No abstract

AimsThe 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 MethodsThe 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.ResultsAcutely, 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.ConclusionsThese 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.

Glucose-dependent insulinotropic polypeptide (GIP) is a hormone released from enteroendocrine K cells in response to meals. Posttranslational processing of the precursor protein pro-GIP at residue 65 by proprotein convertase subtilisin/kexin type 1 (PC1/3) in gut K cells gives rise to the established 42-amino-acid form of GIP (GIP1–42). However, the pro-GIP peptide sequence contains a consensus cleavage site for PC2 at residues 52–55 and we identified PC2 immunoreactivity in a subset of K cells, suggesting the potential existence of a COOH-terminal truncated GIP isoform, GIP1–30. Indeed a subset of mouse and human K cells display GIP immunoreactivity with GIP antibodies directed to the mid portion of the peptide, but not with a COOH-terminal-directed GIP antibody, indicative of the presence of a truncated form of GIP. This population of cells represents ∼5–15% of the total GIP-immunoreactive cells in mice, depending on the region of intestine, and is virtually absent in mice lacking PC2. Amidated GIP1–30 and GIP1–42 have comparable potency at stimulating somatostatin release in the perfused mouse stomach. Therefore, GIP1–30 represents a naturally occurring, biologically active form of GIP.

Adenosine has been demonstrated to inhibit gastric acid secretion. In the rat stomach, this inhibitory effect may be mediated indirectly by increasing the release of somatostatin-like immunoreactivity (SLI). Results show that adenosine analogs augmented SLI release in the isolated vascularly perfused rat stomach. The rank order of potency of the analogs in stimulating SLI release was 2-p- Adenosine has been demonstrated to modulate a variety of physiological functions by acting on purinergic P1 receptors. These G protein-coupled receptors are classified into adenosine A 1 , A 2A , A 2B , and A 3 subtypes based on their pharmacological and structural properties. Each subtype has been cloned in the brain tissues of various species, including human (Fredholm et al., 2001).Clinical studies have suggested that changes in the endogenous level of adenosine may influence gastric acid secretion and play a role in ulcer formation. The activity of adenosine deaminase (ADA), a metabolic enzyme of adenosine, seems to be directly correlated with basal and maximal levels of gastric acid output in the fundic mucosa of achlorhydria, gastritis, and ulcer patients (Namiot et al., 1990). Patients suffering from hypersecretion of gastric acid were shown to exhibit elevated levels of ADA activity. In gastric ulcer patients, ADA activity in the corpus mucosa was also shown to be reduced after ranitidine treatment (Namiot et al., 1991). These studies, therefore, suggest that adenosine inhibits gastric acid secretion and acts as a gastroprotective agent. Article, publication date, and citation information can be found at

No abstract