Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes
Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes
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DOI：
10.1210/jc.2004-0224
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发表时间：
2004-09-01
影响因子：
5.8
通讯作者：
DeFronzo, RA
中科院分区：
文献类型：
--
作者：
Bajaj, M;Suraamornkul, S;DeFronzo, RA
为了研究血浆游离脂肪酸（FFA）浓度持续（7-d）降低对2型糖尿病（T2 DM）遗传易感个体的影响，我们研究了阿昔莫司（一种强效脂解抑制剂）对8名正常葡萄糖耐受受试者的胰岛素作用和脂肪细胞因子浓度的影响（年龄40 +/- 4岁，体重指数26.5 +/- 0.8 kg/m2），至少有两名一级亲属患有T2 DM。受试者接受口服葡萄糖耐量试验（OGTT）和120分钟正常血糖胰岛素钳夹（80 mU/m2）。用3-[H-3]葡萄糖定量胰岛素介导的全身葡萄糖处置（Rd）和内源性（主要是肝脏）葡萄糖产生（EGP）的速率。阿昔莫司显著降低空腹血浆FFA（515 +/- 64至285 +/- 58 μ M，P < 0.05）和OGTT期间的平均血浆FFA（263 ± 32至151 ± 25 μ M，P < 0.05）;在胰岛素钳夹期间胰岛素介导的血浆FFA浓度抑制也增强（162 +/-18至120 +/-15 μ M，P < 0.10）。服用阿昔莫司后，空腹血糖（5.1 +/-1 vs. 5.2 +/-1 mM）没有变化，而OGTT期间平均血糖降低（7.6 +/-5至6.9 +/-5 mM，P < 0.01），平均血浆胰岛素浓度没有变化（402 +/-至444 +/-2 pmol/L）。阿昔莫司给药后，Rd从5.6 +/-5增加至6.8 +/-5 mg/kg。由于胰岛素刺激的非氧化性葡萄糖处置增加（2.5 +/-4至3.5 +/-4 mg/kg中心点分钟，P <0.05），血浆游离脂肪酸（FFA）浓度降低与Rd升高呈显著正相关（r =-0.80，P< 0.02）。基础EGP在阿昔莫司治疗后没有改变（1.9 +/- 0.1 vs. 2.0 +/- 0.1 mg/kg中心点分钟），但胰岛素介导的EGP抑制改善（0.22 +/- 0.09至0.01 +/- 0.01 mg/ kg中心点分钟，P < 0.05）。EGP与空腹血浆FFA浓度（r = 0.49，P = 0.06）和胰岛素钳夹时血浆FFA平均浓度（r = 0.52，P < 0.05）呈正相关。血浆脂联素（7.1 +/- 1.0至7.2 +/- 1.1 μ g/ml），肌酐（4.0 +/- 0.3至3.8 +/- 0.3 ng/ml），IL-6（1.4 +/- 0.3至1.6 +/- 0.4 pg/ml），和TNF a（2.3 +/- 0.3至2.4 +/- 0.3 pg/ml）我们的结论是，在有强烈的T2 DM家族史的受试者中，血浆FFA浓度的持续降低增加外周（肌肉）和肝脏胰岛素敏感性，而不增加脂联素水平或改变脂肪细胞分泌其他脂肪细胞因子。这些结果表明，脂毒性已在遗传易感性T2 DM个体中得到充分证实，并且尽管对脂肪细胞因子浓度缺乏影响，但导致血浆FFA浓度持续降低的药物可能代表了预防高风险、遗传易感性、正常葡萄糖耐受个体中T2 DM的有效方式。
To investigate the effect of a sustained (7-d) decrease in plasma free fatty acid (FFA) concentration in individuals genetically predisposed to develop type 2 diabetes mellitus (T2DM), we studied the effect of acipimox, a potent inhibitor of lipolysis, on insulin action and adipocytokine concentrations in eight normal glucose-tolerant subjects ( aged 40 +/- 4 yr, body mass index 26.5 +/- 0.8 kg/m(2)) with at least two first-degree relatives with T2DM. Subjects received an oral glucose tolerance test (OGTT) and 120 min euglycemic insulin clamp (80 mU/m(2) . min) with 3-[H-3] glucose to quantitate rates of insulin-mediated whole-body glucose disposal (Rd) and endogenous ( primarily hepatic) glucose production (EGP) before and after acipimox, 250 mg every 6 h for 7 d. Acipimox significantly reduced fasting plasma FFA (515 +/- 64 to 285 +/- 58 muM, P < 0.05) and mean plasma FFA during the OGTT ( 263 +/- 32 to 151 +/- 25 mu M, P < 0.05); insulin-mediated suppression of plasma FFA concentration during the insulin clamp also was enhanced ( 162 +/- 18 to 120 +/- 15 muM, P < 0.10). Following acipimox, fasting plasma glucose (5.1 +/-1 vs. 5.2 +/-1 mM) did not change, whereas mean plasma glucose during the OGTT decreased (7.6 +/-5 to 6.9 +/-5 mM, P < 0.01) without change in mean plasma insulin concentration (402 +/- to 444 +/-2 pmol/ liter). After acipimox Rd increased from 5.6 +/-5 to 6.8 +/-5 mg/kg . min (P < 0.01) due to an increase in insulin-stimulated nonoxidative glucose disposal (2.5 +/-4 to 3.5 +/-4 mg/kg center dot min, P < 0.05). The increment in Rd correlated closely with the decrement in fasting plasma FFA concentration ( r = - 0.80, P< 0.02). Basal EGP did not change after acipimox ( 1.9 +/- 0.1 vs. 2.0 +/- 0.1 mg/kg center dot min), but insulin-mediated suppression of EGP improved (0.22 +/- 0.09 to 0.01 +/- 0.01 mg/ kg center dot min, P < 0.05). EGP during the insulin clamp correlated positively with the fasting plasma FFA concentration ( r = 0.49, P = 0.06) and the mean plasma FFA concentration during the insulin clamp ( r = 0.52, P < 0.05). Plasma adiponectin (7.1 +/- 1.0 to 7.2 +/- 1.1 mu g/ml), resistin (4.0 +/- 0.3 to 3.8 +/- 0.3 ng/ml), IL-6 (1.4 +/- 0.3 to 1.6 +/- 0.4 pg/ml), and TNF alpha (2.3 +/- 0.3 to 2.4 +/- 0.3 pg/ml) did not change after acipimox treatment.We concluded that sustained reduction in plasma FFA concentration in subjects with a strong family history of T2DM increases peripheral ( muscle) and hepatic insulin sensitivity without increasing adiponectin levels or altering the secretion of other adipocytokines by the adipocyte. These results suggest that lipotoxicity already is well established in individuals who are genetically predisposed to develop T2DM and that drugs that cause a sustained reduction in the elevated plasma FFA concentration may represent an effective modality for the prevention of T2DM in high-risk, genetically predisposed, normal glucose-tolerant individuals despite the lack of an effect on adipocytokine concentrations.