Hydroxychloroquine: Redefining Therapeutic Boundaries in Diabetes Mellitus — From Glycemic Control to Disease Modification

Hydroxychloroquine (HCQ), a 4-aminoquinoline derivative historically repositioned from antimalarial to rheumatological practice, represents an underutilized yet mechanistically compelling therapeutic agent across the entire diabetes mellitus spectrum. This review systematically examines the pharmacological basis, clinical evidence, and emerging therapeutic positioning of HCQ in Latent Autoimmune Diabetes in Adults (LADA), Type 1 Diabetes Mellitus (T1DM), Type 2 Diabetes Mellitus (T2DM), Maturity Onset Diabetes of the Young (MODY), and post-viral pediatric hyperglycemia. HCQ exerts its glucose-lowering and beta-cell preserving effects through multiple converging mechanisms: inhibition of insulin-degrading enzyme (IDE) prolonging endogenous insulin half-life; blockade of endosomal Toll-like receptor (TLR3/7/9) signaling reducing type I interferon-driven insulitis; suppression of pro-inflammatory cytokines (IL-1β, TNF-α, IFN-γ) interrupting cytokine-mediated beta-cell apoptosis; restoration of IRS-1 insulin signaling; AMPK activation suppressing hepatic gluconeogenesis; and disruption of antigen presentation pathways reducing autoreactive T-cell priming. Clinical observations from real-world practice at a dedicated diabetes care centre in Cuttack, India demonstrate that HCQ, when strategically positioned as second-line therapy in T1DM and fourth/fifth-line therapy in T2DM, produces significant HbA1c reduction, measurable C-peptide preservation, GADA titre decline in autoimmune subtypes, progressive insulin dose de-escalation, and in select cases complete insulin cessation with sustained euglycemia. In post-viral pediatric hyperglycemia, early HCQ intervention during the critical beta-cell preservation window has demonstrated hyperglycemia reversal — an observation with profound implications for the natural history of virus-triggered autoimmune diabetes. A conservative dosing protocol is proposed: 200mg/day in adults and 100mg/day in children aged five years and above, with mandatory pre-treatment quantitative G6PD screening and systematic safety surveillance including serial CBC, LFTs, ECG with QTc measurement, and annual ophthalmological retinal examination. This conservative dosing strategy significantly extends the safe cumulative dose window compared to standard rheumatological dosing, making HCQ particularly suitable for the long treatment durations required in chronic diabetes management. This article argues for formal repositioning of HCQ within diabetes management guidelines, supported by mechanistic evidence, emerging clinical data, and real-world observational findings, and calls for prospective randomized controlled trials to validate these clinical observations at scale. *Keywords:*HydroxychloroquineDiabetes MellitusLADALatent Autoimmune Diabetes in AdultsType 1 DiabetesType 2 DiabetesMODYBeta-cell preservationInsulin de-escalationInsulin-degrading enzymeDisease modificationAutoimmune diabetesPost-viral hyperglycemiaPediatric diabetesC-peptide preservationInsulitisTLR signalingG6PD screeningConservative dosingHCQ safetyDiabetic MedicineImmunomodulationGlycemic controlCuttackIndia