Trends in hypertension management in Type I diabetes across Europe, 1989/1990 - 1997/1999.

AIMS/HYPOTHESIS: Our aim was to examine the change in the management of hypertension in patients with Type I (insulin-dependent) diabetes mellitus in Europe, between 1989-1990 and 1997-1999. METHODS: Seven-year changes in hypertension treatment and control (defined as blood pressure <130/85 mmHg) were examined in a large sample of Type I diabetic patients recruited from 26 centres involved in the EURODIAB Prospective Complications Study. Hypertension was defined as a systolic and/or diastolic blood pressure greater than 140 and/or 90 mmHg respectively, and/or use of blood pressure lowering drugs. RESULTS: Of 1866 Type I diabetic patients, 412 had hypertension at baseline and 631 at follow-up. A greater proportion of hypertensive patients were treated at follow-up (69% vs 40%, p<0.0001), which persisted after adjustment for age or centre. Of those who were treated, a modest increase in the proportion of those controlled for hypertension was found (41% vs 32%, p=0.048), which disappeared after adjustment for age. Among hypertensive patients with albuminuria, the proportions treated also increased, from 35% to 76% ( p<0.0001) in microalbuminuric and 64% to 95% ( p<0.0001) in macroalbuminuric patients. Control of hypertension in albuminuric patients did not change significantly and was below 50%. The use of more than one anti-hypertensive drug increased over a 7-year period, from 19% to 33% ( p<0.0001), and a marked increase was shown in the proportion of those taking an ACE inhibitor (from 57% to 82%, p<0.0001). CONCLUSION/INTERPRETATION: The management of hypertension in Type I diabetic patients across Europe has improved over a 7-year follow-up period. Optimal levels of blood pressure treatment and optimal levels of control have not yet been achieved.

Microalbuminuria in type 1 diabetes: rates, risk factors and glycemic threshold.

BACKGROUND: The occurrence of microalbuminuria in type 1 diabetes is strongly predictive of renal and cardiovascular disease and is still likely to occur despite improvements in glycemic control. A better understanding of microalbuminuria is required to inform new interventions. We determined the incidence and risk factors for microalbuminuria [albumin excretion rate (AER) 20 to 200 microg/min] in the EURODIAB Prospective Complications Study. METHODS: This is a seven-year follow-up (between 1988 and 1991) of 1134 normoalbuminuric men and women (aged 15 to 60) with type 1 diabetes from 31 European centers. Risk factors and AER were measured centrally. RESULTS: The incidence of microalbuminuria was 12.6% over 7.3 years. Independent baseline risk factors were HbA1c (7.1 vs. 6.2%, P = 0.0001) and AER (9.6 vs. 7.8 microg/min, P = 0.0001) and, independent of these, fasting triglyceride (0.99 vs. 0.88 mmol/L, P = 0.01), low-density lipoprotein cholesterol (3.5 vs. 3.2 mmol/L, P = 0.02), body mass index (24.0 vs. 23.4 kg/m2, P = 0.01), and waist to hip ratio (WHR; 0.85 vs. 0.83, P = 0.009). Triglyceride and WHR risk factors were nearly as strong as AER in predicting microalbuminuria (standardized regression effects of 1.3 for triglyceride and WHR and 1.5 for AER). Blood pressure at follow-up, but not at baseline, was also raised in those who progressed. There was no evidence of a threshold of HbA1c on microalbuminuria risk. CONCLUSIONS: The incidence of microalbuminuria in patients with type 1 diabetes remains high, and there is no apparent glycemic threshold for it. Markers of insulin resistance, such as triglyceride and WHR, are strong risk factors. Systemic blood pressure is not raised prior to the onset of microalbuminuria.

Pronatriodilatin gene polymorphisms, microvascular permeability, and diabetic nephropathy in type 1 diabetes mellitus.

