Previous studies by our group have shown that albumin is metabolized in rodents during renal passage and excreted in the urine as a mixture of intact protein and albumin-derived fragments. The aim of this study was to examine whether albumin is metabolized during renal passage in nondiabetic volunteers and in type 1 diabetic patients with varying levels of albuminuria. Nine nondiabetic normoalbuminuric volunteers and 11 type 1 diabetic patients with albumin excretion rates varying from normoalbuminuria to macroalbuminuria were studied. Each subject received an intravenous injection of tritium-labeled albumin ([ 3 H]-albumin). Urine was collected at 4 h and 24 h after injection and analyzed by size exclusion chromatography. The amount of intact and fragmented albumin was quantified, and each fraction was analyzed by radioimmunoassay (RIA) for albumin. [ 3 H]-albumin in nondiabetic volunteers was metabolized during renal passage to small peptide fragments not detectable by conventional RIA (only 0.05-3.8% of the total urinary radioactivity was associated with intact albumin). The process responsible for albumin fragmentation was similar in diabetic patients with normoalbuminuria (intact albumin represented 0.01-4.0% of total urinary radioactivity). However, there was a reduction in the fragmentation ratio (fragmented:intact) in diabetic patients with micro-or macroalbuminuria (intact albumin represented 2.7-55.5%, P = 0.048). This change in the fragmentation ratio was directly related to the degree of albuminuria. These results have important implications for understanding the mechanisms underlying albuminuria in nondiabetic volunteers and type 1 diabetic patients. In nondiabetic volunteers, the renal processing of albumin involves a relatively rapid and comprehensive degradation of albumin to small fragments (range 1-15 kDa). The degradation process is inhibited in diabetic nephropathy in proportion to the level of albuminuria detected by RIA. Diabetes 49:1579-1584, 2000 M icroalbuminuria, as measured by radioimmunoassay (RIA), is generally equated with the development of diabetic nephropathy in type 1 diabetes (1,2). The change in albumin excretion rate (AER) has traditionally been explained as being due to changes in the glomerular permselectivity barrier and intraglomerular pressure (3,4) with the assumption that albumin remains intact during filtration and renal passage. However, recent studies by our group using tritium-labeled albumin ([ 3 H]-albumin) in a rodent model have demonstrated that albumin excretion could be significantly influenced by the metabolism of albumin to small peptide fragments during its renal passage (5-9). The fragmentation is extensive, with 90-95% of the urinary albumin representing a complex fragment population of >30 different fragments with molecular weights in the range of 1-15 kDa. These albumin-derived fragments are not detected by standard immunochemical assays (6,8). A small number of studies have previously identified albumin fragments in human urine, although the source of...
OBJECTIVE -Diabetic subjects have a high prevalence of hypertension, increased total body exchangeable sodium levels, and an impaired ability to excrete a sodium load. This study assessed the effect of dietary sodium restriction on the efficacy of losartan in hypertensive subjects with type 2 diabetes and albumin excretion rates of 10 -200 g/min.RESEARCH DESIGN AND METHODS -In this study, 20 subjects were randomized to losartan 50 mg/day (n ϭ 10) or placebo (n ϭ 10). Drug therapy was given in two 4-week phases separated by a washout period. In the last 2 weeks of each phase, patients were assigned to low-or regular-sodium diets, in random order. In each phase, 24-h ambulatory blood pressure, urinary albumin-to-creatinine ratio (ACR), and renal hemodynamics were measured.RESULTS -Achieved urinary sodium on a low-sodium diet was 85 Ϯ 14 and 80 Ϯ 22 mmol/day in the losartan and placebo groups, respectively. In the losartan group, the additional blood pressureϪlowering effects of a low-sodium diet compared with a regularsodium diet for 24-h systolic, diastolic, and mean arterial blood pressures were 9.7 mmHg (95% confidence interval [CI], 2.2Ϫ17.2; P ϭ 0.002), 5.5 mmHg (2.6Ϫ8.4; P ϭ 0.002), and 7.3 mmHg (3.3Ϫ11.3; P ϭ 0.003), respectively. In the losartan group, the ACR decreased significantly on a low-sodium diet versus on a regular-sodium diet (Ϫ29% [CI Ϫ50.0 to Ϫ8.5%] vs. ϩ14% [Ϫ19.4 to 47.9%], respectively; P ϭ 0.02). There was a strong correlation between fall in blood pressure and percent reduction in the ACR (r ϭ 0.7, P ϭ 0.02). In the placebo group, there were no significant changes in blood pressure or ACR between regularand low-sodium diets. There were no significant changes in renal hemodynamics in either group.CONCLUSIONS -These data demonstrated that a low-sodium diet potentiates the antihypertensive and antiproteinuric effects of losartan in type 2 diabetes. The blood pressure reduction resulting from the addition of a low-sodium diet to losartan was of similar magnitude to that predicted from the addition of a second antihypertensive agent. Diabetes Care 25:663-671, 2002H igh blood pressure is an important modifiable risk factor in preventing diabetic micro-and macrovascular complications. Subjects with diabetes have a high prevalence of hypertension and often require multiple antihypertensive agents to achieve blood pressure targets (1).The role of ACE inhibitors in the prevention and treatment of diabetic nephropathy is well established in patients with type 2 (2) and type 1 diabetes (3). More recently, blockade of the reninangiotensin system (RAS) with angiotensin (ANG)-II receptor antagonists has been shown to attenuate the rate of progression of renal dysfunction in patients with type 2 diabetes (4,5).In nondiabetic subjects with renal disease, the antiproteinuric effects of ACE inhibitors strongly depend on dietary sodium intake (6). Furthermore, the antihypertensive effects of ANG-II receptor antagonists have shown dependence on the baseline activation of the RAS in nondiabetic patients (7). In...
