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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.

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  • Authors+Show Affiliations

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    Cellular and Molecular Endocrinology Laboratory, Centre for Advanced Studies in Zoology, School of Life Science, Visva-Bharati (A Central University), Santiniketan, West Bengal, India.

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    Cellular and Molecular Endocrinology Laboratory, Centre for Advanced Studies in Zoology, School of Life Science, Visva-Bharati (A Central University), Santiniketan, West Bengal, India.

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    Regional Centre for Biotechnology, NCR Delhi, India.

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    Department of Molecular Biology and Biotechnology, Tezpur University, Assam, India.

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    Department of Chemical Sciences, Tezpur University, Assam, India.

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    Department of Chemical Sciences, Tezpur University, Assam, India.

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    Department of Chemical Sciences, Tezpur University, Assam, India.

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    Division of Cellular Endocrinology, National Institute of Immunology, New Delhi, India.

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    Division of Cellular Endocrinology, National Institute of Immunology, New Delhi, India.

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    Division of Cellular Endocrinology, National Institute of Immunology, New Delhi, India.

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    Defence Research Laboratory, Tezpur, Assam, India.

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    Department of Endocrinology & Metabolism, Institute of Post-Graduate Medical Education & Research-Seth Sukhlal Karnani Memorial (IPGME&R-SSKM) Hospital, Kolkata, West Bengal, India.

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    Regional Centre for Biotechnology, NCR Delhi, India.

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    Department of Chemical Sciences, Tezpur University, Assam, India.

    Cellular and Molecular Endocrinology Laboratory, Centre for Advanced Studies in Zoology, School of Life Science, Visva-Bharati (A Central University), Santiniketan, West Bengal, India.

    Source

    PloS one 12:1 2017 pg e0169809

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    28072841