The morbidity and mortality of diabetes mellitus occurs largely from its major complications, which include diabetic kidney disease (DKD), diabetic neuropathy (DN) and retinopathy (DR). Although extensive data exist on disease mechanisms in experimental models, the pathogenesis of human diabetic complications remains unclear except that hyperglycemia is a major risk factor for all complications. Our studies have led to an emerging paradigm that while complication prone tissues share similar elements, they are intrinsically distinct in their response to the diabetic state. Thus, the biological effects of the metabolic abnormalities depend on the cellular microenvironment of the target tissue. Moreover, alterations in lipid profiles have emerged from our studies as a potential basis for both biomarkers of complication progression and for mechanistic understanding of the tissue-specific metabolic alterations that lead to these complications. These observations form the basis of the competing renewal that seeks to broaden our understanding of the unique and shared molecular basis of diabetic complications. Our preliminary data demonstrate that changes in renal lipid-related gene expression and plasma lipids predict long-term progression in human DKD after adjustment for HbA1C. Additionally, while diabetic mouse kidney exhibits increased fatty acid oxidation (FAO), the diabetic nerve and retina demonstrate markedly lower FAO, suggesting tissue specific changes in lipid utilization and metabolism. These findings led to our hypothesis that complication prone tissues demonstrate unique alterations in lipid metabolism that cause dysfunction. Our plan is to: 1) identify lipid biomarkers for the critical responses that lead to the onset, progression and response to therapy of DKD, DN and DR; 2) discover the essential cellular lipid metabolism responses that lead to DKD, DN and DR; and 3) from these responses, identify those that are amenable to novel therapies. Our strategy relies on information-rich sequential and reciprocal genetic, transcriptomic, proteomic and lipidomic comparisons between humans with DKD, DN and DR and the best available murine models of these complications. These studies will be pivotal in identifying novel mechanisms and therapeutic targets in diabetic complications.

Public Health Relevance

Three of the most devastating complications of diabetes are kidney disease, nerve disease and eye disease which both substantially enhance morbidity and mortality. The complex and multifactorial causes of these complications remain poorly understood and treatments for them are limited. Moreover, conventional hypothesis-driven approaches to the understanding of these complications have been incomplete. Therefore, we have devised a team approach to use ?systems biology? to study both diabetic humans and mice with these complications and to identify the most important molecular responses that cause kidney, nerve and eye damage. These pathways can be potential targets for novel therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects (R24)
Project #
5R24DK082841-09
Application #
9507817
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Jones, Teresa L Z
Project Start
2008-09-30
Project End
2019-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Callaghan, Brian C; Xia, Rong; Reynolds, Evan et al. (2018) Better diagnostic accuracy of neuropathy in obesity: A new challenge for neurologists. Clin Neurophysiol 129:654-662
Rumora, Amy E; Lentz, Stephen I; Hinder, Lucy M et al. (2018) Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons. FASEB J 32:195-207
Simó, Rafael; Stitt, Alan W; Gardner, Thomas W (2018) Neurodegeneration in diabetic retinopathy: does it really matter? Diabetologia 61:1902-1912
Sas, Kelli M; Lin, Jiahe; Rajendiran, Thekkelnaycke M et al. (2018) Shared and distinct lipid-lipid interactions in plasma and affected tissues in a diabetic mouse model. J Lipid Res 59:173-183
Jadoon, Adil; Mathew, Anna V; Byun, Jaeman et al. (2018) Gut Microbial Product Predicts Cardiovascular Risk in Chronic Kidney Disease Patients. Am J Nephrol 48:269-277
Wernisch, Stefanie; Afshinnia, Farsad; Rajendiran, Thekkelnaycke et al. (2018) Probing the application range and selectivity of a differential mobility spectrometry-mass spectrometry platform for metabolomics. Anal Bioanal Chem 410:2865-2877
Nair, Viji; Komorowsky, Claudiu V; Weil, E Jennifer et al. (2018) A molecular morphometric approach to diabetic kidney disease can link structure to function and outcome. Kidney Int 93:439-449
Afshinnia, Farsad; Rajendiran, Thekkelnaycke M; Soni, Tanu et al. (2018) Impaired ?-Oxidation and Altered Complex Lipid Fatty Acid Partitioning with Advancing CKD. J Am Soc Nephrol 29:295-306
Hinder, Lucy M; Murdock, Benjamin J; Park, Meeyoung et al. (2018) Transcriptional networks of progressive diabetic peripheral neuropathy in the db/db mouse model of type 2 diabetes: An inflammatory story. Exp Neurol 305:33-43
Brosius, Frank C; Ju, Wenjun (2018) The Promise of Systems Biology for Diabetic Kidney Disease. Adv Chronic Kidney Dis 25:202-213

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