Effect of acute hyperglycaemia on sodium handling and excretion of nitric oxide metabolites, bradykinin, and cGMP in Type 1 diabetes mellitus.

AIMS: The aim of this study was to evaluate the effect of acutely induced hyperglycaemia on renal sodium handling and to explore the role of the bradykinin-nitric oxide-cGMP signalling pathway. PATIENTS AND METHODS: We compared 20 Type 1 diabetic (DM1) patients without microalbuminuria with 15 weight-, age-, and sex-matched healthy controls (C). Clearances of para-aminohippuric acid (CPAH), inulin (Cin), lithium, sodium, and urinary nitrite/nitrate (NOx), cGMP and bradykinin excretion rates were measured in two 90-min periods: a glycaemic clamp-induced euglycaemia (5 mmol/l-period I) and hyperglycaemia (12 mmol/l-period II) (Study 1) and during time-controlled euglycaemia (5 mmol/l-period I and 5 mmol/l-period II) to avoid the effects of time and volume load (Study 2). RESULTS: Cin and CPAH were not significantly different during euglycaemia (period I of Study 1) in DM1 and controls, whereas fractional excretion of sodium was decreased in DM1 (1.84 +/- 0.75 vs. 2.36 +/- 0.67%; P < 0.05) due to an increase in fractional distal tubular reabsorption of sodium (94.01 +/- 1.94 vs. 92.24 +/- 2.47%; P < 0.05). A comparison of changes during Study 1 and Study 2 revealed acute hyperglycaemia did not change renal haemodynamics significantly, while fractional distal tubular reabsorption of sodium increased (DM1: P < 0.05; C: P < 0.01) and fractional excretion of sodium decreased (P < 0.01) in both groups. The urinary excretion rates of NOx were comparable during euglycaemia in DM1 and C. While in C, they significantly increased during Study 1 (period I: 382 +/- 217 vs. period II: 515 +/- 254 nmol/min; P < 0.01) and Study 2 (period I: 202.9 +/- 176.8 vs. period II: 297.2 +/- 267.5 nmol/min; P < 0.05) as a consequence of the water load, no changes were found in DM1. The urinary excretion of bradykinin was lower in DM1 compared with C (0.84 +/- 0.68 vs. 1.20 +/- 0.85 micro g/min; P < 0.01) during euglycaemia; it was not affected by hyperglycaemia. There were no significant differences between DM1 and C and in cGMP urinary excretion rates following hyperglycaemia. CONCLUSION: This study demonstrates that DM1 without renal haemodynamic alterations is associated with impaired renal sodium handling. Moreover, we did not find a relationship between the renal excretion rates of vasoactive mediators and sodium handling due to hyperglycaemia.

Effect of acute hyperglycaemia on selected plasma and urinary cytokine antagonists in Type 1 diabetes mellitus.

AIMS/HYPOTHESIS: Several cytokines have been implicated in the pathogenesis of diabetic nephropathy. Their ability to generate a biological response in vivo is modulated by specific antagonists and soluble receptors. The aims of the study were firstly, to measure the interleukin 1 receptor antagonist (IL-1ra) and tumour necrosis factor alpha soluble receptors p55 (TNFsr1) and p75 (TNFsr2) in plasma and urine, and secondly to test their response to acutely induced hyperglycaemia in Type 1 diabetes mellitus (DM 1). METHODS: Plasma concentrations and urinary excretions of IL-1ra, TNFsr1 and TNFsr2 were measured in two 90-min periods of glycaemic clamp-induced normoglycaemia and hyperglycaemia (5 and 12 mmol/l; study 1) and during time-controlled normoglycaemia (5 and 5 mmol/l; study 2) in 20 Type 1 diabetic patients with normal albumin excretion and normal glomerular filtration rate, and in 11 weight-, age- and sex-matched healthy control subjects. RESULTS: The plasma concentrations of IL-1ra, TNFsr1 and TNFsr2 were comparable in Type 1 diabetic patients and control subjects, and no significant changes during study 1 and study 2 were found. Urinary IL-1ra excretion measured during normoglycaemia was higher in Type 1 diabetic patients compared to control subjects ( p<0.05). In diabetic patients, it decreased in study 1 compared to study 2 ( p<0.05), while it did not change in control subjects. The urinary excretions of TNFsr1 and TNFsr2 during normoglycaemia were comparable in diabetic patients and controls. In diabetic patients, hyperglycaemia decreased TNFsr1 excretion (study 1 vs study 2; p<0.01), while TNFsr1 excretion did not change in control subjects. Hyperglycaemia did not affect TNFsr2 excretion in diabetic patients, while it led to an increase in TNFsr2 excretion in control subjects (study 1 vs study 2; p<0.05). Despite comparable renal haemodynamics, diabetic patients had lower fractional excretion of sodium compared to control subjects ( p<0.01). No significant relationships between cytokine antagonists and renal functions have been found. CONCLUSION/INTERPRETATION: Type 1 diabetic patients with normal renal haemodynamics are associated with impaired regulation of renal IL-1ra, TNFsr1 and TNFsr2 production with a potential impact on local control of cytokine activity in the kidneys.

[Changes in blood pressure, proteinuria and renal hemodynamics in type I diabetes with manifestations of diabetic nephropathy after 2 months of captopril therapy]. / Zmeny krevního tlaku, proteinurie a renální hemodynamiky u diabetiku I. typu s manifestní diabetickou nefropatií po dvou mesících lécby captoprilem.

In 15 type I diabetics with manifest diabetic nephropathy the authors investigated the antihypertensive and antiproteinuric effect of captopril and in seven patients of this group also its effect on renal haemodynamics. Captopril treatment or its combination with hitherto used antihypertensive treatment was associated after two months with a significant drop of the systolic and diastolic blood pressure from 150/95 (120/70-195/110) to 130/90 (110/65-180/115) mmHg, (p < 0.005 < 0.05). The median aortic pressure declined from 118.5 (92-140.8) to 106.5 (84-1334.8) mm Hg (p < 0.005). Nine of 11 patients (82%) could be changed to reduced antihypertensive therapy. The antiproteinuric effect was manifested in 11 patients (73%). Quantitative proteinuria dropped from 2.7 (0.83-8.65) to 1.85 (0.38-8.84) g/24 h., (p < 0.05) without a significant change of serum creatinine: 109 (70-342) vs. 135 (90-288) mumol/l, p = n.s.). The change of proteinuria, as compared with the baseline value, was -41 (-77 - +88)%, (p < 0.05) and did not correlate with the change of the median aortic pressure (correlation coefficient = -0.165, p = n.s.). In the group of seven patients the change of the median aortic pressure was -15% (-26.1 - +6.6), (p < 0.05). No statistically significant change of glomerular filtration was observed: 0.96 (0.32-1.38) vs. 0.96 (0.19-1.71) ml/s, p = n.s.); effective renal plasma flow: 6.32 (2.24-7.74) vs. 7.22 (1.68-10.55) ml/s, (p = n.s.); filtration fraction: 0.136 (0.123-0.220) vs. 0.130 (0.110-0.236), change 0.0 (-43.0 - +31.0)% (p = n.s.) and renal vascular resistance: 15429 (12907-54148) vs. 13243 (7099-77832)%, (p. = n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)