T2D PBMC MMe-like Phenotype

Fakhoury et al. 2022 used PBMC qRT-PCR to profile macrophage phenotypic markers and concluded that circulating PBMCs in type 2 diabetes express an MMe (metabolically activated macrophage)-like phenotype — distinct from classical M1 (pro-inflammatory) and M2 (anti-inflammatory) polarization patterns. ¹

Marker Profile

Marker	M1 Classic	M2 Classic	T2D PBMC (Fakhoury)	Metformin Effect
IL-12	High	Low	High	Decreased
CXCL10	High	Low	Low	No change
CCL17	Low	High	Low	No change
CCR7	High	Low	High	No change

• The co-expression of high IL-12 + high CCR7 (M1-associated) with low CXCL10 + low CCL17 (mixed M1/M2) deviates from both classic M1 and M2 programs. ¹
• Increased IL-12 and CCR7 in T2D PBMCs is consistent with M1-like cells; metformin’s reduction of IL-12 (but not CCR7) suggests partial M1 attenuation. ¹
• Decreased CXCL10 contradicts the M1 marker expectation — CXCL10 is classified as M1 in THP-1 studies, but in T2D PBMCs it is inhibited, possibly reflecting PBMC heterogeneity. ¹
• Decreased CCL17 (M2 marker) is consistent with the authors’ prior finding of reduced CD163 (another M2 marker) in T2D PBMCs. ¹

Metabolically Activated (MMe) Context

• MMe was originally described in adipose tissue macrophages as a pro-inflammatory phenotype driven by metabolic conditions (glucose, insulin, palmitate) rather than classical cytokine activation. ¹
• Ex vivo treatment of monocyte-derived macrophages with glucose, insulin, and palmitate induced a different phenotype than M1 — supporting the MMe concept. ¹
• The Fakhoury data extend the MMe concept to circulating PBMCs — the pattern in PBMCs differs from adipose-tissue M1/M2 patterns and could represent a circulating MMe-like state. ²

Relevance To The Paper

• The MMe-like PBMC phenotype provides a molecular rationale for why T2D PBMC signatures may not align with classical M1/M2 frameworks — this has implications for how the paper interprets PBMC monocyte findings. ²
• Metformin’s partial normalization of the MMe profile (lowering IL-12, raising CYP27A, LOX-1, CXCL16, A2AR) should be considered as a confound when interpreting medication effects in PBMC analyses. ²

Sources

• Fakhoury et al. 2022

Footnotes

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

2. inferred; extension of MMe concept from adipose tissue to PBMCs is the authors’ interpretation ↩ ↩² ↩³