# Integrated Systems Biology Approach to Diabetic Microvascular Complications

> **NIH NIH R24** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $1,364,409

## Abstract

ABSTRACT
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.

## Key facts

- **NIH application ID:** 9990761
- **Project number:** 5R24DK082841-11
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Steven F Abcouwer
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,364,409
- **Award type:** 5
- **Project period:** 2008-09-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990761

## Citation

> US National Institutes of Health, RePORTER application 9990761, Integrated Systems Biology Approach to Diabetic Microvascular Complications (5R24DK082841-11). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9990761. Licensed CC0.

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