Effects Of Glucose-dependent Insulinotropic Polypeptide Research Articles

GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly.

About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.

Evaluation of synergism effect of human glucose-dependent insulinotropic polypeptide (GIP) on Klebsiella pneumoniae carbapenemases (KPC) producer isolated from clinical samples

Antibiotic resistance is increasing among Gram-negative bacteria, prompting the development of new antibiotics as well as alternative treatment approaches. Klebsiella pneumoniae Carbapenemases (KPC) has become a major concern in the treatment of infections, since KPC-producing bacteria are resistant to a number of β -lactam and non β-lactam antibiotics in addition to hydrolyzing carbapenemases. The aim of this study is to examine the synergistic effect of human Glucose-dependent Insulinotropic Polypeptide (GIP) on KPC producer. The K. pneumoniae isolates were identified by using biochemical tests and PCR genotyping. The disc diffusion method was used to assess the antimicrobial susceptibility of each isolate, and the modified Hodge test (MHT) was used to find carbapenemases. Agar well diffusion and minimum inhibitory concentration (MIC) assays were used to validate the synergistic effect of GIP against Klebsiella species. MIC values of chosen antimicrobial compounds demonstrated a considerable synergism impact when combined with human GIP, particularly against KPC strains. The antibacterial activity of the antimicrobial compounds was boosted by 4–16 times due to human GIP, reducing the MIC values. The fractional inhibitory concentration (FIC) ranged from 0.032 to 0.25 for examined antibiotics. Thus, GIP can be considered an antibacterial adjuvant with the potential to supplement the current antibiotic spectrum.

GIP attenuates neuronal oxidative stress by regulating glucose uptake in spinal cord injury of rat.

Glucose-dependent insulinotropic polypeptide (GIP) is a ligand of glucose-dependent insulinotropic polypeptide receptor (GIPR) that plays an important role in the digestive system. In recent years, GIP has been regarded as a hormone-like peptide to regulate the local metabolic environment. In this study, we investigated the antioxidant role of GIP on the neuron and explored the possible mechanism. Cell counting Kit-8 (CCK-8) was used to measure cell survival. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect apoptosis invitro and invivo. Reactive oxygen species (ROS) levels were probed with2', 7'-Dichloro dihydrofluorescein diacetate (DCFH-DA), and glucose intake was detected with 2-NBDG. Immunofluorescence staining and western blot were used to evaluate the protein level in cells and tissues. Hematoxylin-eosin (HE) staining, immunofluorescence staining and tract-tracing were used to observe the morphology of the injured spinal cord. Basso-Beattie-Bresnahan (BBB) assay was used to evaluate functional recovery after spinal cord injury. GIP reduced the ROS level and protected cells from apoptosis in cultured neurons and injured spinal cord. GIP facilitated wound healing and functional recovery of the injured spinal cord. GIP significantly improved the glucose uptake of cultured neurons. Meanwhile, inhibition of glucose uptake significantly attenuated the antioxidant effect of GIP. GIP increased glucose transporter 3 (GLUT3) expression via up-regulating the level of hypoxia-inducible factor 1α (HIF-1α) in an Akt-dependent manner. GIP increases GLUT3 expression and promotes glucose intake in neurons, which exerts an antioxidant effect and protects neuronal cells from oxidative stress both invitro and invivo.

The interplay of glucose-dependent insulinotropic polypeptide in adipose tissue.

Adipose tissue was once known as a reservoir for energy storage but is now considered a crucial organ for hormone and energy flux with important effects on health and disease. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted from the small intestinal K cells, responsible for augmenting insulin release, and has gained attention for its independent and amicable effects with glucagon-like peptide 1 (GLP-1), another incretin hormone secreted from the small intestinal L cells. The GIP receptor (GIPR) is found in whole adipose tissue, whereas the GLP-1 receptor (GLP-1R) is not, and some studies suggest that GIPR action lowers body weight and plays a role in lipolysis, glucose/lipid uptake/disposal, adipose tissue blood flow, lipid oxidation, and free-fatty acid (FFA) re-esterification, which may or may not be influenced by other hormones such as insulin. This review summarizes the research on the effects of GIP in adipose tissue (distinct depots of white and brown) using cellular, rodent, and human models. In doing so, we explore the mechanisms of GIPR-based medications for treating metabolic disorders, such as type 2 diabetes and obesity, and how GIPR agonism and antagonism contribute to improvements in metabolic health outcomes, potentially through actions in adipose tissues.

