Preventing microalbuminuria with benazepril, valsartan, and benazepril-valsartan combination therapy in diabetic patients with high-normal albuminuria: A prospective, randomized, open-label, blinded endpoint (PROBE) study.

Background: Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) prevent microalbuminuria in normoalbuminuric type 2 diabetic patients. We assessed whether combined therapy with the 2 medications may prevent microalbuminuria better than ACE inhibitor or ARB monotherapy.

Methods And Findings: VARIETY was a prospective, randomized, open-label, blinded endpoint (PROBE) trial evaluating whether, at similar blood pressure (BP) control, combined therapy with benazepril (10 mg/day) and valsartan (160 mg/day) would prevent microalbuminuria more effectively than benazepril (20 mg/day) or valsartan (320 mg/day) monotherapy in 612 type 2 diabetic patients with high-normal albuminuria included between July 2007 and April 2013 by the Istituto di Ricerche Farmacologiche Mario Negri IRCCS and 8 diabetology or nephrology units in Italy.

Neural autonomic control in orthostatic intolerance.

Inability to maintain the upright position is manifested by a number of symptoms shared by either human pathophysiology and conditions following weightlessness or bed rest. Alterations of the neural sympathetic cardiovascular control have been suggested to be one of the potential underlying etiopathogenetic mechanisms in these conditions. We hypothesize that the study of the autonomic profile of human orthostatic intolerance syndromes may furnish a valuable insight into the complexity of the sympathetic alterations leading to a reduced gravitational tolerance.

Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the irbesartan diabetic nephropathy trial: clinical implications and limitations.

Elevated arterial pressure is a major risk factor for progression to ESRD in diabetic nephropathy. However, the component of arterial pressure and level of BP control for optimal renal outcomes are disputed. Data from 1590 hypertensive patients with type 2 diabetes in the Irbesartan Diabetic Nephropathy Trial (IDNT), a randomized, double-blind, placebo-controlled trial performed in 209 clinics worldwide, were examined, and the effects of baseline and mean follow-up systolic BP (SBP) and diastolic BP and the interaction of assigned study medications (irbesartan, amlodipine, and placebo) on progressive renal failure and all-cause mortality were assessed.

Alternative splicing of NHE-1 mediates Na-Li countertransport and associates with activity rate.

Sodium-lithium countertransport (SLC) is an ouabain-insensitive exchange of Na for Li found in the erythrocyte membrane of several mammalian species. Although increased SLC activity is presently the most consistent intermediate phenotype of essential hypertension and diabetic nephropathy in humans, the gene responsible for this membrane transport has not been identified. Because of functional similarities, SLC was suggested to represent an in vitro mode of operation of the Na-H exchanger (NHE).

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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).

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.

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.

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.

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.

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.