Combined Hyperglycemia- and Hyperinsulinemia-Induced Insulin Resistance in Adipocytes Is Associated With Dual Signaling Defects Mediated by PKC-ζ

• DOI: 10.1210/en.2017-00312
• Publication Date: 2018-01-23T19:01:36Z
• Authors: Huogen Lu; Elena Bogdanovic; Zhiwen Yu; Charles Cho; Lijiang Liu; Karen Ho; June Guo; Lucy S N Yeung; Reiner Lehmann; Harinder S Hundal; Adria Giacca; I George Fantus
• Keywords: Hyperinsulinemia; Insulin receptor substrate

A hyperglycemic and hyperinsulinemic environment characteristic of type 2 diabetes causes insulin resistance. In adipocytes, defects in both sensitivity maximum response glucose transport have been demonstrated. To investigate the molecular mechanisms, freshly isolated rat adipocytes were incubated control (5.6 mM glucose, no insulin) high (20 mM)/high (100 nM) (HG/HI) for 18 hours to induce Insulin-resistant manifested decreased uptake associated with receptor substrate (IRS)-1 Tyr phosphorylation, association p85 subunit phosphatidylinositol-3-kinase, Akt Ser473 Thr308 accompanied by impaired transporter 4 translocation. contrast, protein kinase C (PKC)-ζ activity was augmented chronic HG/HI. Inhibition PKC-ζ a specific cell-permeable peptide reversed signaling uptake. Transfection dominant-negative, kinase-inactive blocked resistance, whereas constitutively active recapitulated defects. The HG/HI incubation stimulation IRS-1 Ser318 Thr34 targets PKC-ζ. S318A T34A each partially corrected signaling, combined transfection completely normalized signaling. vivo hyperglycemia/hyperinsulinemia rats 48 similarly resulted activation increased phosphorylation Thr34. These data indicate that impairment is mediated dual at