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.

Testicular germ cell apoptosis and sperm defects in mice upon long‐term high fat diet feeding

“…After acclimatization for 7 days, the mice were randomly assigned to control and treated groups. The treated group was reared on high fat diet (HFD) to obtain insulin resistant animals, a widely used model as previously described by us and others (Chatterjee et al, 2013;Mukherjee et al, 2017;Pal et al, 2012). In brief, the HFD consisted of lard (32.5%), corn oil (32.5%), sucrose (20%), and protein (15%), while the standard diet (SD) contained carbohydrate (57.3%), protein (18.1%), and fat (4.5%).…”

Vanadium compounds: New potential antidiabetic drugs

“…Slična situacija je i sa kompleksima peroksovanadijuma. Oni su se u brojnim in silico, in vitro i animalnim studijama pokazali kao efikasni antidijabetički agensi, ali bezbednost i sigurnost njihove primene nije bila prihvatljiva usled povećanja stepena oksidativnog stresa u ćelijama (27).…”

Vanadium in Biological Action: Chemical, Pharmacological Aspects, and Metabolic Implications in Diabetes Mellitus

“…Furthermore, vanadate increases Akt kinase activity and causes its phosphorylation at Ser473 and Thr308, consequently increasing the number of cells at the synthesis (S) phase and transition from gap 1 (G 1 ) to S phase through the E2F-pRb pathway in normal C141 cells [247]. Other studies show that vanadium compounds stimulate kinases in the signal transduction pathways used by insulin beyond the insulin receptor (IR) and the substrate IRS-1, and secondarily, the phosphoinosidide 3 kinase (PI3K), Akt, MAPK pathways (mainly, ERK pathways) together with the activation of the S6 kinases, hence playing an anti-diabetic and anti-lipolytic role, with concomitant insulin-like effects [248][249][250][251][252][253][254][255][256]. Vanadate also stimulates the IRS-1 phosphorylation, the PI3K activity, the ERK signaling pathway, and the p70s6k and p90rsk kinases independently of IR-tyrosine phosphorylation, which in turn phosphorylate and regulate the activity of several transcription factors related with cell proliferation and glycogen synthesis [257][258][259].…”