Effects of Exogenous GIP and GLP-2 on Bone Turnover in Individuals With Type 2 Diabetes.

Individuals with type 2 diabetes (T2D) have an increased risk of bone fractures despite normal or increased bone mineral density. The underlying causes are not well understood but may include disturbances in the gut-bone axis, in which both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are regulators of bone turnover. Thus, in healthy fasting participants, both exogenous GIP and GLP-2 acutely reduce bone resorption. The objective of this study was to investigate the acute effects of subcutaneously administered GIP and GLP-2 on bone turnover in individuals with T2D. We included 10 men with T2D. Participants met fasting in the morning on 3 separate test days and were injected subcutaneously with GIP, GLP-2, or placebo in a randomized crossover design. Blood samples were drawn at baseline and regularly after injections. Bone turnover was estimated by circulating levels of collagen type 1 C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), sclerostin, and PTH. GIP and GLP-2 significantly reduced CTX to (mean ± SEM) 66 ± 7.8% and 74 ± 5.9% of baseline, respectively, compared with after placebo (P = .001). In addition, P1NP and sclerostin increased acutely after GIP whereas a decrease in P1NP was seen after GLP-2. PTH levels decreased to 67 ± 2.5% of baseline after GLP-2 and to only 86 ± 3.4% after GIP. Subcutaneous GIP and GLP-2 affect CTX and P1NP in individuals with T2D to the same extent as previously demonstrated in healthy individuals.

Effect of tirzepatide on glycaemic control and weight loss compared with other glucagon-like peptide-1 receptor agonists in Japanese patients with type 2 diabetes mellitus.

To compare the therapeutic effects of glucose-dependent insulinotropic polypeptide (GIP)/ glucagon-like peptide-1 receptor agonists (GLP-1RAs) or GLP-1RAs in Japanese patients with type 2 diabetes (T2D). We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library up to July 2023. Randomized controlled trials (RCTs) that compared GLP-1RAs or GIP/GLP-1RAs in Japanese patients with T2D were selected. A network meta-analysis was conducted to indirectly compare the treatments, focusing on efficacy in reducing glycated haemoglobin (HbA1c) levels and body weight (BW). A total of 18 RCTs were included in this analysis. Tirzepatide 15 mg showed the most significant reduction in HbA1c levels and BW compared with subcutaneous semaglutide 1.0 mg and oral semaglutide 14 mg (HbA1c: mean difference [95% confidence interval] -0.52 [-0.96; -0.08] and - 1.23 [-1.64; -0.81]; BW: -5.07 [-8.28; -1.86] and -6.84 [-8.97; -4.71], respectively). Subcutaneous semaglutide showed a superior reduction in HbA1c compared with oral semaglutide. Both subcutaneous and oral semaglutide were more effective than conventional GLP-1RAs, such as dulaglutide, liraglutide and lixisenatide. Among Japanese patients with T2D, tirzepatide showed the greatest effectiveness in reducing HbA1c levels and inducing weight loss. The study provides evidence to guide GLP-1RA treatment strategies in Japanese patients with T2D.

GIP_HUMAN [22-51] Peptide Encoded by the Glucose-Dependent Insulinotropic Polypeptide (GIP) Gene Suppresses Insulin Expression and Secretion in INS-1E Cells and Rat Pancreatic Islets.

