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

Table 1 Macrophage subtypes and their distribution characteristics

Macrophage subtype names	Specific distribution in the pancreas	Surface markers and signature molecules	Species	Functional characteristics	Ref.
M1 macrophages	Pancreatic acinar cells	Gpr18, Fpr2	Mouse	pro-inflammatory	[70,71]
M2a macrophages	Pancreatic acinar cells	IL-4, IL-13	Mouse	Mediate tissue repair and wound healing
M2b macrophages	bone marrow-derived Mφ	LPS, IL-1β	Mouse	Modulate immune responses	[72,73]
M2c macrophages	bone marrow-derived Mφ	IL-10	Mouse	Anti-inflammatory
M2d macrophages	bone marrow-derived Mφ	IL-10, VEGF	Mouse	Tumor-associated macrophages	[74]
F4/80+ CD11c+ macrophages	Near the blood vessels within the islets	F4/80+ CD11c+	Mouse	Captured secretory granules and antigen presentation from β-cells	[75]
F4/80+ CD11b+ CD206+ macrophages	Pancreatic stromal macrophages	IL-10, Fizz1	Mouse	Anti-inflammatory	[76]
F4/80+ CD11b+ CD206- macrophages	Peripheral duct cells of the exocrine portion of the pancreas	Ym1, Fizz1	Mouse	Anti-inflammatory

Gpr18: G-protein coupled receptor 18; Fpr2: Formyl peptide receptor 2; IL: Interleukin; LPS: Lipopolysaccharide; VEGF: Vascular endothelial growth factor; Fizz1: Found in inflammatory zone 1; Ym1: Y-macrophage 1.

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.

Table 3 Interventional strategies for pancreatic macrophage metabolic memory

Intervention strategy	Representative agents/methods	Mechanism of action	Specificity for memory erasure	Evidence type	Ref.
Lifestyle intervention	Aerobic exercise	Activates SIRT1 pathway, promotes macrophage M2 polarization, downregulates TNF-α/IL-6, upregulates IL-10	High Rationale: > 8 weeks via H3K4me3/H3K27ac epigenetic remodeling; pancreatic macrophage direct evidence	Preclinical + clinical	[90,91]
		Improves pancreatic macrophage metabolic reprogramming, enhances PKB2-mediated insulin signaling		Obese mice (n = 10/group): Reduces HOMA-IR, upregulates PBMC SIRT1
		H3K27ac, inhibits HDAC3, modulates epigenetic memory		Obese humans (n = 89): Endurance exercise enhances insulin sensitivity
Natural products	Resveratrol, curcumin	Resveratrol: Activates adenosine monophosphate - AMPK/SIRT1/Nrf2, inhibits NF-κB, enhances IL-10 promoter H3K27ac; regulates macrophage polarization (concentration-dependent)	Moderate Rationale: 2 weeks; histone modification; pancreatic macrophage direct evidence	Preclinical + clinical	[92,93]
		Curcumin: Blocks TLR4/MyD88/NF-κB, inhibits NLRP3 inflammasome, reverses IL-6 promoter DNA methylation; alleviates pancreatic β-cell oxidative stress		Cells (3 independent experiments): Resveratrol reduces LPS-induced NO/TNF-α, curcumin inhibits IL-1β
				Human trial (n = 40): 1 g/day resveratrol increases SHBG, improves metabolism
Epigenetic modulators	HDACi, miR-10a mimics	HDAC inhibitors: Inhibit HDAC1/2/3, reduce H3K27me3, activate Nrf2, enhance IL-10 expression	Extremely high Rationale: 4-8 weeks; reverses obesity-induced epigenetic abnormalities; pancreatic macrophage direct evidence	Preclinical + clinical	[94]
		miR-10a mimics: Promotes pancreatic macrophage OXPHOS, increases acetyl-CoA/H3K18ac, inhibits HDAC3, modulates metabolic memory		Mice: Improves glucose/insulin resistance, reduces macrophage infiltration
				Lymphoma patients: MS-275 lowers TNF-α/IL-6
				Human pancreatic macrophages: SAHA upregulates IL-10
miRNA-based intervention	miR-10a mimics, miR-146a mimics, miR-155 antagonists	miR-10a: Regulates metabolic reprogramming, enhances H3K18ac, blocks inflammatory memory	Extremely high Rationale: 6-8 weeks; reverses epigenetic abnormalities; pancreatic macrophage direct evidence	Preclinical	[91,95]
		miR-146a: Targets HDAC2-PI3K axis, inhibits M1 polarization		Mice: MiR-10a reduces M1/M2 ratio, miR-146a improves insulin sensitivity
		miR-155 antagonists: Rescues PDX1, associated with pancreatic β-cell function		Cells: MiR-146a upregulates IL-10, miR-155 antagonists inhibit TNF-α
Other	DMI	Mevalonate: Induces innate immune memory via inflammatory gene H3K27ac/H3K4me3	Moderate Rationale: > 3 weeks; reverses partial inflammatory memory; pancreatic macrophage direct evidence	Preclinical	[91]
		DMI: Enriches TNF/IL-6 promoter H3K4me3, reduces H3K9me3, regulates metabolic memory, inhibits inflammatory responses in pancreatic macrophages		Cells: Mevalonate enhances secondary inflammatory response, DMI inhibits LPS-induced TNF-α
				Animal experiment: DMI improves obesity-related inflammation

SIRT1: Sirtuin 1; TNF-α: Tumor necrosis factor-α; IL-10: Interleukin-10; IL-6: Interleukin-6; PKB2: Protein kinase B2; H3K27ac: Histone 3 lysine 27 acetylation; HDAC3: Histone deacetylase 3; AMPK: AMP-activated protein kinase; Nrf2: Nuclear factor erythroid 2-related factor 2; NF-κB: Nuclear factor kappa B; TLR4: Toll-like receptor 4; MyD88: Myeloid differentiation factor 88; NLRP3: NOD-like receptor pyrin domain-containing protein 3; H3K27me3: Histone 3 lysine 27 trimethylation; OXPHOS: Oxidative phosphorylation; H3K18ac: Histone 3 lysine 18 acetylation; PI3K: Phosphoinositide 3-kinase; PDX1: Pancreatic and duodenal homeobox 1; DMI: Dimethyl itaconate; H3K4me3: Histone 3 lysine 4 trimethylation; H3K9me3: Histone 3 lysine 9 trimethylation; HOMA-IR: Homeostasis model assessment of insulin resistance; PBMC: Peripheral blood mononuclear cell; LPS: Lipopolysaccharide; NO: Nitric oxide; SHBG: Sex hormone-binding globulin; SAHA: Suberoylanilide hydroxamic acid; HDACi: Histone deacetylase inhibitors.