Approximately 30% of diabetic patients develop nephropathy, the appearance of which is partially under genetic control. Atrial natriuretic peptide (ANP) has associated physiologic effects on the kidney. This study was conducted to examine the relationship between a newly identified and known polymorphism at the pronatriodilatin (PND) gene locus and renal involvement in type 1 diabetic subjects. Of 454 type 1 diabetic patients (219 men, 235 women), 323 showed no sign of nephropathy, 79 had incipient renal involvement, and 52 established nephropathy; 58 healthy control subjects were examined for comparison. Allele frequencies (C708 versus T708) were: 0.95 and 0.05 in normoalbuminuric patients, respectively; 0.88 and 0.12 in microalbuminuric patients; 0.96 and 0.04 both in those with overt nephropathy and in healthy control subjects (P = 0.011). Patients with incipient nephropathy were in disequilibrium compared with the total diabetic cohort (P = 0.02). In the same populations, an additional genotype for ScaI polymorphism of the PND gene was tested. The A1 and A2 allele frequencies were: 0.21 and 0.79 in normoalbuminuric patients; 0. 13 and 0.87 in microalbuminuric patients; 0.06 and 0.94 in type 1 diabetic subjects with overt nephropathy; and 0.20 and 0.80 in healthy control subjects, respectively (P < 0.0001). A subset of 55 normotensive patients with type 1 diabetes, well matched for clinical features, plasma ANP levels, and microvascular permeability to macromolecules, was investigated on the basis of the C708/T and A2/A1 polymorphisms. Both transcapillary escape rate of albumin (TERalb) and plasma ANP levels were significantly lower in patients with the T708 than with C708 allele, as well as in the A1 than in A2 allele (TERalb: T708 versus C708: 5.5+/-1.7 versus 7.8+/-2.0%/h, P = 0.0001; plasma ANP levels: 8.3+/-3.9 versus 15.3+/-7.7 pg/ml, P = 0.0003; A1 versus A2: 6.05+/-2.2 versus 7.3+/-2.1%/h, P = 0.044; 8.53+/-4.6 versus 14.5+/-7.4 pg/ml, P = 0.0024, respectively). Thus, in a large ethnically homogeneous cohort of diabetic subjects, our data show: (1) a significant association of C708/T polymorphism with microalbuminuria in long-term diabetes and with both lower plasma ANP levels and widespread albumin leakage; and (2) a strong association between ScaI polymorphism and both diabetic nephropathy and plasma ANP concentrations. These results suggest a possible role of PND gene in conferring protection from nephropathy and microvascular damage in type 1 diabetes.

Amiloride-insensitive Na+-H+ exchange: a candidate mediator of erythrocyte Na+-Li+ countertransport.

Erythrocyte Na+-Li+ countertransport shows an increased activity in essential hypertension and diabetic nephropathy, but its nature remains unknown. This amiloride-insensitive membrane transport may not be a mode of operation of the amiloride-sensitive NHE1, the only Na+-H+ exchange isoform found in human erythrocytes. Whether an independent, although unknown, amiloride-insensitive isoform mediates Na+-Li+ countertransport is unclear. Na+-H+ exchange activity was measured in acid-loaded erythrocytes. Dimethylamiloride, a specific inhibitor of Na+-H+ exchange and phloretin, a known inhibitor of Na+-Li+ countertransport, gave a reduction in H+-driven Na+ influx (by 31 and 37%, respectively). This effect was additive, and a 66% reduction in H+-driven Na+ influx was found in the presence of both inhibitors. Internal acidification, a stimulus for Na+-H+ exchange, enhanced Na+-Li+ countertransport activity (from 287 +/- 55 to 1213 +/- 165 micromol x Lcell(-1) h(-1), mean +/- SEM, P = 0.003). This transport remained sensitive to phloretin under both conditions. Conversely, external acidification decreased Na+-Li+ countertransport activity (as expected for a Na+-H+ exchanger). Competition between internal H+ and Li+ or Na+ for a common binding site was present. Finally, similar kinetic parameters for external Na+ characterized Na+-Li+ countertransport and the phloretin-sensitive component of H+-driven Na+ influx. These findings suggest that both Na+-Li+ countertransport and the amiloride-insensitive, phloretin-sensitive component of H+-driven Na+ influx can be mediated by a previously unrecognized novel amiloride-insensitive Na+-H+ exchange isoform in human erythrocytes.

Independence of dimethylamiloride-sensitive Li+ efflux pathways and Na+-Li+ countertransport in human erythrocytes.