GIP_HUMAN [22-51] is a recently discovered peptide that shares the same precursor molecule with glucose-dependent insulinotropic polypeptide (GIP). In vivo, chronic infusion of GIP_HUMAN [22-51] in ApoE-/- mice enhanced the development of aortic atherosclerotic lesions and upregulated inflammatory and proatherogenic proteins. In the present study, we evaluate the effects of GIP_HUMAN [22-51] on insulin mRNA expression and secretion in insulin-producing INS-1E cells and isolated rat pancreatic islets. Furthermore, we characterize the influence of GIP_HUMAN [22-51] on cell proliferation and death and on Nf-kB nuclear translocation. Rat insulin-producing INS-1E cells and pancreatic islets, isolated from male Wistar rats, were used in this study. Gene expression was evaluated using real-time PCR. Cell proliferation was studied using a BrdU incorporation assay. Cell death was quantified by evaluating histone-complexed DNA fragments. Insulin secretion was determined using an ELISA test. Nf-kB nuclear translocation was detected using immunofluorescence. GIP_HUMAN [22-51] suppressed insulin (Ins1 and Ins2) in INS-1E cells and pancreatic islets. Moreover, GIP_HUMAN [22-51] promoted the translocation of NF-κB from cytoplasm to the nucleus. In the presence of a pharmacological inhibitor of NF-κB, GIP_HUMAN [22-51] was unable to suppress Ins2 mRNA expression. Moreover, GIP_HUMAN [22-51] downregulated insulin secretion at low (2.8 mmol/L) but not high (16.7 mmol/L) glucose concentration. By contrast, GIP_HUMAN [22-51] failed to affect cell proliferation and apoptosis. We conclude that GIP_HUMAN [22-51] suppresses insulin expression and secretion in pancreatic β cells without affecting β cell proliferation or apoptosis. Notably, the effects of GIP_HUMAN [22-51] on insulin secretion are glucose-dependent.

Body weight lowering effect of glucose-dependent insulinotropic polypeptide and glucagon-like peptide receptor agonists is more efficient in RAMP1/3 KO than in WT mice

The glucose-dependent insulinotropic polypeptide (GIPR) and glucagon-like peptide (GLP-1R) receptor agonists are insulin secretagogues that have long been shown to improve glycemic control and dual agonists have demonstrated successful weight loss in the clinic. GIPR and GLP-1R populations are located in the dorsal vagal complex where receptor activity-modifying proteins (RAMPs) are also present. According to recent literature, RAMPs not only regulate the signaling of the calcitonin receptor, but also that of other class B G-protein coupled receptors, including members of the glucagon receptor family such as GLP-1R and GIPR.The aim of this study was to investigate whether the absence of RAMP1 and RAMP3 interferes with the action of GIPR and GLP-1R agonists on body weight maintenance and glucose control. To this end, WT and RAMP 1/3 KO mice were fed a 45% high fat diet for 22 weeks and were injected daily with GLP-1R agonist (2 nmol/kg/d; NN0113-2220), GIPR agonist (30 nmol/kg/d; NN0441-0329) or both for 3 weeks.While the mono-agonists exerted little to no body weight lowering and anorectic effects in WT or RAMP1/3 KO mice, but at the given doses, when both compounds were administered together, they synergistically reduced body weight, with a greater effect observed in KO mice. Finally, GLP-1R and GIP/GLP-1R agonist treatment led to improved glucose tolerance, but the absence of RAMPs resulted in an improvement of the HOMA-IR score. These data suggest that RAMPs may play a crucial role in modulating the pharmacological actions of GLP-1 and GIP receptors.

1853-PUB: Extrapancreatic Effects of GIP on Bone

Glucose-dependent insulinotropic polypeptide (GIP) exhibits extrapancreatic effects through the receptor for GIP (GIPR). In this study, we used Ni-Ti Closed Coil Spring (Ni-Ti) in GIPR-deficient mice (GIPRKO) and wild-type mice (WT) to investigate the effect of GIP on force-induced bone remodeling due to orthodontic tooth movement. It was investigated. Ni-Ti was attached between the maxillary bone and the maxillary left first molar (M1) of GIPRKO and WT, and mechanical load was applied by pulling the M1 in the mesial direction. Remaining amount and bone quality were measured. A histological examination of the maxilla was also performed. As a result, compared to WT, GIPRKO showed a significant increase in tooth movement distance and a significant decrease in residual alveolar bone mass. TRAP staining showed an increase in osteoclasts in GIPRKO compared to WT on the tooth moving side. We also found that GIPRKO reduced osteoblasts in the steady state and suppressed osteoblasts after tooth movement. These results suggest that GIPRK impairs bone remodeling through increased bone resorption due to mechanical load, and that GIP plays an important role in bone remodeling. Disclosure T.Yamauchi: None. S.Goto: None. K.Naruse: None. N.Nakamura: None. M.Miyabe: None. M.Ito: None. R.Hoshino: None. S.Kanada: None. T.Sekiya: None. T.Matsubara: None. K.Miyazawa: None.

