Basement membrane abnormalities in diabetes mellitus: Relationship to clinical microangiopathy

Williamson, Joseph R.; Tilton, Ronald G.; Chang, Katherine; Kilo, Charles

doi:10.1002/dmr.5610040404

Cited by 104 publications

(56 citation statements)

References 256 publications

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“…Although less discordance was observed in the current study than in previous studies of patients with more severe disease (7,8,10,28), nearly 50% of the subjects without signs of diabetic retinopathy still had an increased glomerulopathy index. This finding may be because retinopathy was detected by grading of gross anatomic changes seen on stereoscopic fundus photographs, whereas the glomerulopathy index was based on electron microscopic detection of renal changes.…”

Section: Discussioncontrasting

confidence: 94%

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The Relationship of Diabetic Retinopathy to Preclinical Diabetic Glomerulopathy Lesions in Type 1 Diabetic Patients

et al. 2005

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Few epidemiological data exist regarding the correlation of anatomic measures of diabetic retinopathy and nephropathy, especially early in the disease processes. The aim of this study was to examine the association of severity of diabetic retinopathy with histological measures of diabetic nephropathy in normoalbuminuric patients with type 1 diabetes. The study included participants (n ‫؍‬ 285) in the Renin-Angiotensin System Study (RASS; a multicenter diabetic nephropathy primary prevention trial) who were aged >16 years and had 2-20 years of type 1 diabetes with normal baseline renal function measures. Albumin excretion rate (AER), blood pressure, serum creatinine, and glomerular filtration rate (GFR) were measured using standardized protocols. Diabetic retinopathy was determined by masked grading of 30°color stereoscopic fundus photographs of seven standard fields using the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale. Baseline renal structural parameters, e.g., fraction of the glomerulus occupied by the mesangium or mesangial fractional volume [Vv(Mes/glom)] and glomerular basement membrane width, were assessed by masked electron microscopic morphometric analyses of research percutaneous renal biopsies. No retinopathy was present in 36%, mild nonproliferative diabetic retinopathy in 53%, moderate to severe nonproliferative diabetic retinopathy in 9%, and proliferative diabetic retinopathy in 2% of the cohort. Retinopathy was not related to AER, blood pressure, serum creatinine, or GFR. All renal anatomical end points were associated with increasing severity of diabetic retinopathy, while controlling for other risk factors. These data demonstrate a significant association between diabetic retinopathy and preclinical morphologic changes of diabetic nephropathy in type 1 diabetic patients. Diabetes 54: 527-533, 2005

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Section: Discussioncontrasting

confidence: 94%

“…Previous attempts to correlate diabetic retinal with renal changes have been conducted in patients with severe manifestations of these complications (7,8,10,28). Thickening of basement membrane in both retinal and glomerular capillary vessels has been shown in late stages of diabetic retinopathy and nephropathy (9).…”

Section: Discussionmentioning

confidence: 99%

The Relationship of Diabetic Retinopathy to Preclinical Diabetic Glomerulopathy Lesions in Type 1 Diabetic Patients

et al. 2005

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“…The non-enzymatic glycation of the proteins, and the formation of oxygen radicals are the suggested mechanisms through which glucose causes these biochemical alterations (51-54). The expanding mesangium, which compresses the capillary vasculature and ultimately leads to glomerular closure, is thought to be the primary cause for the development of diabetic nephropathy rather than the loss of the charge and size selectivity of the glomerular filtration barrier (4,55).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Matrix Proteins as Early Markers in Diabetic Nephropathy

