PAA polyplexes displayed a pH-dependent endo/lysosomal escape which was not associated with cytotoxic events, unlike observed with BPEI polyplexes. This is likely due to their greater interactions with biological membranes at acidic than neutral pH.

It is known that there is a strong association between oxidative stress and insulin resistance in type 2 diabetes mellitus (T2DM). Although the role of glibenclamide in diabetes treatment has been evaluated, there is only limited evidence about its antioxidant effects in diabetic patients. Moreover, previous studies showed discrepant results regarding the effects of metformin on antioxidant/ oxidant parameters in type 2 diabetic patients. The present study aimed to evaluate the effects of metformin versus glibenclamide on oxidative stress biomarkers, represented by serum malondialdehyde (MDA), nonenzymatic, and enzymatic antioxidants in type 2 diabetic patients. Forty-six patients with T2DM participated in this study and categorized into 3 groups, Group A included 17 newly diagnosed diabetic patients, group B included 15 diabetic patients received metformin monotherapy (1000 mg/day) for up to 1 year and group C included 14 diabetic patients received glibenclamide monotherapy (5 mg/day) for up to 1 year. Serum MDA, catalase (CAT), vitamin C, E, and reduced glutathione (GSH) were measured. We found significantly lower concentrations of MDA and significantly higher antioxidant levels (CAT, GSH, vitamin C, and E) in the metformin-treated group compared to the glibenclamide counterpart. Our data confirmed that metformin has a more beneficial effect on oxidant/antioxidant status compared to glibenclamide, therefore, provides protection against reactive oxygen species (ROS) induced oxidative damage during diabetes.

Earlier works have revealed increased generation of reactive oxygen species (ROS) and decreased antioxidant levels in type 1 diabetes mellitus (T1DM). The current study aimed to investigate the effect of mixed insulin therapy on oxidative stress and antioxidant status in patients with T1DM. This study involved 75 participants who were divided into three groups: 20 healthy subjects as a control, 25 newly diagnosed patients with T1DM (without treatment) and 30 patients with T1DM treated with insulin (regular and Human Neutral Protamine Hagedorn (NPH)) twice daily. Fasting serum glucose (FSG), serum concentrations of insulin, malondialdehyde (MDA), catalase (CAT), reduced glutathione (GSH), and vitamins (C and E) were measured in all participants. Compared with the healthy control, serum glucose and MDA concentrations were observed to be significantly higher, while significantly lower concentrations of CAT, GSH, and vitamins (C and E) were found in both the treated and untreated diabetic groups. Although insulin therapy caused a significant decrease in blood sugar with a marked elevation in the levels of insulin, CAT, GSH and vitamin E compared to the untreated patients, the changes in the levels of MDA and vitamin C between diabetic groups were not significant. Moreover, the level of insulin resistance was significantly increased in insulin-treated patients as compared to the control and untreated diabetic groups. In conclusion, twice daily treatment with regular and NPH insulin can ameliorate hyperglycemia and improve antioxidant levels in patients with T1DM. However, the insulin regimen used in this study did not reveal a beneficial effect on oxidative stress and insulin resistance. Hence, exogenous antioxidants (vitamins C and E) can be used in combination with insulin to control these parameters.

Metformin and glibenclamide may have beneficial effects on the levels of trace elements in diabetic patients. The aim of the current study was to assess the effects of metformin and glibenclamide on the concentrations of copper (Cu), zinc (Zn) and magnesium (Mg) in patients with type 2 diabetes mellitus. The metformin-treated patients showed significantly lower serum Cu levels compared with the untreated and glibenclamide groups. In addition, treatment with metformin was associated with a significant increase in serum concentrations of Zn compared to the newly diagnosed patients, whereas it did not show a noticeable alteration in the serum level of Mg. In contrast, the glibenclamide treated group revealed significantly higher Zn and Mg levels compared with the newly diagnosed group, while the serum level of Cu was not significantly modified. In conclusion, treatment with metformin led to a reduction in serum Cu and an increase in serum Zn concentrations, whereas glibenclamide treatment displayed enhancement in serum Zn and Mg levels.

Thyroid cancer is a rare type of malignancy. However, thyroid cancer constitutes more than 90 % of endocrine tumors. Metformin (N', N'-dimethybiguanide) is the most commonly prescribed drug in the world, and the annual number of prescriptions for this drug exceeds 120 million. Metformin is the first-line oral treatment for patients with type II diabetes. Metformin has recently been investigated for potential anti-cancer activity in patients with thyroid cancer by stimulating the Adenosine Mono-Phosphate-Activated Protein Kinase (AMPK) pathway in some types of tumors. In general, the anti-cancer mechanism of metformin acts directly by blocking mitochondrial oxidative phosphorylation through down-regulation of mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase. This leads to a state of metabolic stress that in turn stimulates the AMPK pathway due to ATP reduction, and leads to inhibition of the mechanical (mammalian) target of the rapamycin (mTOR) pathway, which subsequently inhibits cancer cell proliferation and stimulates apoptosis and autophagy with cell cycle perturbation. Metformin also acts in an independent manner, in addition to its indirect actions that target insulin resistance. In this review, we reviewed 21 studies on the use of metformin in thyroid cancer, which showed that administration of metformin in diabetic patients is associated with a reduced incidence of thyroid cancer. On the other hand, the use of metformin enhances the response to anticancer drugs in thyroid cancer. Overall, we need further prospective studies to elucidate the synergistic mechanism of metformin when it is used to treat thyroid cancer as adjuvant therapy with anticancer drugs.

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