The in vivo function of the erythrocyte Na+-Li+ countertransport (SLC) is unknown. Whether SLC may reflect an operational mode of the widespread Na+-H+ exchanger (NHE) or may otherwise be expression of an independent membrane transport, remains presently unclear. We explored the presence of 5-(N,N-dimethyl)-amiloride (DMA)-sensitive Li+ pathways in human erythrocytes where the activity of the Na+ pump, Na+-K+ cotransport and anion exchange were suitably inhibited. A total of 0.02 mM DMA had no effect on SLC as expected, but gave a significant inhibition of Li+ efflux into both Na+ and Na+-free media. This DMA-sensitive Li+ pathway, but not SLC, was significantly enhanced by hyperosmolar cell shrinkage, which is a characteristic feature of NHE. In conclusion, DMA-sensitive Li+ pathways, possibly mediated by NHE, are present in erythrocytes and coexist with the DMA-insensitive, SLC. This finding supports the notion that SLC is independent of amiloride-sensitive NHE.

Effects of lisinopril and nifedipine on the progression to overt albuminuria in IDDM patients with incipient nephropathy and normal blood pressure. The Italian Microalbuminuria Study Group in IDDM.

OBJECTIVE: Intervention trials on renal function in IDDM patients with microalbuminuria (MA) should adopt the rate of decline of glomerular filtration rate (GFR) as an outcome measure. However, normotensive IDDM patients with MA show no change in GFR over a follow-up period of 10 years. Thus, in the present study, we used the cumulative incidence of progression to albuminuria (albumin excretion rate [AER] > 200 micrograms/min) from MA as the primary endpoint and the yearly increase in AER at a rate of 50% above baseline as the secondary end-point of renal function. RESEARCH DESIGN AND METHODS: Ninety-two normotensive IDDM patients underwent double-blind, double-dummy treatment with either lisinopril or slow-release nifedipine in comparison with placebo. Ten patients discontinued the study during the 3-year follow-up period. RESULTS: During the 3-year follow-up period, 7 of 34 placebo-treated (20.6%), 2 of 32 lisinopril-treated (6.3%), and 2 of 26 nifedipine-treated (7.7%) patients progressed to clinical albuminuria (Fisher's exact test, P < 0.03). Time-to-event analysis indicated a reduction in the risk of progression to macroalbuminuria of 58.1% (95% CI 27.8-68.4%) in the 32 patients on lisinopril (P < 0.02) and of 62.5% (95% CI 32.5-73.4%) in the 26 patients on nifedipine (P < 0.02) after adjustment for mean blood pressure, glycated hemoglobin, and baseline AER in comparison with the 34 patients on placebo. Baseline AER was 71 micrograms/min (range: 20.7-187.3) in progressors and 73 micrograms/min (range: 20.2-174.1) in nonprogressors (NS). The percentage of patients who showed a > 50% yearly increase of AER above baseline values was significantly lower in the lisinopril group (13 of 32, 40.6%, P < 0.02), but not in the nifedipine group (15 of 26, 57.7%), than in the placebo group (23 of 34, 67.6%). The lisinopril group had significantly lower blood pressure values during follow-up than either the nifedipine (P < 0.05) or the placebo (P < 0.01) group. CONCLUSIONS: Our data show that both lisinopril and nifedipine are effective in delaying the occurrence of macroalbuminuria in normotensive IDDM patients with MA. As overt proteinuria strongly predicts end-stage renal failure, both treatments appear capable of preventing such a complication in normotensive IDDM patients with MA. However, lisinopril appears more powerful in slowing the course of nephropathy.

Microalbuminuria in diabetes.

Microalbuminuria is still the only early abnormality of the diabetic kidney that has an established prognostic value. Microalbuminuria evolves into clinical nephropathy and renal failure in a majority of cases of insulin-dependent diabetic patients, and is defined by the detection of urinary albumin excretion rates of 20-200 microg/min in timed urine collections. The occurrence of microalbuminuria at rates of 5-27 % of non-proteinuric patients and cost-benefit considerations justify the screening for microalbuminuria in diabetic outpatient clinics. Both near-normalisation of glycaemic control and treatment with ACE-inhibitors are indicated in patients with insulin-dependent diabetes to correct the progression of micro- to macroalbuminuria. Other therapeutic perspectives are being considered, but the current notion that the available therapies may not arrest the course of nephropathy at this stage suggests that earlier interventions may be required. Prevention of microalbuminuria and overt nephropathy may require a primary approach to the subset of patients with a genetic predisposition to this complication, and several studies (candidate gene or genomic scan with microsatellite probes) now address the chromosomal loci and the nature of the genes that may be involved.

