Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As angiotensin-converting enzyme inhibition is accompanied by a marked decrease in glomerular protein loss, the hypothesis was tested that an increase of the glomerular transcapillary hydraulic pressure difference by exogenous angiotensin II would increase microalbuminuria in patients with insulin (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). Acute effects of increasing doses of angiotensin II (1, 3 and 6 ng/kg/min) were studied on mean arterial pressure (MAP), glomerular filtration rate (GFR), effective renal plasma flow (ERPF), filtration fraction (FF), total renal vascular resistance (TRVR), and urinary albumin excretion rate (UAER) in 11 IDDM and 11 NIDDM microalbuminuric patients. Angiotensin II infusion changed MAP from 100 +/- 3 mmHg at baseline to 105 +/- 3, 111 +/- 3, and 116 +/- 3 mmHg (P < 0.001), ERPF from 542 +/- 29 to 478 +/- 24, 429 +/- 23, and 382 +/- 19 ml/min (P < 0.001), FF from 20.2 +/- 0.06 to 23.1 +/- 0.7, 27.1 +/- 1.1, and 29.8 +/- 1.2% (P < 0.001), and TRVR from 9454 +/- 809 to 11,158 +/- 930, 13,310 +/- 1206, and 15,538 +/- 1362 dyne s cm-5 (P < 0.001). GFR and UAER, however, did not change significantly. Therefore, during angiotensin II infusion ERPF decreased, while FF and TRVR increased. As UAER and GFR remained unchanged, the presumed rise in intraglomerular capillary pressure by exogenous angiotensin II did not increase UAER. We suggest that during manipulation of the renin-angiotensin system, as in other renal diseases with proteinuria, factors other than glomerular transcapillary hydraulic pressure determine the degree of urinary albumin loss in microalbuminuric IDDM and NIDDM patients.
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PMID:Urinary albumin excretion rate during angiotensin II infusion in microalbuminuric patients with insulin and non-insulin-dependent diabetes mellitus. 913 45

Insulin-dependent diabetes mellitus (IDDM) patients may have an increased intrarenal angiotensin II activity. In diabetic patients, captopril increases the renal hemodynamic response to an amino acid infusion. We investigated the effects of two salt diets on arterial pressure and renal response to a protein load in 10 normotensive (blood pressure < 140/90 mm Hg) IDDM patients (aged 30 +/- 3 years) who had diabetes for 7 +/- 4 years and normoalbuminuria levels [albumin excretion rate 4.8 (2.5-19.1) microg/min]. After 1 week of normal (approximately 100 mmol/day; approximately 100 mEq/l) and 1 week of high (approximately 300 mmol/day; approximately 300 mEq/l) salt intake, renal hemodynamic studies were performed at baseline and after a protein load (meat meal) of 100 g/1.73 m2. The mean 24-hour urinary sodium excretion levels were 99 +/- 27 and 293 +/- 80 mmol (mEq) with normal and high salt intake, respectively. No significant changes were seen in plasma sodium and glucose control with the normal and high salt diets, respectively: plasma sodium 135 +/- 3 vs. 137 +/- 1 mmol/l (mEq/l), (p = 0.08) and glycated hemoglobin 9.1 +/- 1.9 vs. 9.4 +/- 2.1% (p = 0.36). The body weight (70.9 +/- 12 vs. 71.8 +/- 13 kg; p = 0.015) was significantly higher with a high salt diet. The mean arterial pressure was similar with both diets (normal vs. high salt diet 91 +/- 9 vs. 89 +/- 6 mm Hg, p = 0.25). The plasma renin concentration [28 +/- 15 vs. 16 +/- 6 microU/ml(168 +/- 90 vs. 96 +/- 36 pmol/l), p = 0.013] and angiotensin II [8.8 +/- 4.4 vs. 6.4 +/- 3.5 pg/ml (0.052 +/- 0.025 vs. 0.038 +/- 0.021 nmol/l), p = 0.016] were significantly lower with the high salt diet. Following protein loading, the glomerular filtration rate increased with both diets: normal salt diet 114 +/- 26 vs. 128 +/- 30 ml/min/1.73 m2(1.9 +/- 0.43 vs. 2.13 +/- 0.50 ml/s/1.73 m2), p = 0.04; high salt diet 118 +/- 23 vs. 127 +/- 29 ml/min/1.73 m2 (1.97 +/- 0.38 vs. 2.12 +/- 0.48 ml/s/1.73 m2), p = 0.13. The change in renal plasma flow was similar to that of the glomerular filtration rate with normal and high salt intake, respectively: 566 +/- 94 vs. 617 +/- 142 ml/min/1.73 m2 (9.44 +/- 1.57 vs. 10.29 +/- 2.37 ml/s/173 m2), p = 0.0017; 572 +/- 125 vs. 600 +/- 110 ml/min/1.73 m2 (9.54 +/- 2.08 vs. 10.00 +/- 1.83 ml/s/1.73 m2), p = 0.057. In this subset of normotensive normoalbuminuric IDDM patients, a high salt intake did not promote an exaggerated renal response to the protein load despite inhibition of the renin-angiotensin system.
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PMID:Renal functional response to protein loading in type 1 (insulin-dependent) diabetic patients on normal or high salt intake. 927 38