Glucose-dependent insulinotropic polypeptide counteracts diet-induced obesity along with reduced feeding, elevated plasma leptin and activation of leptin-responsive and proopiomelanocortin neurons in the arcuate nucleus.

To clarify the effects of glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (GIPRAs) on feeding and body weight. Acute and subchronic effects of subcutaneous GIPFA-085, a long-acting GIPRA, on blood glucose, food intake, body weight, respiratory exchange ratio and plasma leptin levels were measured in diet-induced obese (DIO) mice and/or functional leptin-deficient ob/ob mice. The effects of GIPFA-085 on the hypothalamic arcuate nucleus (ARC) neurons from lean and DIO mice were studied by measuring cytosolic Ca2+ concentration ([Ca2+ ]i ). Single bolus GIPFA-085 (30, 300 nmol/kg) dose-dependently reduced blood glucose in glucose tolerance tests, elevated plasma leptin levels at 0.5-6hours and inhibited food intake at 2-24 hours after injection in DIO mice. Daily GIPFA-085 (300 nmol/kg) inhibited food intake and increased fat utilization on day 1, and reduced body weight gain on days 3-12 of treatment in DIO, but not ob/ob, mice. GIPFA-085 increased [Ca2+ ]i in the ARC leptin-responsive and proopiomelanocortin (POMC) neurons. GIPFA-085 and leptin cooperated to increase [Ca2+ ]i in ARC neurons and inhibit food intake. GIPFA-085 acutely inhibits feeding and increases lipid utilization, and sustainedly lowers body weight in DIO mice via mechanisms involving rises in leptin and activation of ARC leptin-responsive and POMC neurons. This study highlights the therapeutic potential of GIPRAs for treating obesity and diabetes.

Separate and combined effects of long-term GIP and GLP-1 receptor activation in patients with type 2 diabetes: a structured summary of a study protocol for a double-blind, randomised, placebo-controlled clinical trial

IntroductionDue to reports of severely reduced insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetes (T2D), GIP has not been considered therapeutically viable. Recently, however,...

GIP reduces osteoclast activity and improves osteoblast survival in primary human bone cells.

Drugs targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) are emerging as treatments for type-2 diabetes and obesity. GIP acutely decreases serum markers of bone resorption and transiently increases bone formation markers in short-term clinical investigations. However, it is unknown whether GIP acts directly on bone cells to mediate these effects. Using a GIPR-specific antagonist, we aimed to assess whether GIP acts directly on primary human osteoclasts and osteoblasts. Osteoclasts were differentiated from human CD14+ monocytes and osteoblasts from human bone. GIPR expression was determined using RNA-seq in primary human osteoclasts and in situ hybridization in human femoral bone. Osteoclastic resorptive activity was assessed using microscopy. GIPR signaling pathways in osteoclasts and osteoblasts were assessed using LANCE cAMP and AlphaLISA phosphorylation assays, intracellular calcium imaging and confocal microscopy. The bioenergetic profile of osteoclasts was evaluated using Seahorse XF-96. GIPR is robustly expressed in mature human osteoclasts. GIP inhibits osteoclastogenesis, delays bone resorption, and increases osteoclast apoptosis by acting upon multiple signaling pathways (Src, cAMP, Akt, p38, Akt, NFκB) to impair nuclear translocation of nuclear factor of activated T cells-1 (NFATc1) and nuclear factor-κB (NFκB). Osteoblasts also expressed GIPR, and GIP improved osteoblast survival. Decreased bone resorption and improved osteoblast survival were also observed after GIP treatment of osteoclast-osteoblast co-cultures. Antagonizing GIPR with GIP(3-30)NH2 abolished the effects of GIP on osteoclasts and osteoblasts. GIP inhibits bone resorption and improves survival of human osteoblasts, indicating that drugs targeting GIPR may impair bone resorption, whilst preserving bone formation.

Does glucose lowering restore GIP effects on insulin secretion?

