Microneedle-Based LC-MS/MS Profiling of Dermal Interstitial Fluid Reveals Early Lipid Dysregulation Contributing to Painful Neuropathy in Prediabetic and Type 2 Diabetic Rats

Author

Srinivasa Rao GadamFollow

Publication Date

7-29-2025

Abstract

Painful diabetic neuropathy (PDN), a complication of type 1 and type 2 diabetes, also occurs in obesity and prediabetes, with dyslipidemia as a modifiable risk factor. The distal-to-proximal neuropathy pattern and length-dependent intraepidermal nerve fiber loss suggest peripheral contributions. We hypothesized that elevated neurotoxic lipid intermediates—diacylglycerols (DAG), free fatty acids (FFA), and acylcarnitines (CARs)—in the dermal interstitial fluid (ISF) drive metabolism-associated hyperalgesia in prediabetic and diabetic rats. Using a microneedle array (MIA) with LC-MS/MS, we profiled ISF and serum lipids from high-fat diet (HFD) and HFD + streptozotocin (STZ) rat models alongside Hargreaves testing. ISF lipid changes appeared earlier (weeks 1–4) than serum dyslipidemia (after 10 weeks) and correlated strongly with serum lipids. Elevated ISF triacylglycerols, DAG, CARs, sphingomyelins, phosphatidylcholine, lysophosphatidylcholine, and lysophosphatidylethanolamine negatively correlated with paw withdrawal latency (r = –0.92, P < 0.05). Dermal interstitial dyslipidemia precedes and may contribute to the onset of PDN.

Keywords

Painful diabetic neuropathy, dyslipidemia, microneedle array, interstitial fluid, triacylglycerols, diacylglycerols, acylcarnitines, sphingomyelins, phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine, dermal interstitial dyslipidemia, Hargreaves method, paw withdrawal latency, distal symmetric polyneuropathy

Sponsors

The CTSC infrastructure Grant Number: UL1TR001449 (J.T.B. and R.M.T.), the KL2 fellowship Grant Number: KL2TR001448 (J.T.B. and R.M.T.), and the NIH R03DS031724 project grant (A.B., J.T.B., R.M.T., and Y.Z.) and the Baca Laboratory

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Justin T. Baca

Second Committee Member

Erin D. Milligan

Third Committee Member

Karin W. High

Fourth Committee Member

Amy D. Gardiner

Fifth Committee Member

Matthew J. Campen

Recommended Citation

Gadam, Srinivasa Rao. "Microneedle-Based LC-MS/MS Profiling of Dermal Interstitial Fluid Reveals Early Lipid Dysregulation Contributing to Painful Neuropathy in Prediabetic and Type 2 Diabetic Rats." (2025). https://digitalrepository.unm.edu/biom_etds/284