Metformin’s disruption of gluconeogenesis in type 2 diabetes impairments of the cori and alanine cycles as hidden drivers of metabolic waste accumulation, NF-κBHIF-1α–mediated low-grade inflammation, and multisystem dysfunction

Gluconeogenesis, a dual-purpose pathway in type 2 diabetes mellitus (T2DM), not only synthesizes glucose but also clears metabolic waste via the Cori cycle (lactate recycling through LDH, PC, PEPCK) and Alanine cycle (nitrogen disposal via ALT, GDH, urea cycle), preventing acidosis, ROS accumulation, and ammonia toxicity. Metformin, the cornerstone T2DM therapy, inhibits gluconeogenesis by targeting mitochondrial complex I, elevating AMP/ATP ratios, and activating AMPK-PKCι/λ signaling to repress CREB-CRTC2-driven PEPCK/G6Pase expression, disrupting these cycles. This leads to lactate, pyruvate, and ammonia buildup, triggering pro-inflammatory cascades: HIF-1α stabilization induces IL-6/VEGF, ROS from pyruvate excess activates NF-κB for TNF-α, and ammonia primes NLRP3 inflammasome for IL-1β/IL-18 release, fostering chronic inflammation. Multisystem consequences include musculoskeletal fatigue from ATP deficits, cognitive fog via neuroinflammation, atherosclerosis from endothelial dysfunction, hepatic fibrosis from urea cycle stress, and immune inflammaging impairing macrophage function. Clinical evidence reveals short-term anti-inflammatory benefits (reduced IL-6, CRP) via AMPK and microbiota effects, contrasted by long-term risks like lactic acidosis and neurodegeneration in renal-impaired or elderly patients. This review integrates physiological roles, molecular mechanisms, inflammatory pathways, systemic impacts, and clinical findings, highlighting metformin’s dual-edged profile glycemic efficacy versus “inflammatory debt.” Researchers are urged to explore precision interventions, such as antioxidants or biomarker-guided dosing, to optimize metformin’s pleiotropic potential in T2DM and inflammaging-related disorders, redefining therapeutic paradigms.

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