Pancreatic Islet Transplantation: Effects on the Glomerular Lesions of Experimental Diabetes in the Rat

Abstract

Diabetes was induced in Lewis rats with streptozotocin. Six to nine months later glomeruli showed significant mesangial matrix thickening; by immunofluorescent microscopy large quantities of IgG, (i\C and in some instances, IgM were seen in a mesangial distribution. Sustained normoglycemia was then achieved in nine of these animals by successful pancreatic islet isotransplantation. Three months following transplantation five of these animals had decreased mesangial matrix while four had no further progression of glomerular lesions. All had a marked decrease in IgG, IgM and |3 iC in the mesangium. In contrast, untreated diabetic rats, over the same time period, demonstrated progressive mesangial thickening and focal tuft sclerosis. Immunoglobulins and complement were in the mesangium in quantities equal to or greater than seen in earlier biopsies. Thus, successful pancreatic islet transplantation in the rat results in regression or arrest of the diabetic glomerular lesion. DIABETES 23:748-53, September, 1974.Rats with chronic experimentally induced diabetes mellitus develop progressive glomerulosclerosis, 1 " 4 which is associated with the deposition of large quantities of immunoglobulin and complement in the glomerular mesangium. 5 The precise role of this deposition in the pathogenesis of the mesangial lesion in these rats is unclear. However, the immunohistochemical alterations may well represent a marker for functional alterations in mesangial activity. With this marker it seemed possible to test the hypothesis that cure of the diabetic state in the rat by pancreatic islet transplantation could lead to reversal of the mesangial pathology.From the These studies were carried out in highly inbred Lewis rats (Microbiological Laboratories) weighing approximately 100 gm. at the start of the experiment. Experimental animals were made diabetic, following an eighteen-hour fast, by the injection of 65 mg. per kilogram of streptozotocin, intravenously and 2 ml. of 30 per cent glucose in water solution, intraperitoneally. Control animals were age-matched littermates. Induction of the diabetic state was confirmed by the development of a persistent, heavy glycosuria by Tes-Tape (Eli Lilly) and blood glucose levels in excess of 400 mg. per 100 ml. Diabetic and control rats were maintained on ad libitum water and Purina rat chow.From six to nine months following the induction of diabetes, each of nine diabetic rats received transplants of pancreatic tissue removed from eighteen to twenty-five newborn Lewis rats at two to seven days of age. 6 Briefly, the pancreases, which at this early age are high in islet tissue and low in acinar tissue and enzyme content, were finely minced and washed in Hank's balanced salt solution without glucose. They were then digested for forty minutes at 37°C. by agitation in 6 ml. of modified Puck's saline A (Gibco) containing 0.5 gm. per liter of trypsin and 0.2 gm. per liter EDTA with 30 mg. of added collagenase and then washed three times in Hank's solution. The recipient diabetic rat's peritone...

Effects of insulin and dietary myoinositol on impaired peripheral motor nerve conduction velocity in acute streptozotocin diabetes.

“…The studies reported above suggest that alterations in plasma free MI resulting from renal disease may have beneficial or adverse effects on the derangements responsible for impaired MNCV, depending upon the resulting range of plasma free MI concentration. Alloxan has the potential of inducing acute renal damage (42), and alterations in renal morphology have been reported in rats with chronic streptozotocin diabetes (43,44). In a prior study, we examined MNCV in rats with chronic streptozotocin diabetes of 14 mo duration maintained at the Merck Research Institute by Drs.…”

Pancreas and islet transplantation

“…The influence of islet transplantation on established renal glomerular lesions has been shown in a series of experiments in diabetic rats by Mauer et al [167,281,289] and Steffes et at. [282,290].…”

“…In rats with streptozotocin or alloxan diabetes there is a progressive increase in mesangial matrix volume [281,282,283] and in basement membrane thickness [282,283,284]. Tubular vacuolisation and hyalinisation of arterioles is present [280,281,283]. Immunoglobulin and other macromolecules are deposited within the mesangium [285].…”

“…Kidneys transplanted from normal rats to diabetic rats develop lesions identical to those occurring in the diabetic recipient's own kidneys; conversely, lesions in diabetic rats kidneys disappeared or failed to progress after transplantation to normal rats [286]. The secondary nature of those lesions has also been inferred by their failure to develop in animals receiving pancreas [284,287] or islet [6,168,281,283,288] transplants soon after the induction of diabetes.…”

“…[282,290]. After islet transplantation to rats with diabetes of more than 6 months duration, light microscopic lesions present at the time of transplantation either failed to progress or their was an actual decrease in mesangial matrix material [281]. Immunoglobulin and complement progressively disappeared as the metabolic abnormalities were corrected [289], while in untreated diabetic rats, the renal lesions continued to progress.…”