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

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.