Abstract
Impaired mitochondrial autophagy (mitophagy) and NLRP3 inflammasome activation have been incriminated in the pathogenesis of T2DM. Metformin besides being an insulin sensitizer also induces autophagy; however, its effect on mitophagy and NLRP3 activation in patients with T2DM still remains elusive. Forty‐five drug‐naïve T2DM patients with HbA1C 7%‐9% (53‐75 mmol/mol) were randomly assigned to receive either metformin, voglibose, or placebo for 3 months, and were also recommended for lifestyle intervention programme (n = 15 each). Mitochondrial oxidative stress (MOS) parameters, qPCR and immunoblotting of mitophagy‐related markers (PINK1, PARKIN, MFN2, NIX, LC3‐II, LAMP2), p‐AMPKα (T172), and NLRP3 proteins, as well as transmission electron microscopy (TEM) for assessing mitochondrial morphology were performed in the mononuclear cells of study patients. Both metformin and voglibose showed a similar efficacy towards the reduction in HbA1c and MOS indices. However, multivariate ANCOVA divulged that mRNA and protein expression of mitophagy markers, NLRP3 and p‐AMPKα (T172), were significantly increased only with metformin therapy. Moreover, PINK1 expression displayed a significant positive association with HOMA‐β indices, and TEM studies further confirmed reduced distortions in mitochondrial morphology in the metformin group only. Our observations underscore that metformin upregulates mitophagy and subsequently ameliorates the altered mitochondrial morphology and function, independent of its glucose‐lowering effect. Further, restoration of normal mitochondrial phenotype may improve cellular function, including β‐cells, which may prevent further worsening of hyperglycaemia in patients with T2DM.
Highlights
Type 2 diabetes mellitus (T2DM) is a multifactorial disorder, characterized by an ominous octet with predominant components being insulin resistance and β-cell dysfunction.[1]
The present interventional study reveals that metformin exerts its beneficial effect on mitochondrial health via promoting mitophagy-mediated clearance of damaged mitochondria in patients with T2DM
This observation signifes that upregulation of mitophagy preserves mitochondrial morphology and function, ameliorates oxidative stress, which may subsequently alleviate worsening of hyperglycemia and its related complications in patients with newly diagnosed T2DM receiving metformin therapy
Summary
Type 2 diabetes mellitus (T2DM) is a multifactorial disorder, characterized by an ominous octet with predominant components being insulin resistance and β-cell dysfunction.[1]. Work from Twig and his colleagues reported that mitophagy regulates the mitochondrial turnover in β-cells, which is critical for maintaining the mitochondrial homeostasis, function and survival of β-cells, and the deregulation of this process may result in the progression of T2DM.[10]. In this regard, our previous study suggested that attenuated mitophagy, accompanied with increased mitochondrial oxidative stress in T2DM patients, might contribute to the worsening of hyperglycaemia in these patients.[11]
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