Basu R, Basu A, Chandramouli V, Norby B, Dicke B, Shah P, Cohen O, Landau B R, Rizza R A
Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Diabetologia. 2008 Nov;51(11):2031-40. doi: 10.1007/s00125-008-1138-1. Epub 2008 Sep 4.
AIMS/HYPOTHESIS: We sought to determine whether pioglitazone and metformin alter NEFA-induced insulin resistance in type 2 diabetes and, if so, the mechanism whereby this is effected.
Euglycaemic-hyperinsulinaemic clamps (glucose approximately 5.3 mmol/l, insulin approximately 200 pmol/l) were performed in the presence of Intralipid-heparin (IL/H) or glycerol before and after 4 months of treatment with pioglitazone (n = 11) or metformin (n = 9) in diabetic participants. Hormone secretion was inhibited with somatostatin in all participants.
Pioglitazone increased insulin-stimulated glucose disappearance (p < 0.01) and increased insulin-induced suppression of glucose production (p < 0.01), gluconeogenesis (p < 0.05) and glycogenolysis (p < 0.05) during IL/H. However, glucose disappearance remained lower (p < 0.05) whereas glucose production (p < 0.01), gluconeogenesis (p < 0.05) and glycogenolysis (p < 0.05) were higher on the IL/H study day than on the glycerol study day, indicating persistence of NEFA-induced insulin resistance. Metformin increased (p < 0.001) glucose disappearance during IL/H to rates present during glycerol treatment, indicating protection against NEFA-induced insulin resistance in extrahepatic tissues. However, glucose production and gluconeogenesis (but not glycogenolysis) were higher (p < 0.01) during IL/H than during glycerol treatment with metformin, indicating persistence of NEFA-induced hepatic insulin resistance.
CONCLUSIONS/INTERPRETATION: We conclude that pioglitazone improves both the hepatic and the extrahepatic action of insulin but does not prevent NEFA-induced insulin resistance. In contrast, whereas metformin prevents NEFA-induced extrahepatic insulin resistance, it does not protect against NEFA-induced hepatic insulin resistance.
目的/假设：我们试图确定吡格列酮和二甲双胍是否能改变2型糖尿病中游离脂肪酸（NEFA）诱导的胰岛素抵抗，如果可以，其作用机制是什么。
在糖尿病患者中，于使用吡格列酮（n = 11）或二甲双胍（n = 9）治疗4个月前后，分别在输注脂肪乳剂-肝素（IL/H）或甘油的情况下进行正常血糖-高胰岛素钳夹试验（血糖约5.3 mmol/L，胰岛素约200 pmol/L）。所有参与者均使用生长抑素抑制激素分泌。
在IL/H期间，吡格列酮可增加胰岛素刺激的葡萄糖消失（p < 0.01），并增强胰岛素诱导的葡萄糖生成抑制（p < 0.01）、糖异生抑制（p < 0.05）和糖原分解抑制（p < 0.05）。然而，在IL/H研究日，葡萄糖消失仍较低（p < 0.05），而葡萄糖生成（p < 0.01）、糖异生（p < 0.05）和糖原分解（p < 0.05）高于甘油研究日，表明NEFA诱导的胰岛素抵抗持续存在。二甲双胍可使IL/H期间的葡萄糖消失增加（p < 0.001），达到甘油治疗时的水平，表明其可预防肝外组织中NEFA诱导的胰岛素抵抗。然而，在IL/H期间，二甲双胍治疗时的葡萄糖生成和糖异生（但不包括糖原分解）高于甘油治疗时（p < 0.01），表明NEFA诱导的肝脏胰岛素抵抗持续存在。
结论/解读：我们得出结论，吡格列酮可改善胰岛素的肝脏和肝外作用，但不能预防NEFA诱导的胰岛素抵抗。相比之下，二甲双胍可预防NEFA诱导的肝外胰岛素抵抗，但不能预防NEFA诱导的肝脏胰岛素抵抗。
