ABSTRACT
Dramatic increase of diabetes over the globe is in tandem with the increase in insulin requirement. This is because destruction and dysfunction of pancreatic ß-cells are of common occurrence in both Type1 diabetes and Type2 diabetes, and insulin injection becomes a compulsion. Because of several problems associated with insulin injection, orally active insulin mimetic compounds would be ideal substitute. Here we report a small molecule, a peroxyvanadate compound i.e. DmpzH[VO(O2)2(dmpz)], henceforth referred as dmp, which specifically binds to insulin receptor with considerable affinity (KD-1.17µM) thus activating insulin receptor tyrosine kinase and its downstream signaling molecules resulting increased uptake of [14C] 2 Deoxy-glucose. Oral administration of dmp to streptozotocin treated BALB/c mice lowers blood glucose level and markedly stimulates glucose and fatty acid uptake by skeletal muscle and adipose tissue respectively. In db/db mice, it greatly improves insulin sensitivity through excess expression of PPARγ and its target genes i.e. adiponectin, CD36 and aP2. Study on the underlying mechanism demonstrated that excess expression of Wnt3a decreased PPARγ whereas dmp suppression of Wnt3a gene increased PPARγ expression which subsequently augmented adiponectin. Increased production of adiponectin in db/db mice due to dmp effected lowering of circulatory TG and FFA levels, activates AMPK in skeletal muscle and this stimulates mitochondrial biogenesis and bioenergetics. Decrease of lipid load along with increased mitochondrial activity greatly improves energy homeostasis which has been found to be correlated with the increased insulin sensitivity. The results obtained with dmp, therefore, strongly indicate that dmp could be a potential candidate for insulin replacement therapy.
Subject(s)
Coordination Complexes/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin Resistance , Receptor, Insulin/agonists , Vanadium Compounds/therapeutic use , 3T3 Cells , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Adiponectin/genetics , Adiponectin/metabolism , Adipose Tissue/metabolism , Animals , Blood Glucose/metabolism , CD36 Antigens/genetics , CD36 Antigens/metabolism , Cells, Cultured , Coordination Complexes/therapeutic use , Diabetes Mellitus, Experimental/metabolism , Fatty Acids/blood , Female , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Muscle, Skeletal/metabolism , PPAR gamma/genetics , PPAR gamma/metabolism , Protein Binding , Receptor, Insulin/metabolism , Triglycerides/blood , Vanadium Compounds/chemical synthesis , Vanadium Compounds/pharmacology , Wnt3A Protein/genetics , Wnt3A Protein/metabolismABSTRACT
Sequentially prepared semi-interpenetrating polymer network (semi-IPN) has been developed here via Michael type addition of acrylic acid (AA) and 2-acrylamido-2-methylpropane sulfonic acid (AMPS) on to starch. The semi-IPN hydrogel have proficiency in fast water imbibition towards gel network and swelling tunable character with pH alteration in ambient condition. The synthesized gel has been characterized by Fourier transformed infrared spectroscopy (FTIR) to confirm Michael type grafting of monomers on to starch. The surface morphology, observed from Scanning Electron Microscopy (SEM) exhibited corrugated rough surface on hydrogel which enhances the fast water uptake feature by anomalous Fickian case II diffusion mechanism. Grafting reaction also improves its thermal stability which has been confirmed by thermogravimetric analysis (TGA). Biodegradation study with hen egg lysozyme medium reveals the accelerated enzymatic scission of the starch backbone and progressive mass loss. Degradation of the hydrogel around 60% of its primary mass has been observed within 7days. The physicochemical characterizations of this hydrogel suggest this as a promising pH-tunable, biodegradable candidate for control drug delivery vehicle.