We aimed to determine the natural history of borderline increases in albuminuria in adolescents with insulin-dependent (Type 1) diabetes mellitus (IDDM) and factors which are associated with progression to persistent microalbuminura. Fifty-five normotensive adolescents with IDDM and intermittent microalbuminura (overnight albumin excretion ratte of 20-200 micrograms min-1 on one of three consecutive timed collections, n = 29) or borderline albuminura (mean overnight albumin excretion rate of 7.2-20 micrograms min-1 on one of three consecutive timed collections, n = 30) were followed prospectively at 3 monthly intervals. The endpoint was persistent microalbuminuria defined as a minimum of three of four consecutive overnight albumin excretion rates of greater than 20 micrograms min-1. One hundred and forty-two adolescents with IDDM and normoalbuminura were also followed prospectively. Fifteen of the 59 patients (25.4%) with intermittent (9/29) or borderline (6/30) albuminura progressed to persistent microalbuminura (progressors) over 28 (15-50) months [median (range)] in comparison with two of the 142 patients with normoalbuminuria at entry (relative risk = 12.6; p = 0.001). Progressors to persistent microalbuminura were pubertal and had higher systolic (p = 0.02) and diastolic (p = 0.02) blood pressure, and HbA1c (p = 0.004) than non-progressors. All patients remained normotensive. Glomerular filtration rate, apolipoproteins, dietary phosphorus, protein and sodium intakes, and prevalence of smoking did not differ between progressors and non-progressors. Total renin was higher in the diabetic patients without a difference between progressors and non-progressors. In conclusion there is a relatively high rate of progression to persistent microalbuminuria in pubertal adolescents with borderline increases in albuminura and duration greater than 3 years. These patients require attention to minimize associated factors of poor metabolic control and higher blood pressure in the development of incipient nephropathy.
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PMID:Progression of borderline increases in albuminuria in adolescents with insulin-dependent diabetes mellitus. 930 Feb 27

Approximately 30% of patients with type 1 and type 2 diabetes develop diabetic nephropathy. Apart from metabolic control, genetic predisposition plays an important role in its genesis. Analysis of intermediate phenotypic markers showed that the activity of Na/Li- and Na+/H(+)-countertransport is increased in patients with diabetic nephropathy. The renin-angiotensin system is of crucial importance as a system for therapeutic intervention and as genetic marker for susceptibility to renal disease. Consequently, the analysis of molecular genetic markers has focused on a polymorphism in the gene for the angiotensin II converting enzyme (ACE). However, the analysis of the I/D-polymorphism with respect to development of diabetic nephropathy in type 1 and type 2 diabetes has yielded conflicting results, at least in type 1 diabetes. These discrepant results may be due to differences in definition, sample size and ethnic background of the patients. In IgA glomerulonephritis it has been shown that the DD genotype (which is correlated with higher serum and tissue ACE activity compared to II genotype) is associated with a more rapid deterioration of renal function. The same adverse effect of the DD genotype could also be demonstrated in patients with diabetic nephropathy. Two studies examined the response to treatment according to the different genotypes, with contradictory results. A Japanese study showed a more pronounced reduction in proteinuria under ACE inhibitor treatment in patients with DD genotype, whereas a Danish study showed that patients with the DD genotype exhibited a steeper decline in renal function despite ACE inhibitor treatment. The data available for other candidate genes are fragmentary and negative throughout.
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PMID:Genetic determinants of diabetic renal disease and their impact on therapeutic interventions. 940 16

