Effects Of GIP Research Articles

105-OR: Single-Cell Multiomic Analysis of the Effect of GIP and GIP-1 Mono- and Multi-agonism on the Hypothalamus and Hindbrain

105-OR: Single-Cell Multiomic Analysis of the Effect of GIP and GIP-1 Mono- and Multi-agonism on the Hypothalamus and Hindbrain

Stimulating intestinal GIP release reduces food intake and body weight in mice

ObjectiveGlucose dependent insulinotropic polypeptide (GIP) is well established as an incretin hormone, boosting glucose-dependent insulin secretion. However, whilst anorectic actions of its sister-incretin glucagon-like peptide-1 (GLP-1) are well established, a physiological role for GIP in appetite regulation is controversial, despite the superior weight loss seen in preclinical models and humans with GLP-1/GIP dual receptor agonists compared with GLP-1R agonism alone. MethodsWe generated a mouse model in which GIP expressing K-cells can be activated through hM3Dq Designer Receptor Activated by Designer Drugs (DREADD, GIP-Dq) to explore physiological actions of intestinally-released GIP. ResultsIn lean mice, Dq-stimulation of GIP expressing cells increased plasma GIP to levels similar to those found postprandially. The increase in GIP was associated with improved glucose tolerance, as expected, but also triggered an unexpected robust inhibition of food intake. Validating that this represented a response to intestinally-released GIP, the suppression of food intake was prevented by injecting mice peripherally or centrally with antagonistic GIPR-antibodies, and was reproduced in an intersectional model utilising Gip-Cre/Villin-Flp to limit Dq transgene expression to K-cells in the intestinal epithelium. The effects of GIP cell activation were maintained in diet induced obese mice, in which chronic K-cell activation reduced food intake and attenuated body weight gain. ConclusionsThese studies establish a physiological gut-brain GIP-axis regulating food intake in mice, adding to the multi-faceted metabolic effects of GIP which need to be taken into account when developing GIPR-targeted therapies for obesity and diabetes.

Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of β-cell function and insulin sensitivity in Africans without type 2 diabetes

BackgroundIn vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses.MethodsWe used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones (adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, IL-1RA) on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and β-cell function (HOMA-B) as dependent variables among non-T2D individuals (n = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones).ResultsCirculating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S β = − 0.67, P-value = 1.88 × 10−6 and HOMA-B β = 0.59, P-value = 1.88 × 10−5; IL-1RA ~ HOMA-S β = − 0.51, P-value = 8.49 × 10−5 and HOMA-B β = 0.48, P-value = 5.71 × 10−4). IL-RA was partly mediated via BMI (30-34%), but GIP was not. Inverse variance weighted MR analysis provided evidence for a causal effect of adipsin on T2D (multivariable OR = 1.83, P-value = 9.79 × 10−6), though these associations were not consistent in all sensitivity analyses.ConclusionsThe findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased β-cell function. GIP’s effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans.

1754-P: Reduced Incretin Effect Predicts Diabetes Appearance in a Cohort of Nondiabetic Subjects after Acute Beta-Cell Mass Reduction

