TSH, FT4 and FT3 each have their individual, but also interlocking roles to play in defining the overall patterns of thyroidal expression, regulation and metabolic activity. Equilibria typical of the healthy state are not invariant, but profoundly altered, for example, by L-T4 treatment. Consequently, this suggests the revisitation of strategies for treatment optimization.
Obesity-linked insulin resistance is associated with chronic inflammation and cardiovascular complications. Free fatty acids (FFAs) are prominent candidates for the molecular link between these disorders. In this study, we determined whether FFAs contribute to vascular inflammation via induction of interleukin (IL)-6 in coronary artery endothelial cells (CAECs) and coronary artery smooth muscle cells (CASMCs) and whether this is reflected in vivo. In contrast to our findings regarding IL-6 and gp130 (the glycoprotein of 130 kDa) expression, IL-6 receptor mRNA expression was very low in these cells. Palmitate, but not linoleate, induced a significant increase in IL-6 mRNA expression in CAECs (P < 0.001) and, to a less relevant extent, in CASMCs (P < 0.01). gp130 remained unaffected. As to potency, palmitate was comparable with the IL-6؊inducer IL-1. To substantiate our in vitro data, we examined the plasma FFA pattern in 54 healthy human subjects and studied the relation of individual FFAs with plasma IL-6. IL-6 levels correlated with palmitate, but not with other abundant FFAs, even after adjusting for body fat (r ؍ 0.33, P < 0.05) and total FFAs (r ؍ 0.29, P < 0.05). We show here that the common plasma FFA palmitate induces high levels of IL-6 in CAECs. Furthermore, palmitate correlates with IL-6 in vivo. This points to a potential contribution of palmitate to vascular inflammation. Diabetes 53: 3209 -3216, 2004
The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR)-␥ 2 is associated with reduced transcriptional activity in vitro and increased insulin sensitivity in humans in vivo. The mechanism by which this polymorphism influences insulin sensitivity in humans is unclear. PPAR-␥ 2 is mainly expressed in adipocytes, and free fatty acids released from adipose tissue are key mediators of peripheral insulin resistance. Therefore, we examined insulin suppression of lipolysis in 51 subjects without (Pro/ Pro) and 17 subjects with the polymorphism (X/Ala). Both groups were lean (BMI <27.0 kg/m 2 ) and matched for age, BMI, waist-to-hip ratio, and sex. The isotopically (infusion of d 5 glycerol) determined glycerol rate of appearance was used as an index of lipolysis. Insulin sensitivity of lipolysis was expressed as the insulin concentration resulting in half-maximal suppression (EC 50 ). This was directly determined during a threestep hyperinsulinemic-euglycemic clamp (n ؍ 21) or estimated indirectly during a standard hyperinsulinemic-euglycemic clamp (n ؍ 47). The insulin sensitivity index (ISI) of glucose disposal was 0.095 ؎ 0.006 mol ⅐ kg ؊1 ⅐ min ؊1 ⅐ pmol ؊1 ⅐ l -1 in the control group and 0.129 ؎ 0.008 mol ⅐ kg ؊1 ⅐ min ؊1 ⅐ pmol ؊1 ⅐ l -1 in the X/Ala group (P ؍ 0.003). The EC 50 was 56 ؎ 2 pmol/l in the control group and 44 ؎ 3 pmol/l in the X/Ala group (P ؍ 0.001). The EC 50 of lipolysis and ISI was significantly correlated (r ؍ 0.42, P ؍ 0.002). In conclusion, in lean subjects, the Pro12Ala polymorphism is associated with increased insulin sensitivity of glucose disposal and suppression of lipolysis. This result suggests that an altered transcriptional activity of PPAR-␥ 2 in X/Ala subjects either causes a more efficient suppression of lipolysis in adipose tissue, which in turn results in improved insulin-stimulated glucose disposal in muscle, or, alternatively, beneficially affects insulin signaling in both tissues independently of one another. Diabetes 50: 876 -881, 2001
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