Free Fatty Acids Reduce Splanchnic and Peripheral Glucose Uptake in Patients With Type 2 Diabetes

Bajaj, Mandeep S; Pratipanawatr, Thongchai; Berria, Rachele; Pratipanawatr, Wilailak; Kashyap, Sangeeta R.; Cusi, Kenneth; Mandarino, Lawrence J.; DeFronzo, Ralph A.

doi:10.2337/diabetes.51.10.3043

Cited by 42 publications

(23 citation statements)

References 49 publications

(84 reference statements)

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“…1) Lipotoxicity develops early in life and is fully established in adult insulin-resistant FHϩ subjects; consequently, lipid infusion cannot cause any further reduction in insulin action [except when lipid is given at pharmacological doses (3,6,8)]. This would be in agreement with the elevated plasma FFA levels and/or rates of lipid oxidation (28,33,37,49) reported in previous studies in FHϩ individuals.…”

Section: Lipid Infusions In Humanssupporting

confidence: 80%

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

Kashyap

Belfort

Berria

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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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.

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Section: Lipid Infusions In Humanssupporting

confidence: 80%

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

Kashyap

Belfort

Berria

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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“…4 mM. The fatty acid concentrations used are usually found in plasma of healthy humans (Butler et al 2001, Bajaj et al 2002 et al , Woerle et al 2002. The percentage of ethanol was always lower than 0 .…”

Section: Cell Treatmentmentioning

confidence: 99%

Non-esterified fatty acids and human lymphocyte death: a mechanism that involves calcium release and oxidative stress

Otton¹,

Silva²,

Campoio³

et al. 2007

Journal of Endocrinology

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Although previous studies have shown that a mixture offatty acids in similar proportion to that found in human plasma triggers apoptosis of peripheral blood lymphocytes from healthy subjects, the mechanism involved remains unknown. In the present study, we examined whether the effect of a mixture of fatty acids upon human lymphocyte death involves cytochrome c release from the mitochondria, activation of caspases 3, 6, 8, and 9, production of superoxide anion, nitric oxide (NO), increase in cytosolic Ca 2C levels, and expression of the anti-apoptotic 14-3-3 and the pro-apoptotic FasL, bad, and bid proteins. Peripheral blood lymphocytes from healthy subjects were isolated and treated for up to 48 h with increasing concentrations (0 . 1-0 . 4 mM) of the fatty acid mixture. Cells were then harvested and the cytochrome c release from mitochondrial intermembrane space into cytosol and expression of anti-and pro-apoptotic proteins were investigated by western blot analysis. Activities of caspases 3, 6, 8, and 9 were determined using spectrofluorometric assays. NO production was monitored using DAF-2-FM probe. Cytosolic free calcium concentration ([Ca 2C ] i ) was determined using the fluorescent probe Fura-2-AM. Superoxide anion was assayed using lucigenin and dihydroethidine assays. Lymphocytes treated for 24 h with the fatty acid mixture presented increased cytochrome c release from mitochondria as compared with control lymphocytes without treatment. Activities of caspases 3, 6, and 9 were increased by 146, 22 and 35% respectively by the treatment with 0 . 4 mM concentration of the fatty acid mixture for 24 h. The expression of bid protein was significantly increased in lymphocytes by 40% at 0 . 2 mM and by 80% at 0 . 4 mM fatty acid concentration, whereas FasL, 14-3-3 and bad proteins were not affected by the treatment. Intracellular calcium concentration was increased in a dose-dependent manner after 30 min of fatty acid treatment and addition of BSA (0 . 2%) abolished this increase. Production of NO and superoxide anion was also increased by the fatty acid mixture and BSA loaded in the culture medium prevented this increase. In conclusion, fatty acids induced apoptosis of human lymphocytes by a mechanism that involved cytochrome c release from mitochondria, activation of the caspase cascade, and increase of bid protein content, superoxide and NO production, and of cytosolic calcium concentration.

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“…During insulin plus Intralipid/heparin infusion, glucose uptake in the entire splanchnic bed (splanchnic glucose uptake, SGU) has been found to be reduced in patients with Type 2 diabetes [20], but was either unchanged [21] or increased [22] in healthy individuals. However, glucose disposal by the splanchnic area is predominantly accounted for by extra-hepatic organs, especially during euglycaemia [23].…”

Section: Introductionmentioning

confidence: 99%

Non-esterified fatty acids impair insulin-mediated glucose uptake and disposition in the liver

et al. 2004

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Free Fatty Acids Reduce Splanchnic and Peripheral Glucose Uptake in Patients With Type 2 Diabetes

Cited by 42 publications

References 49 publications

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

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

Non-esterified fatty acids and human lymphocyte death: a mechanism that involves calcium release and oxidative stress

Non-esterified fatty acids impair insulin-mediated glucose uptake and disposition in the liver

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