T2D PBMC Adenosine Receptors and Metformin

Fakhoury et al. 2022 measured adenosine A2A receptor (A2AR) and A3 receptor (A3R) mRNA expression in PBMCs from T2D patients, finding reduced expression that metformin partially reversed for A2AR but not A3R.

Adenosine Receptor Findings

• A2AR and A3R expression were significantly lower in T2D groups vs. disease-free groups (p<0.05). ¹
• Metformin significantly increased A2AR expression (p<0.05) but did not significantly alter A3R. ¹

Mechanistic Context

• Inflammation and metabolic stress cause hypoxia and extracellular adenosine accumulation; adenosine receptor activation normally inhibits NF-κB signaling, exerting anti-inflammatory effects. ¹
• The NF-κB pathway is responsible for triggering transcription of several pro-inflammatory genes and plays a pivotal role in insulin resistance and adipose tissue macrophage activation. ¹
• A2AR plays a protective role in obesity-associated adipose tissue inflammation by suppressing macrophage pro-inflammatory activation, including NF-κB pathway inhibition — A2AR-disrupted mice on high-fat diet show increased adipose inflammation and insulin resistance. ¹
• A3R activation also results in NF-κB pathway inhibition. ¹
• The reduced A2AR/A3R in T2DM PBMCs suggests that NF-κB pathway activation in T2D may be mediated — at least in part — by diminished adenosine receptor suppression. ²

Adenosine–Cholesterol Efflux Link

• A2AR activation has been shown to diminish foam cell formation by increasing the expression and function of cholesterol 27-hydroxylase (CYP27A), enhancing cholesterol efflux. ¹
• Both A2AR and CYP27A are reduced in T2D PBMCs, and metformin increases both — the authors interpret this as metformin enhancing cholesterol efflux from peripheral tissues through A2AR-mediated upregulation of CYP27A. ¹

Relevance To The Paper

• The adenosine receptor findings add an anti-inflammatory signaling axis to the T2D PBMC dysregulation profile, complementing the TNF/NF-kB and interferon-gamma pathways reported by scRNA-seq studies like Zhao and Fang 2025. ²
• Metformin’s dual effect on A2AR and CYP27A illustrates a medication-specific mechanism linking immune signaling and lipid metabolism — a potential confound and an interpretive opportunity in ancestry-aware PBMC studies. ²

Sources

• Fakhoury et al. 2022

Footnotes

1. extracted; from Fakhoury et al. 2022 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸

2. inferred; mechanistic interpretation and relevance framing ↩ ↩² ↩³