In type 2 diabetes incretin effect (IE) is reduced but still contributes to 20-35% of insulin response to oral glucose. One reason is the impairment of GIP and GLP1 effects. The role of IE in nondiabetic people is still under debate. In this study we evaluated changes in GLP1 levels, differential β-cell responses and IE during oral vs intravenous stimuli in nondiabetic humans before and after pancreatoduodenectomy (PD). We enrolled 37 nondiabetic patients affected by periampullary nonmalignant neoplasms scheduled for PD. Subjects underwent a 2-h hyperglycemic clamp (HC), a 830 kcal mixed meal test (MMT), and an oral glucose tolerance test (OGTT) before and after PD. GLP1 secretion was calculated during MMT stimulation. β-cell glucose sensitivity (βCGS, pmol·min−1m−2·mM−1) was calculated as the ratio of insulin secretion and glucose increments during both HC and MMT. IE was calculated as the ratio of βCGS obtained during MMT and HC. Based on post-PD OGTT, we divided nondiabetic subjects into 3 groups according to glucose tolerance after PD: normal glucose tolerance (postNGT, n=11), impaired glucose tolerance (postIGT, n=15), or diabetes (postDM, n=11). Before surgery, postIGT subjects exhibited increased GLP1 secretion during MMT compared to the other 2 groups (GLP1 AUC: postIGT 12638±688 vs postNGT 6994±1773 vs postDM 6443±1687 pmol/L·min, P<0.05). Further, a similar βCGS was observed in the 3 groups following HC stimulation (postNGT 95.2±15.5 vs postIGT 64.3±8.72 vs postDM 73.8±11.8, P=0.2), while a scaled reduction in βCGS was observed in postIGT and post-DM following MMT (postNGT 206±50.0 vs postIGT 111±19.9 vs postDM 88.2±8.45, P<0.05). Accordingly, we observed a scaled reduction of IE in postIGT and postDM groups (postNGT 2.35±0.52 vs post-IGT 1.37±0.13 vs post-DM 0.86±0.18, P<0.05). Our data show that GLP1 secretion increases in people at risk of IGT, possibly to compensate reduced IE, which seems to predict DM appearance after β-cell mass reduction. Disclosure G.Di giuseppe: None. J.J.Holst: Advisory Panel; Novo Nordisk A/S, Eli Lilly and Company, Board Member; Bainan Biotech, Antag Therapeutics, Consultant; Alphasights, Eli Lilly and Company, ShouTi Pharma Inc., Zealand Pharma A/S, Other Relationship; Novo Nordisk, Novo Nordisk Pharma, Mayo Clinic, Boehringer-Ingelheim, Scohia Pharma Inc., Research Support; ARLA, European Union, Novo Nordisk Foundation. A.Giaccari: Speaker's Bureau; Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi. T.Mezza: None. C.Cefalo: None. S.Moffa: None. G.Ciccarelli: None. L.Soldovieri: None. F.Cinti: None. U.Capece: None. F.Impronta: None. A.Mari: Consultant; Eli Lilly and Company. Funding Università Cattolica del Sacro Cuore; European Foundation for the Study of Diabetes; Ministero della Salute

1548-P: GLP-1 and GIP Reduce Insulin Clearance in Individuals with Pancreatic-Insufficient Cystic Fibrosis (PI-CF)

PI-CF is characterized by impaired insulin secretion with disruption of the enteroinsular axis and alterations in incretin secretion and action. We have reported augmented glucose-dependent insulin secretion to glucose-potentiated arginine (GPA) testing with GLP-1 infusion but not GIP, with these effects independent of glucose tolerance in PI-CF. We aimed to assess the effect of incretin infusion on insulin clearance during GPA testing and explore its relationship to second-phase insulin response in individuals with PI-CF in a retrospective analysis. Thirty-two individuals with PI-CF and abnormal glucose tolerance underwent GPA testing of islet function following intravenous infusion of incretin or placebo in a randomized cross-over study design. Sixteen individuals were randomized to incretin infusion with GLP-1 and sixteen with GIP. Insulin clearance was assessed by the molar ratio of acute C-peptide to insulin response over the 5-minutes following glucose-potentiation of arginine-induced insulin and C-peptide secretion (target glucose ~230 mg/dL). Insulin clearance was related to second-phase insulin secretion by hyperbolic function (y=P1/(P2 + x) with a reduction in insulin clearance for increasing second-phase insulin secretion (R2=0.20; p<0.001). A reduction in insulin clearance was observed with both GLP-1 vs. placebo (mean±SD 2.7±2.1 vs. 15.5±5.7; p<0.001) and GIP vs. placebo (2.4±0.8 vs. 18.0±10.8; p<0.001). GLP-1 and GIP appear to reduce insulin clearance in individuals with PI-CF presumably through effects at the liver. Reduced insulin clearance is most apparent following GIP infusion where there is no augmentation of second-phase insulin secretion, supporting that the effect of GIP occurs independently of an increase in pre-hepatic insulin secretion. Further work should explore underlying mechanisms of incretin-induced reduction in insulin clearance in PI-CF that could support therapeutic approaches to improve glucose homeostasis. Disclosure A.Flatt: None. A.Doliba: None. A.J.Peleckis: None. R.C.Rubenstein: None. A.Kelly: None. M.R.Rickels: Consultant; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Dompé. Funding National Institutes of Health (R01DK97830, UL1TR001878, P30DK19525, T32DK007314); Cystic Fibrosis Foundation (to M.R.R.)

