Type 1 diabetes (T1DM) alters carbohydrate, amino acid, and fatty acid metabolism contributing to nephropathy, retinopathy and peripheral neuropathy, three of the most debilitating complications of diabetes. The prevailing view suggests that systemic hyperglycemia drives complications by similar biochemical mechanisms in all tissues. However, this has not been specifically tested, especially in vivo. In these studies, we propose that the normal cellular nutrient utilization in cells of complication-prone tissues is distinct and therefore reaction to insulin deficiency, hyperglycemia and other changes of T1DM will also be distinct. Indeed, our preliminary data demonstrate tissue-specific changes in cellular metabolite levels that are not driven by mass-action alone but appear to be due to selective metabolic reprogramming of the target tissues. In contrast to increased levels in kidney, glycolysis and tricarboxylic acid cycle (TCA) cycle intermediates are decreased in diabetic mouse nerve and retina despite ambient hyperglycemia. Importantly, the increased mouse kidney and human urinary levels of TCA metabolites predict progression of diabetic nephropathy, suggesting that metabolic reprogramming may play a pathogenic role in the progression of complications. These findings lead to our hypothesis that diabetic complications arise from tissue-specific metabolic reprogramming resulting in alterations in fuel utilization which lead to dysfunction of the tissue. To test this hypothesis, we will use sensitive and specific mass spectrometer based metabolomic analysis in models of diabetes to define changes in metabolite levels and flux in three complications-prone tissues, retina, kidney and peripheral nerves. We will extend these studies to humans with T1DM to understand intrinsic differences from non-diabetics in metabolite levels and flux in the kidney. We will define the changes in mRNA and protein expression and post-translational protein modification to determine the basis for altered metabolite levels. Finally, we will utilize appropriately engineered mouse animals to directly test the refined hypotheses arising from these studies.
Our specific aims are to:
Aim 1 : Identify the alterations in steady state abnormalities of intermediary metabolism in kidney, nerve and retina in the best murine models of diabetic complications using state-of-the-art metabolomic approaches Aim 2: Determine metabolite flux in all 3 tissues from the murine models and identify the key regulatory reactions that contribute to the metabolite abnormalities.
Aim 3 : Assess steady state and dynamic metabolite changes in humans with type 1 diabetes with and without microvascular complications.
Aim 4 : Define regulatory mechanisms of altered cellular metabolism in complication-prone tissues and test their effect in murine models.

Public Health Relevance

This proposal will test the hypothesis that diabetic complications arise from specific changes in cellular substrate metabolism which can be defined using modern molecular phenotyping techniques in both animal models and in humans and that interventions to modulate specific metabolic pathways may mitigate or prevent development and progression of these complications. Our study is designed to gain a better understanding of the changes in metabolite levels and flux in complications-prone tissues in animal models and patients with type 1 diabetes mellitus and to determine how the metabolite changes reflect altered levels or activities of specific proteins and lipids which contribute to 'microvascular'complications. We will utilize in vivo and in vitro analysis of mouse models and human patients to achieve these goals.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type 1 Diabetes Targeted Research Award (DP3)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-J (O1))
Program Officer
Castle, Arthur
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
Zip Code
Dinov, Ivo D; Palanimalai, Selvam; Khare, Ashwini et al. (2018) Randomization-Based Statistical Inference: A Resampling and Simulation Infrastructure. Teach Stat 40:64-73
Brosius, Frank C; Ju, Wenjun (2018) The Promise of Systems Biology for Diabetic Kidney Disease. Adv Chronic Kidney Dis 25:202-213
Hinder, Lucy M; Park, Meeyoung; Rumora, Amy E et al. (2017) Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in diabetic nerve and kidney disease. J Cell Mol Med 21:2140-2152
Scerbo, Diego; Son, Ni-Huiping; Sirwi, Alaa et al. (2017) Kidney triglyceride accumulation in the fasted mouse is dependent upon serum free fatty acids. J Lipid Res 58:1132-1142
Wang, Sophia Y; Andrews, Chris A; Herman, William H et al. (2017) Incidence and Risk Factors for Developing Diabetic Retinopathy among Youths with Type 1 or Type 2 Diabetes throughout the United States. Ophthalmology 124:424-430
Hinder, Lucy M; O'Brien, Phillipe D; Hayes, John M et al. (2017) Dietary reversal of neuropathy in a murine model of prediabetes and metabolic syndrome. Dis Model Mech 10:717-725
Feldman, Eva L; Nave, Klaus-Armin; Jensen, Troels S et al. (2017) New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain. Neuron 93:1296-1313
Wang, Sophia Y; Andrews, Chris A; Gardner, Thomas W et al. (2017) Ophthalmic Screening Patterns Among Youths With Diabetes Enrolled in a Large US Managed Care Network. JAMA Ophthalmol 135:432-438
Gardner, Thomas W; Davila, Jose R (2017) The neurovascular unit and the pathophysiologic basis of diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 255:1-6
O'Brien, Phillipe D; Hinder, Lucy M; Parlee, Sebastian D et al. (2017) Dual CCR2/CCR5 antagonist treatment attenuates adipose inflammation, but not microvascular complications in ob/ob mice. Diabetes Obes Metab 19:1468-1472

Showing the most recent 10 out of 68 publications