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)

We examined ten patients with type I diabetes mellitus and ten age- and sex-matched healthy controls. Median duration of diabetes was 7 years (range 0.5-24). None of the diabetic patients had hypertension, microalbuminuria, or proliferative retinopathy. Maximal specific binding capacity for angiotensin II to thrombocytes was significantly increased in diabetics (Bmax 11.9 +/- 1.6 sites per cell vs 7.0 +/- 0.9 in controls; P less than 0.01). In contrast, maximal binding for atrial natriuretic factor tended to be lower in type I diabetics (8.84 +/- 1.25 sites per cell vs 16.8 +/- 2.97; P less than 0.07). There was no difference of apparent dissociation constant (KD) for either receptor. Angiotensin II values (RIA) were greater in diabetics (16.2 +/- 1.5 pg/ml vs 8.5 +/- 1.4 in controls; P less than 0.02) and concentrations of atrial natriuretic factor (RIA) were not significantly different. The data suggest increased angiotensin II binding despite high angiotensin II concentrations in non-nephropathic type I diabetic patients. These findings may be relevant when considering the evolution of hypertension and microangiopathy lesions.
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PMID:Specific binding of angiotensin II and atrial natriuretic factor in non-nephropathic type I diabetes mellitus. 252 55

We measured plasma- and extracellular fluid volume (125I-albumin, 51Cr-EDTA), plasma concentrations of renin, angiotensin I and II, aldosterone and atrial natriuretic peptide by radio-immunoassays in insulin-dependent diabetic (IDDM) patients with (n=28) and without (n=11) nephropathy and in 14 normal control subjects matched for sex and age. Glomerular filtration rate (GFR) (ml/min/1.73 m2, single intravenous bolus 51Cr-EDTA technique) was within normal range in all nephropathic patients; 107 (range 78-134). Mean arterial blood pressure (mmHg) was elevated 102 +/- 13 (+/- S.D.) compared to the diabetic and normal control group, 92 +/- 8 and 87 +/- 5, respectively (p less than 0.01). Plasma volume was identical in all three groups while extracellular volume (1/1.73 m2) was expanded in nephropathic patients, 14.5 +/- 1.5 vs 13.1 +/- 0.9 and 12.4 +/- 1.3 in the diabetic and non-diabetic control groups, respectively (p less than 0.05). A significant correlation between extracellular fluid volume and mean arterial blood pressure was found (n=53, r=0.49, p less than 0.001). Active renin was significantly increased in patients with diabetic nephropathy compared with the normal control subjects, while all the remaining hormones were about the same in the three groups. Our study suggests that fluid retention plays a dominant role in the initiation and maintenance of arterial blood pressure elevation early in the course of diabetic nephropathy.
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PMID:On the pathogenesis of arterial blood pressure elevation early in the course of diabetic nephropathy. 253 16

Angiotensin II receptors on platelets were studied in 13 patients with uncomplicated type I diabetes mellitus and in 15 age-matched normal subjects. Receptor density on cells from the diabetic patients was 15% lower than the normal subjects (5.2 +/- 0.8 SD sites/platelet in diabetic patients and 6.4 +/- 0.8 in normals, P less than 0.001), but there were no differences in receptor affinity as measured by Kd (4.9 +/- 1.5 X 10(-10) mol/l in diabetic patients and 5.4 +/- 1.4 X 10(-10) mol/l in normals). Plasma concentrations of renin and angiotensin II were similar in both groups. The reduced density of angiotensin II receptors on platelets from patients with insulin-dependent diabetes may reflect a generalized abnormality of angiotensin II receptor regulation.
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PMID:Reduced number of angiotensin II receptors on platelets in insulin-dependent diabetes. 301 90

