Akansha Mishra

Elevated Hepatic miR-22-3p Expression Impairs Gluconeogenesis by Silencing the Wnt-Responsive Transcription Factor Tcf7

Levels of miR-22-3p, a highly abundant hepatic microRNA, are abnormally increased in mouse models of insulin resistance and type 2 diabetes, yet its contribution to deregulated hepatic metabolism under diseased states is not well understood. Here, we unravel a novel link between elevated hepatic miR-22-3p expression and impaired gluconeogenesis in diabetic db/db mice via the regulation of Tcf7 (transcription factor 7). Our data demonstrate that miR-22-3p binds to the 3′ untranslated region of TCF7 and downregulates it, and this microRNA-mediated regulation of TCF7 increases the expression of enzymes of the gluconeogenic pathway in HepG2 cells. Small interfering RNA–mediated knockdown of TCF7 in HepG2 cells also causes similar upregulation of gluconeogenic genes. Furthermore, in vivo silencing of miR-22-3p by antagomiR administration lowered random as well as fasting glucose levels in diabetic mice. miR-22-3p antagonism improved glucose tolerance and insulin sensitivity. Importantly, the hepatic Tcf7 levels were restored along with reduced hepatic glucose output, which was also reflected by the decreased expression of gluconeogenic genes. Our results support a critical role for miR-22-3p and its target, Tcf7, in the pathogenesis of diabetes by upregulating gluconeogenesis. Moreover, targeting the miR-22/Tcf7/Wnt axis might hold therapeutic potential for the treatment of altered hepatic physiology during insulin resistance and type 2 diabetes.

Inhibition of Alpha-Glucosidase by Acacia nilotica Prevents Hyperglycemia along with Improvement of Diabetic Complications via Aldose Reductase Inhibition

Postprandial hyperglycemia is a prominent and early defect in diabetes and regulating blood glucose elevation may attenuate progression towards diabetes associated secondary complications. Here we investigated the alphaglucosidase inhibitory potential of the ethanolic extract of the stem bark of Acacia nilotica (EEAN). The EEAN showed a remarkable alpha-glucosidase inhibitory effect with IC50 value around 8 μg/ml. Kinetic studies revealed that the extract inhibited alpha-glucosidase in competitive manner and caused conformational changes in secondary structure of the enzyme protein. In vivo analysis showed that EEAN significantly suppresses the sucrose-induced postprandial glucose elevation in normal rats and exerts antihyperglycemic effect in streptozotocin (STZ)-induced diabetic rats in a dose-dependent fashion. Further, treatment of diabetic animals after 10 week of STZ-treatment with EEAN (250 mg/ kg) for 21 days, significantly reduced the elevated levels of blood glucose, %HbA1C, urea, uric acid and creatinine, and significantly increased the depressed plasma insulin level. The EEAN also showed inhibitory potential on aldose reductase activity with an IC50 of 7.5 μg/ml. The results suggest that EEAN possess antihyperglycemic activity through inhibition of alpha-glucosidase along with antidiabetogenic effect on polyol pathway through aldose reductase inhibition.

Naturally Occurring Carbazole Alkaloids from Murraya koenigii as Potential Antidiabetic Agents

This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/db mice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1-6) on glucose uptake and GLUT4 translocation in L6-GLUT4myc myotubes, followed by an investigation of their activity (2-5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, in vivo pharmacokinetic studies of compounds 2 and 4 clearly showed that compound 4 was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes.

Design, Synthesis, Biological Screening, and Molecular Docking Studies of Piperazine-Derived Constrained Inhibitors of DPP-IV for the Treatment of Type 2 Diabetes

Novel piperazine‐derived conformationally constrained compounds were designed, synthesized, and evaluated for in vitro Dipeptidyl peptidase‐IV (DPP‐IV) inhibitory activities. From a library of compounds synthesized, 1‐(2‐(4‐(7‐Chloro‐4‐quinolyl)piperazin‐1‐yl)acetyl)pyrrolidine (2g) was identified as a potential DPP‐IV inhibitor exhibiting better inhibitory activity than P32/98, reference inhibitor. The in vivo studies carried out in STZ and db/db mice models indicated that the compound 2g showed moderate antihyperglycemic activity as compared to the marketed drug Sitagliptin. A two‐week repeated dose study in db/db mice revealed that compound 2g significantly declined blood glucose levels with no evidence of hypoglycemia risk. Furthermore, it showed improvement in insulin resistance reversal and antidyslipidemic properties. Molecular docking studies established good binding affinity of compound 2g at the DPP‐IV active site and are in favor of the observed biological data. These data collectively suggest that compound 2g is a good lead molecule for further optimization studies.

