Endocrine Abstracts

Background: Impaired mitophagy (mitochondrial autophagy) and NLRP3 inflammasome activation have been implicated in the etiopathogenesis of insulin resistance and T2DM. Metformin beside being an insulin-sensitizer, also induces autophagy. However, further research is warranted in elucidating its effect on mitophagy and NLRP3 activation in patients with T2DM.

Methods: 45 drug-naïve, newly diagnosed T2DM patients, with HbA_1C 53–75 mmol/mol (7–9%) were randomly assigned to receive either metformin or voglibose (active comparator) or placebo for 3 months, along with lifestyle intervention (n=15 each). Mitochondrial oxidative stress (MOS) parameters, quantitative real-time PCR and immunoblotting of mitophagy-related markers (PINK1, PARKIN, MFN2, NIX, LC3-II, LAMP-2), p-AMPKα (T172) and NLRP3 proteins, as well as transmission electron microscopy (TEM) for assessing mitochondrial morphology, were performed in the study subjects.

Results: Both metformin and voglibose showed a similar efficacy towards the reduction in FPG and HbA_1c levels, and MOS indices. However, a significant upregulation in mitophagy and NLRP3 expression was observed with metformin monotherapy. Further, multivariate ANCOVA anaylsis revealed that mRNA and protein expression of mitophagy markers, NLRP3, and p-AMPKα (T172), increased significantly only with metformin, as compared to voglibose and placebo. TEM studies further confirmed reduced distortions in mitochondrial morphology, in the metformin group. Moreover, PINK1 expression showed a significant positive association with HOMA-β indices.

Conclusions: Our observations underscore the beneficial effects of metformin on mitochondrial morphology and function via promoting mitophagy. Hence, pharmacological modulation of mitophagy may represent a novel therapeutic approach to prevent or contain the worsening of β-cell function in subjects with T2DM by restoring mitochondrial health.