Obesity-associated Blunted Subcutaneous Adipose Tissue Blood Flow After Meal Improves After Bariatric Surgery.

ContextGlucose-dependent insulinotropic peptide (GIP) and meal ingestion increase subcutaneous adipose tissue (SAT) perfusion in healthy individuals. The effects of GIP and a meal on visceral adipose tissue (VAT) perfusion are unclear.ObjectiveOur aim was to investigate the effects of meal and GIP on VAT and SAT perfusion in obese individuals with type 2 diabetes mellitus (T2DM) before and after bariatric surgery.MethodsWe recruited 10 obese individuals with T2DM scheduled for bariatric surgery and 10 control individuals. Participants were studied under 2 stimulations: meal ingestion and GIP infusion. SAT and VAT perfusion was measured using 15O-H2O positron emission tomography–magnetic resonance imaging at 3 time points: baseline, 20 minutes, and 50 minutes after the start of stimulation. Obese individuals were studied before and after bariatric surgery.ResultsBefore bariatric surgery the responses of SAT perfusion to meal (P = .04) and GIP-infusion (P = .002) were blunted in the obese participants compared to controls. VAT perfusion response did not differ between obese and control individuals after a meal or GIP infusion. After bariatric surgery SAT perfusion response to a meal was similar to that of controls. SAT perfusion response to GIP administration remained lower in the operated-on than control participants. There was no change in VAT perfusion response after bariatric surgery.ConclusionThe vasodilating effects of GIP and meal are blunted in SAT but not in VAT in obese individuals with T2DM. Bariatric surgery improves the effects of a meal on SAT perfusion, but not the effects of GIP. Postprandial increase in SAT perfusion after bariatric surgery seems to be regulated in a GIP-independent manner.

Molecular Docking of Compounds in Moringa oleifera Lam with Dipeptidyl Peptidase-4 Receptors as Antidiabetic Candidates

Background: Diabetes mellitus (DM) type 2 is a metabolic disorder that needs special attention because it can damage several organs if the severity increases. One of the treatments for diabetes mellitus (DM) type 2 is by inhibiting Dipeptidyl peptidase 4 (DPP-IV) with vildagliptin to prolong the hypoglycemic effect of GLP-1 and GIP. Objective: In the search for candidate compounds as new antidiabetic compounds, an in silico test with molecular docking was carried out to predict the antidiabetic activity of 10 Moringa oleifera Lam (MO) plant compounds at the DPP-IV receptor (PDB ID: 6B1E). Method: The study was conducted using the molecular docking method. Result: Validation of the vildagliptin DPP-IV ligand obtained free energy values of -9.27 kcal/mol and RMSD 1.49 Å (RMSD < 2 Å), then tested with 10 test compounds obtained 8 test compounds that have the potential to be antidiabetic. Conclusion: Serpentine compounds have better potential as an antidiabetic drug than other target compounds because they have the closest Gibbs energy (∆G) value to the natural ligand of Vidaglibtin, which is -7.90 kcal/mol. This value is still lower than the free energy of vildagliptin, which is -9.37 kcal/mol. Therefore further testing is needed to ensure the potential of the compound as a candidate for antidiabetic drugs.