Modes of operation of an electroneutral Na+/Li+ countertransport in human skin fibroblasts.

An elevated activity of erythrocyte Na+/Li+ countertransport (SLC) is an intermediate phenotype of human essential hypertension, but cells other than erythrocytes have not been studied. Therefore, we have examined several transport modes of Na+/Li+ exchange in human skin fibroblasts. External Na+-stimulated Li+ efflux was 152 +/- 31 (SE) nmol x mg protein(-1) x min(-1) (n = 8). At intracellular pH 7.3, intracellular Na+-stimulated Li+ influx, intracellular Li+-stimulated Na+ influx, and external Li+-stimulated Na+ efflux were very similar, indicating the presence of a tightly coupled 1:1 SLC. This pathway was not affected by 5-(N,N-dimethyl)-amiloride and changes in the membrane potential, but phloretin and intracellular acidification (intracellular pH 6.8) were markedly inhibitory. Kinetic analyses of the external Na+ site also compared with SLC, although the internal site appeared to show a low affinity for Li+. We conclude that an SLC pathway similar to that in human erythrocytes is expressed in human skin fibroblasts.

Arterial hypertension and microalbuminuria in IDDM: the Italian Microalbuminuria Study.

Arterial hypertension and poor glycaemic control are central to the development of microalbuminuria in insulin-dependent diabetes mellitus (IDDM). Recent consensus has established sensitive criteria for their detection and treatment, although the proportion of patients who may benefit is unclear. Between 1988 and 1990, we measured urinary albumin to creatinine concentration ratio (A/C) in 3,636 adult out-patients with IDDM of more than 3 years duration, serum creatinine under 133 mumol/l and who were not undergoing antihypertensive treatment. A/C indicating microalbuminuria (> or = 2.38/2.96 mg/mmol, male/female) was found in 620 of 3,451 patients without proteinuria, and associated with hypertension (blood pressure > or = 140 and/or 90 mmHg; p = 0.0016; rate: 39.6%), independent of diabetes duration (p = 0.0082) and male gender (p = 0.0350; relative risk = 1.16; 95% confidence interval: 1.01-1.32). Hypertension was less common among those with normal A/C (27.5%, p < 0.0001) but was positively related with diabetes duration. Of the 1,015 patients with A/C > or = 2.0 mg/mmol 529 were reexamined. Glycated haemoglobin levels exceeded 3 SD above the mean of normal in 84.3% of the 198 microalbuminuric patients (AER = 20-200 micrograms/min), but were comparably poor (79.2%) in normoalbuminuria. Duration of diabetes was inversely related to glycated haemoglobin only in microalbuminuria (0.05 < p < 0.1). Intervention to lower blood pressure remains mainly restricted to those patients with long-term diabetes and slower development of kidney disease. Near-normalisation of glycaemia remains the priority for the majority of patients with microalbuminuria.

Sodium-lithium countertransport and triglycerides in diabetic nephropathy.

Elevated erythrocyte sodium-lithium countertransport (SLC) activity is an intermediate phenotype of essential hypertension among Caucasians, and is controversially associated with nephropathy in Type 1 (insulin-dependent) diabetes. Hypertriglyceridemia is a frequent concomitant of elevated SLC in the general population, and may be found in diabetic nephropathy. The present study was designed to investigate the influence of kidney disease, serum triglycerides and blood pressure on the interindividual variability of SLC in Type 1 diabetes. SLC and fasting major serum lipids were studied in 35 Type 1 diabetic patients with persistently elevated urinary albumin excretion and in a group of patients matched for age, sex and duration of diabetes, but with normoalbuminuria. SLC was elevated in patients with clinical nephropathy (N = 10; median: 420 mumol.1RBC-1.hr-1) and in patients with microalbuminuria (N = 25; median: 405 mumol.1RBC-1.hr-1) compared with normoalbuminuric patients (median: 296 mumol.1RBC-1.hr-1; P < 0.01 vs. both groups). Hypertriglyceridemia and hypercholesterolemia were found only among patients with macroalbuminuria. Analysis of covariance indicated that the association of elevated SLC with kidney disease (P < 0.006 in all models) was largely independent of serum triglycerides, but also of total cholesterol, insulin dose and measures of glycemic control. Only diastolic blood pressure was positively associated with SLC (P < 0.02) independently from nephropathy (P < 0.005) also after restricting analysis to the normoalbuminuric patients. Kidney disease and raised blood pressure remain major concomitants of elevated SLC in Type 1 diabetics.

