Background: Although obesity is considered as the main cause of Type II diabetes (T2DM), non-obese individuals may still develop T2DM and obese individuals may not. Method: The mRNA expression of PI3K/AKT axis from 100 non-obese and obese participants with insulin sensitivity and insulin resistance states were compared in this study toward the understanding of obesity heterogeneity molecular mechanism. Result: In present study, there was no statistically significant difference in gene expression levels of IRS1 and PTEN between groups, whereas PI3K, AKT2 and GLUT4 genes were expressed at a lower level in obese diabetic group compared to other groups and were statistically significant. PDK1 gene was expressed at a higher level in nonobese diabetic group compared to obese diabetic and non-obese non-diabetics groups. No statistically significant difference was identified in gene expression pattern of PI3K/AKT pathway between obese non-diabetics and nonobese non-diabetics. Conclusion: The components of PI3K/AKT pathway which is related to the fasting state, showed reduced expression in obese diabetic group due to the chronic over-nutrition which may induced insensitivity and reduced gene expression. The pathogenesis of insulin resistance in the absence of obesity in non-obese diabetic group could be due to disturbance in another pathway related to the non-fasting state like gluconeogenesis. Therefore, the molecular mechanism of insulin signalling in non-obese diabetic individuals is different from obese diabetics which more investigations are required to study insulin signalling pathways in greater depth, in order to assess nutritional factors, contribute to insulin resistance in obese diabetic and non-obese diabetic individuals.

Background: GSK3 is a serine/threonine kinase that is involved in the storage of glucose into glycogen through the negative regulation of glycogen synthase. Defects in GSK3 and glycogen synthase function are early stages of the development of insulin resistance, which may cause impaired glycogen synthesis in Type II diabetes. Methods: In this cross-sectional study, the gene expression level of GSK3 from Type II diabetic and non-diabetic participants was compared via real-time RT-PCR. To investigate the relationships between GSK3 expression and indicators of insulin resistance, Pearson's correlation analysis was performed. To compare the differences between GSK3 expression levels based on BMI categories, one-way ANOVA was used. Results: Gene expression of GSK3 was slightly higher in diabetic participants compared to non-diabetics, but it was statistically insignificant. Also, no significant difference was found based on BMI categories in the two groups. No significant association between GSK3 expression and indicators of insulin resistance was observed in non-diabetic participants. There was only a positive significant correlation between GSK3 expression and FBS in diabetic participants. Conclusion: These results indicate that the regulation of GSK3 may occur at the translation level, as gene expression level was unaltered between diabetic and non-diabetic participants. Also, since circulating levels of both glucose and insulin regulate GSK3 activity, tissue specificity for the expression and post-translation regulations of GSK3 may exist, which cause hyperactivation or overexpression in some target tissues in diabetes. Furthermore, it is probable that glycogen synthase activity is also regulated by non-insulin mediated mechanisms like exercise or allosteric changes, independent of GSK3 expression.

Background: HSP70 represents the most highly induced member of the stress protein family which is constitutively expressed in normal cell conditions as chaperon and rapidly upregulated in response to stress conditions. Vitamin E compounds are considered to be the most potent oxidation chain breaking compounds. Although α-tocopherol, has been long considered as the most potent antioxidant among the vitamin E isomers, many studies have recently suggested a higher antioxidant potency of tocotrienols compared to tocopherols. Present study was carried out to investigate the effects of tocotrienol supplementation compared to α-tocopherol on HSP70 expression.Methods: To assess whether the increase in HSP70 secondary to the stress caused by the oxidant could decrease in the presence of vitamin E; two groups of cells were incubated for 4 hours with α-tocopherol and palm tocotrienol-rich fraction respectively with concentration of 10, 20 and 30 μg/ml after the cells were pre-exposed to oxidative stress.Results: The comparison between the negative control which represents the basal expression of HSP70 and the positive control that represents the expression of HSP70 as a response to the oxidant, has clearly indicated that treatment with 100 μM copper sulphates for 24 hours resulted in a significant up-regulation of HSP70 expression. The present study has shown that the overall effect of vitamin E compounds seems to reduce the increase in HSP70 expression. α-tocopherol tended to trigger a more constant rate of response to the dose given but unable to significantly induced the decrease of the HSP70 expression as compared to tocotrienol.Conclusion: Treatment with vitamin E has conferred significant protection against stress induced cellular damage. Whether the reduction of HSP70 by vitamin E is deleterious or beneficial is still controversial and needs to be considered.

Background: Although obesity is considered as the main cause of Type II diabetes (T2DM), non-obese individuals may still develop T2DM and obese individuals may not. Method: The mRNA expression of PI3K/AKT axis from 100 non-obese and obese participants with insulin sensitivity and insulin resistance states were compared in this study toward the understanding of obesity heterogeneity molecular mechanism. Result: In present study, there was no statistically significant difference in gene expression levels of IRS1 and PTEN between groups, whereas PI3K, AKT2 and GLUT4 genes were expressed at a lower level in obese diabetic group compared to other groups and were statistically significant. PDK1 gene was expressed at a higher level in non-obese diabetic group compared to obese diabetic and non-obese non-diabetics groups. No statistically significant difference was identified in gene expression pattern of PI3K/AKT pathway between obese non-diabetics and non-obese non-diabetics.Conclusion: The components of PI3K/AKT pathway which is related to the fasting state, showed reduced expression in obese diabetic group due to the chronic over-nutrition which may induced insensitivity and reduced gene expression. The pathogenesis of insulin resistance in the absence of obesity in non-obese diabetic group could be due to disturbance in another pathway related to the non-fasting state like gluconeogenesis. Therefore, the molecular mechanism of insulin signalling in non-obese diabetic individuals is different from obese diabetics which more investigations are required to study insulin signalling pathways in greater depth, in order to assess nutritional factors, contribute to insulin resistance in obese diabetic and non-obese diabetic individuals.

Insulin-stimulated glucose transport occurs via PI3K/AKT -dependent pathway which results in GLUT4 translocation from intracellular vesicles to plasma membrane and glucose uptake. PTEN , as a phosphatase, is the main antagonist of the PI3K/AKT pathway’s kinases. Present study was performed to investigate underlying mechanism responsible for defects in insulin signalling, hence, RT-PCR was employed to investigate mRNA expression level of IRS1/PI3K/PDK1/AKT2/GLUT4/PTEN in diabetic and non-diabetic participants and serum vitamin D was measured by HPLC. Findings provide evidence that IRS1 gene expression was preserved while PI3K/PDK1/AKT2/GLUT4 were expressed significantly lower in diabetics compared to non-diabetics. Albeit there was no significant difference in PTEN expression between groups, PTEN was up-regulated by the years of having diabetes. As T2DM has been characterized by defects in insulin signalling at transcriptional level and post-translational modifications, it is difficult to conclude what exactly happens since only gene expression was considered, nevertheless it can be concluded that insulin resistance is not caused through an alteration in PTEN expression as a primary defect but may be caused by decreased PI3K/PDK1/AKT2/GLUT4 signalling and dysregulation of feedback loops. Particularly, PTEN expression showed a significant relation with duration of diabetes, suggesting that PTEN may not be the cause of the reduced expression of PI3K/AKT pathway in diabetes while it can be the effect of that. No significant correlations between serum vitamin D concentration and gene expression level of GOIs were observed in either group of participants which could be due to the non-linearity relationships as insulin signaling is a cascade with amplifying properties.