AimsSome studies have shown that in type 2 diabetic patients the potentiation of insulin secretion by glucose-dependent insulinotropic polypeptide (GIP) is compromised but can be partially restored if glucose is lowered. Renewed interest for this phenomenon has been expressed in the context of the new dual GIP-GLP-1 (glucagon-like peptide-1) receptor agonists, which have shown greater efficacy of this drug class compared with single GLP-1 receptor agonists, including on insulin secretion. However, contrasting evidence has been reported on the recovery of GIP action with glucose lowering. In our study, we reconsider all publications relevant for the problem and analyze the results using a uniform methodology. Data synthesisWe show that, while some contradictions might be explained by heterogeneous analysis methods, it is possible to interpret all the available data coherently and conclude that the effect of glucose lowering is relevant only when glucose concentration is virtually normalized. ConclusionsWhile a significant restoration of GIP action may not occur with some traditional diabetes treatments, GIP action improvement might become relevant when glucose is virtually normalized and could explain part of the success of the double GIP-GLP-1 receptor agonists.

The Gut-Bone Axis in Diabetes.

To describe recent advances in the understanding of how gut-derived hormones regulate bone homeostasis in humans with emphasis on pathophysiological and therapeutic perspectives in diabetes. The gut-derived incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is important for postprandial suppression of bone resorption. The other incretin hormone, glucagon-like peptide 1 (GLP-1), as well as the intestinotrophic glucagon-like peptide 2 (GLP-2) has been shown to suppress bone resorption in pharmacological concentrations, but the role of the endogenous hormones in bone homeostasis is uncertain. For ambiguous reasons, both patients with type 1 and type 2 diabetes have increased fracture risk. In diabetes, the suppressive effect of endogenous GIP on bone resorption seems preserved, while the effect of GLP-2 remains unexplored both pharmacologically and physiologically. GLP-1 receptor agonists, used for the treatment of type 2 diabetes and obesity, may reduce bone loss, but results are inconsistent. GIP is an important physiological suppressor of postprandial bone resorption, while GLP-1 and GLP-2 may also exert bone-preserving effects when used pharmacologically. A better understanding of the actions of these gut hormones on bone homeostasis in patients with diabetes may lead to new strategies for the prevention and treatment of skeletal frailty related to diabetes.

Impacts of Glucose-Dependent Insulinotropic Polypeptide on Orthodontic Tooth Movement-Induced Bone Remodeling.

Glucose-dependent insulinotropic polypeptide (GIP) exerts extra-pancreatic effects via the GIP receptor (GIPR). Herein, we investigated the effects of GIP on force-induced bone remodeling by orthodontic tooth movement using a closed-coil spring in GIPR-lacking mice (GIPRKO) and wild-type mice (WT). Orthodontic tooth movements were performed by attaching a 10-gf nickel titanium closed-coil spring between the maxillary incisors and the left first molar. Two weeks after orthodontic tooth movement, the distance of tooth movement by coil load was significantly increased in GIPRKO by 2.0-fold compared with that in the WT. The alveolar bone in the inter-root septum from the root bifurcation to the apex of M1 decreased in both the GIPRKO and WT following orthodontic tooth movement, which was significantly lower in the GIPRKO than in the WT. The GIPRKO exhibited a significantly decreased number of trabeculae and increased trabecular separation by orthodontic tooth movement compared with the corresponding changes in the WT. Histological analyses revealed a decreased number of steady-state osteoblasts in the GIPRKO. The orthodontic tooth movement induced bone remodeling, which was demonstrated by an increase in osteoblasts and osteoclasts around the forced tooth in the WT. The GIPRKO exhibited no increase in the number of osteoblasts; however, the number of osteoclasts on the coil-loaded side was significantly increased in the GIPRKO compared with in the WT. In conclusion, our results demonstrate the impacts of GIP on the dynamics of bone remodeling. We revealed that GIP exhibits the formation of osteoblasts and the suppression of osteoclasts in force-induced bone remodeling.

Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis.

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

Endogenous Glucose-Dependent Insulinotropic Polypeptide Contributes to Sitagliptin-Mediated Improvement in β-Cell Function in Patients With Type 2 Diabetes.

