PloS one, 2017-01, Vol.12 (1), p.e0169809-e0169809
2017
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Details
- Autor(en) / Beteiligte
- Titel
- A Small Insulinomimetic Molecule Also Improves Insulin Sensitivity in Diabetic Mice
- Ist Teil von
- PloS one, 2017-01, Vol.12 (1), p.e0169809-e0169809
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2017
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0169809Titel-ID: cdi_plos_journals_1869938596
- Format
- –
- Schlagworte
- 3T3 Cells, Adiponectin, Adiponectin - genetics, Adiponectin - metabolism, Adipose tissue, Adipose Tissue - metabolism, AMP-Activated Protein Kinases - genetics, AMP-Activated Protein Kinases - metabolism, Animals, Bioenergetics, Biology and Life Sciences, Blood glucose, Blood Glucose - metabolism, Care and treatment, CD36 antigen, CD36 Antigens - genetics, CD36 Antigens - metabolism, Cells, Cultured, Coordination Complexes - pharmacology, Coordination Complexes - therapeutic use, Diabetes, Diabetes mellitus, Diabetes Mellitus, Experimental - drug therapy, Diabetes Mellitus, Experimental - metabolism, Energy balance, Fatty acids, Fatty Acids - blood, Female, Gene expression, Glucose, Homeostasis, Hypoglycemic Agents - chemical synthesis, Hypoglycemic Agents - pharmacology, Hypoglycemic Agents - therapeutic use, Injection, Insulin, Insulin Resistance, Kinases, Medicine and Health Sciences, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mimetic compounds, Mitochondria, Muscle, Skeletal - metabolism, Muscles, Oral administration, Pancreas, Physical Sciences, Physiological aspects, PPAR gamma - genetics, PPAR gamma - metabolism, Protein Binding, Protein-tyrosine kinase receptors, Receptor, Insulin - agonists, Receptor, Insulin - metabolism, Rodents, Sensitivity, Signaling, Skeletal muscle, Streptozocin, Triglycerides - blood, Tyrosine, Vanadium Compounds - chemical synthesis, Vanadium Compounds - pharmacology, Vanadium Compounds - therapeutic use, Wnt3A Protein - genetics, Wnt3A Protein - metabolism