Improved biological activity of Gly2- and Ser2-substituted analogues of glucose-dependent insulinotrophic polypeptide

Abstract

The therapeutic potential of glucagon-like peptide-1

A Novel, Long-Acting Agonist of Glucose-Dependent Insulinotropic Polypeptide Suitable for Once-Daily Administration in Type 2 Diabetes

“…Thus, although native GIP is a weak stimulus to insulin secretion in ob/ob mice at the age studied, plasma and pancreatic insulin concentrations were raised in ob/ob mice receiving the novel fatty acid-derivatized analog. This is consistent with the action of GIP as a promoter of proinsulin gene expression (Wang et al, 1996) and exemplifies the increased potency reported for N-terminally modified GIP analogs in animal models of diabetes (O'Harte et al, 2000Gault et al, 2002aGault et al, , 2003aHinke et al, 2002). Furthermore, the insulin response to glucose was significantly enhanced in ob/ob mice receiving N-AcGIP(LysPAL 37 ).…”

“…The prospect for this is encouraging in that the once-postulated specific defect in GIP stimulation of insulin secretion in diabetes (Nauck et al, 1993) is now recognized to represent one aspect of a generalized pancreatic ␤ cell dysfunction that extends to many secretagogues including incretin hormones (Kjems et al, 2003;Meier et al, 2003b). Additionally, DPP IV-resistant N-terminally modified analogs of GIP have been shown to induce a protracted insulin response in both animals and humans with type 2 diabetes (O'Harte et al, 2000Gault et al, 2002aGault et al, , 2003aLindsay et al, 2002).…”

“…Moreover, because the insulinotropic actions of GIP are glucose-dependent (Bailey and Flatt, 1995), the risk of hypoglycemia, a major drawback with nonendogenous insulin-releasing drugs, is minimized (Collins, 2002). Accordingly, an important opportunity currently exists to generate a safe and efficient GIP-based pharmaceutical agent for the treatment of type 2 diabetes (O'Harte et al, 2000Gault et al, 2002aGault et al, , 2003aHinke et al, 2002).…”

“…In the past 6 years, a number of N-terminally modified analogs of GIP have been developed that exhibit profound resistance to DPP IV (O'Harte et al, 2000Gault et al, 2002aGault et al, , 2003a. Several of these, most notably those modified at Tyr 1 of GIP with an addition of an acetyl, glucitol, pyroglutamyl, or Fmoc adduct, exhibit enhanced activity at the GIP receptor in vitro (O'Harte et al, 1998Gault et al, 2002aGault et al, , 2003a.…”

“…Several of these, most notably those modified at Tyr 1 of GIP with an addition of an acetyl, glucitol, pyroglutamyl, or Fmoc adduct, exhibit enhanced activity at the GIP receptor in vitro (O'Harte et al, 1998Gault et al, 2002aGault et al, , 2003a. As a result of degradation resistance and enhanced cellular activity, these analogs display enhanced and protracted antihyperglycemic and insulin-releasing activity when administered acutely to animals with genetically-inherited obesity-diabetes (O'Harte et al, 2000Gault et al, 2002aGault et al, , 2003a. To increase potency and generate a long-acting GIP analog, possibly suitable for once-daily injection in diabetes, the problem of renal clearance needs to be overcome.…”