Download PDF
Horm Metab Res 2004; 36(4): 203-209
DOI: 10.1055/s-2004-814446
Original Basic
© Georg Thieme Verlag Stuttgart · New York

No In Vitro Effects of Fatty Acids on Glucose Uptake, Lipolysis or Insulin Signaling in Rat Adipocytes

M.  Lundgren1 , J.  W.  Eriksson1
  • 1Department of Medicine, Umeå University Hospital, Umeå, Sweden
Further Information

Publication History

Received 19 March 2003

Accepted after Revision 2 November 2003

Publication Date:
28 April 2004 (online)

Also available at
    Permissions and Reprints

Abstract

Elevated plasma levels of free fatty acids (FFA) can produce insulin resistance in skeletal muscle tissue and liver and, together with alterations in β-cell function, this has been referred to as lipotoxicity. This study explores the effects of FFAs on insulin action in rat adipocytes. Cells were incubated 4 or 24 h with or without an unsaturated FFA, oleate or a saturated FFA, palmitate (0.6 and 1.5 mM, respectively). After the culture period, cells were washed and insulin effects on glucose uptake and lipolysis as well as cellular content of insulin signaling proteins (IRS-1, PI3-kinase, PKB and phosphorylated PKB) and the insulin regulated glucose transporter GLUT4 were measured. No significant differences were found in basal or insulin-stimulated glucose uptake in FFA-treated cells compared to control cells, regardless of fatty acid concentration or incubation period. Moreover, there were no significant alterations in the expression of IRS-1, PI3-kinase, PKB and GLUT4 following FFA exposure. Insulin’s ability to stimulate PKB phosphorylation was also left intact. Nor did we find any alterations following FFA exposure in basal or cAMP-stimulated lipolysis or in the ability of insulin to inhibit lipolysis. The results indicate that oleate or palmitate does not directly influence insulin action to stimulate glucose uptake and inhibit lipolysis in rat fat cells. Thus, lipotoxicity does not seem to occur in the fat tissue itself.

