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While cases of obesity-induced type 2 diabetes (T2D) are on the upswing, current therapies help only manage the symptoms. Of late, L-glutamine has been implicated in the amelioration of T2D by virtue of its glucagon like peptide-1 (GLP-1) secretagogue property. Alongside, there are mixed reports on adiponectin (insulin sensitizer) potentiating property of statins. We aimed to investigate the effect of pitavastatin (P) and L-glutamine (LG) combination on glycemic control and pancreatic β-cell regeneration in a high-fat diet (HFD)+Streptozotocin (STZ) induced T2D mouse model. C57BL6/J mice treated with HFD+STZ were randomly assigned into four groups: Diabetic control, L-glutamine, Pitavastatin and P+LG. Control group was fed with the chow diet. Significant amelioration in insulin resistance along with plasma glucose, lipid profile, adiponectin levels, and mitochondrial complexes I, II, III activities were observed in P+LG group as compared to HFD+STZ treated group. Phosphoenolpyruvate carboxykinase, glucose 6-phophatase, glycogen phosphorylase, and GLUT2 transcript levels were reduced with increased glycogen synthase transcript levels in liver. Further, the protein levels of Insulin receptor 1-β, pAkt/Akt, and AdipoR1 were restored in the skeletal muscle and a significant increase in islet number as a result of β-cell regeneration and reduced β-cell death were also observed in the combination drug treated group. Thus, L-glutamine and pitavastatin in combination can induce β-cell regeneration and regulate glucose homeostasis to bring about amelioration of HFD+STZ induced T2D.

Introduction Altered circadian rhythms underlie manifestation of several cardiovascular disorders, however a little is known about the mediating biomolecules. Multiple transcriptional-translational feedback loops control circadian-clockwork wherein; micro RNAs (miRNAs) are known to manifest post transcriptional regulation. This study assesses miR34a-5p as a mediating biomolecule. Method 8–10-week-old male C57BL/6J mice (n = 6/group) were subjected to photoperiodic manipulation induced chronodisruption and thoracic aortae were examined for miRNA, gene (qPCR) and protein (Immunoblot) expression studies. Histomorphological changes were assessed for pro-atherogenic manifestations (fibrillar arrangement, collagen/elastin ratio, intima-media thickening). Computational studies for miRNA-mRNA target prediction were done using TargetScan and miRDB. Correlative in vitro studies were done in serum synchronized HUVEC cells. Time point based studies were done at five time points (ZT 0, 6, 12, 18, 24) in 24h. Results Chronodisruption induced hypomethylation in the promoter region of miR34a-5p, in the thoracic aortae, culminating in elevated miRNA titers. In a software-based detection of circadian-clock-associated targets of miR34a-5p, Clock and Sirt1 genes were identified. Moreover, miR34a-5p exhibited antagonist circadian oscillations to that of its target genes CLOCK and SIRT1 in endothelial cells. Luciferase reporter gene assay further showed that miR34a-5p interacts with the 3’UTR of the Clock gene to lower its expression, disturbing the operation of positive arm of circadian clock system. Elevated miR34a-5p and impeded SIRT1 expression in a chronodisruptive aortae exhibited pro-atherogenic changes observed in form of gene expression, increased collagen/elastin ratio, fibrillar derangement and intimal-media thickening. Conclusion The study reports for the first time chronodisruption mediated miR34a-5p elevation, its circadian expression and interaction with the 3’UTR of Clock gene to impede its expression. Moreover, elevated miR34a-5p and lowered SIRT1 expression in the chronodisruptive aortae lead off cause-consequence relationship of chronodisruption mediated proatherogenic changes.