Koopmans S J, Ohman L, Haywood J R, Mandarino L J, DeFronzo R A
Department of Medicine, University of Texas Health Science Center, San Antonio, USA.
Diabetes. 1997 Oct;46(10):1572-8. doi: 10.2337/diacare.46.10.1572.
Epidemiological studies have suggested an association among chronic hyperinsulinemia, insulin resistance, and hypertension. However, the causality of this relationship remains uncertain. In this study, chronically catheterized conscious rats were made hyperinsulinemic for 7 days (approximately 90 mU/l, i.e., threefold over basal), while strict euglycemia was maintained (approximately 130 mg/dl, coefficient of variation < 10%) by using a modification of the insulin/glucose clamp technique. Control rats received vehicle infusion. Baseline mean arterial pressure and heart rate were 125 +/- 5 mmHg and 427 +/- 12 beats/min and remained unchanged during the 7-day infusion of insulin (127 +/- 7 mmHg; 401 +/- 12 beats/min) or vehicle (133 +/- 4 mmHg; 411 +/- 10 beats/min). Baseline plasma epinephrine (88 +/- 15 pg/ml), norepinephrine (205 +/- 31 pg/ml), and sodium balance (0.34 +/- 0.09 mmol) remained constant during the 7-day insulin or vehicle infusion. After 7 days of insulin or vehicle infusion, in vivo insulin action was determined in all rats using a 2-h hyperinsulinemic (1 mU/min) euglycemic clamp with [3-3H]glucose infusion to quantitate whole-body glucose uptake, glycolysis, glucose storage (total glucose uptake minus glycolysis), and hepatic glucose production. Compared with vehicle-treated rats, 7 days of sustained hyperinsulinemia resulted in a reduction (P < 0.01) in insulin-mediated glucose uptake, glucose storage, and glycolysis by 39, 62, and 26%, respectively. Hepatic glucose production was normally suppressed after 7 days of hyperinsulinemia. Neither insulin-stimulated glucose uptake nor glucose storage correlated with blood pressure or heart rate. In conclusion, 7 days of euglycemic hyperinsulinemia induces severe insulin resistance with respect to whole-body glucose metabolism but does not increase blood pressure, catecholamine levels, or sodium retention. This indicates that hyperinsulinemia-induced insulin resistance is not associated with the development of hypertension in rats who do not have a genetic predisposition for hypertension. Because hyperinsulinemia was initiated in normal rats under euglycemic conditions, additional (inherited or acquired) factors may be necessary to observe an effect of hyperinsulinemia and/or insulin resistance to increase blood pressure.
流行病学研究表明，慢性高胰岛素血症、胰岛素抵抗和高血压之间存在关联。然而，这种关系的因果性仍不确定。在本研究中，通过改良的胰岛素/葡萄糖钳夹技术，使长期插管的清醒大鼠持续高胰岛素血症7天（约90 mU/l，即基础水平的三倍），同时维持严格的血糖正常（约130 mg/dl，变异系数<10%）。对照大鼠接受载体输注。基线平均动脉压和心率分别为125±5 mmHg和427±12次/分钟，在7天的胰岛素输注（127±7 mmHg；401±12次/分钟）或载体输注（133±4 mmHg；411±10次/分钟）期间保持不变。基线血浆肾上腺素（88±15 pg/ml）、去甲肾上腺素（205±31 pg/ml）和钠平衡（0.34±0.09 mmol）在7天的胰岛素或载体输注期间保持恒定。在胰岛素或载体输注7天后，对所有大鼠进行体内胰岛素作用测定，采用2小时高胰岛素血症（1 mU/分钟）血糖正常钳夹并输注[3-3H]葡萄糖，以定量全身葡萄糖摄取、糖酵解、葡萄糖储存（总葡萄糖摄取减去糖酵解）和肝葡萄糖生成。与载体处理的大鼠相比，7天的持续高胰岛素血症导致胰岛素介导的葡萄糖摄取、葡萄糖储存和糖酵解分别降低（P<0.01）39%、62%和26%。高胰岛素血症7天后，肝葡萄糖生成通常受到抑制。胰岛素刺激的葡萄糖摄取和葡萄糖储存均与血压或心率无关。总之，7天的血糖正常性高胰岛素血症可诱导全身葡萄糖代谢方面的严重胰岛素抵抗，但不会增加血压、儿茶酚胺水平或钠潴留。这表明，在没有高血压遗传易感性的大鼠中，高胰岛素血症诱导的胰岛素抵抗与高血压的发生无关。由于高胰岛素血症是在血糖正常的正常大鼠中引发的，可能需要额外的（遗传或获得性）因素才能观察到高胰岛素血症和/或胰岛素抵抗对血压升高的影响。
