The Diabetes Complications Group is a multidisciplinary consortium of research scientists, clinicians, health professionals, and technicians dedicated to the elucidation of disease mechanisms as they relate to the complications of diabetes. The Group's goal is to translate the understanding of disease mechanisms (i.e., neuropathy, retinopathy, and nephropathy) into novel preventative and curative treatments for diabetic complications.
The Group currently includes seven projects conducted by six principal investigators, supported by an R24 Collaborative Research Grant from the National Institutes of Health for a total award of nearly $7 million. Each project is focused on a different aspect of diabetic complications.
There are three Research Cores: Morphology, Molecular Biochemistry, and Oxidative Stress, which provide services to the investigators in order to extend their research efforts. These services include planning, executing, and collecting data for animal experiments; providing cell culture services; and performing oxidative stress measurements in tissues and cells.
The aims of the research are three-fold: (1) To define the molecular responses to individual treatments or disease progression in humans with diabetic nephropathy (DN) and diabetic polyneuropathy (DPN) and to explore these responses in intervention studies of murine DN and DPN. (2) To identify protein and metabolite products in human and murine DN and DPN predicted by molecular responses in aim 1 and targeted oxidative stress responses. (3) To validate, in plasma and urine samples, the predicted changes in protein and small molecule levels or activities in the critical functional pathways identified in the first two aims and develop biomarkers for human DN and DPN.
Experimental approaches to improve the understanding and treatment of major diabetic complications have focused on single mechanisms or pathways and resulted in the identification of specific mechanisms that drive diabetic damage. With the recent emergence of genome-wide profiling capabilities and comprehensive data integration strategies, biomedical research is at a point where it can move toward a more holistic view of tissue responses to complex chronic diseases. This is of particular relevance to diabetic end-organ damage, since multiple mechanisms converge to slowly alter the cellular milieu in target tissues in diabetes, mandating the integration of separate pathways to elucidate the complex pattern of responses in the treatment or prevention of diabetic complications.
Indeed, therapies that have worked best to prevent progression of diabetic nephropathy (DN) and polyneuropathy (DPN) affect multiple pathways and mechanisms, whereas those that target a single, “critical” pathway have often yielded disappointing results. The Center’s team of scientists is using a systems biology approach to: (1) efficiently identify the essential cellular responses that lead to DN and DPN, (2) identify those responses that are most amenable to conventional and novel therapies, and (3) discover biomarkers for the critical cellular alterations that lead to complications and respond to effective therapies. Their strategy relies on information-rich sequential and reciprocal transcriptomic, protein and metabolite comparisons between humans with DN and DPN and the best extant murine models of these complications.
The hypothesis of the researchers is that a complex network of responses, including but not limited to those altered by oxidant stress, leads to the onset and progression of diabetic microvascular complications. These critical responses will be identified by performing genome-wide RNA and metabolite profiles from kidney and nerve of humans with DN and DPN. The expression data sets of human end-organ damage from untreated and treated animals will be compared to data sets obtained from kidney and nerve from murine models with DN and DPN. Three different treatment paradigms known to ameliorate DN and DPN will be used as independent tools in the mouse models to identify new critical responses that lead to complications and are responsible for effective treatment in humans. This reciprocal cross-species approach will identify candidate pathways and molecules whose regulation alters disease progression. Finally, we will return to the murine models of DN and DPN to discover new biomarkers that will be useful in the diagnosis and therapeutic management of human DN and DPN.
University of Michigan (U-M) Resources
- Michigan Diabetes Research and Training Center
- U-M Clinical Research Studies
- U-M Comprehensive Diabetes Center
- U-M Neuropathy Center
- American Association of Clinical Endocrinologists Clinical Practice Guidelines for the Management of Diabetes Mellitus
- American Association of Diabetes Educators
- American Dietetic Association
- Canadian Diabetes Association
- Centers for Disease Control and Prevention
- Council for the Advancement of Diabetes Research and Education (CADRE)
- Diabetes at Work
- Diabetes Links (from the National Center for Chronic Disease Prevention and Health Promotion)
- Diabetic Complications Consortium (NIDDK funded)
- Juvenile Diabetes Research Foundation
- National Center for Chronic Disease Prevention and Health Promotion
- National Guideline Clearinghouse
- National Institutes of Health
- Better Diabetes Care
- National Diabetes Education Program
- National Diabetes Information Clearinghouse
- National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)
- NIDDK Frequently Asked Questions
- NIDDK Education Programs
- NIDDK Health Information
- National Kidney Foundation
- National Lipid Education Council
- The Neuropathy Association
- Program for the Understanding of Neurological Diseases