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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic factors contribute significantly to the development of diabetic nephropathy in patients with insulin-dependent diabetes mellitus. This report discusses some models of diabetic nephropathy that incorporate genetic susceptibility and presents strategies for identifying the responsible genes. To identify variation at a locus, newly developed methods are discussed that employ denaturing gradient gel electrophoresis to study sequence differences in both polymerase chain reaction-amplified DNA fragments and genomic DNA. These techniques are illustrated with studies of the angiotensinogen gene and the insulin receptor gene. In preliminary data from a comparison between individuals with and without diabetic nephropathy, no DNA sequence difference in that part of the angiotensinogen gene that codes for angiotensin I was found. However, with a probe corresponding to exons 7 and 8 of the insulin receptor gene and denaturing gradient gel electrophoresis of Rsal digestions of genomic DNA, different distributions of a DNA polymorphism were found in patients with fast as compared with slowly progressing nephropathy. The interpretation of this finding and the need for further studies are discussed. In conclusion, the advent of methods of molecular genetics makes possible studies on genetic determinants of diabetic nephropathy. However, more clinical and epidemiologic data are needed to find out how many genes are involved and how they interact with exposure to diabetes. Foremost, DNA from families with two or more siblings with diabetic nephropathy must be collected to permit the necessary genetic studies.
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PMID:Molecular genetic approaches to the identification of genes involved in the development of nephropathy in insulin-dependent diabetes mellitus. 145 65

A placebo-controlled, double-blind clinical trial has been initiated to determine whether angiotensin-converting enzyme inhibitor (ACEI) therapy with captopril (25 mg three times daily) slows the progressive loss of renal function in patients with type 1 diabetes mellitus. Entry criteria include; (1) ages 18 to 50 yr; (2) onset of insulin-dependent diabetes before the age of 30 yr, insulin dependent for at least 7 yr; (3) 24-h urine protein excretion > 500 mg, plus: (a) diabetic retinopathy or (b) if no retinopathy, a renal biopsy diagnosis of diabetic nephropathy; (4) serum creatinine (SCr) < 2.5 mg/dL; (5) informed consent. Patients follow strict medical management protocols. Systemic blood pressure is controlled to predefined goals (< 140-90 mm Hg). The primary outcome of the Study is a doubling of the patients' entry SCr to at least 2 mg/dL confirmed by a > 50% decrease in GFR by radioactive iothalamate clearance technique. Baseline characteristics of the cohort at entry into the Study are (mean +/- SD): male/female, 52%/48%; age, 35 +/- 8 yr; duration of diabetes, 21 +/- 7 yr; duration of proteinuria, 2.8 +/- 3.3 yr; duration of retinopathy, 4.5 +/- 4.1 yr; 50% of cohort presented with hypertension, duration, 4 +/- 4.7 yr; blood pressure, 139/86 +/- 19/12; SCr, 1.35 +/- 0.44 mg/dL; GFR 78 +/- 32 mL/min; BUN, 24 +/- 11 mg/dL; proteinuria, 3.1 +/- 3.3 g/day; cholesterol, 236 +/- 50 mg/dL; total glycosylated hemoglobin, 11.1 +/- 2.1%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A controlled clinical trial of angiotensin-converting enzyme inhibition in type I diabetic nephropathy: study design and patient characteristics. The Collaborative Study Group. 145 67

Diabetic nephropathy is a serious complication of insulin-dependent diabetes mellitus (IDDM) that affects 30% to 40% of IDDM patients with a predictable time of onset. Epidemiologic data suggest that either a genetic susceptibility, perhaps for hypertension (HTN), or an environmental exposure selects out that subset of IDDM patients and destines them to develop diabetic nephropathy. Hopefully, assessing glomerular hyperfiltration, urinary albumin excretion rate (AER), glycemic control, mean arterial pressure (MAP), and perhaps early morphologic changes will allow early identification of this high-risk group of IDDM patients before overt nephropathy is present. Once nephropathy appears, renal function inexorably declines, although the natural history of this progression may be changing with earlier therapeutic intervention. IDDM patients with nephropathy suffer a high mortality rate compared with IDDM patients without nephropathy or with nondiabetic end-stage renal disease patients. This is primarily due to malignant atherosclerotic disease manifested as coronary, peripheral, and cerebral arterial disease. Therapeutic interventions of demonstrated benefit in slowing the rate of decline of glomerular filtration rate (GFR) include blood pressure control and low-protein diets. Strict blood sugar control or treatment with aldose reductase inhibitors, converting enzyme inhibitors (CEIs), or inhibitors of advanced glycosylation end-product formation are of possible benefit, but are awaiting clinical trial results.
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PMID:Diabetic nephropathy in insulin-dependent patients. 146 80