The mechanism by which angiotensin-converting enzyme (ACE) inhibition influences renal perfusion and function has assumed growing importance as alternatives for blocking the system have emerged. Neither renin inhibitors nor angiotensin II (Ang II) antagonists are likely to trigger responses similar to ACE inhibitor-induced involvement of kinins, prostaglandins, or nitric oxide. Several observations suggest species variation in the contribution of these pathways to the renal response to ACE inhibition. In humans, recent investigation suggests that virtually all of the renal response is due to a fall in Ang II formation. Perhaps most persuasive is the surprising observation that the renal hemodynamic response to renin inhibitors exceeds by more than 50% the response to ACE inhibition in healthy humans. To the extent that kinins or prostaglandins contribute to the renal response to ACE inhibition, one would anticipate a smaller response to renin inhibition. Possible explanations include an unanticipated additional action of renin inhibitors, better tissue penetration of these highly lipophilic agents, or more effective blockade of Ang II formation through an action at the rate-limiting step or non-ACE-dependent Ang II generation. Substantial evidence favors the latter two possibilities. Whatever the explanation, these observations raise the intriguing possibility that the undoubted therapeutic efficacy of ACE inhibition in renal injury, documented most rigorously for type I diabetes mellitus, might be exceeded with the newer classes of agent.
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PMID:Renal circulation and blockade of the renin-angiotensin system. Is angiotensin-converting enzyme inhibition the last word? 755 19

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

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

It is well documented that diabetic patients with chronic complications have decreased renin secretion and elevations in the renin precursor prorenin. It is uncertain, however, whether the abnormal processing of prorenin is reflective of microvascular disease, hypertension, or autonomic neuropathy. Dechaux et al. (Transplant Proc. 18:1598-1599, 1986) observed abnormalities in prorenin processing in uncomplicated diabetes and suggested that it was the result of subclinical autonomic neuropathy. To test this hypothesis, we measured renin, prorenin, and autonomic function in early type 1 diabetes at a time when there is little or no microvascular disease or hypervolemia. Thirty-seven patients (10 males, 27 females) enrolled 2-22 months after diagnosis in a longitudinal study in which renin, prorenin, and autonomic function were measured annually for 3 years. Forty-one age-matched control subjects were also studied. PRA in the diabetic patients at the time of the second and third evaluations was 1.71 +/- 0.24 ng angiotensin I/mL x h and 1.67 +/- 0.24 ng angiotensin I/mL x h, respectively, significantly lower (P < 0.05) than that of the control subjects in whom PRA was 2.96 +/- 0.38 ng angiotensin I/mL x h. Prorenin was not different in the diabetic patients in comparison with controls. The renin to prorenin ratio in the diabetic patients at the time of the first, second, and third evaluations was 0.260 +/- 0.03, 0.235 +/- 0.05, and 0.227 0.05, respectively, significantly lower (P < 0.01) than in control subjects in whom the renin to prorenin ratio was 0.475 +/- 0.08. Despite this, at the time of the first and second evaluations, there was no evidence of autonomic dysfunction and no correlation between any test of autonomic function and the renin to prorenin ratio. At the time of the third evaluation, however, the intermediate frequency (0.04-0.15 Hz) power spectra while patients were supine (an index of sympathetic modulation of heart rate variability) showed a highly significant (P < .001) correlation with the renin to prorenin ratio. High frequency (0.15-0.40 Hz) spectra from supine patients at the third evaluation also correlated with the renin to prorenin ratio (P < 0.01). We conclude abnormal processing of prorenin develops in diabetic patients prior to microvascular disease, even before the first evidence of autonomic dysfunction. Although the latter may play a contributory role, additional as yet unidentified mechanisms seem to interrupt the processing of prorenin in early diabetes.
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PMID:Decreased prorenin processing develops before autonomic dysfunction in type 1 diabetes. 1069 Aug 59

