Insulinotropic Polypeptide Receptor Research Articles

1668-P: Differentiated Metabolic Effects of DA-1726, a Balanced GLP1R/GCGR Dual Agonist

DA-1726 is a novel oxyntomodulin analogue preparing for phase I clinical trials for obesity. In this study, the pharmacological effect of DA-1726 compared to other competitor peptides was evaluated. DA-1726 showed superior efficacy compared to other glucagon-like peptide-1 receptor (GLP1R)/glucagon receptor (GCGR) dual agonist (Cotadutide; COTA) in reducing body weight (14.4% for DA-1726 and 6.4% for COTA vs. DIO control at 30 nmol/kg, p<0.05) and improving plasma glucose, insulin, and HOMA-IR (-91% for DA-1726 vs. -52% for COTA) in diet-induced obese mice. In addition, superior plasma triglyceride (TG) reduction and similar reduction of total cholesterol (T-CHO) compared to COTA were confirmed by DA-1726. These data suggested that the balanced dual agonist DA-1726 was superior to a GLP1R-biased dual agonist in metabolic effects. Meanwhile, enhanced glucagon action of GLP1R/GCGR dual agonists may increase the risk of hyperglycemia when GLP1R agonism is reduced. Thus, DA-1726 was injected for 3 weeks and glucose tolerance test was performed at 72-h after the last dosing. DA-1726 did not impair glucose tolerance even at minimal plasma concentrations during repeated dosing up to 100 nmol/kg. In the case of repeated dosing of 100 nmol/kg, the plasma drug concentration at 72-h after the final injection is similar to the concentration that induces about 50% activation of receptors under 4% human albumin condition. In a comparative study with a GLP1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual agonist (Tirzepatide; TIR), DA-1726 showed a similar maximum efficacy on weight loss (31.2% for DA-1726 and 31.3% for TIR vs. DIO control, p<0.05). However, DA-1726 was more efficacious in improving plasma metabolic parameters such as glucose, TG, and T-CHO compared to TIR, indicating differential metabolic effects caused by GCGR agonism. Taken together, these data suggest that DA-1726 is a well-balanced GLP1R/GCGR dual agonist that effectively reduces body weight and glycemic control. Disclosure Y.Chae: None. I.Jung: None. T.Kim: None. S.Lee: None. M.Kim: Employee; Dong-A ST. H.Kim: None.

Potential of a glucagon-like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor/glucagon receptor triagonist for the treatment of obesity and type 2 diabetes.

Triagonists of GLP-1R/ GIPR /GCGR, including SAR441255, bind to each receptor and induce specific effects through each receptor signaling pathway, thus result in weight loss and glycemic control in obese T2D animal models.

The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect

Incretin hormones are peptides released in the intestine in response to the presence of nutrients in its lumen. The main incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 stimulates insulin secretion, inhibits glucagon secretion at pancreatic α cells and has also extrapancreatic influences as slowing of gastric emptying which increases the feeling of satiety. GIP is the main incretin hormone in healthy people, causative of most the incretin effects, but the insulin response after GIP secretion in type 2 diabetes mellitus (T2DM) is strongly reduced. Therefore, in the past GIP has been considered an unappealing therapeutic target for T2DM. This conception has been changing during recent years, since it has been reported that resistance to GIP can be reversed and its effectiveness restored by improving glycemic control. This fact paved the way for the development of a GIP receptor agonist-based therapy for T2DM, looking also for the possibility of finding a combined GLP-1/GIP receptor agonist. In this framework, the novel dual GIP and GLP-1 receptor agonist tirzepatide seems to be not just a new antidiabetic medication. Administered as a subcutaneous weekly injection, it is a manifold single pharmacological agent that has the ability to significantly lower glucose levels, as well as improve insulin sensitivity, reduce weight and amend dyslipidemia favorably modifying the lipid profile. Tirzepatide and additional dual GLP-1/GIP receptor agonists that could eventually be developed in the future seem to be a promising furthest advance for the management of several cardiometabolic settings. Obviously, it is too early to be overly hopeful since it is still necessary to determine the long-term effects of these compounds and properly verify the potential cardiovascular benefits. Anyway, we are currently facing a novel and very appealing therapeutic option.

Prevention of streptozotocin‑induced Neuro‑2a cell death by C8‑B4 microglia transformed with repetitive low‑dose lipopolysaccharide

Diabetes‑associated neuronal dysfunction (DAND) is one of the serious complications of diabetes, but there is currently no remedy for it. Streptozotocin [2‑deoxy‑2‑(3‑methy1‑3‑nitrosoureido) D‑glucopyranose; STZ] is one of the most well‑established diabetes inducers and has been used invivo and invitro DAND models. The aim of the present study was to demonstrate that C8‑B4 microglia transformed by the stimulus of repetitive low‑dose lipopolysaccharide (LPSx3‑microglia) prevent STZ‑induced Neuro‑2a neuronal cell death invitro. The ELISA results showed that neurotrophin‑4/5 (NT‑4/5) secretion was promoted in LPSx3‑microglia and the cell viability assay with trypan blue staining revealed that the culture supernatant of LPSx3‑microglia prevented STZ‑induced neuronal cell death. In addition, reverse transcription‑quantitative PCR showed that neurons treated with the culture supernatant of LPSx3‑microglia promoted the gene expression of B‑cell lymphoma‑extra large and glucose‑dependent insulinotropic polypeptide receptor. Furthermore, the inhibition of tyrosine kinase receptor B, a receptor of NT‑4/5, suppressed the neuroprotective effect of LPSx3‑microglia. Taken together, the present study demonstrated that LPSx3‑microglia prevent STZ‑induced neuronal death and that NT‑4/5 may be involved in the neuroprotective mechanism of LPSx3‑microglia.

