A.S. Reddi

Diabetic Nephropathy: An Update

Nephropathy is a serious microvascular complication in patients with insulin-dependent diabetes mellitus. In the United States, diabetes accounts for one fourth of new cases of end-stage renal disease each year. Complication rates and costs are much higher for diabetic than for nondiabetic patients with end-stage renal disease. Despite numerous studies, the pathophysiology of diabetic renal disease is not completely understood. We reviewed the current status of the structural, functional, biochemical, pathogenetic, and treatment modalities of diabetic renal disease and examined future therapeutic interventions.

Diabetic microangiopathy. I. Current status of the chemistry and metabolism of the glomerular basement membrane

In recent years, the nature of the renal glomerular basement membrane has been the subject of numerous investigations. In diabetes mellitus, the renal glomerulus is characterized primarily by thickening of the basement membrane and excessive accumulation of basement membrane-like material in the mesangial region. Compositional analyses have shown that basement membranes are glycoprotein in nature. Studies of the glomerular basement membranes in diabetes have indicated a change from normal chemical composition. Furthermore, studies of the metabolism of diabetic kidneys in experimental animals, using cortical homogenates and isolated glomeruli, have demonstrated higher anabolic and lower catabolic enzyme activities. However, contradictory data have been reported with regard to both the chemical composition and metabolism of the kidney in human and experimental diabetes. This review attempts to examine these reports in detail and discuss the possible causes for these discrepancies.

Diabetic microangiopathy in KK mice. II. Suppression of Glomerulosclerosis by pyridinolcarbamate.

Abstract KK mice with genetic diabetic glomerulosclerosis were treated with 250 mg/kg of pyridinolcarbamate (PDC), an antibradykinin agent, by 20 days of age and the kidney glucosyltransferase activity was measured. This enzyme facilitates the attachment of glucose to hydroxylysine-galactose unit of the basement membrane, which is glycoprotein in nature. No effect of PDC on the glucosyltransferase activity was observed up to 50 days of treatment. However, after 80 days of treatment, the enzyme activity was significantly increased. This finding was associated with a similar increase in total protein synthesis by the renal cortex of the treated KK mice. Amelioration of severity to only mild glomerulosclerosis was observed after 50 days of PDC administration. However, after 80 days of drug treatment, no severe type of glomerulosclerosis was present. PDC had no effect on either the fasting blood sugars or serum immunoreactive insulin levels. However, the oral glucose tolerance appeared to be improved in mice treated for 80 days. Glycogen synthesis by diaphragm muscle and total lipid synthesis by epididymal fat pad were significantly increased after 80 days of drug treatment, indicating increased tissue sensitivity to endogenous insulin. The observation that glucosyltransferase activity responded to PDC treatment with concomitant prevention of diabetic glomerulosclerosis suggests a relationship between this enzyme activity and glycoprotein synthesis in the kidney. It is suggested that PDC is a potential drug for the treatment of diabetic glomerulosclerosis.

Diabetic microangiopathy in KK mice: III. Effect of prolonged glyburide treatment on glomerulosclerosis

Abstract KK mice with spontaneous hereditary diabetes and human diabetic-like glomerulosclerosis were treated with either 0.5 or 2.5 mg/kg of glyburide, a sulfonylurea compound, from 2 months of age. Both, saline and glyburide-treated mice were sacrificed at 4, 6, 9, and 12 months of age, and their kidneys were examined by light microscopy. The data indicate that early glyburide treatment is effective in ameliorating or delaying the progression of diabetic glomerulosclerosis. This effect seems to be related to the early control of hyperglycemia in KK mice.

Riboflavin nutritional status and flavoprotein enzymes in normal and genetically diabetic kk mice.

Abstract Riboflavin nutritional status in normal control Swiss albino (SA) and genetically diabetic (KK) mice aged 8–9 mo was assessed by determining the glutathione reductase activity in erythrocyte hemolysates, with and without addition of flavin adenine dinucleotide (FAD); the ratio (activity with added FAD)/(activity without FAD) was expressed as the activity coefficient (AC). AC values from 0.9 to 1.3 were considered normal and those greater than 1.3 were regarded as evidence of riboflavin deficiency. Among SA mice, 35% were found to be riboflavin deficient. Among KK mice, 83% were riboflavin deficient. The difference in prevalance was significant (p

Elevated kidney glucosyltransferase activity in genetic prediabetic mice

Glucosyltransferase activity in the renal cortex of genetic diabetic KK mice was significantly increased at 40 days of age when compared to that of Swiss albino and F1 hybrid mice. This increase in enzyme activity in the absence of glucose intolerance can be regarded as an earlier genetic marker for the diagnosis of diabetic microangiopathy.

