Tirzepatide (TZP), a GIP receptor and GLP-1 receptor (GIPR/GLP-1R) dual agonist, has demonstrated profound effects on glycemic control and bodyweight lowering in T2D subjects. However, the mechanism of action for the dual agonism of TZP is incompletely understood. Adipose expresses GIPR but not GLP-1R and therefore presents a key target tissue to investigate TZP biology. Using differentiated human adipocytes, we explored TZP regulation of lipid and carbohydrate metabolism. TZP demonstrated significant modulation of lipid accumulation, efflux, and oxidation. Similar to insulin, TZP increased expression and secretion of active LPL. While it had no effect on its own, TZP dose dependently suppressed insulin stimulated de novo lipogenesis in [14C]glucose and [14C]acetate incorporation assays. Insulin and TZP counter-regulated lipolysis characterized by insulin suppression and TZP stimulation of glycerol release. Uncoupled oxygen consumption was increased by TZP and subsequently reduced by CPT1 inhibition (etomoxir) demonstrating regulation of fatty acid oxidation. In adipose glycemic control, TZP exhibited both direct and insulin-dependent regulation of glucose transport. TZP at low dose (10pM) provided indirect (insulin sensitizing) effects while higher doses (10 nM) directly stimulated [14C]glucose uptake in adipocytes. While acute GIP infusion in a rat hyperinsulinemic/euglycemic clamp demonstrated no change in total body glucose infusion rate (GIR), chronic treatment (two week) with TZP or GIPR agonist increased GIR and adipose tissue [14C]glucose accumulation. This suggests both tissue-specific and whole-body insulin sensitization through GIPR agonism. Taken together, this data demonstrates GIPR specific activity of TZP in regulating adipose function. These findings and ongoing pathway integration studies will provide clues to the metabolic benefit of TZP GIPR/GLP-1R dual agonism compared with GLP-1R agonism alone.

Disclosure

R.J. Samms: Employee; Self; Eli Lilly and Company. M.E. Christe: Employee; Self; Eli Lilly and Company. X. Ruan: Employee; Self; Eli Lilly and Company. J. Moyers: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. A. Regmi: Employee; Self; Eli Lilly and Company. W.C. Roell: Employee; Self; Eli Lilly and Company.

© 2019 by the American Diabetes Association.
2019
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