The PI3K/Akt signaling axis and type 2 diabetes mellitus (T2DM): From mechanistic insights into possible therapeutic targets.

Type 2 diabetes mellitus (T2DM) is an immensely debilitating chronic disease that progressively undermines the well-being of various bodily organs and, indeed, most patients succumb to the disease due to post-T2DM complications. Although there is evidence supporting the activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway by insulin, which is essential in regulating glucose metabolism and insulin resistance, the significance of this pathway in T2DM has only been explored in a few studies. The current review aims to unravel the mechanisms by which different classes of PI3Ks control the metabolism of glucose; and also to discuss the original data obtained from international research laboratories on this topic. We also summarized the role of the PI3K/Akt signaling axis in target tissues spanning from the skeletal muscle to the adipose tissue and liver. Furthermore, inquiries regarding the impact of disrupting this axis on insulin function and the development of insulin resistance have been addressed. We also provide a general overview of the association of impaired PI3K/Akt signaling pathways in the pathogenesis of the most prevalent diabetes-related complications. The last section provides a special focus on the therapeutic potential of this axis by outlining the latest advances in active compounds that alleviate diabetes via modulation of the PI3K/Akt pathway. Finally, we comment on the future research aspects in which the field of T2DM therapies using PI3K modulators might be developed.

Investigating the impact of metformin on severity of COVID-19 in patients with Type 2 diabetes mellitus: Focusing on laboratory findings.

BACKGROUND: In the terrifying pandemic caused by SARS-CoV-2, diabetic patients exhibiting more severe outcomes and mortality rate is high among them. Based on recent studies, metformin as the most prescribed drug for T2DM treatment may improve severe outcomes in diabetic patients infected with SARS-CoV-2. On the other hand, abnormal laboratory findings can help to differentiate between the severe and non-severe form of COVID-19. According to the mentioned issues, the effect of metformin on severity of COVID-19 was examined in T2DM patients with SARS-CoV-2 infection. METHODS: The study included 187 individuals diagnosed with COVID-19, 104 patients were diabetic and divided into two groups according to their anti-diabetic drugs: patients who were treated only with metformin and patients who were treated with other anti-diabetic drugs. The other participants were non-diabetic and diagnosed with COVID-19. Biochemical parameters were measured by routine laboratory methods before, during and after SARS-CoV-2 infection. RESULTS: During infection, FBS, creatinine, ALT, AST, Ferritin and LDH were significantly lower in metformin users than non-users (p-value: .02, .01, .03, .04, .0009 and .01, respectively). Also, after recovery, there were statistically significant differences between metformin users and non-users with respect to most of the study parameters, except FBS, BUN and ALP (p-value: .51, .28 and .35, respectively). CONCLUSION: Our result suggested that metformin might be associated with better outcomes in diabetic patients infected with SARS-CoV-2.

The influence of SLC22A3 rs543159 and rs1317652 genetic variants on metformin therapeutic efficacy in newly diagnosed patients with type 2 diabetes mellitus: 25 weeks follow-up study.

BACKGROUND AND AIMS: Among anti-diabetic medications, metformin has been proven to be the preferred initial pharmacologic agent for type 2 diabetes mellitus (T2DM) treatment. Despite its safety and efficacy, the response to metformin varies between individuals. Genetic variations, especially within genes involved in pharmacokinetics and pharmacodynamics of metformin (e.g SLC22A3), have been suggested to be responsible for the observed inter-individual differences. By considering the undeniable role of organic cation transporter 3 in hepatic uptake of metformin, this study was aimed to investigate the association of rs543159 and rs1317652 variants in SLC22A3 gene with response to metformin monotherapy in newly diagnosed patients with T2DM. METHODS: The study included 200 T2DM patients who received metformin monotherapy for 25 weeks. The patients were classified into 2 groups according to their HbA1c values: the responders (reduction in HbA1c levels by at least 1% after 25 weeks treatment with metformin) and non-responders (less than 1% reduction in HbA1c levels after 25 weeks treatment with metformin). We used tetra ARMS-PCR method to determine genotypes of the target variants. RESULTS: For the rs543159, CA and AA genotypes were more frequent in responders as compared to non-responders (OR = 2.48; 95% CI = 1.28-4.78, P-value = 0.0057) under the dominant model. In case of rs1317652 CC and CT genotypes were more frequent in metformin responders as compared to non-responder group (OR = 2.49; 95% CI = 1.32-4.70, P-value = 0.0043) under the dominant model. Parameters such as fasting blood sugar (FBS), HbA1c, and total cholesterol (TC) levels were significantly lower in the responder group after 25 weeks of metformin monotherapy. Moreover, according to the result of multiple linear regression rs543159 and base line HbA1c values are significantly associated with response to metformin monotherapy. CONCLUSION: Our results suggested that rs543159 and rs1317652 in SLC22A3 gene might be associated with variability in response to metformin therapy in T2DM patients.