabetogenes, and the cause of type II diabetes (Banting Lecture). Diabetes43 :1066 –1084,1994
      OpenUrlAbstract/FREE Full Text
    27. ↵
      Previs SF, Withers DJ, Ren J-M, White MF, Shulman GI: Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo. J Biol Chem275 :38990 –38994,2000
      OpenUrlAbstract/FREE Full Text
    28. ↵
      Yamauchi T, Tobe K, Tamemoto H, Ueki K, Kaburagi Y, Yamamoto-Honda R, Takahashi Y, Yoshizawa F, Aizawa S, Akanuma Y, Sonenberg N, Yazaki Y, Kadowaki T: Insulin signaling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. Mol Cell Biol16 :3074 –3084,1996
      OpenUrlAbstract/FREE Full Text
    29. ↵
      Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI: Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A98 :7522 –7527,2001
      OpenUrlAbstract/FREE Full Text
    30. Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI: Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem275 :8456 –8460,2000
      OpenUrlAbstract/FREE Full Text
    31. Chalkley SM, Hettiarachchi M, Chisholm DJ, Kraegen EW: Five-hour fatty acid elevation increases muscle lipids and impairs glycogen synthesis in the rat. Metabolism47 :1121 –1126,1998
      OpenUrlCrossRefPubMedWeb of Science
    32. Franch J, Knudsen J, Ellis BA, Pedersen PK, Cooney GJ, Jensen J: Acyl-CoA binding protein expression is fiber type-specific and elevated in muscles from the obese insulin-resistant Zucker rat. Diabetes51 :449 –454,2002
      OpenUrlAbstract/FREE Full Text
    33. ↵
      Ellis BA, Poynten A, Lowy AJ, Furler SM, Chisholm DJ, Kraegen EW, Cooney GJ: Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle. Am J Physiol279 :E554 –E560,2000
      OpenUrlWeb of Science
    34. Bachmann OP, Dahl DB, Brechtel K, Machann J, Haap M, Maier T, Loviscach M, Stumvoil M, Claussen CD, Schick F, Haring HU, Jacob S: Effects of intravenous and dietary lipid challenge on intramyocellular lipid content and the relation with insulin sensitivity in humans. Diabetes50 :2579 –22584,2001
      OpenUrlAbstract/FREE Full Text
    35. Boden G, Lebed B, Schatz M, Homko C, Lemieux S: Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes50 :1612 –1617,2001
      OpenUrlAbstract/FREE Full Text
    36. Perseghin G, Scifo P, De Cobelli F, Pagliato E, Battezzati A, Arcelloni C, Vanzulli A, Testolin G, Pozza G, Del Maschio A, Luzi L: Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic patients. Diabetes48 :1600 –1606,1999
      OpenUrlAbstract
    37. Krssak M, Petersen KF, Dresner A, DiPietro L, Vogel SM, Rothman DL, Roden M, Shulman GI: Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia42 :113 –116,1999
      OpenUrlCrossRefPubMedWeb of Science
    38. Sinha R, Dufour S, Petersen KF, LeBon V, Enoksson S, Ma Y-Z, Savoye M, Rothman DL, Shulman GI, Caprio S: Assessment of skeletal muscle triglyceride content by 1H nuclear magnetic resonance spectroscopy in lean and obese adolescents. Diabetes51 :1022 –1027,2002
      OpenUrlAbstract/FREE Full Text
    39. Virkamaki A, Korsheninnikova E, Seppala-Lindroos A, Vehkavaara S, Goto T, Halavaara J, Hakkinen A-M, Yki-Jarvinen H: Intramyocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle. Diabetes50 :2337 –2343,2001
      OpenUrlAbstract/FREE Full Text
    40. ↵
      Houmard JA, Tanner CJ, Yu C, Cunningham PG, Pories WJ, MacDonald KG, Shulman GI: Effect of weight loss on insulin sensitivity and intramuscular long-chain fatty acyl-CoAs in morbidly obese subjects. Diabetes51 :2959 –2963,2002
      OpenUrlAbstract/FREE Full Text
    41. ↵
      Schmitz-Peiffer C, Browne CL, Oakes ND, Watkinson A, Chisholm DJ, Kraegen EW, Biden TJ: Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rats. Diabetes46 :169 –178,1997
      OpenUrlAbstract/FREE Full Text
    42. Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, Goodyear LJ, Kraegen EW, White MF, Shulman GI: Free fatty acid-induced insulin resistance is associated with activation of protein kinase C θ and alterations in the insulin signaling cascade. Diabetes48 :1270 –1274,1999
      OpenUrlAbstract
    43. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE: Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IKK-beta. Science293 :1673 –1677,2001
      OpenUrlAbstract/FREE Full Text
    44. ↵
      Kim JK, Kim Y-J, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI: Prevention of fat-induced insulin resistance by salicylate. J Clin Invest108 :437 –446,2001
      OpenUrlCrossRefPubMedWeb of Science
    45. ↵
      Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI: Mechanism by which fatty acids inhibit insulin action of IRS-1 associated phosphatidylinositol 3-kinase in muscle. J Biol Chem277 :50230 –50236,2002
      OpenUrlAbstract/FREE Full Text
    46. ↵
      Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science259 :87 –91,1993
      OpenUrlAbstract/FREE Full Text
    47. De Fea K, Roth RA: Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry36 :12939 –12947,1997
      OpenUrlCrossRefPubMed
    48. Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A, Dunaif A, White MF: Insulin/IGF-1 and TNF-α stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest107 :181 –189,2001
      OpenUrlCrossRefPubMedWeb of Science
    49. ↵
      Tanti J-F, Gremeaux T, Obberghen EV, Marchand-Brustel YL: Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling. J Biol Chem269 :6051 –6057,1994
      OpenUrlAbstract/FREE Full Text
    50. ↵
      Sreenan S, Keck S, Fuller T, Cockburn B, Burant CF: Effects of troglitazone on substrate storage and utilization in insulin resistant rats. Am J Physiol276 :E1119 –E1129,1999
    51. ↵
      Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes. Nature409 :307 –312,2001
      OpenUrlCrossRefPubMedWeb of Science
    52. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y: Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol20 :1595 –1599,2000
      OpenUrlAbstract/FREE Full Text
    53. ↵
      Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kageshika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med7 :941 –946,2001
      OpenUrlCrossRefPubMedWeb of Science
    54. ↵
      Hevener AL, Reichart D, Janez A, Olefsky J: Thiazolidinedione treatment prevents free fatty acid-induced insulin resistance in male Wistar rats. Diabetes50 :2316 –2322,2001
      OpenUrlAbstract/FREE Full Text
    55. ↵
      Brunmair B, Gras F, Neschen S, Roden M, Wagner L, Waldhausl W, Furnsinn C: Direct thiazolidinedione action on isolated rat skeletal muscle fuel handling is independent of peroxisome proliferator-activated receptor-γ-mediated changes in gene expression. Diabetes50 :2309 –2315,2001
      OpenUrlAbstract/FREE Full Text
    56. ↵
      Park KS, Cirarldi TP, Lindgren K, Abrams-Carter L, Mudaliar S, Nikoulina SE, Tufari SR, Veerkamp JH, Vidal-Puig A, Henry RR: Troglitazone effects on gene expression in human skeletal muscle of type II diabetes involve up-regulation of peroxisome proliferators-activated receptor-γ. J Clin Endocrinol Metab83 :2830 –2835,1998
      OpenUrlCrossRefPubMedWeb of Science
    PreviousNext
    Back to top

