Trevisan R, Fioretto P, Semplicini A, Opocher G, Mantero F, Rocco S, Remuzzi G, Morocutti A, Zanette G, Donadon V
Department of Internal Medicine, University of Padua, Italy.
Diabetes. 1990 Mar;39(3):289-98. doi: 10.2337/diab.39.3.289.
Because insulin shows an antinatriuretic effect in healthy humans, insulin therapy resulting in circulating hyperinsulinemia may lead to sodium retention and in turn to hypertension in individuals with insulin-dependent diabetes mellitus (IDDM). Moreover, it has been proved that atrial natriuretic peptide (ANP) plays a major role in modulating natriuresis in humans. This study investigated the relationship between insulin and ANP in modulating sodium metabolism in normotensive and hypertensive IDDM subjects compared with control groups of normotensive and hypertensive nondiabetic subjects. IDDM normotensive and hypertensive subjects had mean +/- SE duration of IDDM of 7 +/- 2 and 8 +/- 2 yr, respectively, and had no clinical features of diabetic nephropathy. All subjects received a saline infusion (2 mmol.kg-1.90 min-1) during euglycemia. IDDM normotensive and hypertensive subjects received a subcutaneous insulin infusion (15 mU.kg-1.h-1), resulting in twofold higher plasma free-insulin levels (16 +/- 2 and 19 +/- 3 microU/ml, respectively) than in nondiabetic normotensive and hypertensive subjects (7 +/- 2 and 8 +/- 2 microU/ml, respectively). During saline challenge, sodium excretion increased by 22 +/- 4% in normotensive and 49 +/- 9% in hypertensive nondiabetic subjects but by only 11 +/- 0.4% in normotensive (P less than 0.01) and 8 +/- 2% in hypertensive (P less than 0.01) IDDM subjects. The impaired natriuretic response to saline challenge was mainly due to greater rates of sodium reabsorption by kidney proximal tubules in IDDM than nondiabetic subjects. At baseline, plasma ANP concentrations were significantly higher in both IDDM groups than in control groups (normotensive IDDM and control subjects: 38 +/- 4 and 19 +/- 2 pg/ml, respectively, P less than 0.01; hypertensive IDDM and control subjects: 45 +/- 6 and 27 +/- 4 pg/ml, respectively, P less than 0.05). After saline challenge, ANP concentrations rose to 39 +/- 4 pg/ml in normotensive and 49 +/- 5 pg/ml in hypertensive control subjects, whereas no significant change above baseline value was seen in IDDM subjects. Both IDDM groups showed a 10-12% greater exchangeable Na+ pool than control subjects regardless of the presence of hypertension. Subcutaneous insulin infusion, resulting in circulating plasma free-insulin levels in normotensive control subjects comparable to those in IDDM patients, inhibited natriuresis, increased proximal tubule sodium reabsorption at the level of the kidney, and inhibited an adequate ANP stimulation by saline challenge. We conclude that hyperinsulinemia leads to increased proximal tubule sodium reabsorption and impaired ANP response during saline administration. Both mechanisms account for sodium retention in normotensive and hypertensive IDDM patients.(ABSTRACT TRUNCATED AT 400 WORDS)
由于胰岛素在健康人体中显示出抗利尿钠作用，导致循环中高胰岛素血症的胰岛素治疗可能会导致钠潴留，进而在胰岛素依赖型糖尿病（IDDM）患者中引发高血压。此外，已证明心房利钠肽（ANP）在调节人体利钠作用中起主要作用。本研究调查了与血压正常和高血压的非糖尿病对照组相比，血压正常和高血压的IDDM患者中胰岛素和ANP在调节钠代谢方面的关系。血压正常和高血压的IDDM患者的IDDM平均病程分别为7±2年和8±2年，且无糖尿病肾病的临床特征。所有受试者在血糖正常期间接受生理盐水输注（2 mmol·kg⁻¹·90 min⁻¹）。血压正常和高血压的IDDM患者接受皮下胰岛素输注（15 mU·kg⁻¹·h⁻¹），导致血浆游离胰岛素水平分别比非糖尿病血压正常和高血压患者（分别为7±2和8±2 μU/ml）高出两倍（分别为16±2和19±3 μU/ml）。在生理盐水激发试验期间，血压正常的非糖尿病受试者钠排泄增加22±4%，高血压的非糖尿病受试者增加49±9%，但血压正常的IDDM受试者仅增加11±0.4%（P<0.01），高血压的IDDM受试者增加8±2%（P<0.01）。IDDM患者对生理盐水激发试验的利钠反应受损主要是由于IDDM患者肾近端小管的钠重吸收率高于非糖尿病患者。基线时，两个IDDM组的血浆ANP浓度均显著高于对照组（血压正常的IDDM和对照受试者分别为38±4和19±2 pg/ml，P<0.01；高血压的IDDM和对照受试者分别为45±6和27±4 pg/ml，P<0.05）。生理盐水激发试验后，血压正常的对照受试者ANP浓度升至39±4 pg/ml，高血压的对照受试者升至49±5 pg/ml，而IDDM受试者未观察到高于基线值的显著变化。无论是否存在高血压，两个IDDM组的可交换钠池均比对照受试者大10 - 12%。皮下胰岛素输注使血压正常的对照受试者循环血浆游离胰岛素水平与IDDM患者相当，抑制了利钠作用，增加了肾脏水平的近端小管钠重吸收，并抑制了生理盐水激发试验对ANP的充分刺激。我们得出结论，高胰岛素血症导致生理盐水给药期间近端小管钠重吸收增加和ANP反应受损。这两种机制都导致血压正常和高血压的IDDM患者钠潴留。（摘要截短至400字）