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the United States, and accounts for 35% of all the patients with ESRD entering a dialysis program; 63% of patients with diabetic nephropathy have type II diabetes mellitus. Hypertension is a major risk factor for renal disease and is common in people with diabetes mellitus. Strategies for preventing the progression of renal failure in patients with diabetes mellitus include glycemic control, and control of blood pressure. Blocking the renin-angiotensin system (RAS) slows the progression of established diabetic nephropathy in type I diabetes mellitus, and inhibiting angiotensin II formation retards or impedes the progression from microalbuminuria to established diabetic nephropathy (macroproteinuria) in people with type I diabetes mellitus. The situation could be the same for people with type II diabetes mellitus. The ability of RAS blockade using irbesartan, an AT1 angiotensin II receptor antagonist, to slow the progression in renal failure has been compared with that of the calcium channel blocker amlodipine and placebo in a pilot study. The results suggest that blockade of the RAS, in this case with irbesartan, is at least equivalent to calcium channel blockers with respect to antihypertensive efficacy, but provides better renoprotective benefits.
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PMID:Renoprotection and renin-angiotensin system blockade in diabetes mellitus. 943 77

Nephropathy is a frequent complication of long term diabetes. Diabetic nephropathy is the major determinant of premature morbidity and mortality both in insulin-dependent (IDDM) and in non-insulin dependent-diabetes mellitus (NIDDM). There is good evidence that genetic predisposition plays a major role in development of diabetic nephropathy. This hypothesis is based on the observation that diabetic nephropathy clusters within families, both in IDDM and NIDDM. Components of the renin-angiotensin system (RAS) are plausible candidate genes to examine for a association with microalbuminuria and diabetic nephropathy. In this study we compared the distribution of PstI melting polymorphism at the ACE locus among NIDDM patients with diabetic nephropathy and in patients who, despite long duration of NIDDM, remain without this complication. The 220 NIDDM patients for whom DNA was available were classified into two groups according to their renal status: normoalbuminuric control subjects (n = 80) who are NIDDM patients with an A/C ratio < 2.5 and nephropathy cases (n = 140) who are NIDDM patients with A/C ratio > 2.5. Albumin excretion rate was assayed by radioimmunoassay. HbA1c was assayed using HPLC methods, creatinine--using Jaffe methods and DNA analysis using PCR reaction, and then after the amplification product was digested with PstI enzyme. The study revealed that PstI sequence differences ("+/= and -") in the ACE gene do not contribute to genetic susceptibility to diabetic nephropathy in NIDDM.
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PMID:[Is PstI polymorphism of the angiotensin I converting enzyme gene associated with nephropathy development in non-insulin-dependent diabetes mellitus (preliminary study)]. 949 4

Diabetic nephropathy (DN) clusters in families with type 1 diabetes and the degree of clustering suggests that a major gene having a common disease allele may be responsible. To investigate the chromosomal regions containing genes for the renin-angiotensin system, we performed a linkage study using pairs of siblings with type 1 diabetes who were discordant for DN. Theoretical considerations supported by simulation studies indicated that such discordant pairs, rather than the usual concordant pairs, would be more effective in detecting a major susceptibility gene for DN. We applied this novel strategy to test for linkage between DN and chromosomal regions containing genes for the ACE, angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1). Two polymorphic markers were genotyped in the vicinity of each of the three loci in 66 discordant sib pairs and were analyzed with multipoint methods. The regions containing ACE and AGT loci were not linked with DN, while the region containing the AT1 locus showed linkage with DN. As a result of these positive findings, eight additional polymorphic markers spanning a 63-cM region around AT1 locus were genotyped. Linkage was demonstrated between DN and a 20-cM region that includes AT1 (P = 7.7 x 10(-5)), an obvious candidate gene for DN. To investigate whether AT1 could account for the observed linkage, we sequenced all exons, splicing junctions, and the promoter region and examined the identified polymorphisms/mutations for association with DN using the transmission disequilibrium test. Four new polymorphisms in the gene were found, but neither these nor previously described polymorphisms were associated with DN. Thus, while our study does not implicate AT1 itself in the etiology of DN, it provides very strong evidence that a 20-cM region around AT1 contains a major locus for susceptibility to DN.
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PMID:Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis. 964 45

