Skip to main content

Advertisement

Log in

The Effect of Insulin on the Intracellular Distribution of 14(R,S)-[18F]Fluoro-6-thia-heptadecanoic Acid in Rats

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study was to determine the effect of hyperinsulinemia on myocardial and hepatic distribution and metabolism of 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA).

Procedures

Mitochondrial retention and intracellular lipid incorporation of [18F]FTHA were compared to that of [14C]-2-bromopalmitate or [14C]palmitate during hyperinsulinemic clamp vs. saline infusion in male Wistar rats.

Results

Mitochondrial 18F activity was increased in the heart (1.7 ± 0.4 vs. 0.5 ± 0.1% ID/g, P < 0.05), whereas it was reduced in the liver (1.1 ± 0.3 vs. 1.8 ± 0.4% ID/g, P < 0.05) during insulin vs. saline infusion, respectively. Mitochondrial [14C]-2-bromopalmitate activity was affected by insulin in a similar way in both tissues. The fractional esterification of [18F]FTHA into triglycerides was impaired compared to [14C]palmitate in both tissues, and [18F]FTHA was insensitive to the shift of esterification of fatty acids into complex lipids in response to insulin.

Conclusions

[18F]FTHA is sensitive to insulin-induced modifications of free fatty acid oxidative metabolism in rats but is insensitive to changes in nonoxidative fatty acid metabolism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI (1996) Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 97:2859–2865

    Article  PubMed  CAS  Google Scholar 

  2. Boden G, Chen X, Capulong E, Mozzoli M (2001) Effects of free fatty acids on gluconeogenesis and autoregulation of glucose production in type 2 diabetes. Diabetes 50:810–816

    Article  PubMed  CAS  Google Scholar 

  3. Mason TM, Goh T, Tchipashvili V, Sandhu H, Gupta N, Lewis GF, Giacca A (1999) Prolonged elevation of plasma free fatty acids desensitizes the insulin secretory response to glucose in vivo in rats. Diabetes 48:524–530

    Article  PubMed  CAS  Google Scholar 

  4. Carpentier A, Mittelman SD, Lamarche B, Bergman RN, Giacca A, Lewis GF (1999) Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation. Am J Physiol Endocrinol Metab 276:E1055–E1066

    CAS  Google Scholar 

  5. Carpentier A, Mittelman SD, Bergman RN, Giacca A, Lewis GF (2000) Prolonged elevation of plasma free fatty acids impairs pancreatic β-cell function in obese nondiabetic humans but not in individuals with Type 2 diabetes. Diabetes 49:399–408

    Article  PubMed  CAS  Google Scholar 

  6. Staehr P, Hother-Nielsen O, Landau BR, Chandramouli V, Holst JJ, Beck-Nielsen H (2003) Effects of free fatty acids per se on glucose production, gluconeogenesis, and glycogenolysis. Diabetes 52:260–267

    Article  PubMed  CAS  Google Scholar 

  7. Lewis GF, Carpentier A, Adeli K, Giacca A (2002) Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 23:201–229

    Article  PubMed  CAS  Google Scholar 

  8. Kelley DE, Goodpaster BH (2001) Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance. Diabetes Care 24:933–941

    Article  PubMed  CAS  Google Scholar 

  9. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:664–671

    Article  PubMed  CAS  Google Scholar 

  10. Oakes ND, Furler SM (2002) Evaluation of free fatty acid metabolism in vivo. Ann N Y Acad Sci 967:158–175

    Article  PubMed  CAS  Google Scholar 

  11. DeGrado TR, Coenen HH, Stocklin G (1991) 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA): evaluation in mouse of a new probe of myocardial utilization of long chain fatty acids. J Nucl Med 32:1888–1896

    PubMed  CAS  Google Scholar 

  12. Patlak CS, Blasberg RG (1985) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 5:584–590

    PubMed  CAS  Google Scholar 

  13. Stone CK, Pooley RA, DeGrado TR, Renstrom B, Nickles RJ, Nellis SH, Liedtke AJ, Holden JE (1998) Myocardial uptake of the fatty acid analog 14-fluorine-18-fluoro-6-thia-heptadecanoic acid in comparison to beta-oxidation rates by tritiated palmitate. J Nucl Med 39:1690–1696

    PubMed  CAS  Google Scholar 

  14. Ebert A, Herzog H, Stocklin GL, Henrich MM, DeGrado TR, Coenen HH, Feinendegen LE (1994) Kinetics of 14(R,S)-fluorine-18-fluoro-6-thia-heptadecanoic acid in normal human hearts at rest, during exercise and after dipyridamole injection. J Nucl Med 35:51–56

    PubMed  CAS  Google Scholar 

  15. Maki MT, Haaparanta M, Nuutila P, Oikonen V, Luotolahti M, Eskola O, Knuuti JM (1998) Free fatty acid uptake in the myocardium and skeletal muscle using fluorine-18-fluoro-6-thia-heptadecanoic acid. J Nucl Med 39:1320–1327

    PubMed  CAS  Google Scholar 

  16. Turpeinen AK, Takala TO, Nuutila P, Axelin T, Luotolahti M, Haaparanta M, Bergman J, Hamalainen H, Iida H, Maki M, Uusitupa MIJ, Knuuti J (1999) Impaired free fatty acid uptake in skeletal muscle but not in myocardium in patients with impaired glucose tolerance—studies with PET and 14(R, S)-[F-18]fluoro-6-thia-heptadecanoic acid. Diabetes 48:1245–1250