Diabetic microangiopathy in KK mice: V. Effect of early glyburide treatment on kidney glucosyltransferase activity

Abstract KK mice with spontaneous hereditary diabetes were treated with 0.5 mg/kg of glyburide once a day by intubation for 5 days a week from 20 days of age. A representative number of KK mice received 0.9% saline (0.1 ml/10 g) and served as controls for glyburide treated mice. The SA mice were not treated with saline. After an 18 hr fast, both saline and glyburide-treated mice were sacrificed at 40, 50, 70, and 100 days of age. Glyburide-treated mice showed a decreased trend in blood sugar levels, and this was significant in 50- and 70-day-old mice. The serum IRI levels increased significantly in the 70-day-old glyburide-treated mice. Glyburide caused a significant decrease in glucosyltransferase activity in the renal cortex of the KK mice at 40, 50, and 70 days of age. Early glyburide treatment is effective not only in preventing the progression of glomerulosclerosis but also in normalizing biochemical changes contributory to genetic diabetic glomerulosclerosis in KK mice.

Delay of progression of diabetic microangiopathy

Three muscle biopsies were performed in 53 overt type II diabetics over a period of approximately 2 years. At baseline, 21 (40%) had an abnormally increased capillary basement membrane width in muscle. Thirty-five subjects received glipizide and 18, placebo. At baseline, no statistically significant difference was found in the muscle capillary basement membrane width between the two groups (P = NS). In the subjects receiving placebo, the mean width of the muscle capillary basement membrane increased (P = NS), but in those receiving glipizide, the mean decreased from 193 +/- 13 nm (SEM) to 161 +/- 10 nm (P = .02). Fasting plasma glucose and glycosylated hemoglobin A1 significantly decreased (P less than .001) after two years in those receiving glipizide. In 15 subjects, mean glycosylated hemoglobin A1 reached the normal range, and mean muscle capillary basement membrane width decreased to a level close to that found in subjects without diabetes (P = NS). Determinations of enzyme activities involved in the synthesis and degradation of glycoproteins revealed a 2-year significant decrease of muscle glucosyltransferase (synthesis) activity (P less than .01) in the glipizide-treated subjects as opposed to a significant increase (P less than .001) in those receiving placebo. Muscle N-acetyl-beta-glucosaminidase activity (degradation) was statistically increased (P less than .001) in those subjects taking glipizide, but decreased in those taking placebo (P less than .001).

Pre- and postnatal distribution of lipids in the liver of genetic diabetic mice

Triglycerides, phospholipids, cholesterol and cholesterol esters were determined by thin layer chromatography in the fetal and neonate livers of normal (Swiss albino) and genetic diabetic (KK) mice. In general, the lipids were elevated in the fetal liver of the KK mice. Despite this elevation in liver lipids, no increase in the weight of the newborn was observed.

Diabetic microangiopathy in KK mice: IV. Effect of pyridinolcarbamate on kidney glucosyltransferase activity and glomerulosclerosis

Abstract KK mice with genetic diabetic glomerulosclerosis were treated either with saline or 250 mg/kg of pyridinolcarbamate (PDC), an anti-atherosclerotic agent, from 2 months of age. Both groups of mice were sacrificed at 4 and 6 months of age and their kidneys were used for the determination of glucosyltransferase activity and for light microscopic studies. No effect of PDC on enzyme activity was found in mice treated for 2 months (age of mice was 4 months). However, in mice treated with PDC for 4 months (age of mice was 6 months), the glucosyltransferase activity was significantly increased. PDC delayed the progression of glomerulosclerosis from mild to the severe form after 2 and 4 months of treatment, resulting in only 31 and 16% of mild glomerulosclerosis, respectively. The data suggest that chronic treatment of PDC delays or even prevents the progression of the severe form of genetic diabetic glomerulosclerosis in KK mice. The differential response of glucosyltransferase activity to PDC treatment in KK mice with varying degrees of glomerulosclerosis suggests a relationship between this enzyme activity and glycoprotein synthesis in kidneys of these mice.