Werner Oppermann

Glomerular lesions in a strain of genetically diabetic mice.

Summary In a strain of genetically determined, spontaneously diabetic mice (KK mice) lesions similar to those seen in human diabetic nephropathy were found in the glomeruli. These lesions increased with age and consisted of diffuse and nodular mesangial changes, exudative lesions, and alterations of the basement membranes.

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.

A sensitive micromethod for the simultaneous determination of insulin and growth hormone by double antibody precipitation

Summary 1. A sensitive and relatively simple micro-radioimmunoassay is described, by which immunoreactive insulin and growth hormone can be measured simultaneously in a volume of only 0.025 ml of serum, allowing the determination of concentrations as low as 2.5 uU/ml for insulin and 0.5 mμg/ml for growth hormone. 2. The assay offers a precision (coefficient of variation 8–12 per cent), comparable to the macromethods, which measure the two hormones separately. 3. This method requires a relatively short incubation time and allows the processing of large numbers of samples with reduced and consequently less expensive reagent volumes. 4. It also provides the possibility of measuring two hormones simultaneously in newborn infants and small laboratory animals, where sample size is very limited.

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.

Related Factors in the Progression of Microangiopathy in KK Mice

Publisher Summary This chapter discusses certain findings based on studies of 130 KK and 64 S1 mice equally distributed according to age and sex. To identify the glomerular lesions more precisely, a temporary histological working classification was employed. The chapter illustrates an incidence of significant glomerular lesions among KK and control mice of both sexes. The diabetic syndrome in KK mice is not only associated with a higher incidence of glomerulosclerosis at an early age but it also accelerates the development of kidney pathology. There is no correlation between the degree of impairment in tolerance to glucose and the incidence of severe glomerulopathy when the glucose area levels throughout life are employed for evaluation of the degree of glucose dysmetabolism in KK mice. Correlative studies of severe glomerulopathy and degree of intolerance to glucose, based on 2 SD, gave similar negative results.

Early Diabetes During Pregnancy

What criteria should be applied to screen for diabetes in pregnancy? What diagnostic criteria should then be used for the diagnosis of diabetes? What parameters will allow us to evaluate the validity of the approach selected? In an attempt to answer these questions, 472 pregnant women with high risk for diabetes (of the 6741 deliveries in the 2 yr of the study period) were followed in specialized medical-obstetrical clinics. Only women with adequate clinical data and a precise definition of their diabetic status were included.

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.

Ultrastructure of glomerular lesions in KK mice.

Publisher Summary This chapter discusses the ultrastructure of glomerular lesions in KK mice. In an experiment described in the chapter, electron microscope examinations were made in 20 KK mice and 18 controls from a group of 320 KK and 180 control mice. All animals were maintained on an 11 % fat diet under standard laboratory conditions. Electron microscopy revealed an increase in mesangial cells and matrix which in the early phases and in young animals did not result in widening of the mesangial space. It was found that with increase in mesangium, the mesangial space may be markedly widened. Usually, the mesangial accumulation is accompanied by cells; however, in a few instances, there are small, dense accumulations of mesangial matrix without mesangial cells. As the mesangium proliferates, it grows into the capillary wall and tends to be get inserted between the basement membrane and the endothelium. In advanced cases, the capillary lumen may be partly occluded by the mass of mesangium. Collagen fibrils are found in the mesangial matrix in some instances. Electron-dense deposits are also seen in the mesangial matrix, beneath the capillary endothelium, in the basement membrane, and occasionally partly occluding the capillary lumen.

Deterioration of tolerance to glucose and progression of the microangiopathy: effect of treatment (preliminary report).

Publisher Summary This chapter describes a study in which muscle biopsies were performed in 96 subjects divided into five groups. Twenty-five were normal control subjects with normal tolerance to glucose and no family history of diabetes. Thirty-two were prediabetics with normal tolerance to glucose and family histories ranging from both parents to only one relative having overt diabetes. It was found that when the mean basement membrane width (BMW) of the 25 normal control subjects was compared with the mean BMW of the 32 genetic prediabetics, no difference was found between the two groups. This also applied when sexes were compared. When prediabetics were matched with normal control subjects according to age, six prediabetics were found to have BMWs above 2 SD of the mean for the control group of the same age. Two had glucose areas above the mean + 1 SD of control subjects, and two had elevated insulin areas. When regression analyses were made of the data from the prediabetic and chemical diabetic groups, no significant correlation was found between BMW and glucose values.

A new concept for the evaluation of the blood glucose and insulin responses of healthy subjects following an oral glucose load

SummaryOral glucose tolerance was performed in healthy volunteers. The patterns of the blood sugar and the plasma insulin following the glucose ingestion were subjected to a critical biostatistical analysis. The evaluation of the data prompted us to establish a new criterion for ‘normal response’, which is based upon the % increment in the blood sugar above the fasting level. The employment of that concept and method revealed that three different kinds of responses can be detected within a control group, and point toward the existence of an unnoticed segment of the healthy population which possesses an underlying disorder in its metabolic behavior.