Dipeptidyl peptidase 4 (DPP-4) degrades the incretin hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors improve glycemic control in type 2 diabetes, but the importance of protecting GIP from degradation for their clinical effects is unknown. We included 12 patients with type 2 diabetes (mean ± SD BMI 27 ± 2.6 kg/m2, HbA1c 7.1 ± 1.4% [54 ± 15 mmol/mol]) in this double-blind, placebo-controlled, crossover study to investigate the contribution of endogenous GIP to the effects of the DPP-4 inhibitor sitagliptin. Participants underwent two randomized, 13-day treatment courses of sitagliptin (100 mg/day) and placebo, respectively. At the end of each treatment period, we performed two mixed-meal tests with infusion of the GIP receptor antagonist GIP(3-30)NH2 (1,200 pmol/kg/min) or saline placebo. Sitagliptin lowered mean fasting plasma glucose by 1.1 mmol/L compared with placebo treatment. During placebo treatment, postprandial glucose excursions were increased during GIP(3-30)NH2 compared with saline (difference in area under the curve ± SEM 7.3 ± 2.8%) but were unchanged during sitagliptin treatment. Endogenous GIP improved β-cell function by 37 ± 12% during DPP-4 inhibition by sitagliptin. This was determined by the insulin secretion rate/plasma glucose ratio. We calculated an estimate of the absolute sitagliptin-mediated impact of GIP on β-cell function as the insulinogenic index during sitagliptin treatment plus saline infusion minus the insulinogenic index during sitagliptin plus GIP(3-30)NH2. This estimate was expressed relative to the maximal potential contribution of GIP to the effect of sitagliptin (100%), defined as the difference between the full sitagliptin treatment effect, including actions mediated by GIP (sitagliptin + saline), and the physiological response minus any contribution by GIP [placebo treatment + GIP(3-30)NH2]. We demonstrate insulinotropic and glucose-lowering effects of endogenous GIP in patients with type 2 diabetes and that endogenous GIP contributes to the improved β-cell function observed during DPP-4 inhibition.

357-OR: Improved Glycemic Control in Persons with Type 2 Diabetes Improves Beta-Cell Actions of Endogenous Glucose-Dependent Insulinotropic Polypeptide

The insulinotropic effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) is severely reduced or even absent in persons with type 2 diabetes but may be partly regained following improved glycemic control. Here, we examined the beta cell response to endogenous GIP before and after a period of plasma glucose (PG) normalization. In a randomized, double-blind design, 15 metformin-treated persons with dysregulated type 2 diabetes (HbA1c 8.3±0.3% (67±3 mmol/mol) ([mean±SEM]) were subjected to two 75 g-oral glucose tolerance tests (OGTT) with continuous infusions of GIP receptor antagonist (GIP (3-30) NH2) and placebo (saline) , respectively, before and in the end of a 3-4 week period of PG normalization achieved using administration of empagliflozin and individually dosed insulin based on continuous glucose monitoring (CGM) (fasting PG (FPG) target: 72-1mg/mL (4.0-5.9 mmol/L) ; 2-hour postprandial PG target: <162 mg/mL (<9.0 mmol/L)) . At the end of the PG normalization period, FPG was reduced from 195±mg/mL (10.8±0.6 mmol/L) to 114±4 mg/mL (6.3±0.2 mmol/L) (P<0.001) and area under curve (AUC) for PG during OGTT diminished (3,409±95 vs. 2,428±91 mmol/L×min, P<0.001) . Before the period of PG normalization, GIP (3-30) NH2 did not affect oral glucose tolerance. PG normalization amplified GIP (3-30) NH2-induced lowering of beta cell glucose sensitivity (∆baseline-subtracted AUCplasma C-peptide:PG ratio: 1,579±380 vs. 3,296±617 pmol/mmol×min, P=0.021) and resulted in a significant effect of GIP (3-30) NH2 on oral glucose tolerance (baseline-subtracted AUCPG: 1,146±65 vs. 1,225±58 mmol/L×min, P=0.025) . In persons with dysregulated type 2 diabetes, a period of PG normalization increased beta cell sensitivity to GIP, translating into a detectable contribution of endogenous GIP to oral glucose tolerance. Disclosure B.Hoe: None. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. M.B.Lynggaard: None. L.S.Gasbjerg: Speaker's Bureau; Eli Lilly and Company, Stock/Shareholder; Antag Therapeutics. M.M.Helsted: None. S.Stensen: Employee; Novo Nordisk A/S. B.Hartmann: Board Member; Bainan Biotech. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. M.B.Christensen: None. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd. Funding The Novo Nordisk Foundation

