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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Healthy Body Weight Research » Research » Publications at this Location » Publication #64916


item CARLSON, E. - UND
item AUDETTE, J. - UND
item Klevay, Leslie
item NGUYEN, H. - UND
item EPSTEIN, P. - UND

Submitted to: Acta Diabetologia
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/30/1996
Publication Date: N/A
Citation: N/A

Interpretive Summary: Although treatment of diabetes mellitus with insulin can prevent or eliminate many of the short-term complications of this relatively common illness, over the long-term, death may occur because of kidney failure even with the best of treatment. One third of all renal dialysis patients are diabetic. This study addressed the mechanism by which kidneys fail in diabetes mellitus. A special strain of mouse with a hereditary defect of the pancreas was used to study the development of kidney damage. These mice became diabetic quite early in life. The mice were found to have low serum insulin and very high blood sugar proving that they were, in fact, diabetic. Anatomical changes in the kidney were preceded by increases in some specific nitrogenous compounds in blood. These compounds have been used to evaluate treatment of the human illness. Although the mice had a large increase in urine volume (which often is among the first signs of human illness), they did not have much protein in urine. This study demonstrates the utility of using this type of mouse in the study of mechanisms of human illness and represents a new method of research.

Technical Abstract: Previous animal models of diabetic nephropathy have utilized diabetic animals for which the underlying defect was uncertain or the diabetes was induced by potentially nonspecific toxins. In this report we describe the renal abnormalities in a transgenic mouse model which develops early onset diabetes due to overexpression of calmodulin in pancreatic beta cells. Functional renal impairment was apparent at about 80 days of age, as indicated by significant elevations in serum creatinine and blood urea nitrogen. Neither of these serum parameters deteriorated with age. Morphometric analysis revealed an age-related increase in glomerular basement membrane thickness in controls and a 22% increase in transgenic diabetics over controls at 112 days of age that developed to increases of 43% and 37% at 182 and 300 days respectively. Mesangial matrix volume was also markedly increased in the transgenics. Surprisingly, even in the oldest diabetic mice there was no reduction in glomerular basement membrane anionic sites. Despite an eight fold increase in urine volume these mice did not become proteinuric. These results indicate that proteinuria of diabetes may be delayed or prevented by maintenance of a normal complement of glomerular basement membrane anionic sites. They also demonstrate that transgenic mice can provide a valuable model for discriminating between different aspects of diabetic nephropathy.