Diabetic nephropathy has become the single most important cause of endstage renal failure in most countries of the Western world. Against this background, the role of the renin-angiotensin system (RAS) and its blockade command considerable interest. In diabetic patients and in diabetic animals, the circulating components of the RAS are suppressed. Although the evidence is not completely uniform, there are indirect arguments (renal hemodynamic response to RAS blockade, AT1 receptor expression), however, which would be consistent with increased intrarenal action of angiotensin (ANG) II. There is solid evidence that ACE inhibitors effectively interfere with progression of micro-albuminuria both in IDDM and NIDDM. They also prevent progression of advanced renal failure in IDDM, while there is only preliminary evidence in this respect for NIDDM. ACE inhibitors are superior to conventional antihypertensive agents (with the possible exception of some calcium channel blockers), but such superiority is seen only when the levels of blood pressure are relatively high. In diabetic animals, treatment with ANG II receptor blockers interferes with the development of glomerular lesions. In acute and subacute studies on diabetic patients, ANG II receptor blockers reduced albuminuria (or proteinuria) more than beta-blockers. Head-on comparison of equipotent doses ACE inhibitors and ANG II receptor blockers in non-diabetic patients produced equal reductions in proteinuria. The long-term effects of ANG II receptor blockers on progression of advanced diabetic nephropathy is the object of two large international studies. The results will not be available before the year 2000.
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PMID:Diabetes--renal function--what are the special problems? 983 74

The range of known actions of amylin are reviewed together with the proposal that an important role for amylin may be the hormonal integration of diverse physiological systems activated with feeding. Major targets for the action of amylin are found within the kidney. Components of the amylin system (AS) have been shown to influence the activity of components of the renin-angiotensin system (RAS), and vice versa, in normal, hypertensive and diabetic models. For instance, amylin injected into humans and rats elicits a rapid rise in plasma renin activity. Furthermore, in two models of hypertension (the spontaneously hypertensive rat (SHR) and the model with subtotal nephrectomy (STNx)), the density of amylin-binding sites in the renal cortex associated with the proximal tubules, was associated with elevation of blood pressure. In normotensive controls and in the STNx model, but not in the SHR model, treatment with angiotensin-converting enzyme (ACE) inhibitors reduced blood pressure and the density of amylin binding in the renal cortex. In Sprague-Dawley rats, angiotensin II (Ang II) infusion was associated with increased density of amylin-binding sites as well as elevated blood pressure. Thus, there appears to be a direct relationship between the activity of Ang II and the binding sites for amylin in the renal cortex. From these studies it has been postulated that the activation of the AS in the kidney may play a role in the genesis and/or development of hypertension in certain contexts. The transient expression of amylin mRNA has been detected perinatally, using in situ hybridization, in the subnephrogenic zone of the metanephros and is associated with proximal tubules of the developing nephron. These cells situated close to the glomeruli, represent a subset of brush border epithelial cells. Amylin immunoreactivity (IR) is also found in these cells and colocalizes with angiotensinogen IR. Thus a second important role for amylin is described in which it plays a role as a growth factor in the developing kidney and in renal regrowth in the adult kidney. In a model of IDDM (streptozotocin diabetes), amylin and angiotensinogen IR are both restricted to a subset of brush border epithelial cells close to glomeruli which, in the developing kidney, expressed amylin mRNA. Thus in this IDDM model, we hypothesize that amylin mRNA transcription which is normally downregulated in the adult, is upregulated in this subset of these brush border epithelial cells, and that it stimulates the activity of a local RAS by an intracellular mechanism, leading to the biosynthesis of Ang II. It remains to be determined that if amylin is playing a role in stimulating local Ang II production at these sites, this provides a mechanism for activation of TGF-beta, ultimately leading to interstitial fibrosis.
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PMID:Interaction of the renal amylin and renin-angiotensin systems in animal models of diabetes and hypertension. 993 Mar 78

Good evidence exists that genetic predisposition is a major determinant in the development of renal and cardiovascular complications of diabetes. In particular, the role of familial predisposition is well established in diabetic nephropathy which may cluster within families, both in type I (IDDM) and in type II (NIDDM) diabetes. The genes responsible for predisposition to renal and cardiovascular complications are not known, but those of the renin-angiotensin system (RAS) are plausible candidates. Beside the large number of studies aimed at evaluating the role of polymorphisms in these genes, particularly in angiotensin-converting enzyme (ACE) gene, in development of renal disease, no clear-cut evidence has been provided until now. Furthermore, a number of trials have shown that ACE-inhibitors (ACEi) may reduce the rate of progression of renal failure. If the RAS genotype were able to foresee the response to ACEi it would provide new strategies for a specific treatment of subjects at higher risk.
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PMID:Gene polymorphism of the renin-angiotensin system and progression of diabetic nephropathy. 1020 97


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