Nanoparticle Delivered Human Biliverdin Reductase-Based Peptide Increases Glucose Uptake by Activating IRK/Akt/GSK3 Axis: The Peptide Is Effective in the Cell and Wild-Type and Diabetic Ob/Ob Mice.
Insulin's stimulation of glucose uptake by binding to the IRK extracellular domain is compromised in diabetes. We have recently described an unprecedented approach to stimulating glucose uptake. KYCCSRK (P2) peptide, corresponding to the C-terminal segment of hBVR, was effective in binding to and inducing conformational change in the IRK intracellular kinase domain. Although myristoylated P2, made of L-amino acids, was effective in cell culture, its use for animal studies was unsuitable. We developed a peptidase-resistant formulation of the peptide that was efficient in both mice and cell culture systems. The peptide was constructed of D-amino acids, in reverse order, and blocked at both termini. Delivery of the encapsulated peptide to HepG2 and HSKM cells was confirmed by its prolonged effect on stimulation of glucose uptake (>6 h). The peptide improved glucose clearance in both wild-type and Ob/Ob mice; it lowered blood glucose levels and suppressed glucose-stimulated insulin secretion. IRK activity was stimulated in the liver of treated mice and in cultured cells. The peptide potentiated function of IRK's downstream effector, Akt-GSK3-(α, β) axis. Thus, P2-based approach can be used for improving glucose uptake by cells. Also, it allows for screening peptides in vitro and in animal models for treatment of diabetes.
Department of Biophysics and Biochemistry, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Peter E M
PE
Gibbs
Department of Biophysics and Biochemistry, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Tihomir
T
Miralem
Department of Biophysics and Biochemistry, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Nicole
N
Lerner-Marmarosh
Department of Biophysics and Biochemistry, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Mahin D
MD
Maines
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008820:Mice, Obese; D053758:Nanoparticles; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D011972:Receptor, Insulin / Q000187:drug effects* / Q000378:metabolism
D001786:Blood Glucose; D010446:Peptide Fragments; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D005947:Glucose