Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes

Sangeeta R. Kashyap, Renata Belfort, Rachele Berria, Swangjit Suraamornkul, Thongchai Pratipranawatr, Jean Finlayson, Andrea Barrentine, Mandeep Bajaj, Lawrence Mandarino, Ralph DeFronzo, Kenneth Cusi

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83 Scopus citations


Muscle insulin resistance develops when plasma free fatty acids (FFAs) are acutely increased to supraphysiological levels (∼1,500-4,000 μmol/l). However, plasma FFA levels >1,000 μmol/l are rarely observed in humans under usual living conditions, and it is unknown whether insulin action may be impaired during a sustained but physiological FFA increase to levels seen in obesity and type 2 diabetes mellitus (T2DM) (∼600-800 μmol/l). It is also unclear whether normal glucose-tolerant subjects with a strong family history of T2DM (FH+) would respond to a low-dose lipid infusion as individuals without any family history of T2DM (CON). To examine these questions, we studied 7 FH+ and 10 CON subjects in whom we infused saline (SAL) or low-dose Liposyn (LIP) for 4 days. On day 4, a euglycemic insulin clamp with [3-3H]glucose and indirect calorimetry was performed to assess glucose turnover, combined with vastus lateralis muscle biopsies to examine insulin signaling. LIP increased plasma FFA ∼1.5-fold, to levels seen in T2DM. Compared with CON, FH+ were markedly insulin resistant and had severely impaired insulin signaling in response to insulin stimulation. LIP in CON reduced insulin-stimulated glucose disposal (Rd) by 25%, insulin-stimulated insulin receptor tyrosine phosphorylation by 17%, phosphatidylinositol 3-kinase activity associated with insulin receptor substrate-1 by 20%, and insulin-stimulated glycogen synthase fractional velocity over baseline (44 vs. 15%; all P < 0.05). In contrast to CON, a physiological elevation in plasma FFA in FH+ led to no further deterioration in Rd or to any additional impairment of insulin signaling. In conclusion, a 4-day physiological increase in plasma FFA to levels seen in obesity and T2DM impairs insulin action/insulin signaling in CON but does not worsen insulin resistance in FH+. Whether this lack of additional deterioration in insulin signaling in FH+ is due to already well-established lipotoxicity, or to other molecular mechanisms related to insulin resistance that are nearly maximally expressed early in life, remains to be determined.

Original languageEnglish (US)
Pages (from-to)E537-E546
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number3 50-3
StatePublished - Sep 2004


  • Free fatty acids
  • Insulin resistance
  • Insulin signal transduction

ASJC Scopus subject areas

  • General Medicine


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