1362-P: Endogenous Glucose-Dependent Insulinotropic Polypeptide Facilitates Postprandial Intestinal Lipid Uptake in Healthy Men, but Not in Patients with Type 2 Diabetes

The gut hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates glucose-induced insulin secretion and increases triglyceride deposition in subcutaneous adipose tissue, and these effects are attenuated in both type 2 diabetes (T2D) and obesity. Using the GIP receptor antagonist GIP (3-30) NH2, we investigated the effect of endogenous GIP on circulating lipoproteins (chylomicrons, VLDL, LDL, HDL) during a meal in healthy men and patients with T2D. We measured apolipoprotein B48 (ApoB48) (as a marker of chylomicron count) and plasma lipoprotein triglyceride and cholesterol content during two liquid meal tests (1,894 kJ) with double-blind infusions of GIP (3-30) NH2 or placebo (saline) in randomized order in 12 healthy men (19-65 years, BMI 20.3-25.5 kg/m2) and in patients with T2D (44-72 years, HbA1c 6.2-11% (37-70 mmol/mol) , BMI 27.4-41.2 kg/m2) . Compared to placebo, the GIP (3-30) NH2 infusion lowered postprandial responses of ApoB48 (incremental area under the curve (iAUC0-180 min) (median (95%CI)) : 215 (156-258) vs. 4 (363-541) mg×L-1×min, P=0.0049) , chylomicron-triglyceride content (iAUC0-270 min: 32.7 (-2.32-72.1) vs. 49.5 (1.21-170) mmol× L-1×min P=0.083) and HDL-triglyceride content (iAUC0-270min: -0.90 (-1.95-0.18) vs. 0.95 (-0.72-3.95) mmol× L-1×min, P=0.016) . In patients with T2D, infusion of GIP (3-30) NH2 did not change postprandial responses of ApoB48 or lipoprotein-triglyceride content. In both groups, there were no differences in lipoprotein-cholesterol contents. Disclosure L.S.Gasbjerg: Speaker's Bureau; Eli Lilly and Company, Stock/Shareholder; Antag Therapeutics. C.Christoffersen: None. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. M.M.Rosenkilde: Research Support; Antag Therapeutics, Bainan Biotech, Stock/Shareholder; Antag Therapeutics, Bainan Biotech, Synklino ApS. M.M.Helsted: None. S.Stensen: Employee; Novo Nordisk A/S. L.S.L.Krogh: None. A.H.Sparre-ulrich: Other Relationship; Antag Therapeutics. B.Hartmann: Board Member; Bainan Biotech. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd. M.B.Christensen: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. Funding EFSD (no. 94815) ; Novo Nordisk Foundation (no. 13777)

A Novel Dual Incretin Agent, Tirzepatide (LY3298176), for the Treatment of Type 2 Diabetes Mellitus and Cardiometabolic Health.

The incretin hormone system is the target of multiple type 2 diabetes mellitus (T2DM) treatments because defects in this system play major roles in the pathogenesis of diabetes. Currently, the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended for patients with atherosclerotic cardiovascular (CV) disease and those at high risk for atherosclerotic CV disease. In addition to the favorable CV effects, GLP-1 RAs also provide robust lowering of hemoglobin A1c and weight. Although these factors make GLP-1 RAs attractive options for T2DM, the currently available agents have no effect on glucose-dependent insulinotropic polypeptide (GIP). Patients with T2DM are known to have GIP defect which is significant due to its profound insulinotropic effects. Tirzepatide is a novel incretin agent currently recently approved by the Food and Drug Administration for the treatment of T2DM. This first-in-class agent serves as a coagonist for both the GLP-1 and GIP receptors. In this review, we report on the pharmacologic mechanism of GLP-1, GIP, and coagonist effects on the cardiometabolic system. In addition, we review the glycemic lowering, weight loss effects, and other cardiometabolic outcomes of tirzepatide based on phase 2 and 3 data. The safety profile of tirzepatide is consistent across all phase 3 trials. The most common adverse effects are gastrointestinal symptoms, but they generally have a low risk for discontinuation. Overall, preliminary data suggest that tirzepatide is an efficacious and safe agent for the treatment of T2DM.