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The effect of long term, aggressive antihypertensive treatment on kidney function in diabetic nephropathy was studied prospectively in 11 insulin dependent diabetics (mean age 30). During the mean pretreatment period of 32 (range 23-66) months the glomerular filtration rate decreased significantly and albuminuria and the arterial blood pressure increased significantly. During the 72 (range 32-91) month period of antihypertensive treatment the average arterial blood pressure fell from 143/96 mmHg to 129/84 mm Hg and albuminuria decreased from 1038 [tg/min to 504 [tg/min. The rate of decline in the glomerular filtration rate decreased from 0-89 (range 0.44-1.46) ml/min/month before treatment to 0-22 (range 0-01-0.40) mllmin/month during treatment. The rate of decline in the glomerular filtration rate was significantly smaller during the second three years compared with the first three years in patients who received long term antihypertensive treatment (-6 years). One patient died from acute myocardial infarction (glomerular filtration rate 46 ml/min/ 1-74 m2).Effective antihypertensive treatment postpones renal insufficiency in diabetic nephropathy.

Patients with Type 1 (insulin-dependent) diabetes without proteinuria were studied to define those patients who will later develop persistent proteinuria (more than 0.5 g protein/24 h). Two investigations were performed; 71 patients were studied longitudinally for 6 years and another 227 patients were studied cross-sectionally. All were less than 50 years of age and had developed diabetes before the age of 40 years. At entry into the study they had no proteinuria (Albustix method), had normal blood pressure and urinary albumin excretion rates less than 200 micrograms/min (normal less than or equal to 20 micrograms/min). The best predictor of persistent proteinuria or an albumin excretion rate greater than 200 micrograms/min was the initial urinary albumin excretion rate. During the longitudinal study, seven patients with an urinary albumin excretion rate of more than 70 micrograms/min at the start of the study developed persistent proteinuria or an albumin excretion rate greater than 200 micrograms/min. In contrast, only three out of the remaining 64 patients with urinary albumin excretion rate less than or equal to 70 micrograms/min developed urinary albumin excretion rate greater than 200 micrograms/min. Patients with an urinary albumin excretion rate greater than 70 micrograms/min are thus at risk of developing diabetic nephropathy. We designate this stage of renal involvement incipient nephropathy. Patients with incipient nephropathy were further characterized in the cross-sectional study. Compared with normoalbuminuric patients, patients with incipient nephropathy had increased systolic and diastolic blood pressure, but normal serum creatinine. The glomerular filtration rate was higher than normal in patients with incipient nephropathy though not different from that of normoalbuminuric patients.

The microvascular permeability to small and large molecules was studied during good and poor metabolic regulation in ten short duration juvenile diabetics. The following variables were measured; daily urinary albumin and beta2-microglobulin-excretion rates, whole body transcapillary escape rate of albumin (TER), glomerular filtration rate (GFR), capillary filtration coefficient (CFC), and capillary diffusion capacity (CDC). The urinary albumin and beta2-microglobulin concentration were measured by sensitive radioimmunoassays; TER was detemined from the initial disappearance of intravenously injected 125I-labelled human serum albumin; GFR was measured on the forearm by straingauge plethysmography and CDS for 51Cr-EDTA clearance; CFC was measured on the forearm by straingauge plethysmography and CDC, for 51Cr-EDTA was determined in the jyperaemic anterio tibial muscle by the local clearance technique. All the above mentioned variables, except CDC, were significantly increased during poor metabolic regulation, indicating a functional microangiopathy. The mechanisms of these alterations appear to be increased filtration pressure in the microcirculation and/or increased porosity of the microvasculature. The findings of increased microvascular albumin passage are compatible with the hypothesis that the organic - histologicallly demonstrated - diabetic microangiopathy is a long-term effect of periods of increased extravasation of plasma proteins, with subsequent protein deposition in the microvascular wall, i.e. the concept to plasmatic vasculosis.