Clinical diabetic nephropathy in man is the consequence of the development of a specific constellation of glomerular, tubular, vascular, and interstitial structural abnormalities accompanied by highly characteristic immunohistochemical alterations that, together, are unique to diabetes. Because changes resembling the specific pathology of diabetes do not develop in patients with conditions that lead to long-standing glomerular hyperfunction (such as unilateral nephrectomy), it is unlikely that glomerular hemodynamic abnormalities per se can be the cause of diabetic nephropathy. Whether hemodynamic abnormalities represent a risk factor that, in the presence of the diabetic state, can accelerate the rate of development of the basic lesions of diabetic nephropathy is currently unclear. However, there is considerable evidence that when the renal lesions of diabetes are far advanced, factors such as systemic hypertension can determine the rate of renal functional deterioration in diabetes as in other disorders. Although the diabetic rat may be a useful model for the study of aspects of the pathogenesis of diabetic nephropathy, much confusion has resulted from the inclusion of focal segmental glomerular sclerosis as a diabetic lesion. Similarly, the acceptance of all increases in urinary protein excretions in this model as resulting from or reflecting of diabetic nephropathology can be misleading. It is concluded that treatment aimed at manipulating renal hemodynamics in diabetic patients without evidence of renal disease should remain in the realm of clinical research.
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PMID:An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics. 146 81

Angiotensin-converting enzyme (ACE) inhibitors decrease albuminuria in patients with diabetic nephropathy. To study the change in albuminuria in relation to changes in systemic and renal hemodynamics, nine normotensive patients with type 1 (insulin-dependent) diabetes mellitus and persistent proteinuria were given a single oral dose of 25 mg of the ACE inhibitor captopril. Blood pressure, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and albumin excretion rate (AER) were measured in two periods of 40 minutes before and in four periods of 40 minutes after administration of captopril. A constant water diuresis was maintained. Blood pressure did not decrease significantly (130/79 +/- 4/3 v 124/74 +/- 4/3 mm Hg; mean +/- SEM), median AER decreased from 403 (interquartile range [IQR], 812) micrograms/min to 333 (707) micrograms/min (P < 0.01). GFR did not change (123 +/- 13 v 117 +/- 14 mL/min), but ERPF increased significantly from 609 +/- 56 to 714 +/- 55 mL/min (P < 0.01). Consequently, the filtration fraction (FF; quotient of GFR and ERPF) decreased from 0.20 +/- 0.014 to 0.17 +/- 0.014 (P < 0.01). A strong correlation was found between the decrease of AER and the decrease of FF (rs = 0.75; P < 0.02). No correlation was found between the decrease in AER and changes in GFR or blood pressure. In the normotensive patient with diabetic nephropathy, captopril causes an acute reduction of AER, which is probably mediated by a lowering of the intraglomerular pressure.
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PMID:Captopril acutely lowers albuminuria in normotensive patients with diabetic nephropathy. 146 82

Diabetic nephropathy leading to kidney failure is a major complication of type I (insulin-dependent) diabetes mellitus and is associated with progressive proteinuria. In the present 6-month study, effects of two structurally dissimilar aldose reductase inhibitors (sorbinil and ponalrestat or Statil) were examined on prevention of proteinuria in insulin-dependent spontaneously diabetic BB rats and compared with age-matched BB resistant controls. Prior to aldose reductase inhibitor treatment, all diabetic BB rats exhibited hyperglycemia (> 300 mg/dl), glycosuria (> 2,000 mg/dl) and 24-hour urinary protein excretion ranging from 5.01 to 11.23 mg/day. After daily administration of ponalrestat (20 mg/kg) for 3 months, 24-hour urinary protein excretion was 11.53 +/- 1.76 mg/day in ponalrestat-treated rats, despite persistence of hyperglycemia (444 +/- 31 mg/dl) and glycosuria (> 2,000 mg/dl); by contrast, urinary protein excretion was 17.76 +/- 2.59 mg/day in the control group of untreated BB diabetic rats. Ponalrestat initially protected against excretion of an array of urinary proteins having molecular weights between 30,000 and 100,000 daltons. These effects sustained throughout the 4th month of treatment, tended to change toward valves in control rats by the 5th month. At the end of 6 months, ponalrestat-treated diabetic rats excreted 18.73 +/- 3.20 mg/day of protein, similar to valves in untreated BB diabetic rats; both demonstrated a 4-fold increase in urinary protein excretion when compared to age-matched BB resistant controls. Proteinuria was attributed to an increase in albumin and an array of proteins having molecular weights between 30,000 and 100,000 daltons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of sorbinil and ponalrestat (Statil) diminution of proteinuria in the BB rat. 146 75