OBJECTIVE -Transforming growth factor- (TGF-) is a prosclerotic growth factor implicated in the pathogenesis of diabetic nephropathy. In addition to high glucose, other factors implicated in renal fibrosis and increased TGF- synthesis include angiotensin II and high dietary sodium intake. The aim of this study was to examine the effect of angiotensin receptor blockade (ARB) and dietary sodium restriction on the plasma concentration and urinary excretion of TGF- in hypertensive patients with type 2 diabetes and elevated albumin excretion rate (AER). RESEARCH DESIGN AND METHODS-Twenty-one subjects with hypertension and AER between 10 and 200 g/min were randomized to receive either 50 mg losartan daily (n ϭ 11) or placebo (n ϭ 10). Drug therapy was given in two 4-week phases, separated by a 4-week washout period. In the last 2 weeks of each phase, patients were assigned to regular-or lowsodium diets in random order. Parameters measured at week 0 and 4 of each phase included plasma TGF- concentration, TGF- urinary excretion, AER, clinic mean arterial blood pressure, and urinary sodium excretion.RESULTS -Plasma TGF- was unaffected by losartan treatment or sodium intake. In the losartan group, urinary TGF- excretion decreased by 23.2% (Ϫ39.2 and 13.6) [median (interquartile range)] and 38.5% (Ϫ46.8 and Ϫ6.1) in the regular-and low-sodium phases, respectively (P Ͻ 0.05 for drug effect). In the placebo group, median changes of 0.0% (Ϫ12.1 and 44.4) and 0.0% (Ϫ29.2 and 110.7) occurred in the regular-and low-sodium phases, respectively. Sodium restriction did not affect urinary TGF- excretion in either losartan-or placebo-treated patients (P ϭ 0.54 for overall dietary effect), and there was no evidence of interaction between drug and diet (P ϭ 0.29).CONCLUSIONS -In hypertensive type 2 diabetic patients with elevated AER, the ARB losartan, but not sodium restriction, reduced urinary TGF- excretion. These data suggest that the renoprotective effects of losartan in patients with type 2 diabetes and nephropathy may include a reduction in renal TGF- production.
OBJECTIVEThis prospective randomized double-blind placebo-controlled crossover study examined the effects of sodium chloride (NaCl) supplementation on the antialbuminuric action of telmisartan with or without hydrochlorothiazide (HCT) in hypertensive patients with type 2 diabetes, increased albumin excretion rate (AER), and habitual low dietary salt intake (LDS; <100 mmol sodium/24 h on two of three consecutive occasions) or high dietary salt intake (HDS; >200 mmol sodium/24 h on two of three consecutive occasions).RESEARCH DESIGN AND METHODSFollowing a washout period, subjects (n = 32) received 40 mg/day telmisartan for 4 weeks followed by 40 mg telmisartan plus 12.5 mg/day HCT for 4 weeks. For the last 2 weeks of each treatment period, patients received either 100 mmol/day NaCl or placebo capsules. After a second washout, the regimen was repeated with supplements in reverse order. AER and ambulatory blood pressure were measured at weeks 0, 4, 8, 14, 18, and 22.RESULTSIn LDS, NaCl supplementation reduced the anti-albuminuric effect of telmisartan with or without HCT from 42.3% (placebo) to 9.5% (P = 0.004). By contrast, in HDS, NaCl supplementation did not reduce the AER response to telmisartan with or without HCT (placebo 30.9%, NaCl 28.1%, P = 0.7). Changes in AER were independent of changes in blood pressure.CONCLUSIONSThe AER response to telmisartan with or without HCT under habitual low salt intake can be blunted by NaCl supplementation. By contrast, when there is already a suppressed renin angiotensin aldosterone system under habitual high dietary salt intake, the additional NaCl does not alter the AER response.
Large birthweight, or macrosomia, is one of the commonest complications for pregnancies affected by diabetes. As macrosomia is associated with an increased risk of a number of adverse outcomes for both the mother and offspring, accurate antenatal prediction of fetal macrosomia could be beneficial in guiding appropriate models of care and interventions that may avoid or reduce these associated risks. However, current prediction strategies which include physical examination and ultrasound assessment, are imprecise. Biomarkers are proving useful in various specialties and may offer a new avenue for improved prediction of macrosomia. Prime biomarker candidates in pregnancies with diabetes include maternal glycaemic markers (glucose, 1,5-anhydroglucitol, glycosylated hemoglobin) and hormones proposed implicated in placental nutrient transfer (adiponectin and insulin-like growth factor-1). There is some support for an association of these biomarkers with birthweight and/or macrosomia, although current evidence in this emerging field is still limited. Thus, although biomarkers hold promise, further investigation is needed to elucidate the potential clinical utility of biomarkers for macrosomia prediction for pregnancies affected by diabetes.
It is unknown if high prolactin levels during pregnancy contribute to the development of gestational diabetes. We hypothesized that higher prolactin levels are associated with reduced glucose tolerance, as determined by higher 2‐h glucose level from an oral glucose tolerance test in pregnancy. The 75‐g oral glucose tolerance test was carried out at 28 weeks of gestation in 69 participants. A multiple regression analysis was used to determine the relationship between serum prolactin and 2‐h glucose levels. Multivariable regression analysis showed an independent and significant relationship between third trimester prolactin and 2‐h glucose levels post oral glucose tolerance test. Higher prolactin levels were associated with higher glucose levels independent of age, body mass index, gravidity and parity. Higher prolactin levels associated with reduced glucose tolerance in the third trimester of pregnancy suggests the possible independent role of prolactin in the pathogenesis of gestational diabetes.
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