There is an individual susceptibility to diabetic nephropathy, and oxidative stress is believed to play an important role in the pathogenesis of diabetic complications. Active oxygen species induce antioxidant enzyme expression in tissues, an effect considered to be a defensive mechanism. To test whether altered intracellular antioxidant enzyme production might explain the predisposition to diabetic nephropathy, we studied the effect of long-term (12 weeks) exposure to normal (5 mmol/l) or high (22 mmol/l) glucose concentrations on fibroblast antioxidant enzyme gene expression and protein activity in type 1 diabetic patients with and without nephropathy, nondiabetic nephropathic patients, and nondiabetic control subjects. Under conditions of normal glucose concentration in the culture media, CuZnSuperoxide-dismutase, MnSuperoxide-dismutase, catalase, and glutathione-peroxidase activity and mRNA expression were not different among the four groups. Under high-glucose conditions, CuZnSuperoxide-dismutase mRNA and activity increased similarly in all groups (P < 0.001 vs. basal), whereas MnSuperoxide-dismutase did not change. In contrast, catalase mRNA and activity as well as glutathione-peroxidase mRNA and activity increased in fibroblasts from type 1 diabetic patients without nephropathy (P < 0.001), in fibroblasts from nondiabetic nephropathic patients (P < 0.001), and in fibroblasts from nondiabetic control subjects (P < 0.001), but not in fibroblasts from type 1 diabetic patients with nephropathy. Exposure to high glucose concentrations significantly increased lipid peroxidation in cells, higher levels being found in cells from diabetic patients with nephropathy (P < 0.001). These data, while confirming that exposure to high glucose concentrations induces an antioxidant defense in skin fibroblasts from normal subjects, demonstrate a failure of this defensive mechanism in cells from type 1 diabetic patients with nephropathy, whereas skin fibroblasts from diabetic patients without complications or from nondiabetic nephropathic patients have an intact antioxidant response to glucose-induced oxidative stress.

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The nature of the association between essential hypertension and insulin resistance remains unknown. We measured plasma glucose and insulin levels after an oral glucose tolerance test (OGTT), as well as insulin sensitivity (using a euglycemic hyperinsulinemic clamp), glucose turnover (Rd; using [6,6-2H2]- and [3-3H]glucose isotopic dilution), and forearm net balance of glucose (using arterial-venous difference) in 22 hypertensive patients with high (H2) red blood cell (RBC) sodium-lithium countertransport (Na(+)-Li+ CT; greater than 0.41 mmol.l RBC-1.h-1), 21 hypertensive patients with normal (H1) Na(+)-Li+ CT, and 22 normotensive controls (C). After OGTT, H2 patients had higher plasma glucose and insulin levels than H1 and C. During euglycemic hyperinsulinemia (approximately 100 microU/ml) Rd was lower in H2 [21.7 +/- 1.4 (SE) mumol.kg-1.min-1] than in H1 (44.3 +/- 2.9; P less than 0.01) and C (48.1 +/- 3.0; P less than 0.01), and an inverse correlation was found between rates of Na(+)-Li+ CT and Rd in H1 and H2 (rs = -0.76; P less than 0.01). Forearm glucose uptake was 40-50% lower in H2 compared with H1 and C (P less than 0.01). Lactate concentration increased more in C (from 511 +/- 24 to 1,207 +/- 69 microM) and in H1 (from 564 +/- 40 to 1,122 +/- 99) than in H2 (from 581 +/- 42 to 950 +/- 102, P less than 0.05 vs. both). Forearm blood flow increased more in C (31%, P less than 0.05) and H1 (22%, P less than 0.05) than in H2 (12%).(ABSTRACT TRUNCATED AT 250 WORDS)

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)

SUMMARYAim: To compare the antisecretory effects of rabeprazole and esomeprazole in an open, randomized, two-way crossover, clinical pharmacology study. Methods: Twenty-four healthy subjects (14 men, 10 women; mean age 26.8 years) received rabeprazole 20 mg or esomeprazole 20 mg daily on days 1-5, with a 14-day Ôwash-outÕ. Intragastric pH was recorded continuously, and serum gastrin measured, on days 0, 1 and 5. Results: On day 0, mean intragastric pH AUC was significantly higher before the esomeprazole than before the rabeprazole treatment in four of the five time intervals analysed. On days 1 and 5, mean intragastric pH AUC was higher after rabeprazole than esomeprazole during 5-11, 14-24 and 0-24 h after dosing. Mean pH AUC in the first 5 h after dosing on day 5 was higher after esomeprazole than rabeprazole (P ¼ 0.012). On day 1, mean per cent times pH > 3 and > 4 were significantly greater after rabeprazole than esomeprazole during 0-14, 14-24 and 0-24 h. On day 5, mean serum gastrin AUC 0-4 was higher (P ¼ 0.017) after rabeprazole than esomeprazole (335 vs. 316 pg ⁄ mL.h). Conclusion: In this clinical pharmacology study, rabeprazole 20 mg daily was more effective than esomeprazole 20 mg daily in increasing intragastric pH and maintaining pH > 3 and > 4. On day 5, mean pH AUC was higher after esomeprazole than rabeprazole.