title: A Small Insulinomimetic Molecule Also Improves Insulin Sensitivity in Diabetic Mice.
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 β-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.
authors.affiliation: Cellular and Molecular Endocrinology Laboratory, Centre for Advanced Studies in Zoology, School of Life Science, Visva-Bharati (A Central University), Santiniketan, West Bengal, India.
authors.forename: Sandip
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Cellular and Molecular Endocrinology Laboratory, Centre for Advanced Studies in Zoology, School of Life Science, Visva-Bharati (A Central University), Santiniketan, West Bengal, India.
authors.forename: Mrittika
authors.initials: M
authors.lastname: Chattopadhyay
authors.affiliation: Regional Centre for Biotechnology, NCR Delhi, India.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Department of Molecular Biology and Biotechnology, Tezpur University, Assam, India.
authors.forename: Suman
authors.initials: S
authors.lastname: Dasgupta
authors.affiliation: Department of Chemical Sciences, Tezpur University, Assam, India.
authors.forename: Sahid
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Department of Chemical Sciences, Tezpur University, Assam, India.
authors.forename: Saitanya K
authors.initials: SK
authors.lastname: Bharadwaj
authors.affiliation: Department of Chemical Sciences, Tezpur University, Assam, India.
authors.forename: Dhrubajyoti
authors.initials: D
authors.lastname: Talukdar
authors.affiliation: Division of Cellular Endocrinology, National Institute of Immunology, New Delhi, India.
authors.forename: Abul
authors.initials: A
authors.lastname: Usmani
authors.affiliation: Division of Cellular Endocrinology, National Institute of Immunology, New Delhi, India.
authors.forename: Bhola S
authors.initials: BS
authors.lastname: Pradhan
authors.affiliation: Division of Cellular Endocrinology, National Institute of Immunology, New Delhi, India.
authors.forename: Subeer S
authors.initials: SS
authors.lastname: Majumdar
authors.affiliation: Defence Research Laboratory, Tezpur, Assam, India.
authors.forename: Pronobesh
authors.initials: P
authors.lastname: Chattopadhyay
authors.affiliation: Department of Endocrinology & Metabolism, Institute of Post-Graduate Medical Education & Research-Seth Sukhlal Karnani Memorial (IPGME&R-SSKM) Hospital, Kolkata, West Bengal, India.
authors.forename: Satinath
authors.initials: S
authors.lastname: Mukhopadhyay
authors.affiliation: Regional Centre for Biotechnology, NCR Delhi, India.
authors.forename: Tushar K
authors.initials: TK
authors.lastname: Maity
authors.affiliation: Department of Chemical Sciences, Tezpur University, Assam, India.
authors.forename: Mihir K
authors.initials: MK
authors.lastname: Chaudhuri
authors.affiliation: Cellular and Molecular Endocrinology Laboratory, Centre for Advanced Studies in Zoology, School of Life Science, Visva-Bharati (A Central University), Santiniketan, West Bengal, India.
authors.forename: Samir
authors.initials: S
authors.lastname: Bhattacharya
mesh_terms: D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D056831:Coordination Complexes / Q000494:pharmacology* / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D005227:Fatty Acids / Q000097:blood; D005260:Female; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011972:Receptor, Insulin / Q000819:agonists* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D017968:Vanadium Compounds / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C000621804:3,5 dimethylpyrazole-peroxy-vanadate; D052242:Adiponectin; D001786:Blood Glucose; D018955:CD36 Antigens; D056831:Coordination Complexes; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D014280:Triglycerides; D017968:Vanadium Compounds; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D011972:Receptor, Insulin; D055372:AMP-Activated Protein Kinases