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Aims: The gastrointestinal hormone GIP promotes pancreatic islet function and exerts pro-survival actions on cultured β-cells. However, GIP also promotes lipogenesis, thus potentially restricting its therapeutic use. The current studies evaluated the effects of a truncated GIP analog, D-Ala²-GIP1-30 (D-GIP1-30), on glucose homeostasis and β-cell mass in rat models of diabetes. Materials and Methods: The insulinotropic and pro-survival potency of D-GIP1-30 was evaluated in perfused pancreas preparations and cultured INS-1 β-cells, respectively, and receptor selectivity evaluated using wild type and GIP receptor knockout mice. Effects of D-GIP1-30 on β-cell function and glucose homeostasis, in vivo, were determined using Lean Zucker rats, obese Vancouver diabetic fatty rats, streptozotocin treated rats, and obese Zucker diabetic fatty rats, with effects on β-cell mass determined in histological studies of pancreatic tissue. Lipogenic effects of D-GIP1-30 were evaluated on cultured 3T3-L1 adipocytes. Results: Acutely, D-GIP1-30 improved glucose tolerance and insulin secretion. Chronic treatment with D-GIP1-30 reduced levels of islet pro-apoptotic proteins in Vancouver diabetic fatty rats and preserved β-cell mass in streptozotocin treated rats and Zucker diabetic fatty rats, resulting in improved insulin responses and glycemic control in each animal model, with no change in body weight. In in vitro studies, D-GIP1-30 exhibited equivalent potency to GIP1-42 on β-cell function and survival, but greatly reduced action on lipoprotein lipase activity in 3T3-L1 adipocytes. Conclusions: These findings demonstrate that truncated forms of GIP exhibit potent anti-diabetic actions, without pro-obesity effects, and that the C-terminus contributes to the lipogenic actions of GIP. [ABSTRACT FROM AUTHOR]

Glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-stimulated insulin secretion, insulin biosynthesis, and j3-cell proliferation and survival. In previous studies GIP was shown to promote a-cell survival by modulating the activity of multiple signaling modules and regulating gene transcription of pro-and anti-apoptotic bcl-2 family proteins. We have now evaluated the mechanisms by which GIP regulates the dynamic interactions between cytoplasmic bcl-2 family members and the mitochondria in INS-1 cells during apoptosis induced by treatment with staurosporine (STS), an activator of the mitochondria-mediated apoptotic pathway. STS induced translocation of bad and bimEL, activation of mitochondrial bax, release of mitochondrial cytochrome c, cleavage of caspase-3, and apoptosis. Each response was significantly diminished by GIP. Using selective enzyme inhibitors, overexpression of dominant-negative Akt, and Akt siRNA, it was demonstrated that GIP promoted j3-cell survival via Akt-dependent suppression of p38 MAPK and JNK and that combined inhibition was sufficient to explain the entire pro-survival responses to GIP during STS treatment. This signaling pathway also explained the pro-survival effects of GIP on INS-1 cells exposed to two other promoters of stress: thapsigargin (endoplasmic reticulum stress) and etoposide (genotoxic stress). Importantly, we discovered that GIP suppressed p38 MAPK and JNK via Akt-mediated changes in the phosphorylation state of the apoptosis signal-regulating kinase 1 in INS-1 cells and human islets, resulting in inhibition of its activity. Inhibition of apoptosis by GIP is therefore mediated via a key pathway involving Akt-dependent inhibition of apoptosis signal-regulating kinase 1, which subsequently prevents the pro-apoptotic actions of p38 MAPK and JNK. Glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-stimulated insulin secretion, insulin bio- synthesis, and β-cell proliferation and survival. In previous studies GIP was shown to promote β-cell survival by modulating the activity of multiple signaling modules and regulating gene transcription of pro-and anti-apoptotic bcl-2 family proteins. We have now evaluated the mechanisms by which GIP regulates the dynamic interactions between cytoplasmic bcl-2 family members and the mitochondria in INS-1 cells during apoptosis induced by treatment with staurosporine (STS), an activator of the mitochondria-mediated apoptotic pathway. STS induced translocation of bad and bimEL, activation of mitochondrial bax, release of mitochondrial cytochrome c, cleavage of caspase-3, and apoptosis. Each response was significantly diminished by GIP. Using selective enzyme inhibitors, overexpression of dominant-negative Akt, and Akt siRNA, it was demonstrated that GIP promoted β-cell survival via Akt-dependent suppression of p38 MAPK and JNK and that combined inhibition was sufficient to explain the entire pro-survival responses to GIP during STS treatment. This signaling pathway also explained the pro-survival effects of GIP on INS-1 cells exposed to two other promoters of stress: thapsigargin (endoplasmic reticulum stress) and etoposide (genotoxic stress). Importantly, we discovered that GIP suppressed p38 MAPK and JNK via Akt-mediated changes in the phosphorylation state of the apoptosis signal-regulating kinase 1 in INS-1 cells and human islets, resulting in inhibition of its activity. Inhibition of apoptosis by GIP is therefore mediated via a key pathway involving Akt-dependent inhibition of apoptosis signal-regulating kinase 1, which subsequently prevents the pro-apoptotic actions of p38 MAPK and JNK. [ABSTRACT FROM AUTHOR]