The Diabetes Control and Complications Trial (DCCT) clearly demonstrated that tight glycemic control profoundly reduces the progression of vascular complications in patients with type 1 diabetes (T1D). In the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) observational study, both the conventional (CONV) and intensive treatment (INT) DCCT groups were shifted to INT. Surprisingly, the former CONV group continue to develop micro- and macrovascular complications at significantly greater rates than the previous INT group. This concept, called metabolic memory, has been a major enigma in the field of T1D. Recent evidence suggests that epigenetic factors like chromatin histone modifications (PTMs) regulate genes associated with diabetic complications and metabolic memory. However, the role of epigenetic marks like DNA methylation (DNA-me) in human T1D complications progression and metabolic memory is not clear and we propose to address this major gap in knowledge in the current proposal. Based on our recently published data showing alterations in key histone PTMs in sixty patients from the EDIC cohort, as well as new preliminary DNA-me data, our objective is to now explore DNA-me associated mechanisms underlying diabetes complications progression using valuable archived genomic DNA from a bigger cohort of DCCT patients. These samples will be obtained in collaboration with EDIC from their Central Biochemistry laboratory where genomic DNA has been archived from nearly all the DCCT participants at DCCT closeout (1991-1993). In addition, data already generated from our recent study with EDIC cohort patients will also be used for integration with new data generated in this proposal.
Four Specific Aims will be evaluated to test the Central Hypothesis that persistent epigenetic changes (DNA-me and histone PTMs) induced by hyperglycemia at key susceptible genome regions during the DCCT can lead to a metabolic memory of the more persistent complications noted during EDIC in the DCCT CONV cohort that was shifted from CONV to INT therapy. The results of these investigations can help establish firmer associations between epigenetics, complications progression and potentially human metabolic memory. This proposal is both timely and significant because human epigenomics is at the forefront of medical research and yet, not much is known in the field of human diabetic complications. These investigations, which use only archived material, can make a significant impact by advancing our understanding of key epigenetic mechanisms underlying the progression of T1D complications despite glycemic control. This, in turn, could determine whether improved early glycemic control can prevent hyperglycemia induced epigenetic changes, and thus lead to newer and more effective therapeutic interventions. Together, these innovative studies address a key scientific gap and clinical need in the field of T1D and its complications that are in line wth the goals of this NIDDK DP3 initiative.
We propose to perform studies with stored biosamples from patients with type 1 diabetes experiencing accelerated complications and metabolic memory to uncover novel epigenetic mechanisms triggered by early hyperglycemia that may be associated with these pathologies. The completed studies could lead to the identification of much needed new biomarkers and more effective therapies for the debilitating complications of type 1 diabetes.
|Leung, Amy; Amaram, Vishnu; Natarajan, Rama (2018) Linking diabetic vascular complications with LncRNAs. Vascul Pharmacol :|
|Reddy, Marpadga A; Das, Sadhan; Zhuo, Chen et al. (2016) Regulation of Vascular Smooth Muscle Cell Dysfunction Under Diabetic Conditions by miR-504. Arterioscler Thromb Vasc Biol 36:864-73|
|Kato, Mitsuo; Wang, Mei; Chen, Zhuo et al. (2016) An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy. Nat Commun 7:12864|
|Grassi, Michael A; Rao, Vidhya R; Chen, Siquan et al. (2016) Lymphoblastoid Cell Lines as a Tool to Study Inter-Individual Differences in the Response to Glucose. PLoS One 11:e0160504|
|Chen, Zhuo; Miao, Feng; Paterson, Andrew D et al. (2016) Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort. Proc Natl Acad Sci U S A 113:E3002-11|
|Yuan, Hang; Reddy, Marpadga A; Deshpande, Supriya et al. (2016) Epigenetic Histone Modifications Involved in Profibrotic Gene Regulation by 12/15-Lipoxygenase and Its Oxidized Lipid Products in Diabetic Nephropathy. Antioxid Redox Signal 24:361-75|
|Reddy, Marpadga A; Natarajan, Rama (2015) Recent developments in epigenetics of acute and chronic kidney diseases. Kidney Int 88:250-61|
|Caramori, M Luiza; Kim, Youngki; Natarajan, Rama et al. (2015) Differential Response to High Glucose in Skin Fibroblasts of Monozygotic Twins Discordant for Type 1 Diabetes. J Clin Endocrinol Metab 100:E883-9|
|Schones, Dustin E; Leung, Amy; Natarajan, Rama (2015) Chromatin Modifications Associated With Diabetes and Obesity. Arterioscler Thromb Vasc Biol 35:1557-61|
|Kato, Mitsuo; Natarajan, Rama (2014) Diabetic nephropathy--emerging epigenetic mechanisms. Nat Rev Nephrol 10:517-30|