GIP-(3–42) does not antagonize insulinotropic effects of GIP at physiological concentrations

Abstract

dent insulinotropic polypeptide ] is degraded by dipeptidyl peptidase IV (DPP IV), forming . In mice, high concentrations of synthetic GIP-(3-42) may function as a GIP receptor antagonist, but it is unclear whether this occurs at physiological concentrations. In COS-7 cells transiently transfected with the human GIP receptor, GIP-(1-42) and -(3-42) bind with affinities (IC50) of 5.2 and 22 nM, respectively. GIP-(1-42) was a potent agonist, stimulating cAMP accumulation (EC50, 13.5 pM); GIP-(3-42) alone had no effect. When incubated together with native GIP, GIP-(3-42) behaved as a weak antagonist (IC50, 92 and 731 nM for inhibition of cAMP accumulation elicited by 10 pM and 1 nM native GIP, respectively). In the isolated perfused rat pancreas, GIP-(3-42) alone had no effect on insulin output and only reduced the response to GIP (1 nM) when coinfused in Ͼ50-fold molar excess (IC50, 138 nM). The ability of GIP-(3-42) to affect the antihyperglycemic or insulinotropic actions of GIP-(1-42) was examined in chloralose-anesthetized pigs given intravenous glucose. Endogenous DPP IV activity was inhibited to reduce degradation of the infused GIP-(1-42), which was infused alone and together with GIP-(3-42), at rates sufficient to mimic postprandial concentrations of each peptide. Glucose, insulin, and glucagon responses were identical irrespective of whether GIP-(1-42) was infused alone or together with GIP-(3-42). We conclude that, although GIP-(3-42) can weakly antagonize cAMP accumulation and insulin output in vitro, it does not behave as a physiological antagonist in vivo. glucose homeostasis; dipeptidyl peptidase IV; inhibitor; valine-pyrrolidide GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE (GIP), like glucagon-like peptide-1 (GLP-1), is degraded by dipeptidyl peptidase IV (DPP IV) in vivo to form an NH 2 -terminally truncated metabolite (6,7,15). This metabolite, GIP-(3-42), has been reported both to lack insulinotropic activity (3, 33) and to act as a GIP receptor antagonist in mice (10).In previous studies (4, 5), our group showed that DPP IV inhibition reduces the NH 2 -terminal degradation of both incretin hormones in vivo, resulting in a potentiation of their insulinotropic effects. Furthermore, DPP IV inhibition increases the levels of endogenous intact GLP-1 and GIP in the circulation (9,22), and this is associated with improved glucose tolerance in rodents and man (1,2,29,30,34). These effects could be due to the enhanced levels of intact incretins found after DPP IV inhibition, the reduced levels of potentially antagonistic metabolites, or a combination of both factors. It was previously not possible to assess the true efficacy of the incretin hormones independently of their metabolites in vivo, because both endogenous and exogenous GLP-1 and GIP are rapidly degraded by endogenous DPP IV. Any observed effect, therefore, is the result of the combination of effects of the intact forms of each peptide together with any effects of their primary metabolites. However, the present availability of DPP IV inhibitors...

Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3–42) and GLP-1(9–36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

“…These effects were not associated with the inhibition of insulin secretion, which suggests that endogenously produced GIP is not involved in the modulation of b-cell function through antagonism of the normal stimulatory effects of GIP. It should also be noted that recent results have shown GIP not to antagonise the insulinotrophic effects of GIP at physiological concentrations (Deacon et al 2006), although dosing concentrations employed in the present study far exceeded the physiological concentration of GIP. Possible improvement of insulin Figure 4 Effects of daily GIP and GLP-1(9-36)amide administration on insulin sensitivity in ob/ob mice.…”

Dipeptidyl Peptidase-4 Inhibition and the Treatment of Type 2 Diabetes

“…Hence, it seems reasonable to consider whether differences in the ratios of intact to cleaved incretin peptides have biological implications. Although GIP(3-42) may be a weak GIP receptor antagonist in vitro, it does not exert glucoregulatory actions in vivo (71,72).…”

Comparison of sub-chronic metabolic effects of stable forms of naturally occurring GIP(1-30) and GIP(1-42) in high fat fed mice

“…Thus, GIP is rapidly metabolised by the ubiquitous enzyme dipeptidylpeptidase IV (DPP IV) to release the N-terminal dipeptide Tyr 1 -Ala 2 , giving rise to a biologically inactive fragment (Deacon et al 2006). However, N-terminally modified analogues of GIP have profound resistance to DPP IV-mediated degradation, such as [D-Ala 2 ]GIP (Hinke et al 2002, Widenmaier et al 2010.…”