Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly evolved into a global pandemic. The hyperglycemia in patients with diabetes mellitus (DM) substantially compromises their innate immune system. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) receptors to enter the affected cell. Uncontrolled hyperglycemia-induced glycosylation of ACE2 and the S protein of SARS-CoV-2 could facilitate the binding of S protein to ACE2, enabling viral entry. Downregulation of ACE2 activity secondary to SARS-CoV-2 infection, with consequent accumulation of angiotensin II and metabolites, eventually leads to poor outcomes. The altered binding of ACE2 with SARS-CoV-2 and the compromised innate immunity of patients with DM increase their susceptibility to COVID-19; COVID-19 induces pancreatic β-cell injury and poor glycemic control, which further compromises the immune response and aggravates hyperglycemia and COVID-19 progression, forming a vicious cycle. Sequential cleavage of viral S protein by furin and transmembrane serine protease 2 (TMPRSS2) triggers viral entry to release the viral genome into the target cell. Hence, TMPRSS2 and furin are possible drug targets. As type 1 DM exhibits a Th1-driven autoimmune process, the relatively lower mortality of COVID-19 in type 1 DM compared to type 2 DM might be attributed to an imbalance between Th1 and Th2 immunity. The anti-inflammatory effects of dipeptidyl peptidase-4 inhibitor may benefit patients with DM and COVID-19. The potential protective effects of sodium–glucose cotransporter-2 inhibitor (SGLT2i), including reduction in lactate level, prevention of lowering of cytosolic pH and reduction in pro-inflammatory cytokine levels may justify the provision of SGLT2i to patients with DM and mild or asymptomatic COVID-19. For patients with DM and COVID-19 who require hospitalization, insulin-based treatment is recommended with cessation of metformin and SGLT2i. Further evidence from randomized or case–control clinical trials is necessary to elucidate the effectiveness and pitfalls of different types of medication for DM.

Although mTOR inhibitors have been approved as first-line therapy for treating metastatic clear cell renal cell carcinoma (ccRCC), the lack of useful markers reduces their therapeutic effectiveness. The objective of this study was to estimate if inositol monophosphatase 2 (IMPA2) downregulation refers to a favorable outcome in metastatic ccRCC receiving mTOR inhibitor treatment. Gene set enrichment analysis predicted a significant activation of mTORC1 in the metastatic ccRCC with IMPA2 downregulation. Transcriptional profiling of IMPA2 and mTORC1-related gene set revealed significantly inverse correlation in ccRCC tissues. Whereas the enforced expression of exogenous IMPA2 inhibited the phosphorylation of Akt/mTORC1, artificially silencing IMPA2 led to increased phosphorylation of Akt/mTORC1 in ccRCC cells. The pharmaceutical inhibition of mTORC1 activity by rapamycin reinforced autophagy initiation but suppressed the cellular migration and lung metastatic abilities of IMPA2-silenced ccRCC cells. In contrast, blocking autophagosome formation with 3-methyladenine rescued the mitigated metastatic potential in vitro and in vivo in IMPA2-overexpressing ccRCC cells. Our findings indicated that IMPA2 downregulation negatively activates mTORC1 activity and could be a biomarker for guiding the use of mTOR inhibitors or autophagy inducers to combat metastatic ccRCC in the clinic.

Approximately 30% of clear cell renal cell carcinoma (ccRCC) patients develop metastatic spread at the first diagnosis. Therefore, identifying a useful biomarker to predict ccRCC metastasis or therapeutic effectiveness in ccRCC patients is urgently needed. Previously, we demonstrated that lactotransferrin (LTF) downregulation enhanced the metastatic potential of ccRCC. Here, we show that LTF expression conversely associates with the mTORC1 activity as simulated by gene set enrichment analysis (GSEA). Moreover, Western blot analyses revealed that the LTF knockdown promoted, but the inclusion of recombinant human LTF protein suppressed, the phosphorylation of Akt/mTOR proteins in the detected ccRCC cells. Kaplan–Meier analyses demonstrated that the signature of combining an upregulated mTORC1 activity with a downregulated LTF expression referred to a worse overall and progression-free survival probabilities and associated with distant cancer metastasis in TCGA ccRCC patients. Furthermore, we found that the LTF-suppressed Akt/mTOR activation triggered an increased formation of autophagy in the highly metastatic ccRCC cells. The addition of autophagy inhibitor 3-methyadenine restored the LTF-suppressed cellular migration ability of highly metastatic ccRCC cells. Receiver operating characteristic (ROC) analyses showed that the expression of the LTF and MTORC1 gene set, not the autophagy gene set, could be the useful biomarkers to predict 5-year overall survival rate and cancer progression in ccRCC patients. Significantly, the signature of combining mTORC1 upregulation and LTF downregulation was shown as an independent prognostic factor in a multivariate analysis under the progression-free survival condition using the TCGA ccRCC database. Finally, the treatment with mTOR inhibitor rapamycin predominantly reduced the formation of autophagy and ultimately mitigated the cellular migration ability of ccRCC cells with LTF knockdown. Our findings suggest that LTF downregulation is a biomarker for guiding the use of mTOR inhibitors to combat metastatic ccRCC in the clinic.