National Institute of Child Health and Human Development.
National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
J Clin Invest. 2020 Jul 1;130(7):3592-3602. doi: 10.1172/JCI135431.
BACKGROUNDPostreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptor-level IR (e.g., insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis.METHODSCross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma β-hydroxybutyrate) were measured.RESULTSLipolysis was 2- to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% [interquartile range 0.1%-0.5%]), in contrast to lipodystrophy (10.6% [interquartile range 2.8%-17.1%], P < 0.0001). β-hydroxybutyrate was 2- to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation.CONCLUSIONThese data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis.TRIAL REGISTRATIONClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases, US Department of Agriculture/Agricultural Research Service 58-3092-5-001.
受体后胰岛素抵抗（IR）与高血糖和肝脂肪变性有关。然而，受体水平的 IR（例如胰岛素受体致病性变异，INSR）会导致高血糖而无脂肪变性。我们研究了人类 4 种 IR 病理状况，以研究控制脂质代谢和糖异生的途径。
对严重受体 IR（INSR，n=7）与严重（脂肪营养不良，n=14）、中度（2 型糖尿病，n=9）或轻度（肥胖，n=8）受体后 IR 进行横断面研究。测量脂肪分解（甘油周转率）、肝葡萄糖生成（HGP）、糖异生（体水氘掺入葡萄糖）、肝甘油三酯（磁共振波谱）和肝脂肪氧化（血浆β-羟基丁酸）。
与其他所有组相比，INSR 的脂肪分解率高出 2-3 倍，与 2 型糖尿病和肥胖相比，INSR 和脂肪营养不良的 HGP 高出 2 倍（P<0.001），表明脂肪组织和肝脏严重的 IR。与其他组（52%-59%）相比，INSR 受试者的 HGP 中糖异生的贡献率更高，约为 77%（P=0.0001）。尽管脂肪分解率高，但 INSR 患者的肝甘油三酯水平较低（0.5%[四分位距 0.1%-0.5%]），与脂肪营养不良（10.6%[四分位距 2.8%-17.1%]）相比，差异具有统计学意义（P<0.0001）。与其他组相比，INSR 的β-羟基丁酸高出 2-7 倍（P<0.0001），这与更高的肝脂肪氧化一致。
这些数据支持脂肪组织 IR 在受体和受体后 IR 中增加甘油和 FFA 向肝脏的可用性，从而发挥关键的致病作用。然而，FFA 的命运在这些人群中是不同的。在受体水平的 IR 中，FFA 氧化驱动糖异生而不是重新酯化形成甘油三酯。相比之下，在后受体 IR 中，FFA 既有助于糖异生，也有助于肝脂肪变性。
ClinicalTrials.gov NCT01778556、NCT00001987 和 NCT02457897。
美国国立糖尿病、消化和肾脏疾病研究所，美国农业部/农业研究服务部 58-3092-5-001。
