Diabetes, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
Hepatology. 2012 May;55(5):1389-97. doi: 10.1002/hep.25539. Epub 2012 Mar 18.
The role of adipose tissue insulin resistance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains unclear. To evaluate this, we measured in 207 patients with NAFLD (age = 51 ± 1, body mass index = 34.1 ± 0.3 kg/m(2) ) and 22 controls without NAFLD (no NAFLD) adipose tissue insulin resistance by means of a validated index (Adipo-IR(i) = plasma free fatty acids [FFA] x insulin [FPI] concentration) and as the suppression of plasma FFA during an oral glucose tolerance test and by a low-dose insulin infusion. We also explored the relationship between adipose tissue insulin resistance with metabolic and histological parameters by dividing them based on quartiles of adipose tissue insulin resistance (Adipo-IR(i) quartiles: Q1 = more sensitive; Q4 = more insulin resistant). Hepatic insulin resistance, measured as an index derived from endogenous glucose production x FPI (HIRi), and muscle insulin sensitivity, were assessed during a euglycemic insulin clamp with 3-[(3) H] glucose. Liver fat was measured by magnetic resonance imaging and spectroscopy, and a liver biopsy was performed to assess liver histology. Compared to patients without steatosis, patients with NAFLD were insulin resistant at the level of adipose tissue, liver, and skeletal muscle and had higher plasma aspartate aminotransferase and alanine aminotransferase, triglycerides, and lower high-density lipoprotein cholesterol and adiponectin levels (all P < 0.01). Metabolic parameters, hepatic insulin resistance, and liver fibrosis (but not necroinflammation) deteriorated as quartiles of adipose tissue insulin resistance worsened (all P < 0.01).
Adipose tissue insulin resistance plays a key role in the development of metabolic and histological abnormalities of obese patients with NAFLD. Treatment strategies targeting adipose tissue insulin resistance (e.g., weight loss and thiazolidinediones) may be of value in this population.
非酒精性脂肪性肝病（NAFLD）的发病机制中，脂肪组织胰岛素抵抗的作用尚不清楚。我们通过一种已验证的指数（Adipo-IR(i)=血浆游离脂肪酸[FFA]×胰岛素[FPI]浓度）以及口服糖耐量试验中血浆 FFA 的抑制作用和小剂量胰岛素输注，评估了 207 例 NAFLD 患者（年龄=51±1，体重指数=34.1±0.3kg/m(2)）和 22 例无 NAFLD 对照组的脂肪组织胰岛素抵抗，并将其分为脂肪组织胰岛素抵抗（Adipo-IR(i)四分位组：Q1=更敏感；Q4=更胰岛素抵抗）四分位组，探讨了脂肪组织胰岛素抵抗与代谢和组织学参数之间的关系。通过 3-[（3）H]葡萄糖正葡萄糖钳夹评估肝胰岛素抵抗（由内源性葡萄糖生成×FPI 得出的指数表示）和肌肉胰岛素敏感性，通过磁共振成像和光谱测量肝脂肪，并进行肝活检以评估肝组织学。与无脂肪变性的患者相比，NAFLD 患者的脂肪组织、肝脏和骨骼肌均存在胰岛素抵抗，且其血浆天门冬氨酸氨基转移酶和丙氨酸氨基转移酶、甘油三酯水平升高，高密度脂蛋白胆固醇和脂联素水平降低（均 P<0.01）。随着脂肪组织胰岛素抵抗四分位组的恶化，代谢参数、肝胰岛素抵抗和肝纤维化（但不是坏死性炎症）恶化（均 P<0.01）。
脂肪组织胰岛素抵抗在肥胖的 NAFLD 患者代谢和组织学异常的发生发展中起关键作用。针对脂肪组织胰岛素抵抗的治疗策略（如减重和噻唑烷二酮类药物）可能对这一人群有价值。
