Diabetes and Osteoarthritis: Exploring the Interactions and Therapeutic Implications of Insulin, Metformin, and GLP-1-Based Interventions

Abstract

Diabetes mellitus (DM) and osteoarthritis (OA) are prevalent chronic conditions with shared pathophysiological links, including inflammation and metabolic dysregulation. This study investigates the potential impact of insulin, metformin, and GLP-1-based therapies on OA progression. Methods involved a literature review of clinical trials and mechanistic studies exploring the effects of these medications on OA outcomes. Results indicate that insulin, beyond its role in glycemic control, may modulate inflammatory pathways relevant to OA, potentially influencing joint health. Metformin, recognized for its anti-inflammatory properties via AMPK activation, shows promise in mitigating OA progression by preserving cartilage integrity and reducing inflammatory markers. GLP-1-based therapies, known for enhancing insulin secretion and improving metabolic profiles in DM, also exhibit anti-inflammatory effects that may benefit OA by suppressing cytokine-mediated joint inflammation and supporting cartilage repair mechanisms. Conclusions suggest that these medications, while primarily indicated for diabetes management, hold therapeutic potential in OA by targeting common underlying mechanisms. Further clinical trials are warranted to validate these findings and explore optimal therapeutic strategies for managing both DM and OA comorbidities effectively.

Keywords: cartilage; inflammation; insulin resistance; obesity.

Figure 1

Illustration depicting the multifaceted effects of insulin on immune cells (T cells and macrophages), chondrocytes, and osteoclasts, emphasizing its regulatory role in immune response modulation, cartilage maintenance, and bone metabolism. Th17—T helper 17 cells, Glut1—Glucose transporter 1, mTOR—mammalian target of rapamycin, MMP-13—Matrix metalloproteinase-13, IL-1β—Interleukin-1 beta, IL-8—Interleukin-8, PGE2—Prostaglandin E2, M1—M1 macrophages (classically activated macrophages), M2—M2 macrophages (alternatively activated macrophages), RANK—Receptor activator of nuclear factor kappa-B, RANKL—RANK ligand. Figure 1 has been created in BioRender.com (accessed on 2 July 2024).

Figure 2

Metformin’s activation of AMP-activated protein kinase (AMPK) leads to the inhibition of mTOR (mammalian target of rapamycin), a pivotal regulator of lymphocyte immunometabolism and the equilibrium between pro-inflammatory and anti-inflammatory cell populations within joint tissues. This inhibition results in decreased production of pro-inflammatory Th1 and Th17 cells, along with M1 macrophages, thereby promoting a predominance of anti-inflammatory Treg cells and M2 macrophages. ATP—Adenosine triphosphate, AMP—Adenosine monophosphate, AMPK—AMP-activated protein kinase, mTORC1—Mechanistic target of rapamycin complex 1, mTORC2—Mechanistic target of rapamycin complex 2, MLST8 (MLST8 protein)—mammalian lethal with SEC13 protein 8, PRAS40—Proline-rich AKT substrate 40 kDa, Ras—Rat sarcoma protein, Raf—Rapidly accelerated fibrosarcoma protein, MEK—mitogen-activated protein kinase kinase, ERK—extracellular signal-regulated kinase, RSK—Ribosomal S6 kinase, PI3K—phosphoinositide 3-kinase, Akt—protein kinase B (Akt), TSC1/2—tuberous sclerosis complex 1/2, Rheb—Ras homolog enriched in brain, GDP—Guanosine diphosphate, MSIN1—MAPK (mitogen-activated protein kinase)-interacting protein 1, MLSTS (MLSTS protein)—mammalian lethal with SEC13 protein, Reg A/B (regulatory proteins A/B), GTP—Guanosine triphosphate, Reg C/D (regulatory proteins C/D), Treg—regulatory T cells, M1—M1 macrophages (classically activated macrophages), M2—M2 macrophages (alternatively activated macrophages), Th1—T helper 1 cells, Th17—T helper 17 cells. Figure 2 has been created in BioRender.com (accessed on 2 July 2024).