The role of the cystic fibrosis transmembrane conductance regulator (CFTR) in duodenal alkaline secretion has not been directly examined. The aims of this series of experiments were to determine if CFTR mediates basal and stimulated duodenal epithelial HCO3- secretion. Utilizing the cystic fibrosis murine model (cftr(m1UNC)), we compared normal [CFTR(+/+)] littermates (34-46 days old) with CFTR(-/-) animals (34-39 days old). Anesthesia was induced and maintained with intraperitoneal Hypnorm-midazolam. The proximal duodenum (4-7 mm) was cannulated and perfused with 154 mM NaCl. Either forskolin (10(-6)-10(-4) M) or carbachol (10(-6)-10(-3) M) was perfused intraluminally to activate adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca2+-mediated HCO3- secretion, respectively. Effluent volumes were weighed and HCO3- quantitated by back titration. Basal HCO3- secretion was diminished significantly (P < 0.01) in CFTR(-/-)vs. normal CFTR(+/+) mice (2.8 +/- 0.5 vs. 5.3 +/- 0.4 micromol x cm(-1) x h(-1)). Moreover, in CFTR(-/-) mice, both forskolin- and carbachol-stimulated peak HCO3- secretions were fourfold less compared with those in CFTR(+/+) littermates (3.7 +/- 0.2 vs. 15.6 +/- 2.1 and 4.7 +/- 0.3 vs. 14.2 +/- 2.5 micromol x cm(-1) x h(-1), respectively; P < 0.01). In conclusion, CFTR plays a significant role in mediating basal, cAMP-, and Ca2+-activated duodenal epithelial HCO3- secretion.

GFR, RPF, and kidney size were measured in nine young recently diagnosed insulin-dependent diabetics before (days 0) and 3 and 8 days after the beginning of the initial insulin treatment and in comparable control subjects. Kidney function was measured by a constant infusion technique using I-125-iothalamate and 131-I-hippuran. Kidney size was determined by means of ultrasound. Before insulin treatment elevated values for GFR (+44%, P less than 0.01), RPF (+18%, P less than 0.05), and kidney size (+29%, P less than 0.01) were found. Near-normal metabolic control was achieved in all patients using either multiple subcutaneous injections of insulin or an artificial betacell. GFR decreased from 160 +/- 9 SEM to 141 +/- 6 ml/min X 1.73 m2 (P less than 0.01) and further to 133 +/- 5 ml/min X 1.73 m2 (P less than 0.01, compared to day 0). Renal plasma flow was 601 +/- 33 and 588 +/- 44 ml x 1.73 m2 at days 0 and 3, respectively (NS) and decreased to 558 +/- 35 ml/min x 1.73 m2 at day 0 (P less than 0.01). By contrast no statistically significant changes in kidney volume were observed; the results on day 0, 3 and 8 were 145 +/- 7, 162 +/- 11 and 143 +/- 9 ml/1.73 m2, respectively. The present study demonstrates that kidney size and function are elevated at the onset of insulin-dependent diabetes. Near-normal metabolic control; for 8 days induces a reduction but not a complete normalization in kidney function. From the present observations it is suggested that the rapidly reversible part of the elevation in GFR cannot be explained by concomitant changes in kidney and glomerular size (morphological origin) but is probably due to a reduction in renal plasma flow and to a decreased transglomerular pressure (functional origin).

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Chromatographically determined haemoglobin A1c concentration was measured during short-term (1-24h) changes in glucose concentration in vitro and in vivo. In vitro at 37 degrees C the HbA1c concentration increased with glucose concentration and time both in normal and diabetic erythrocytes. In normal erythrocytes incubated in 20--100 mmol/l glucose, the increases in the HbA1c concentration were maximal after 4--6 h and then stable for the next 18--20 h. During the first hour, increases in the HbA1c concentration were linear with time and on average 0.034% HbA1c x h-1 x mmol/l glucose-1. In erythrocytes, after a rapidly produced increase (2 h), HbA1c decreased to preincubation concentrations during a further incubation of the erythrocytes in a glucose-free medium at 37 degrees C for 4--6 h. The mean rate of linear decrease was 0.017% x h-1 x mmol/l glucose-1. After incubation of erythrocytes in 100 mmol/l glucose for 24 h, 1.3% HbA1c remained stable for 6 h in saline. The rapid increase in HbA1c concentration, as determined by chromatography, was not due to stable HbA1c (ketoamine linked glucose) as no increase was found in the HbA1c concentrations determined by the thiobarbiturate method. In juvenile diabetics controlled by an artificial beta-cell, rapid changes of blood glucose concentration (up to 20 mmol/l) resulted in increases in HbA1c concentration of as much as 1.9% within 12 h (mean 1.1%). Rapid in vivo increases in HbA1c concentration were reversible by normalization of the blood glucose concentration. That rapid changes in HbA1c may occur in daily diabetic life was evidenced by differences in HbA1c concentration between blood samples from out-patient diabetics incubated in saline for 16 hours at 4 degrees C and 37 degrees C (range of differences 0.2--1.4% HbA1c). The differences correlated to the blood glucose concentration at the time of sampling blood for HbA1c determination. Thus, incubation of blood at a low glucose concentration prior to determination of the glycosylated haemoglobin concentration may overcome interference from rapidly produced HbA1c.