Twincretin as a potential therapeutic for the management of type2 diabetes with obesity.

Unimolecular peptide‐based dual agonists against glucagon‐like peptide‐1 receptor (GLP‐1R) and glucose‐dependent insulinotropic polypeptide receptor (GIPR) have been gaining much attention recently as novel antidiabetic agents that can potentially control glycemia and bodyweight. Although GLP‐1 and GIP both enhance insulin secretion and subsequently ameliorate postprandial glucose excursion, most research has focused on GLP‐1R as a therapeutic target for type 2 diabetes. This is partly because the effects of GIPR activation on glycemia and bodyweight have been controversial. GIPR‐deficient mice showed impaired glucose tolerance with reduced β‐cell function and resistance to high‐fat diet‐induced obesity, whereas GIPR agonists improved glycemia and prevented high‐fat diet‐induced obesity in mice. Conflicting results in mice might be explained by pharmacological levels of GIP signal in the central nervous systems decreasing food intake and overcoming the obesogenic effects of GIP at physiological levels in adipose tissues. Thus, GIPR activation at pharmacological levels might result in bodyweight reduction. Indeed, bodyweight reduction by GIPR/GLP‐1R dual agonists was greater than GLP‐1R single agonists in individuals with type 2 diabetes. Thus, GLP‐1R/GIPR dual agonists can add additional therapeutic efficacy to tailored diabetes care, especially among obese individuals with type 2 diabetes. However, caution should be exercised as to whether or not these drugs are appropriate for the management of Asian type 2 diabetes patients, which are primarily characterized by non‐obesity and impaired β‐cell function, as well as in that of elderly adults with type 2 diabetes, who tend to develop sarcopenia and frailty as a result of poor energy intake.

Biological and functional characteristics of a novel low–molecular weight antagonist of glucose‐dependent insulinotropic polypeptide receptor, SKL‐14959, in vitro and in vivo

We recently discovered a glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist, SKL-14959. GIP plays a role in the glucose and lipid metabolism, and is associated with obesity and insulin resistance. Therefore, we aimed to ascertain the inhibitory potency and glucose and lipid metabolism of SKL-14959. SKL-14959 was evaluated for its binding affinity to each GIP, glucagon-like peptide-1 (GLP-1) and glucagon receptors by each labelled and non-labelled ligand; GIP-stimulated cyclic AMP (cAMP) production in CHO cells expressing human GIP receptor in vitro. Oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT) were performed to examine the insulinotropic effect on endogenous and exogenous GIP. Oil tolerance tests were also conducted to examine the lipid metabolism and the postheparin plasma lipase activity, lipoprotein lipase (LPL) and hepatic lipase (HL). SKL-14959 selectively bound to GIP receptor and inhibited GIP-stimulated cAMP production with the Ki value of 55 nM and an IC(50) value of 2.9 µM, respectively. SKL-14959·Na significantly increased blood glucose levels, inhibited insulin secretion in OGTT and inhibited the plasma glucose lowering of exogenous GIP in IPGTT. Furthermore, SKL-14959 increased plasma triacylglycerol (TG) levels as well as suppressed the postheparin plasma lipase activity in an oil load test. These data indicate that SKL-14959 is distinguished in the physiological phenotype of GIP following direct binding to the receptor.

Internalization and trafficking of the glucose-dependent insulinotropic polypeptide (GIP) receptor is dependent on intracellular calcium signaling

Internalization and trafficking of the glucose-dependent insulinotropic polypeptide (GIP) receptor is dependent on intracellular calcium signaling

Characterization of chimeric glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1) receptor proteins

Characterization of chimeric glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1) receptor proteins

Glucose-dependent insulinotropic polypeptide stimulated insulin release from a tumor-derived β-cell line (βTC3)

The beta TC3 tumor cell line was examined for the presence of functional glucose-dependent insulinotropic polypeptide (GIP) receptors. Increasing amounts of natural porcine GIP decreased the binding of HPLC-purified [125I]GIP to beta TC3 cells in a concentration-dependent manner. Displacement of GIP was significant at concentrations as low as 500 pM, and the radioligand was fully displaced at 100 nM. GIP(1-30) produced a displacement of [125I]GIP comparable with that produced by GIP(1-42), and glucagon yielded 20% displacement at a concentration of 1 microM but was without effect at 100 mM. Incubation of beta TC3 cells in the presence of glucose concentrations of 2-20 mM yielded a concentration-dependent stimulation of immunoreactive insulin (IRI) release. GIP and glucagon-like peptide-I(7-36) amide (tGLP-I) at concentrations of 1 nM or greater significantly stimulated IRI release in the presence of 2 mM glucose. The threshold glucose concentration for GIP-stimulated IRI release from beta TC3 cells was 0.5 mM, and maximal potentiation of IRI release by GIP occurred at 5 mM glucose. Somatostatin significantly inhibited GIP-stimulated IRI release in the presence of 5 mM glucose. It is concluded that beta TC3 cells have functional GIP receptors and may provide a useful model for the study of IRI secretion at the cellular level.