Microalbuminuria predicts the development of diabetic nephropathy. Large daily variations in albumin excretion rates are frequently observed. Because seminal fluid contains protein and albumin, we reasoned that sexual activity, ejaculation, or residual urethral semen could contribute to albumin content in urine and thus effect determination of albumin excretion rate. Our study was designed to determine the effect of ejaculation of albumin excretion rate and to ascertain if patients routinely should be advised to refrain from sexual activity during or before the urine collection period. Ten normotensive, nondiabetic men (age 31.0 +/- 2.3 years) collected 24-h urine specimens on three occasions: after 3 days of abstinence from sexual activity, during a 24-h period which included one ejaculatory episode, and on a day following sexual activity. Results for albumin excretion rate were: abstinence day: 4.8 +/- 0.7 micrograms/min; sex day: 6.3 +/- 1.1 microgram/min; post-sex day: 4.9 +/- 1.0 micrograms/min. There was no significant difference between these values when compared directly or after log transformation. There also were no differences in urinary creatinine excretion or clearance. We conclude that in nondiabetic individuals ejaculation does not influence albumin excretion rate.
J Diabetes Complications
PMID:The effect of ejaculation on albumin excretion rate. 147 41

In type I diabetes, the quality of life and, in essence, the long-term prognosis or life expectancy of the patient are invariably related to the manifestation of untoward complications. Increased arterial blood pressure (hypertension) has a great influence in these complications. Cumulative evidence has shown that proteinuric type I diabetic patients are easily susceptible to hypertension and its accompanying sequelae. The debilitating effects of hypertension on the progressive development of diabetic nephropathy leading to renal dysfunction and mortality in renal transplant patients have been documented. Proliferative retinopathy and cardiovascular lesions are also frequent devastating complications in hypertensive-diabetic patients. The mechanism of sodium/lithium countertransport activity and the genetic predisposition to hypertension require further elucidation.
J Diabetes Complications
PMID:Comments on the clinical impact of hypertension in type I diabetes. 147 46

The genetically determined acetylator phenotype in diabetic children with and without increased urinary albumin excretion was investigated. Acetylator phenotype was determined according to Evans, and 24-hour albumin excretion rate (AER) was measured by immunoturbidometry in 86 children and adolescents with type 1 (insulin-dependent) diabetes mellitus and in 100 age-matched healthy controls. In diabetics, the fast acetylator phenotype was found in 36 (41.9%) patients and the slow one in 50 (58.1%); the control group had 52 (52%) fast and 48 (48%) slow acetylators. There were no significant differences in acetylator phenotypes between diabetic patients and control subjects (chi 2 = 1.0, NS). Among patients with normal albumin excretion (n = 70, mean age: 12.9 +/- 3.5 years, mean diabetes duration: 5.3 +/- 3.8 years, AER < 20 micrograms/min), 35 (50%) fast acetylators and 35 (50%) slow acetylators were found. In patients with elevated albumin excretion (n = 16, mean age: 14.0 +/- 3.2 years, mean diabetes duration: 4.9 +/- 3.0 years, AER > 20 micrograms/min), 1 (6.3%) patient was a fast acetylator and 15 (93.7%) were slow acetylators. A significant difference has been found between the two groups in the rate of fast/slow acetylators (chi 2 = 8.79, p < 0.01). The strong correlation between the slow acetylator phenotype and microalbuminuria in diabetics suggests that: (a) genetic factors may play a role in the development of diabetic nephropathy; (b) the acetylator status could be a useful tool to detect patients 'at risk' of nephropathy.
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PMID:Association of microalbuminuria with slow acetylator phenotype in type 1 diabetes mellitus. 147 91

Patients with Type 2 (non-insulin-dependent) diabetes mellitus complicated by microalbuminuria or albuminuria, have an increased risk of developing macrovascular disease and of early mortality. Because lipoprotein abnormalities have been associated with diabetic nephropathy, this study tested the hypothesis that levels of apolipoprotein (a) are elevated in patients with Type 2 diabetes and increased levels of urinary albumin loss. Levels of apolipoprotein (a) in diabetic patients with microalbuminuria (n = 26, geometric mean 195 U/l, 95% confidence interval 117-324) and albuminuria (n = 19, 281 U/l, 165-479) were higher than in non-diabetic control subjects (n = 140, 107 U/l, 85-134, p < 0.05), and in the albuminuric group than diabetic patients without urinary albumin loss (n = 58, 114 U/l, 76-169, p < 0.05). Patients with microalbuminuria and albuminuria had levels comparable with patients undergoing elective coronary artery graft surgery (n = 40, 193 U/l, 126-298). Apolipoprotein (a) levels were higher in diabetic patients with macrovascular disease than in those without (n = 49, 209 U/l, 143-306 vs n = 54, 116 U/l, 78-173, p < 0.05). These preliminary results suggest that raised apolipoprotein (a) levels of Type 2 diabetic patients with microalbuminuria and albuminuria may contribute to their propensity to macrovascular disease and early mortality.
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PMID:Plasma apolipoprotein (a) is increased in type 2 (non-insulin-dependent) diabetic patients with microalbuminuria. 147 15


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