Effect of myo-inositol supplementation on the development of renal pathological changes in the Cohen diabetic (type 2) rat

Cohen, Arthur; Wald, H.; Popovtzer, M.; Rosenmann, E.

doi:10.1007/s001250050369

Cited by 3 publications

(7 citation statements)

References 31 publications

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“…Interestingly enough, in earlier studies on the phenotype of this model, little emphasis was placed on kidney function (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). No data were provided with respect to the level of protein excretion or kidney function in all but one study in which varying levels of proteinuria were reported in both CDs and CDr strains, ranging from low to abnor- mally high (7). In that particular study, however, no information was available as to the level of genetic homogeneity of the CDs strain, raising the possibility of crossstrain contamination affecting the level of protein excretion.…”

Section: ͻ0001mentioning

confidence: 99%

“…Earlier studies on the renal phenotype of this model placed much emphasis on histopathology, but paid little or no attention to kidney function (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Preliminary studies by our group indicated that in the CDs strain, an unusual type of nephropathy evolves with no significant proteinuria but with progressive impairment of kidney function.…”

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confidence: 99%

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Nonproteinuric Diabetes-Associated Nephropathy in the Cohen Rat Model of Type 2 Diabetes

Yagil

Barak²,

Ben-Dor³

et al. 2005

Diabetes

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The Cohen diabetic rat is an experimental model reminiscent of human type 2 diabetes. The aim of this study was to characterize the development of end-organ damage in this model. Cohen diabetic sensitive (CDs) and Cohen diabetic resistant (CDr) rats were fed regular diet or a diabetogenic diet. Glucose tolerance, renal function, and renal and retinal histology were studied at set intervals. CDs fed diabetogenic diet were the only strain that expressed the diabetic metabolic phenotype. In this strain, urinary protein excretion did not increase with the development of diabetes, but plasma urea and creatinine levels increased and creatinine clearance decreased. Light microscopy revealed in CDs enlarged glomeruli with increased mesangial matrix and thickening of the glomerular capillary wall; electron microscopy demonstrated thickened basement membrane and mesangial abundance. There was increased staining for type IV collagen in glomeruli and interstitium of CDs. The retinas of diabetic CDs demonstrated pathology consistent with nonproliferative diabetic retinopathy. The histological findings in the kidneys, the absence of proteinuria, the impairment in glomerular filtration, and the development of retinopathy in CDs are consistent with diabetes-associated nephropathy that is similar to a nonalbuminuric type of nephropathy associated with type 2 diabetes in humans. Diabetes 54:1487-1496, 2005 T he Cohen diabetic rat is an experimental rodent model reminiscent of human type 2 diabetes (1,2). The model consists of two strains: the Cohen diabetic sensitive (CDs) rat, which invariably develops diabetes when fed a diabetogenic diet, and the Cohen diabetic resistant (CDr) rat, which remains normoglycemic even when fed a similar diet (1). The original colony was established over 30 years ago (2). We recently rebred animals from the original colony and characterized the metabolic phenotype of the new colony (1). We subsequently set forth to investigate whether target organ damage related to diabetes develops in this model. Because nephropathy is among the most common and morbid complications of diabetes, our focus was on the kidney.Earlier studies on the renal phenotype of this model placed much emphasis on histopathology, but paid little or no attention to kidney function (3-13). Preliminary studies by our group indicated that in the CDs strain, an unusual type of nephropathy evolves with no significant proteinuria but with progressive impairment of kidney function. In the current study, we present the results of our investigation on the development of end-organ damage in animals from the new Cohen diabetic rat colony. We provide histopathological evidence of the diabetes-related renal and retinal lesions and characterize functional aspects of the diabetic renal injury in this model. We demonstrate that the CDs is an experimental model of type 2 diabetes that develops a nonproteinuric type of diabetic nephropathy. RESEARCH DESIGN AND METHODSThe animals that were used in this study were male CDs and CDr rats that had been r...

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Section: ͻ0001mentioning

confidence: 99%

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confidence: 99%

Nonproteinuric Diabetes-Associated Nephropathy in the Cohen Rat Model of Type 2 Diabetes

Yagil

Barak²,

Ben-Dor³

et al. 2005

Diabetes

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“…The Cohen diabetic rat shares common genetic, metabolic, and morphologic features with human noninsulin-dependent diabetes (Cohen et al, 1995) (Table 1). It is a nonobese model of type II diabetes induced by genetic selection of healthy "Sabra" rats from the Hebrew University Strain.…”

Section: Animalsmentioning

confidence: 99%

“…Serum creatinine and urinary albumin were measured as previously described in this animal model (Cohen et al, 1995). Serum calcium and phosphate were measured by routine hospital testing in five diabetic rats and five control rats from Group C.…”

Section: Biochemical Assaymentioning

confidence: 99%

“…The degree of glomerulosclerosis was graded according to the number of glomeruli involved (focal or generalized) and the extent of glomerular involvement (segmental or diffuse). The morphologic changes were graded on a scale of 0 to 4, as previously described (Cohen et al, 1995). Briefly, in Grades 1 and 2 there is focal involvement of the glomeruli (15% to 50%), in Grade 3 there is more generalized involvement, and in Grade 4 tubular or interstitial changes or xanthomatous and/or lipohyaline glomerular changes are seen as well.…”

Section: Pathologic Evaluationmentioning

confidence: 99%

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Osteoporosis in the Cohen Diabetic Rat: Correlation Between Histomorphometric Changes in Bone and Microangiopathy