Magnetic resonance imaging of the kidney in type 1 (insulin-dependent) diabetes mellitus.

Reductions in the physiological cortical to medullary signal intensity ratio are found in magnetic resonance scans of the kidney in non-diabetic glomerular disease. Whether this abnormality can also characterise patients with Type 1 (insulin-dependent) diabetes mellitus and nephropathy is not known. We measured the cortical to medullary signal intensity ratio in magnetic resonance images of the kidney in 34 patients with Type 1 diabetes (ten with either clinical proteinuria or raised serum creatinine or both, nine with microalbuminuria, seven with normal urinary albumin excretion and long duration of diabetes and eight with Type 1 diabetes of short duration). The cortical to medullary signal intensity ratio showed a trend to cluster at lower values in the normoalbuminuric patients with normal serum creatinine rather than in the nine healthy individuals, independent of Type 1 diabetes duration (1.47 +/- 0.06 and 1.41 +/- 0.13 vs 1.63 +/- 0.16; five groups Scheffé F-test p = 0.05-0.1). Among the Type 1 diabetic patients, significant reductions in the cortical to medullary signal intensity ratio characterised overt nephropathy (1.19 +/- 0.15, p less than 0.05 vs all groups), but not microalbuminuria (1.47 +/- 0.13, p = NS), concomitantly with low glomerular filtration rate and elevated fractional excretion of uric acid, but independent of glycaemic control. The determinants of the renal cortical to medullary signal intensity ratio in Type 1 diabetes are uncertain. Reductions in the cortical to medullary signal intensity ratio may be a late finding in diabetic nephropathy, and parallel the accompanying impairment in kidney haemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies to human albumin epitopes in type 1 (insulin-dependent) diabetes mellitus.

The presence of antibodies to glycosylated albumin was studied by means of a newly developed sandwich enzyme-linked immunosorbent assay in 29 long-standing Type 1 (insulin-dependent) diabetic patients with microvascular complications and in 20 normal subjects. Two types of antibody reactivity were detected. One directed against glucitol-albumin expressing G and M isotypes. The second, predominantly belonging to the IgG class, reacted with an epitope shared by non-glycosylated albumin and the ketoamine adduct of albumin glycosylation. Both types of antibodies, with affinity constant ranging from 10(4) to 10(7) (mol/l)-1 were found in normal and diabetic subjects, but higher titres were significantly more prevalent in the diabetic patients. These antibodies may represent the result of immune tolerance breakdown or, alternatively, be natural antibodies. Although their function remains to be established, their raised prevalence in Type 1 diabetes may be relevant to diabetic microvascular disease.

Increased sodium-lithium countertransport activity in red cells of patients with insulin-dependent diabetes and nephropathy.

Susceptibility to diabetic nephropathy may be related to a predisposition to arterial hypertension. We have studied the activity of sodium-lithium countertransport in red cells, a marker of risk for essential hypertension, in white European adults with insulin-dependent diabetes and diabetic nephropathy, a matched group of patients with diabetes without renal disease, and nondiabetic patients with renal disease. Measures of metabolic control and concentrations of plasma free insulin and growth hormone were similar in the two diabetic groups. The degree of impairment in renal function was similar in the diabetic and nondiabetic patients with renal disease. Body-mass index and plasma potassium concentrations were similar in all three groups. Diastolic blood pressure was elevated to a similar degree in the two groups with renal disease, as compared with that in the diabetic patients without renal disease. The rates of sodium-lithium countertransport in red cells were significantly higher in the diabetic patients with renal disease (mean +/- SD, 0.55 +/- 0.19 mmol of lithium per liter of red cells per hour) than in the diabetic patients without renal disease (0.33 +/- 0.16; P less than 0.005) and in the nondiabetic patients with renal disease (0.31 +/- 0.14; P less than 0.001). Predisposition to hypertension, as indicated by elevated sodium-lithium countertransport activity in red cells, may serve as a marker for the risk of renal disease in patients with insulin-dependent diabetes.