Uncontrolled hypertension leads to an increased risk of cardiovascular disease and stroke. Hypertensive patients with concomitant type 2 diabetes are at even greater risk of cardiovascular complications; also, this high-risk patient population is at increased risk of renal disease and, ultimately, renal failure. Prospective morbidity and mortality trials have demonstrated that tight blood pressure control improves the cardiovascular prognosis and provides target organ protection. Current treatment guidelines recommend a target blood pressure of < 130/85 mm Hg for patients with hypertension and diabetes. Angiotensin II (A-II), a major component of the renin-angiotensin system, plays an essential role in the pathophysiology of hypertension and diabetes-related renal disease. Currently, the treatment of choice for hypertensive patients with diabetes is angiotensin-converting enzyme (ACE) inhibition, but most of the data are limited to patients with type 1 diabetes. Although ACE inhibition is clearly a mechanism for blocking A-II formation, inhibition at this site may not be complete, as alternate pathways exist for A-II formation. Thus, for interrupting the renin-angiotensin system, A-II receptor antagonists theoretically provide advantages over ACE inhibitors in that they directly inhibit A-II by binding to the AT(1) receptor subtype. The objectives of this review are to: 1) provide an overview of the associated risk of cardiovascular complications with concomitant hypertension and diabetes; 2) demonstrate the cardiovascular benefits of effective blood pressure control in this patient population; 3) review the current treatment guidelines for managing high-risk hypertensive patients; and 4) discuss major, ongoing clinical studies with A-II receptor antagonists in patients with concomitant hypertension, type 2 diabetes, and renal disease. (c)2001 Le Jacq Communications, Inc.
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PMID:Management of high-risk hypertensive patients with diabetes: potential role of angiotensin II receptor antagonists. 1149 50

The Reduction in End Points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and the Irbesartan Diabetic Nephropathy Trial (IDNT) are two recently reported trials with hard end points, conducted in patients in advanced stages of diabetic nephropathy. Two other studies--the Irbesartan Microalbuminuria Study (IRMA)-2 and the Microalbuminuria Reduction with Valsartan study (MARVAL)--were trials conducted in patients with type 2 diabetes with microalbuminuria, a cardiovascular risk factor associated with early-stage diabetic nephropathy. These trials all had a common theme--that is, does an angiotensin receptor blocker (ARB) interfere with the natural history of diabetic nephropathy in a blood pressure-independent fashion? Without question, the results of these trials legitimatize the use of the ARB class in forestalling the deterioration in renal function, which is almost inevitable in the patient with untreated diabetic nephropathy. These data can now be added to the vast array of evidence supporting angiotensin-converting enzyme (ACE) inhibitor use in patients with nephropathy associated with type 1 diabetes. It now appears a safe conclusion that the patient with diabetic nephropathy should receive therapy with an agent that interrupts the renin-angiotensin system. These studies have not resolved the question as to whether an ACE inhibitor or an ARB is the preferred agent in people with nephropathy from type 1 diabetes, though the optimal doses of these drugs remain to be determined. Head-to-head studies comparing ACE inhibitors to ARBs in diabetic nephropathy are not likely to occur, so it is unlikely that comparable information will be forthcoming with ACE inhibitors. An evidence-based therapeutic approach derived from these trials would argue for ARBs to be the foundation of therapy in the patient with type 2 diabetes and nephropathy.
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PMID:Type 2 diabetes: RENAAL and IDNT--the emergence of new treatment options. 1182 41

Losartan is an orally active, selective, nonpeptide, angiotensin II AT(1) receptor antagonist. Losartan 50 or 100 mg/day was significantly more effective than placebo in reducing the incidence of a doubling of serum creatinine, end-stage renal disease (ESRD) or death (43.5% vs 47.1%, p = 0.02) in a pivotal, well designed trial (Reduction of Endpoints in Non insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan [RENAAL] study) in 1513 patients with type 2 diabetes mellitus and proteinuria. Losartan also significantly reduced the incidence of doubling of serum creatinine level (p = 0.006), ESRD (p = 0.002), ESRD or death (p = 0.01) and doubling of serum creatinine and ESRD (p = 0.01) compared with placebo in the RENAAL trial. There were similar incidences of overall mortality and morbidity and mortality from cardiovascular causes between treatment groups. In addition, data from several nonblind and double-blind studies indicates that losartan effectively reduces the mean albumin excretion rate. Two double-blind studies show that losartan has similar effects to enalapril on kidney function. Data from 4058 patients (3300 with essential hypertension) who have received losartan (10-150 mg/day) in clinical trials indicate it is well tolerated. In the RENAAL study 17.2% and 21.7% of losartan and placebo recipients discontinued treatment because of adverse events, but causality was not determined.
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PMID:Losartan in diabetic nephropathy. 1255 62


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