Design and synthesis of lupeol analogues and their in vitro PTP-1B inhibitory activity

Synthetic analogues of the naturally occurring triterpenoid, lupeol by modification of A-ring and isopropylene moiety with different carboxylic acid functionalities and their biological activity were investigated. The analogues were designed by considering the incorporation of ester and amide linkages in the parent molecule. They were assayed for protein tyrosine phosphatase-1B (PTP-1B) inhibitory activity. Among them, compounds 9a, 9b, 14a, 14b and 14c showed significant dose-dependant inhibition at 10 μM concentration. Our report is marked by readily accessible synthesis, excellent yield and significant PTP-1B inhibitory effect.Graphical abstractA synthetic approach and in vitro PTP-1B inhibition of novel analogues of lupeol are described. Compounds 9a, 9b, 14a, 14b and 14a represent a new class of PTP-1B inhibitors in type 2 diabetes

Acacia catechu hard wood: potential anti-diabetic cum anti-dyslipidemic

The ethanolic as well as aqueous extracts of the hard wood of Acacia catechu showed improvement on oral glucose tolerance post-sucrose load in normal rats and streptozotocin (STZ)-induced diabetic rats. Around 22 and 27% improvement in glucose tolerance was observed post 7 and 14 days of feeding the ethanolic extracts, respectively, on STZ-induced diabetic rats. Whereas around 17 and 26% improvement on glucose tolerance was observed post 7 and 14 days of feeding the ethanolic extract in the high fructose high fat diet (HFD) fed-low dosed STZ-treated rats. The ethanolic extract of A. catechu hard wood also showed marked anti-dyslipidemic activity on HFD fed Syrian golden hamster as evidenced by around 43 and 26% decline in serum triglycerides and total cholesterol, respectively. The ethanolic and aqueous extracts also showed marked inhibition on eye lens aldose reductase either from normal or STZ-induced diabetic rats. Further studies are warranted to isolate and identify the active ingredients from the ethanolic and aqueous extracts of A. catechu hard wood.

Deoxyandrographolide promotes glucose uptake through glucose transporter-4 translocation to plasma membrane in L6 myotubes and exerts antihyperglycemic effect in vivo.

Skeletal muscle is the principal site for postprandial glucose utilization and augmenting the rate of glucose utilization in this tissue may help to control hyperglycemia associated with diabetes mellitus. Here, we explored the effect of Deoxyandrographolide (DeoAn) isolated from the Andrographis paniculata Nees on glucose utilization in skeletal muscle and investigated its antihyperglycemic effect in vivo in streptozotocin-induced diabetic rats and genetically diabetic db/db mice. In L6 myotubes, DeoAn dose-dependently stimulated glucose uptake by enhancing the translocation of glucose transporter 4 (GLUT4) to cell surface, without affecting the total cellular GLUT4 and GLUT1 content. These effects of DeoAn were additive to insulin. Further analysis revealed that DeoAn activated PI-3-K- and AMPK-dependent signaling pathways, account for the augmented glucose transport in L6 myotubes. Furthermore, DeoAn lowered postprandial blood glucose levels in streptozotocin-induced diabetic rats and also suppressed the rises in the fasting blood glucose, serum insulin, triglycerides and LDL-Cholesterol levels of db/db mice. These findings suggest the therapeutic efficacy of the DeoAn for type 2 diabetes mellitus and can be potential phytochemical for its management.

Glucose uptake stimulatory potential and antidiabetic activity of the Arnebin-1 from Arnabia nobelis.

The enhanced disposal of glucose by the peripheral tissue is an important mechanism to regulate hyperglycemia. Here, we investigated the effect of Arnebin-1 from Arnebia nobilis, on glucose disposal in skeletal muscle cells and explored its in vivo antihyperglycemic potential. In L6 myotubes, Arnebin-1 stimulated glucose uptake, mediated through the enhanced translocation of the glucose transporter-4 (GLUT4) to plasma membrane, without changing the amount of GLUT4 or GLUT1. These effects of Arnebin-1 were synergistic with that of insulin. The effect of Arnebin-1 on glucose uptake was abolished in presence of wortmannin, and Arnebin-1 significantly stimulated the phosphorylation of Akt and downstream marker GSK-3β. Moreover, treatment with Arnebin-1 lowered postprandial blood glucose levels in streptozotocin-induced diabetic rats, and improved glucose tolerance and suppressed the rises in the fasting blood glucose, serum insulin, triglycerides, and total cholesterol in db/db mice, associated with enhanced expression of the major marker of the PI-3-Kinase-mediated signaling cascade in skeletal muscle. These findings suggest that Arnebin-1 exert antihyperglycemic activity through stimulating glucose disposal in peripheral tissues via PI-3-Kinase-dependent pathway.