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This work was to study--using morphometric methods--whether glomerular alterations are demonstrable in the guinea pig kidney even in streptozotocin diabetes of only short duration. In 25, 50, 100 and 150-days diabetes was investigated the blood sugar, the glucose tolerance test, histological and morphometric studies. Storage of glycogen in the kidney was to be found in numerous treated animals whereby it was evident that the cells of the macula densa showed no storage. The morphometric studies performed under blind conditions have shown that with a duration of diabetes of 50 and 100 days the number of cells in the mesangium is increased and that an increase of the mesangial matrix is demonstrable. Hence the mesangium is in the foreground of the initial alterations in diabetes mellitus.

Weak nonspecific immunological stimuli can irritate the glomerular mesangium as observed following administration of insulin preparations of varying degrees of purity. In the present study further substances were investigated with regard to this effect. We wished to examine which substances obtained during purification of insulin are mainly responsible for the antigenicity, and whether porcine and bovine MC insulin have the same antigenic properties. Rabbits were treated for up to 90 days with bovine MC insulin, bovine proinsulin, bovine a + b-component, porcine a-component and porcine b-component. The kidneys were analysed morphometrically and antibody titers to bovine insulin, a-component, porcine PP and proinsulin were determined in the various test groups. It was found that bovine MC insulin and porcine MC insulin possess the same immunological activity, i.e. no antibody formation to either of the two insulins was demonstrable. Similarly, there were no differences in the morphometric findings; slight transient mesangial changes were demonstrable after both insulins. However a-component and b-component showed a pronounced immunogenic potency with antibody formation. Marked and partly persisting mesangial alterations were demonstrable, with the antigenicity of the a-component being particularly marked. The implication of the study is that a "pure" or optimally purified insulin should be used in the therapy of diabetes mellitus.

Immunohistological study of 123 kidney biopsies of non-glomerulonephritic kidney diseases showed that deposits of immunoglobulins are found more often in cases of malignant than in cases of benign nephrosclerosis. Primary malignant nephrosclerosis is mostly associated with glomerular deposits of immunoglobulins. Positive immunohistological findings are frequent in cases of diabetic glomerulosclerosis, mainly within glomeruli, but also in tubular basement membranes and Bowman's capsule. In cases of glomerular amyloidosis we see cloudy-bandlike deposits, but are unable to differentiate cases with or without the nephrotic syndrome. If we consider an immunopathogenetic mechanism for the diseases discussed in terms of the present findings, it seems possible for primary malignant nephrosclerosis as well as for certain glomerular changes associated with acute renal failure or rejection of transplants. In diabetic glomerulosclerosis (apart from special forms with perimembranous lesions) and glomerular amyloidosis, we consider such a mechanism to be unlikely. By separating the non-glomerulonephritic diseases into different types of deposits we found pictures that correspond with immunocomplex diseases. Pictures resembling anti-basement membrane diseases have not been seen. Characteristic patterns of deposits were not found, thus immunohistology is without additional diagnostic value in the field of non-glomerulonephritis disease.

Thirty rabbits were immunized with MC insulin and high-molecular impurities of commercial insulin preparations (a+b component) over 30, 60 and 90 days. The serum insulin antibody titer was determined in animals as the insulin binding capacity. Further, a quantitative morphological analysis of the various types of glomerular cells and of the mesangium was performed on the glomeruli as a blind study. Significant mesangial cell proliferation and an increase in mesangial matrix were found on treatment with the a+b component whereas the animals treated with MC insulin exhibited only a transient and slight mesangial activation after 30 days. There was a positive correlation between the magnitude of the insulin binding capacity and the mesangial activation. Hence, the glomerular changes which are observed after treatment with insulin which is not highly purified must be attributed to the high treatment with insulin which is not highly purified must be attributed to the high molecular weight contaminants. Heterologous pure insulin must be regarded as having virtually no immunological effect.

To investigate whether glomerulosclerotic changes can be transmitted by spleen cells, two-month-old diabetic KK-mice received a spleen homogenate transplanted subcutaneously. the donors were two-year-old diabetic KK-mice. Control animals received physiological saline. Kidneys and pancreas were removed four or ten months after the transplantation. Apart from histological and partly immunohistological studies the kidneys (glomeruli) were also evaluated morphometrically on a blind basis. Blood sugar levels were determined together with serum insulin concentrations in some animals. Marked widening of the mesangium and an increase in mesangial cells was found in the transplanted animals four months after the transplantation when compared with the control animals, a finding that was confirmed by morphometric studies. All transplanted animals exhibited a lymphoplasmocytic periductulitis and some showed insulitis in the pancreas. Degranulation of beta-cells was observed in some animals. Serum insulin was significantly reduced one month after the transplantation and blood sugar levels in the transplanted animals were continuously higher after three month than the values in the control animals. The investigations show that transplantation of spleen cells induces progression of diabetic glomerulosclerotic renal alterations and also causes periductulitis and in isolated cases insulitis.

Glomerular changes develop in rats with streptozotocin diabetes. The structure of these lesions (nodular and diffuse glomerulosclerosis, mesangial cell proliferation, basement membrane thickening, glomerular aneurysms, fibrinoid caps, glomerular adhesions) is described in the present paper and the effect of normalization of metabolism by islet transplantation on the glomerular changes is studied with histological, immunohistological and morphometric methods. Isogenous islets were transplanted into the portal vein of streptozotocin-diabetic rats after diabetes of 7 months' duration. The kidneys of normal, diabetic and transplanted animals of the same age were studied 2.5 months later. Studies of the kinetics of immunocomplexes in the mesangium were also performed. The renal changes (glomerulosclerosis, mesangial cell proliferation) were largely reversible after islet transplantation and the blood glucose level and glucose tolerance were normalized. In the diabetic animals the delayed uptake and elimination of immunocomplexes in the mesangium was normalized after the transplantation. It is possible, that the cause of the lesions is a functional disturbance of the mesangium induced by insulin deficiency and/or hyperglycaemia.