Aldose reductase in the etiology of diabetic complications: I. Introduction

Harrison, H E; Stribling, Donald; Armstrong, Frank M.; Perkins, C. M.

doi:10.1016/0891-6632(89)90003-2

Cited by 8 publications

(3 citation statements)

References 35 publications

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“…It has been suggested that a decrease in intracellular myo-inositol (32,33), an increase in lactate formation (29, 34,35), and changes in redox state (36,37,38) may be involved. Some suggest an increased production of vasodilatory prostaglandins (25,39,40) and abnormalities in ascorbic acid metabolism (41).…”

Section: Discussionmentioning

confidence: 99%

Reduction of Glomerular Hyperfiltration in Normoalbuminuric IDDM Patients by 6 mo of Aldose Reductase Inhibition

1991

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Hyperglycemia causes enhanced glucose metabolism by the polyol pathway in tissues not requiring insulin for glucose uptake. It has been suggested that the high level of aldose reductase activity may cause functional and structural abnormalities in diabetes and may be involved in the development of late complications. To elucidate the effect of an aldose reductase inhibitor (ponalrestat) on kidney function in uncomplicated insulin-dependent diabetes mellitus (IDDM), 20 normoalbuminuric IDDM patients were randomized to follow either 6 mo of treatment with ponalrestat (n = 11, mean ± SD age 30 ± 8 yr, diabetes duration 10 ± 6 yr) or 6 mo of placebo (age 33 ± 7 yr, diabetes duration 12 ± 6 yr). The glomerular filtration rate (clearance of [ 125 l]iothalamate) was significantly reduced from 140 ± 18 to 129 ± 10 ml • min~1 • 1.73 m" 2 , IP = 0.02) in the ponalrestattreated patients, whereas no change was seen after placebo (142 ± 12 vs. 141 ± 12 ml • min" 1 • 1.73 rrr 2 ). The renal plasma flow (clearance of 131 l-labeled hippuran), urinary albumin excretion rate (radioimmunoassay), fractional albumin clearance, and renal vascular resistance were unchanged in both groups. HbA 1c showed a modest increase during ponalrestat (7.9 ± 1.8 vs. 8.7 ± 1.5%, 2P = 0.01) but was unchanged during placebo. No side effects of ponalrestat were observed. Thus, inhibition of aldose reductase may reduce the characteristic hyperfiltration in uncomplicated IDDM. Diabetes 40:527-31, 1991 I n tissues with insulin-independent glucose uptake, hyperglycemia gives rise to enhanced glucose metabolism by the polyol pathway. Thus, the primary pathways for glucose are saturated, and the high intracellular glucose concentration leads to flux through the polyol pathway despite the low affinity of aldose reductase for glucose. The possibility that increased polyol-pathway activity could be a link between hyperglycemia and diabetic complications has attracted much interest and has been widely studied in experimental models of diabetes. Studies in rats with chemically induced diabetes have indicated that the biochemical and metabolic alterations that accompany a high level of polyol-pathway activity may be involved both in functional and structural renal abnormalities (1,2).In human insulin-dependent diabetes mellitus (IDDM), the characteristic functional abnormality during the early stage is glomerular hyperfunction with hyperfiltration and some degree of hyperperfusion (3-5). The aim of this study was to elucidate the possible influence of long-term inhibition of aldose reductase on glomerular filtration rate (GFR) and renal plasma flow (RPF) in normoalbuminuric IDDM patients. RESEARCH DESIGN AND METHODSTwenty male IDDM patients were studied. The patients were characterized as normoalbuminuric with a urinary albumin excretion rate (UAER) <20 |xg/min. Clinical data are given in Table 1 for the patients being randomized to active treatment (ponalrestat) and placebo, respectively (see below). The patients were normotensive, and none had proliferative reti...

