Diabetes mellitus, an increasingly common disease, can cause diabetic nephropathy (DN) and diabetic cardiomyopathy (DCM), leading often to the need for dialysis and kidney transplantation, and to heart failure or stroke. Current knowledge of genes associated with an increased risk for diabetic complications is very limited. Diabetic complications at present are treated by intense glycemic control and management of end organ damages; specific treatment is lacking. Developing and studying mouse models of diabetes that recapitulate the complications seen in the later stages of human diabetes is a powerful approach to enhance our knowledge of genetic risk factors and can contribute to developing preventive and therapeutic measures. During the past grant period we modified several genes expected to affect blood pressure or cardiac/kidney function to obtain a low expressing form of the chosen gene (L) that could be switched to high (H) globally or in a tissue-specific or time-controlled manner with a tamoxifen-inducible Cre. The most serious effects on cardiac/renal function were observed in male mice that were type1diabetic because they had the Akita mutation in the Ins2 gene and had high expression (H/H) of Elmo1, the gene coding for Engulfment and cell motility protein 1. [Associations of SNPs in the ELMO1 gene with DN have been demonstrated in multiple populations.] Accordingly, Specific Aim (i) will focus on increasing our knowledge of the mechanisms that underlie the harmful effects of high Elmo1 expression on DCM and DN, and Specific Aim (ii) will determine the cell types in which Elmo1 high expression acts in enhancing these diabetic complications. Diabetes increases production of the superoxide anion (O2.), a free radical that generates reactive oxygen species (ROS), and the diabetic Elmo1 H/H and Elmo1 H/+ mice have high levels of plasma TBARS (a measure of ROS). Vitamin B12, a normal body constituent generally regarded as safe by the FDA, is a superoxide dismutase mimic, but its potential for inactivating ROS is normally limited because absorption of B12 from the diet is controlled by the small amount of intrinsic factor secreted by the gastric mucosa. However, our preliminary work shows that feeding B12 at high doses enables absorption of the vitamin by an intrinsic- factor-independent pathway that overcomes this limitation; plasma TBARS are normalized, and DCM is no longer seen in young adult Elmo1 H/H diabetic male mice treated with B12. Accordingly, Specific Aim (iii) will optimize the dose of B12 needed to prevent/correct the DCM and DN in Elmo1 H/H diabetic males, compare it with another SOD mimetic (EUK-34) and with tempol, a free radical scavenger, and will determine whether the vitamin affects resistance to microorganisms.
Specific Aim (iv) will determine whether B12 has the same benefits in Elmo1 H/H: Ins2 Akita/+ females, and in db/db Elmo1 H/H mice expected to develop type2 DM.

Public Health Relevance

Diabetes mellitus is an increasingly common disease that can diminish the quality of life and seriously damage many organs, including the kidneys and the heart, leading often to the need for dialysis and kidney transplantation, and to heart disease or stroke. While environmental and genetic factors both play important roles in determining the risk for developing these diabetic complications, our knowledge of which genes are high-risk is limited, and specific treatments are lacking. Our proposed work will study mice that have genetic variations in one gene that is known to be associated with diabetic kidney disease in humans, and will use the resulting information to identify possible new modes of treating or preventing the diabetic complications caused by variations in this gene.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Varagic, Jasmina
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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