Unlocking pancreatic metabolic memory: Can early interventions reverse obesity and block diabetes before it strikes?

Table 2 Key mechanisms and outcomes of pancreatic macrophage-mediated metabolic memory

Mechanism pathway	Triggering factors	Macrophage state	Key mediators	β-cell outcome	Evidence model or study type	Ref.
Epigenetic modifications in pancreatic macrophages	High glucose, palmitic acid, obesity, diabetic complications (e.g., ischemia-reperfusion)	Impaired M2 polarization; enhanced pro-inflammatory M1-like phenotype; increased inflammatory signaling and phagocytic activity; activation of apoptosis pathways	DNMT1, peroxisome PPARγ1, Dnm3os, MALAT1	Improved systemic insulin sensitivity	Obese mouse models, in vitro macrophages, patient samples	[77-79]
Non-coding RNAs in pancreatic macrophages	HG and palmitic acid stimulation	Upregulation of E330013P06 and Dnm3os promotes inflammation and foam-cell formation; downregulation of the anti-inflammatory lncRNA mist accelerates inflammation	E330013P06, Dnm3os, mist	No direct impact on β-cells explicitly stated in the source	Mouse models; monocyte/macrophage experiments	[80]
Metabolic memory of pancreatic macrophages	History of hyperglycemia; effects persist even after normalization of metabolic parameters	Sustained pro-inflammatory state and metabolic dysfunction mediated by “trained immunity”	DNA methylation, histone modifications (e.g., H3K4me3, H3K9ac), non-coding RNAs (e.g., miRNA, lncRNA)	Islet β-cell dysfunction, insulin secretion defects; potential β-cell damage due to chronic inflammation	In vitro cell experiments, animal models, human cohort studies	[81]
Macrophage-derived cytokines and lipid mediators	Obesity, hyperglycemia, growth factors, oxidative stress, inflammatory cytokines	Enhanced pro-inflammatory M1-like phenotype	Exosomal miR-212-5p	Impaired insulin secretion	Mouse models, in vitro cell experiments	[82-85]
Epigenetic interactions	hIAPP aggregation and exposure	Modulates inflammatory phenotype and polarization; establishes long-term epigenetic memory (“trained immunity”); regulates secretion of factors (e.g., tPA, TGF-β)	tPA	Protects β-cells by reducing hIAPP-aggregate-induced toxicity	In vitro studies	[86-89]

DNMT1: DNA methyltransferase 1; PPARγ1: Peroxisome proliferator-activated receptor gamma 1; Dnm3os: Dynamin 3 opposite strand; MALAT1: Metastasis-associated lung adenocarcinoma transcript 1; HG: High glucose; H3K4me3: Histone H3 lysine 4 trimethylation; H3K9ac: Histone H3 lysine 9 acetylation; miRNA: MicroRNA; lncRNA: Long non-coding RNA; tPA: Tissue plasminogen activator; TGF-β: Transforming growth factor-β; hIAPP: Human islet amyloid polypeptide.