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Section: Discussionmentioning

confidence: 99%

Reduction of Glomerular Hyperfiltration in Normoalbuminuric IDDM Patients by 6 mo of Aldose Reductase Inhibition

1991

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“…Whereas it is accepted that aldose reductase is implicated in pathogenesis of diabetic glomerulopathy [19–22], its role in podocytes has not yet been investigated. Podocytes are terminally differentiated cells, covering glomerular basement membrane with interdigitating foot processes connected by slit diaphragms.…”

Section: Introductionmentioning

confidence: 99%

Osmolarity and Glucose Differentially Regulate Aldose Reductase Activity in Cultured Mouse Podocytes

Lewko

Latawiec

Maryn

et al. 2011

Experimental Diabetes Research

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Podocyte injury is associated with progression of many renal diseases, including diabetic nephropathy. In this study we examined whether aldose reductase (AR), the enzyme implicated in diabetic complications in different tissues, is modulated by high glucose and osmolarity in podocyte cells. AR mRNA, protein expression, and activity were measured in mouse podocytes cultured in both normal and high glucose and osmolarity for 6 hours to 5 days. Hyperosmolarity acutely stimulated AR expression and activity, with subsequent increase of AR expression but decrease of activity. High glucose also elevated AR protein level; however, this was not accompanied by respective enzyme activation. Furthermore, high glucose appeared to counteract the osmolarity-dependent activation of AR. In conclusion, in podocytes AR is modulated by high glucose and increased osmolarity in a different manner. Posttranslational events may affect AR activity independent of enzyme protein amount. Activation of AR in podocytes may be implicated in diabetic podocytopathy.

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“…Accordingly, the aim of this study was to examine the acute effects of OFTT on serum uric acid concentrations in people with metabolic syndrome and type 2 diabetes. In addition, since fructose can be generated from glucose by the polyol pathway which is activated in type 2 diabetes, we also evaluated the effects of an oral glucose tolerance test (OGTT) on serum uric acid concentrations in people with type 2 diabetes. Our hypothesis was that ingestion of fructose would be associated with a greater rise in serum uric acid concentrations in people with type 2 diabetes compared to their peers without diabetes but with a similar body mass index (BMI).…”

Section: Introductionmentioning

confidence: 99%

Fructose tolerance test in obese people with and without type 2 diabetes

Al‐Ozairi

Rivard

Sánchez-Lozada

et al. 2019

Journal of Diabetes

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Background Fructose is distinct among common sugars in its ability to raise serum uric acid, and some studies suggest fructose‐induced uric acid production may have a role in the ability of this sugar to induce metabolic syndrome. A fructose tolerance test has been previously developed to evaluate the relative ability of fructose to raise uric acid in individuals. However, the effect of fructose to raise uric acid in people with diabetes has not been studied. Methods People with type 2 diabetes (n = 143) and without diabetes controls (n = 132) with similar body mass index (BMI) underwent an oral fructose tolerance test. As a comparison, participants also had their uric acid levels measured after an oral glucose tolerance test on a different day. Results Serum uric acid was lower in people with type 2 diabetes compared to controls with a similar BMI, especially those with poor glucose control (glycosylated hemoglobin [HbA1c] ≥ 8%). Fructose administration raised serum uric acid in both groups, with a lower absolute rise in people with diabetes. People with diabetes with a blunted rise in serum uric acid had higher baseline serum uric acid concentrations and a higher BMI. People without diabetes with a higher BMI also showed a blunted serum uric acid response. Oral glucose administration lowered serum uric acid in both participants, with a greater fall in those with diabetes. Conclusion Both the presence of diabetes and obesity blunt the serum uric acid response to fructose ingestion. These data demonstrate altered fructose‐dependent urate metabolism in type 2 diabetes.

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Aldose reductase in the etiology of diabetic complications: I. Introduction

Cited by 8 publications

References 35 publications

Reduction of Glomerular Hyperfiltration in Normoalbuminuric IDDM Patients by 6 mo of Aldose Reductase Inhibition

Reduction of Glomerular Hyperfiltration in Normoalbuminuric IDDM Patients by 6 mo of Aldose Reductase Inhibition

Osmolarity and Glucose Differentially Regulate Aldose Reductase Activity in Cultured Mouse Podocytes

Fructose tolerance test in obese people with and without type 2 diabetes

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