Selective and extremely long inhibition of prolactin release in man by 1-ethyl-3-(3'-dimethylaminopropyl)-3-(6'-allylergoline-8'-beta- carbonyl)-urea-diphosphate (FCE 21336).

The effects on anterior pituitary function of FCE 21336 (1-ethyl-3-(3'-dimethylaminopropyl)-3-(6'-allylergoline-8'-beta-ca rbonyl)-urea- diphosphate), a synthetic ergoline derivative with selective dopamine agonistic properties, were studied. Circulating PRL, GH, TSH, cortisol and LH levels were determined up to 96 h after single oral doses of 50, 100, 200 and 300 micrograms of the compound to eight healthy males, and up to 168 h after single oral doses of 400 and 600 micrograms to six healthy males, according to double-blind, within subjects, experimental designs vs placebo. Vital signs, ECG, laboratory tests and the appearance of newly observed signs and symptoms were monitored. A dose-related decrease of serum PRL in comparison with both basal and post-placebo levels was observed after 200 micrograms and greater doses of the compound, with inhibition of spontaneous circadian rhythm. Maximal inhibition (PRL less than 2 ng ml-1) was observed in one out of five subjects after 200, three out of seven subjects after 300, four out of six after 400 and five out of six subjects after 600 micrograms. The effect was of rapid onset and long duration; the maximum or nearly maximum decrease was observed within 3 h after dosing as well as up to 96 h (200 and 300 micrograms) and up to 168 h (400 and 600 micrograms). No modifications of GH, TSH, LH and cortisol as well as of vital signs, ECG and laboratory tests were apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

Glomerular response mechanisms to glycemic changes in insulin-dependent diabetics.

Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by constant inulin and PAH infusion during euglycemia and intravenous dextrose-induced moderate hyperglycemia in seven insulin-dependent diabetics with persistently elevated GFR, seven diabetics with normal GFR, and in six normal control subjects. In euglycemia, RPF was higher and calculated renal vascular resistance (RVR) lower in the hyperfiltering than the normofiltering group (P less than 0.05 for both variables), but filtration fraction (FF) was similar in all groups. During hyperglycemia, mean GFR rose significantly from 157 +/- 20 to 174 +/- 30 ml/min/1.73 m2 (11.9%; P less than 0.05) in the hyperfiltering group only. There was no statistically significant change in mean GFR in the normofiltering diabetic (116 +/- 6 vs. 114 +/- 13 ml/min/1.73 m2) and the normal control groups (117 +/- 15 vs. 113 +/- 14 ml/min/1.73 m2). RPF and FF rose by 5.8% and 9.2%, respectively, in the hyperfiltering group only, with no change in the normofiltering or normal control groups. No change in RVR was found in any group. Total tubular sodium reabsorption was higher during euglycemia in the hyperfiltering diabetics (P less than 0.01), and rose significantly during hyperglycemia (P less than 0.05) in this group only. Overnight euglycemia did not remove the increased glomerular filtration and flow of hyperfiltering diabetics. Hyperglycemia further accentuated hyperfiltration by elevating renal plasma flow and filtration fraction.

Calcitonin and insulin secretion in normal man: study with somatostatin and calcium.

An increase in extracellular calcium concentration abolishes somatostatin-induced inhibition of insulin release from rat pancreas in vitro; since calcium fails to have a similar effect in vivo, and calcitonin (CT) is capable of inhibiting insulin release, we investigated calcium-stimulated CT secretion during somatostatin administration in normal human males. No significant differences between calcium-stimulated CT secretion during somatostatin infusion and in basal conditions were found. In addition, we confirmed that endogenous CT elicited by calcium administration significantly reduces basal insulin secretion. Thus, we suggest that calcium-induced CT release in vivo may counteract the reversal effect of calcium on the suppressor activity of somatostatin on insulin secretion as shown in vitro.