    Article  PubMed  CAS  Google Scholar 

  17. Iozzo P, Turpeinen AK, Takala T, Oikonen V, Solin O, Ferrannini E, Nuutila P, Knuuti J (2003) Liver uptake of free fatty acids in vivo in humans as determined with 14(R, S)-[(18)F]fluoro-6-thia-heptadecanoic acid and PET. Eur J Nucl Med Mol Imaging 30:1160–1164

    Article  PubMed  CAS  Google Scholar 

  18. Takala TO, Nuutila P, Pulkki K, Oikonen V, Gronroos T, Savunen T, Vahasilta T, Luotolahti M, Kallajoki M, Bergman J, Forsback S, Knuuti J (2002) 14(R, S)-[(18)F]Fluoro-6-thia-heptadecanoic acid as a tracer of free fatty acid uptake and oxidation in myocardium and skeletal muscle. Eur J Nucl Med Mol Imaging 29:1617–1622

    Article  PubMed  CAS  Google Scholar 

  19. Oakes ND, Thalen PG, Jacinto SM, Ljung B (2001) Thiazolidinediones increase plasma-adipose tissue FFA exchange capacity and enhance insulin-mediated control of systemic FFA availability. Diabetes 50: 1158–1165

    Article  PubMed  CAS  Google Scholar 

  20. Taghibiglou C, Carpentier A, Rudy D, Aiton A, Lewis GF, Adeli K (2000) Mechanisms of hepatic VLDL overproduction in insulin resistance: evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J Biol Chem 275:8416–8425

    Article  PubMed  CAS  Google Scholar 

  21. Carpentier A, Taghibiglou C, Leung N, Szeto L, Van Iderstine SC, Uffelman KD, Buckingham R, Adeli K, Lewis GF (2002) Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster. J Biol Chem 277:28795–28802

    Article  PubMed  CAS  Google Scholar 

  22. DeGrado TR (1991) Synthesis of 14(R, S)-[18F] fluoro-6thia-heptadecanoic acid (FTHA). J Labeled Compd Radiopharm 29:989–995

    Article  CAS  Google Scholar 

  23. Fernandez-Vizarra E, Lopez-Perez MJ, Enriquez JA (2002) Isolation of biogenetically competent mitochondria from mammalian tissues and cultured cells. Methods 26:292–297

    Article  PubMed  CAS  Google Scholar 

  24. Felber JP, Ferrannini E, Golay A, Meyer HU, Theibaud D, Curchod B, Maeder E, Jequier E, DeFronzo RA (1987) Role of lipid oxidation in pathogenesis of insulin resistance of obesity and type II diabetes. Diabetes 36:1341–1350

    Article  PubMed  CAS  Google Scholar 

  25. Thiebaud D, Jacot E, DeFronzo RA, Maeder E, Jequier E, Felber JP (1982) The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes 31:957–963

    PubMed  CAS  Google Scholar 

  26. Sidossis LS, Wolfe RR (1996) Glucose and insulin-induced inhibition of fatty acid oxidation: the glucose–fatty acid cycle reversed. Am J Physiol Endocrinol Metab 270:E733–E738

    CAS  Google Scholar 

  27. Carpentier A, Frisch F, Cyr D, Genereux P, Patterson BW, Giguere R, Baillargeon JP (2005) On the suppression of plasma non-esterified fatty acids by insulin during enhanced intravascular lipolysis in humans. Am J Physiol Endocrinol Metab 289:E849–E856

    Article  PubMed  CAS  Google Scholar 

  28. Chabowski A, Coort SL, Calles-Escandon J, Tandon NN, Glatz JF, Luiken JJ, Bonen A (2004) Insulin stimulates fatty acid transport by regulating the expression of FAT/CD36 but not FABPpm. Am J Physiol Endocrinol Metab 287:E781–E789

    Article  PubMed  CAS  Google Scholar 

  29. Luiken JJ, Dyck DJ, Han XX, Tandon NN, Arumugam Y, Glatz JF, Bonen A (2002) Insulin induces the translocation of the fatty acid transporter FAT/CD36 to the plasma membrane. Am J Physiol Endocrinol Metab 282:E491–E495

    PubMed  CAS  Google Scholar 

  30. Luiken JJ, Van Nieuwenhoven FA, America G, Van der Vusse GJ, Glatz JF (1997) Uptake and metabolism of palmitate by isolated cardiac myocytes from adult rats: involvement of sarcolemmal proteins. J Lipid Res 38:745–758

    PubMed  CAS  Google Scholar 

  31. Luiken JJ, Willems J, Van der Vusse GJ, Glatz JF (2001) Electrostimulation enhances FAT/CD36-mediated long-chain fatty acid uptake by isolated rat cardiac myocytes. Am J Physiol Endocrinol Metab 281:E704–E712

    PubMed  CAS  Google Scholar 

  32. Okita RT, Okita JR (2001) Cytochrome P450 4A fatty acid omega hydroxylases. Curr Drug Metab 2:265–281

    Article  PubMed  CAS  Google Scholar 

  33. Woodcroft KJ, Novak RF (1999) Insulin differentially affects xenobiotic-enhanced, cytochrome P-450 (CYP)2E1, CYP2B, CYP3A, and CYP4A expression in primary cultured rat hepatocytes. J Pharmacol Exp Ther 289:1121–1127

    PubMed  CAS  Google Scholar 

Download references

Acknowledgement

These studies were supported by an operating grant from the Canadian Institutes of Health Research (MOP 53094).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to André C. Carpentier MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ci, X., Frisch, F., Lavoie, F. et al. The Effect of Insulin on the Intracellular Distribution of 14(R,S)-[18F]Fluoro-6-thia-heptadecanoic Acid in Rats. Mol Imaging Biol 8, 237–244 (2006). https://doi.org/10.1007/s11307-006-0042-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-006-0042-7

Key words

Navigation