Diabetic neuropathy (DN) is a painful and debilitating condition that affects 50% of people with diabetes. Despite its high prevalence, the precise biological mechanisms of DN are not known and no disease arresting treatment is currently available. There is therefore a critical need for the identification of therapeutic targets and preventative strategies for DN. Recent data show that sphingolipid metabolism is altered in type 2 diabetes (T2D), resulting in the accumulation of atypical, neurotoxic deoxysphingolipids (dSLs). dSLs are known to increase in the setting of low levels of the amino acid L-serine and high levels of L-alanine, but the cause of dSL accumulation in diabetes is not known. Importantly, oral supplementation with the amino acid L-serine suppresses formation of dSLs and improves neuropathy in animal models of DN, suggesting that dSLs could play a role in DN. The proposed study aims to define the specific dSL molecules that are most closely associated with DN and evaluate the contribution of altered L-alanine to L-serine ratios to dSL accumulation in T2D. Defining the specific molecules in the dSL pathway that are most closely associated with DN and understanding the cause for their formation could lead to the development of targeted therapeutic interventions for the disease. Advanced mass spectrometry techniques have been used to demonstrate elevations in select dSLs (1- deoxydihyroceramides) in a small cohort of adults with morbid obesity, T2D and DN. Results showed that 1) L- serine levels were lower and L-alanine levels higher in subjects with DN as compared to controls; and 2) that increased L-alanine to L-serine ratios correlated positively with dSLs and with DN severity.
In Aim 1 of the proposed studies, the same state of the art techniques will be used to examine detailed dSL profiles and amino acid levels cross-sectionally and longitudinally in the Treatment Options for T2D in Adolescents and Youth (TODAY) cohort. These studies will examine whether L-alanine to L-serine ratios are associated with dSL accumulation in youth onset T2D in a cross sectional comparison (Aim 1a); and test whether elevations in L-alanine to L-serine ratios and dSLs are associated with an increased odds of developing DN using a retrospective case-control study design (Aim 1b).
In Aim 2, correlations between dSLs and L-alanine to L-serine ratios to DN severity will be examined in an adult T2D cohort (without the confounder of morbid obesity) at the University of Colorado using validated DN measures including nerve fiber density on skin biopsy. The K23 grant will allow the candidate to pursue training in 1) clinical outcome measures specific to DN, 2) epidemiologic principles and statistical methods, and 3) fundamentals of lipid biology and mass spectrometry. The mentorship and advising of Drs. Jane Reusch, Robert Murphy, Bryan Bergman, Eva Feldman, and Leslie Lange, whose expertise spans endocrinology, DN, epidemiology and lipid biology, is ideally suited for this project. The University of Colorado Denver offers the optimal environment for this work, with a leading clinical research program in T2D, and extensive infrastructure for supporting junior investigators.

Public Health Relevance

Diabetic neuropathy is a painful and debilitating condition that affects 50% of patients with diabetes, and for which limited effective treatments are available. There is increasing evidence that atypical sphingolipids may be contributing to the development of diabetic neuropathy, and that treatment with the amino acid L-serine may reduce the levels of these toxic lipids. The goal of the proposed studies is to determine which sphingolipid molecules are most relevant to diabetic neuropathy and could serve as potential treatment targets for this debilitating and currently untreatable diabetic complication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23DK118202-01A1
Application #
9974766
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Jones, Teresa L Z
Project Start
2020-08-15
Project End
2025-05-31
Budget Start
2020-08-15
Budget End
2021-05-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Neurology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045