Key words

Glucose transport - Rat adipocytes - Oleate - Palmitate

References

  • 1 Gordon E. Non-Esterified Fatty Acids in the Blood of Obese and Lean Subjects.  Am J Clin Nutr. 1960;  8 740-747
    PubMedGoogle Scholar
  • 2 Reaven G M, Hollenbeck C, Jeng C Y, Wu M S, Chen Y D. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM.  Diabetes. 1988;  37 1020-1024
    CrossrefPubMedGoogle Scholar
  • 3 Belfrage P, Fredrikson G, Nilsson N O, Stralfors P. Regulation of adipose-tissue lipolysis by phosphorylation of hormone-sensitive lipase.  Int J Obes. 1981;  5 635-641
    PubMedGoogle Scholar
  • 4 Smith C J, Manganiello V C. Role of hormone-sensitive low Km cAMP phosphodiesterase in regulation of cAMP-dependent protein kinase and lipolysis in rat adipocytes.  Mol Pharmacol. 1989;  35 381-386
    PubMedGoogle Scholar
  • 5 Degerman E, Belfrage P, Manganiello V C. Structure, localization, and regulation of cGMP-inhibited phosphodiesterase (PDE3).  J Biol Chem. 1997;  272 6823-6826
    CrossrefPubMedGoogle Scholar
  • 6 Holman G D, Kasuga M. From receptor to transporter: insulin signalling to glucose transport.  Diabetologia. 1997;  40 991-1003
    CrossrefPubMedGoogle Scholar
  • 7 Boden G, Jadali F. Effects of lipid on basal carbohydrate metabolism in normal men.  Diabetes. 1991;  40 686-692
    CrossrefPubMedGoogle Scholar
  • 8 Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes.  J Clin Invest. 1995;  96 1261-1268
    PubMedGoogle Scholar
  • 9 Roden M, Price T B, Perseghin G, Petersen K F, Rothman D L, Cline G W, Shulman G I. Mechanism of free fatty acid-induced insulin resistance in humans.  J Clin Invest. 1996;  97 2859-2865
    CrossrefPubMedGoogle Scholar
  • 10 Thompson A L, Lim-Fraser M Y, Kraegen E W, Cooney G J. Effects of individual fatty acids on glucose uptake and glycogen synthesis in soleus muscle in vitro.  Am J Physiol Endocrinol Metab. 2000;  279 E577-584
    PubMedGoogle Scholar
  • 11 Svedberg J, Bjorntorp P, Smith U, Lonnroth P. Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes.  Diabetes. 1990;  39 570-574
    CrossrefPubMedGoogle Scholar
  • 12 Rebrin K, Steil G M, Mittelman S D, Bergman R N. Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs.  J Clin Invest. 1996;  98 741-749
    CrossrefPubMedGoogle Scholar
  • 13 Boden G. Free fatty acids (FFA), a link between obesity and insulin resistance.  Front Biosci. 1998;  3 D169-175
    PubMedGoogle Scholar
  • 14 Sako Y, Grill V E. A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation.  Endocrinology. 1990;  127 1580-1589
    PubMedGoogle Scholar
  • 15 Paolisso G, Gambardella A, Amato L, Tortoriello R, D'Amore A, Varricchio M, D'Onofrio F. Opposite effects of short- and long-term fatty acid infusion on insulin secretion in healthy subjects.  Diabetologia. 1995;  38 1295-1299
    PubMedGoogle Scholar
  • 16 Zhou Y P, Grill V. Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans.  J Clin Endocrinol Metab. 1995;  80 1584-1590
    CrossrefPubMedGoogle Scholar
  • 17 Carpentier A, Mittelman S D, Lamarche B, Bergman R N, Giacca A, Lewis G F. Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation.  Am J Physiol. 1999;  276 E1055-1066
    PubMedGoogle Scholar
  • 18 Randle P, Garland P, Hales C, Newsholme E. The glucose fatty acid cycle: it's role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.  Lancet. 1963;  1 785-789
    PubMedGoogle Scholar
  • 19 Dresner A, Laurent D, Marcucci M, Griffin M E, Dufour S, Cline G W, Slezak L A, Andersen D K, Hundal R S, Rothman D L, Petersen K F, Shulman G I. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity.  J Clin Invest. 1999;  103 253-259
    CrossrefPubMedGoogle Scholar
  • 20 Griffin M E, Marcucci M J, Cline G W, Bell K, Barucci N, Lee D, Goodyear L J, Kraegen E W, White M F, Shulman G I. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.  Diabetes. 1999;  48 1270-1274
    CrossrefPubMedGoogle Scholar
  • 21 Eriksson J W, Smith U, Waagstein F, Wysocki M, Jansson P A. Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients: is cellular insulin resistance a secondary phenomenon?.  Diabetes. 1999;  48 1572-1578
    PubMedGoogle Scholar
  • 22 Hardy R W, Ladenson J H, Henriksen E J, Holloszy J O, McDonald J M. Palmitate stimulates glucose transport in rat adipocytes by a mechanism involving translocation of the insulin sensitive glucose transporter (GLUT4).  Biochem Biophys Res Commun. 1991;  177 343-349
    CrossrefPubMedGoogle Scholar
  • 23 Usui I, Haruta T, Takata Y, Iwata M, Uno T, Takano A, Ueno E, Ishibashi O, Ishihara H, Wada T, Sasaoka T, Kobayashi M. Differential effects of palmitate on glucose uptake in rat-1 fibroblasts and 3T3-L1 adipocytes.  Horm Metab Res. 1999;  31 546-552
    PubMedGoogle Scholar
  • 24 Hunnicutt J W, Hardy R W, Williford J, McDonald J M. Saturated fatty acid-induced insulin resistance in rat adipocytes.  Diabetes. 1994;  43 540-545
    PubMedGoogle Scholar
  • 25 Van Epps-Fung M, Williford J, Wells A, Hardy R W. Fatty acid-induced insulin resistance in adipocytes.  Endocrinology. 1997;  138 4338-4345
    CrossrefPubMedGoogle Scholar
  • 26 Rustan A C, Solberg R, Reseland J E, Andersen M H, Drevon C A, Aas V. Fatty acids modulate leptin and leptin receptor (OB-Rb) gene expression and leptin secretion in cultured human skeletal muscle cells.  Diabetologia. 2002;  45 Suppl 2 A59-A60 (Abstract)
    PubMedGoogle Scholar
  • 27 Thalén P, Frangioudakis G, Camejo G, Furler S, Kraegen E, Ljung B, Oakes N. Contribution of circulating triglyceride to fatty acid loading in individual tissues in vivo.  Diabetes. 2003;  52 (Suppl 1) A9 (abstract)
    PubMedGoogle Scholar
  • 28 Smith U, Sjostrom L, Bjorntorp P. Comparison of two methods for determining human adipose cell size.  J Lipid Res. 1972;  13 822-824
    PubMedGoogle Scholar
  • 29 Buren J, Liu H X, Jensen J, Eriksson J W. Dexamethasone impairs insulin signalling and glucose transport by depletion of insulin receptor substrate-1, phosphatidylinositol 3-kinase and protein kinase B in primary cultured rat adipocytes.  Eur J Endocrinol. 2002;  146 419-429
    CrossrefPubMedGoogle Scholar
  • 30 Kashiwagi A, Verso M A, Andrews J, Vasquez B, Reaven G, Foley J E. In vitro insulin resistance of human adipocytes isolated from subjects with noninsulin-dependent diabetes mellitus.  J Clin Invest. 1983;  72 1246-1254
    PubMedGoogle Scholar
  • 31 Buren J, Liu H X, Lauritz J, Eriksson J W. High glucose and insulin in combination cause insulin receptor substrate-1 and -2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes: possible implications for insulin resistance in type 2 diabetes.  Eur J Endocrinol. 2003;  148 157-167
    CrossrefPubMedGoogle Scholar
  • 32 Lindmark S, Wiklund U, Bjerle P, Eriksson J W. Does the autonomic nervous system play a role in the development of insulin resistance? A study on heart rate variability in first-degree relatives of Type 2 diabetes patients and control subjects.  Diabet Med. 2003;  20 399-405
    CrossrefPubMedGoogle Scholar

Dr. J. W. Eriksson

Department of Medicine · Umeå University Hospital

SE-901 85 Umeå · Sweden

Phone: +46(90)-7851853

Fax: +46(90)137633

Email: jan.eriksson@medicin.umu.se

      >