Novel ABCA1 peptide agonists with antidiabetic action.

Affiliation

Geriatric Research, Education, and Clinical Center (GRECC), VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA; Division of Endocrinology, Gerontology and Metabolism, Stanford University School of Medicine, Stanford, CA, 94305, USA. Electronic address: [Email]

Abstract

Previously, apoE-derived ABCA1 agonist peptides have been shown to possess anti-atherosclerotic and possibly antidiabetic properties. Here we assessed the in vitro and in vivo actions of a second generation of ABCA1 peptide agonists, CS6253 and T6991-2, on glucose homeostasis. The results show that these two peptides improve glucose tolerance in a prediabetic diet-induced obesity mouse model by enhancing insulin secretion. It was further demonstrated that T6991-2 also improved glucose tolerance in leptin-deficient (ob/ob) mice. CS6253 increased insulin secretion both under basal conditions and in response to high glucose stimulation in pancreatic INS-1 β-cells rendered leptin receptor deficient with specific siRNA. Additional in vitro cell studies suggest that the CS6253 agonist attenuates hepatic gluconeogenesis and glucose transport. It also potentiates insulin-stimulated glucose uptake and utilization. These observed anti-diabetic actions suggest additional benefits of the CS6253 and T6991-2 ABCA1 peptide agonists for cardiovascular disease beyond their direct anti-atherosclerosis properties previously described.

Keywords

Atherosclerosis,Diet induced diabetes,Glucose homeostasis,HDL mimetic,Insulin secretagogue,Type 2 diabetes,

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