Amir

Rosenmann

Sherman

et al. 2002

Laboratory Investigation

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SUMMARY:Osteoporosis is well documented in type I diabetes, but its occurrence is controversial in type II diabetes.Microangiopathy is a major complication of type I and type II diabetes. We studied bone and microvascular changes in the Cohen diabetic rat, a unique nonobese model of noninsulin-dependent diabetes mellitus. The aim of this study was to find whether there is a temporal correlation between the onset of these two complications. The diabetic rats were divided into three groups (A, B, and C) according to duration of diabetes (2 months, 3 months, and 7 to 8 months, respectively). Trabecular bone area was assessed by computerized image analysis and microangiopathy by means of renal function tests, histologic examination of the kidneys, and ultrastructural measurement of the width of capillary basement membranes. Bone density of the distal femur and vertebra was significantly reduced in the diabetic rats relative to the control rats in all three groups (Group A femur: 11.5 Ϯ 1.6% versus 21.8 Ϯ 3.0%, p Ͻ 0.02; Group A vertebra: 15.9 Ϯ 1.6% versus 28.5 Ϯ 2.0%, p Ͻ 0.02; Group C femur: 7.9 Ϯ 1.1% versus 29.6 Ϯ 3.5%, p Ͻ 0.001; Group C vertebra: 11.4 Ϯ 0.7% versus 37.1 Ϯ 1.9%, p Ͻ 0.002). Renal function tests were normal in the Group A diabetic rats and there was marked albuminuria in the Group C diabetic rats. Histologic changes in the kidneys were seen only in the Group C diabetic rats. Five of 15 Group C diabetic rats showed no albuminuria or histologic evidence of kidney damage. The bone density in this subgroup was reduced relative to controls to the same degree as that of the rats with renal damage. There was no evidence of capillary basement membrane thickening in the Group A diabetic rats. Our findings indicate that in the Cohen diabetic rat, osteoporosis precedes the onset of microangiopathy. Microangiopathy probably does not play an important role in the pathogenesis of osteoporosis in this animal model. (Lab Invest 2002, 82:1399 -1405.

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Up-regulation of Human myo-Inositol Oxygenase by Hyperosmotic Stress in Renal Proximal Tubular Epithelial Cells

Prabhu

Arner

Vunta

et al. 2005

Journal of Biological Chemistry

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myo-Inositol oxygenase (MIOX) catalyzes the oxidative cleavage of myo-inositol (MI) to give D-glucuronic acid, a committed step in MI catabolism. D-Glucuronic acid is further metabolized to xylitol via the glucuronate-xylulose pathway. Although accumulation of polyols such as xylitol and sorbitol is associated with MI depletion in diabetic complications, no causal relationship has been established. Therefore we are examining the role of MIOX in diabetic nephropathy. Here we present evidence that the basis for the depletion of MI in diabetes is likely to be mediated by the increased expression of MIOX, which is induced by sorbitol, mannitol, and xylitol in a porcine renal proximal tubular epithelial cell line, LLC-PK1. To understand the molecular mechanism of regulation of MIOX expression by polyols, we have cloned the human MIOX gene locus of 10 kb containing 5.6 kb of the 5 upstream sequence. Analysis of the 5 upstream sequence led to the identification of an osmotic response element (ORE) in the promoter region, which is present ϳ2 kb upstream of the translation start site. Based on luciferase reporter and electrophoretic mobility shift assays, polyols increased the ORE-dependent expression of MIOX. In addition, we demonstrate that the activity of the promoter is dependent on the binding of the transcription factor, tonicity element-binding protein, or osmotic response elementbinding protein, to the ORE site. These results suggest that the expression of MIOX is up-regulated by a positive feedback mechanism where xylitol, one of the products of MI catabolism via the glucuronate-xylulose pathway, induces an overexpression of MIOX. myo-Inositol (MI),1 the dominant form of the physiological inositol isomers, is utilized in many tissues and cell types as a precursor for the synthesis of second messengers and also as an organic osmolyte (1). The first committed step in MI metabolism is catalyzed by the monooxygenase, myo-inositol oxygenase (MIOX; EC 1.13.99.1), which occurs predominantly in the proximal tubular epithelial cells of the kidney cortex (2). The enzymatic reaction involves the oxidative cleavage of the ring in MI between C-6 and C-1 to give D-glucuronic acid. The D-glucuronate formed in animals by this mechanism is successively converted in subsequent steps to L-gluonate, 3-keto-L-gulonate, L-xylulose, xylitol, D-xylulose, and D-xylulose 5-phosphate, which then enters the pentose phosphate cycle (Fig. 1). Studies in human pentosuric patients confirmed that this is the only pathway of MI catabolism (3). We have recently reported the cloning and expression of MIOX, where we demonstrated that D-chiro-inositol, a MI isomer that exhibits insulin-like signaling properties (4), is also a substrate for MIOX (2).myo-Inositol has been suggested to play an important role in the etiology of diabetes mellitus, particularly with respect to the progression of diabetic nephropathy, neuropathy, retinopathy, and diabetic cataract. In diabetic complications, increased glucose levels are associated with high sorbitol accumu...

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Effect of myo-inositol supplementation on the development of renal pathological changes in the Cohen diabetic (type 2) rat

Cited by 3 publications

References 31 publications

Nonproteinuric Diabetes-Associated Nephropathy in the Cohen Rat Model of Type 2 Diabetes

Nonproteinuric Diabetes-Associated Nephropathy in the Cohen Rat Model of Type 2 Diabetes

Osteoporosis in the Cohen Diabetic Rat: Correlation Between Histomorphometric Changes in Bone and Microangiopathy

Up-regulation of Human myo-Inositol Oxygenase by Hyperosmotic Stress in Renal Proximal Tubular Epithelial Cells

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