Jäckle-Meyer

Szukics²,

Neubauer³

et al. 1995

CCLM

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Summary: Basement membrane thickening and mesangial expansion characterize the renal involvement in diabetes mellitus and precede any symptoms of renal dysfunction, e. g., albuminuria and changes in glomerular filtration rate. Since the morphological changes can only be diagnosed by biopsy, this study was designed to investigate whether the urinary excretion of renal extracellular matrix proteins might reflect the morphological alterations.To specify the extent of renal involvement in diabetes, the patients, type I as well as type II diabetics, were classified according to their urinary albumin excretion: normal albumin excretion below 30 μg/min, microalbuminuria from 30 to 300 μg/min, and overt albuminuria above 200 μg/min. Laminin, collagen IV, and fibronectin, all intrinsic components of the renal extracellular matrix, were determined in serum and urine by radioimmunoassay or enzymelinked-immunosorbent-assay, respectively. The results are given as median values (x). Additionally, the urinary fragment pattern of fibronectin was analysed qualitatively by immunoblotting.Laminin concentrations in serum and in urine did not change in diabetics. Collagen IV decreased in serum of patients with increased albumin excretion (controls: χ = 255 μg/l, normoalbuminuric patients: χ = 56 μg/l J microalbuminuric patients: χ = 52 μg/l, and patients with overt albuminuria: χ = 70 μg/l; α < 0.01) and increased in urine (controls, normoalbuminuric and microalbuminuric patients: not detectable, patients with overt albuminuria: χ = 5 ng/12 h; α < 0.001). Fibronectin was elevated in serum (controls: χ = 355 mg/1; normoalbuminuric patients: χ = 640 mg/1, microalbuminuric patients: χ = 710 mg/1, and patients with overt albuminuria: χ = 630 mg/1; α < 0.0001) and in urine, even in patients with normal albumin excretion (controls: χ = 16.8 μg/12 h, normoalbuminuric patients: x= 121 μg/12h, microalbuminuric patients: x = 108μg/12h, patients with overt albuminuria: χ = 186 \ig/l2 h; α < 0.01). The urinary fragment pattern of fibronectin, consisting of two main bands of a relative molecular mass of M r 75000 and 45000, was not altered in controls and diabetics. Type I and type II diabetic patients did not show significant differences in any quantities tested.It was shown in this study that the determination of laminin and collagen IV in serum and urine gave no information exceeding the routinely used quantities of kidney function. But the renal fibronectin excretion was elevated before any functional changes occurred. It was concluded that this might be indicative of the early mesangial expansion in diabetes mellitus. The determination of urinary fibronectin could therefore probably serve as a more sensitive marker for renal involvement in diabetes mellitus than microalbuminuria or changes in glomerular filtration rate.

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“…Vascular functional changes induced by elevated glucose levels are strongly linked to increased flux of glucose via the sorbitol pathway (1)(2)(3)(4). However, the nature ofthe sorbitol-linked metabolic imbalance(s) which mediate these vascular changes remains unclear (2,5).…”

Section: Introductionmentioning

confidence: 99%

Diacylglycerol accumulation and microvascular abnormalities induced by elevated glucose levels.

Wolf¹,

Williamson²,

Easom³

et al. 1991

J. Clin. Invest.

171

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The present experiments were undertaken to examine the hypothesis that glucose-induced increased de novo synthesis of 1,2-diacyl-sn-glycerol (which has been observed in a number of different tissues, including retinal capillary endothelial cells exposed to elevated glucose levels in vitro) and associated activation of protein kinase C may play a role in mediating glucoseinduced vascular functional changes. We report here that twice daily instillation of 30 mM glucose over 10 -d in a rat skin chamber granulation tissue model induces approximately a 2.7-fold increase in diacylglycerol (DAG) levels (versus tissues exposed to 5 mM glucose) in association with marked increases in vascular clearance of albumin and blood flow. The glucose-induced increase in DAG levels as well as the vascular functional changes are prevented by addition of 3 mM pyruvate. Pharmacological activation of protein kinase C with the phorbol ester TPA in the presence of 5 mM glucose increases microvascular albumin clearance and blood flow, and similar effects are observed with 1-monoolein (MOG), a pharmacological inhibitor of the catabolism of endogenous DAG. A pharmacological inhibitor of protein kinase C (staurosporine) greatly attenuates the rise in microvascular albumin clearance (but not the rise in blood flow) induced by glucose or by MOG. These findings are compatible with the hypothesis that elevated concentrations of glucose increase tissue DAG content via de novo synthesis, resuIting in protein kinase C activation, and that these biochemical events are among the factors that generate the increased microvascular albumin clearance. (J. Clin. Invest. 1991.

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Basement membrane abnormalities in diabetes mellitus: Relationship to clinical microangiopathy

Cited by 104 publications

References 256 publications

The Relationship of Diabetic Retinopathy to Preclinical Diabetic Glomerulopathy Lesions in Type 1 Diabetic Patients

The Relationship of Diabetic Retinopathy to Preclinical Diabetic Glomerulopathy Lesions in Type 1 Diabetic Patients

Extracellular Matrix Proteins as Early Markers in Diabetic Nephropathy

Diacylglycerol accumulation and microvascular abnormalities induced by elevated glucose levels.

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