    In this Issue

    June 2003, 52(6)
    • Table of Contents
    • Index by Author
    Sign up to receive current issue alerts
    View Selected Citations (0)
    Print
    Download PDF
    Article Alerts
    Sign In to Email Alerts with your Email Address
    Email Article

    Thank you for your interest in spreading the word about Diabetes.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    Differential Effects of Rosiglitazone on Skeletal Muscle and Liver Insulin Resistance in A-ZIP/F-1 Fatless Mice
    (Your Name) has forwarded a page to you from Diabetes
    (Your Name) thought you would like to see this page from the Diabetes web site.
    CAPTCHA
    This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
    Citation Tools
    Differential Effects of Rosiglitazone on Skeletal Muscle and Liver Insulin Resistance in A-ZIP/F-1 Fatless Mice
    Jason K. Kim, Jonathan J. Fillmore, Oksana Gavrilova, Lily Chao, Takamasa Higashimori, Hyejeong Choi, Hyo-Jeong Kim, Chunli Yu, Yan Chen, Xianqin Qu, Martin Haluzik, Marc L. Reitman, Gerald I. Shulman
    Diabetes Jun 2003, 52 (6) 1311-1318; DOI: 10.2337/diabetes.52.6.1311

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
    Add to Selected Citations
    Share

    Differential Effects of Rosiglitazone on Skeletal Muscle and Liver Insulin Resistance in A-ZIP/F-1 Fatless Mice
    Jason K. Kim, Jonathan J. Fillmore, Oksana Gavrilova, Lily Chao, Takamasa Higashimori, Hyejeong Choi, Hyo-Jeong Kim, Chunli Yu, Yan Chen, Xianqin Qu, Martin Haluzik, Marc L. Reitman, Gerald I. Shulman
    Diabetes Jun 2003, 52 (6) 1311-1318; DOI: 10.2337/diabetes.52.6.1311
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
    • Tweet Widget
    • Facebook Like
    • Google Plus One

    Jump to section

    • Article
      • Abstract
      • RESEARCH DESIGN AND METHODS
      • RESULTS
      • DISCUSSION
      • Acknowledgments
      • Footnotes
      • REFERENCES
    • Figures & Tables
    • Info & Metrics
    • PDF

    Related Articles

    Cited By...

    More in this TOC Section

    • Fetal Programming of Perivenous Glucose Uptake Reveals a Regulatory Mechanism Governing Hepatic Glucose Output During Refeeding
    • Increased Phosphorylation of Skeletal Muscle Glycogen Synthase at NH2-Terminal Sites During Physiological Hyperinsulinemia in Type 2 Diabetes
    • Glucose 6-Phosphate Regulates Hepatic Glycogenolysis Through Inactivation of Phosphorylase
    Show more Metabolism and Signal Transduction

    Similar Articles

    Navigate

    • Current Issue
    • Online Ahead of Print
    • Scientific Sessions Abstracts
    • Collections
    • Archives
    • Submit
    • Subscribe
    • Email Alerts
    • RSS Feeds

    More Information

    • About the Journal
    • Instructions for Authors
    • Journal Policies
    • Reprints and Permissions
    • Advertising
    • Privacy Policy: ADA Journals
    • Copyright Notice/Public Access Policy
    • Contact Us

    Other ADA Resources

    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • Scientific Sessions Abstracts
    • Standards of Medical Care in Diabetes
    • BMJ Open - Diabetes Research & Care
    • Professional Books
    • Diabetes Forecast

     

    • DiabetesJournals.org
    • Diabetes Core Update
    • ADA's DiabetesPro
    • ADA Member Directory
    • Diabetes.org

    © 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.