Researchers uncover connection between two common diabetes drugs with implications for foot ulcer healing

By Pooja Toshniwal PahariaReviewed by Danielle Ellis, B.Sc.Sep 9 2024

Patients who take both insulin injections and oral metformin have significantly increased amounts of metformin found in wounds 

A recent ACS Pharmacology & Translational Science study examined the biogenic amines and small-molecule metabolites in diabetic foot ulcer (DFU) wound exudates to identify their potential roles in wound healing.

Background

DFUs refer to an adverse diabetic complication. They prolong hospitalizations and cause amputations that hinder routine activities. They are a major challenge in wound care due to their chronic nature, impaired healing processes, and slow recovery. Despite advancements in wound management, DFUs often do not heal.

Understanding the underlying processes is crucial for developing effective therapeutic strategies. Analyzing metabolites in DFU exudates can provide valuable insights into molecular pathways that enhance or inhibit wound healing. Profiling the metabolites could provide insights into the local wound environment and find biomarkers for therapy.

About the study

The present study’s researchers comprehensively analyzed the metabolic composition of diabetic food ulcer exudates. Researchers explored the contribution of small molecules and biogenic amines to wound repair. They also evaluated the effects of medications on the metabolic profiles of diabetic foot ulcer exudates.

Researchers collected wound fluid samples from 25 diabetic patients. Study participants, aged 18 to 80, suffered from insulin-dependent or insulin-independent diabetes mellitus. They had moderately draining foot ulcers below the malleolus, which standard treatment did not heal. They excluded individuals with active sepsis from infected foot ulcers and those undergoing treatment with hyperbaric oxygen, topical enzymatic wound debriding agents, tissue, or cellular products.

Data extraction included age, sex, body mass index (BMI), smoking habits, glycated hemoglobin (HbA1c), antidiabetic drug use, inflammatory biomarkers, cardiovascular disease, corticosteroid usage, and abnormal immune or thyroid function. Ultrahigh-pressure liquid chromatography (HILIC) quadrupole time-of-flight tandem mass spectrometry (QTOF-MS) with electrospray ionization (ESI) analyzed the samples. Researchers annotated raw data using the mzRT and the National Institute of Standards and Technology (NIST) libraries.

Data quantification parameters included the specific mass-to-charge (mz) values and retention times (rt). The team normalized peak heights to the summation value for the internal standards (iTIC) to control for instrument sensitivity deviations that arise due to machine maintenance, tuning, and aging. To determine a molecule’s relative abundance, they divided its peak height by the total peak height of all molecules detected in every exudate and multiplied this number by 100. They used one-way analysis of variance (ANOVA) and Tukey tests for further analyses.

Results and discussion

The researchers detected 721 metabolites, including 402 verified using the Metabolomics Standards Initiative (MSI) criteria. They recognized 16 small-molecule metabolites that significantly contributed to the wound exudates. These metabolites were lactic acid, betaine, choline, carnitine, metformin, and creatine. Other molecules included xanthine, acetylcarnitine, glutamine, betonicine, beclomethasone, monosaccharide, 4-aminopentanoic acid, glycerophosphocholine, and lysophosphatidylcholine 20:5.

The metabolites identified in the DFU exudates affect wound repair processes like collagen synthesis, anti-inflammatory responses, energy metabolism, and angiogenesis. Betaine helps maintain osmotic balance, while lactic acid regulates pH and stimulates keratinocytes. Carnitine exerts antioxidant effects and enhances cellular function. Collectively, these small-molecule metabolites address various biochemical and physiological aspects of wound healing crucial for efficient tissue regeneration and repair. However, the team found considerable variability in betaine, choline, and lactic acid levels. The differences may arise due to the confounding effects of diet, physical activity, and health status, which warrants further research.

The combined systemic administration of metformin and insulin significantly elevated metformin concentration in wound exudates (from 0.3% to 3.1%). Metformin does not affect insulin metabolism or elimination, suggesting significant pharmacodynamic interactions between the two that future studies could explore. In vitro studies report that metformin can enhance wound repair by promoting faster tissue repair, reducing oxidative stress and inflammation, and promoting angiogenesis. Clinicians use metformin as a first-line treatment for insulin-independent diabetes. Health professionals must consider the synergistic actions of metformin and insulin to enhance DFU treatment strategies.

Implications

The study highlights the complex composition of diabetic foot ulcer exudates. The findings indicate that researchers could tailor wound care treatments to individual metabolic profiles for more precise and effective care. Moreover, an improved understanding of the function and distribution of the metabolites concerning wound healing could aid in identifying biomarkers of disease progression and response to treatment.

Increased metformin levels among individuals receiving metformin with insulin indicate that certain drug combinations could improve outcomes and reduce DFU-related amputations. However, future studies should investigate the mechanisms underlying these interactions.

Future studies should correlate the metabolic profiles with clinical outcomes to determine the clinical relevance of the metabolites and develop more precise treatment protocols. The presence of pharmaceutical compounds such as metformin and beclomethasone in the wound exudates indicates that healthcare providers may need to adjust drug therapies to optimize wound healing outcomes.