Different mechanisms of GIP and GLP-1 action explain their different therapeutic efficacy in type 2 diabetes

Background and aimsThe reduced action of incretin hormones in type 2 diabetes (T2D) is mainly attributed to GIP insensitivity, but efficacy estimates of GIP and GLP-1 differ among studies, and the negligible effects of pharmacological GIP doses remain unexplained. We aimed to characterize incretin action in vivo in subjects with normal glucose tolerance (NGT) or T2D and provide an explanation for the different insulinotropic activity of GIP and GLP-1 in T2D subjects. MethodsWe used in vivo data from ten studies employing hormone infusion or an oral glucose test (OGTT). To homogeneously interpret and compare the results of the studies we performed the analysis using a mathematical model of the β-cell incorporating the effects of incretins on the triggering and amplifying pathways. The effect on the amplifying pathway was quantified by a time-dependent factor that is greater than one when insulin secretion (ISR) is amplified by incretins. To validate the model results for GIP in NGT subjects, we performed an extensive literature search of the available data. Resultsa) the stimulatory effects of GIP and GLP-1 differ markedly: ISR potentiation increases linearly with GLP-1 over the whole dose range, while with GIP infusion it reaches a plateau at ~100 pmol/L GIP, with ISR potentiation of ~2 fold; b) ISR potentiation in T2D is reduced by ~50% for GIP and by ~40% for GLP-1; c) the literature search of GIP in NGT subjects confirmed the saturative effect on insulin secretion. ConclusionWe show that incretin potentiation of ISR is reduced in T2D, but not abolished, and that the lack of effects of pharmacological GIP doses is due to saturation of the GIP effect more than insensitivity to GIP in T2D.

1906-P: Glucose-Dependent Insulinotropic Polypeptide (GIP) Reduces Bone Resorption in Patients with Type 2 Diabetes

In healthy individuals, GIP enhances insulin secretion and reduces bone resorption As GIP has impaired insulinotropic effects in patients with type 2 diabetes (T2D), we investigated the effect of glucose and GIP on bone resorption in these patients. In a randomized, double-blinded, cross-over study, 12 male patients with T2D underwent six study days with 90-minute GIP or matching placebo (saline) infusions on paired days with plasma glucose (PG) clamped at three levels: Fasting hyperglycemia (mean PG ∼8 mmol/l), aggravated hyperglycemia (mean PG ∼12 mmol/l), or insulin-induced hypoglycemia (mean PG 3-8 mmol/l). Primary outcome measure was CTX (a marker of bone resorption expressed as %-change from baseline ± SD). On days with fasting hyperglycemia, CTX was suppressed by 36±15% during GIP compared to 0±9% during saline infusion (p<0.0001). On days with aggravated hyperglycemia, CTX was suppressed by 47±23% during GIP compared to 10±9% during saline infusion (p=0.0005). On days with insulin-induced hypoglycemia, CTX was suppressed by 40±15% during GIP compared to 12±11% during saline infusion (p<0.0001). In conclusion, Short-term GIP infusions during hyperglycemia reduce bone resorption by more than a third suggesting that GIP has preserved effects on bone in patients with T2D. Disclosure M.B. Christensen: None. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. N.R. Jørgensen: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.

Insights into incretin-based therapies for treatment of diabetic dyslipidemia.

Derangements in triglyceride and cholesterol metabolism (dyslipidemia) are major risk factors for the development of cardiovascular diseases in obese and type-2 diabetic (T2D) patients. An emerging class of glucagon-like peptide-1 (GLP-1) analogues and next generation peptide dual-agonists such as GLP-1/glucagon or GLP-1/GIP could provide effective therapeutic options for T2D patients. In addition to their role in glucose and energy homeostasis, GLP-1, GIP and glucagon serve as regulators of lipid metabolism. This review summarizes the current knowledge in GLP-1, glucagon and GIP effects on lipid and lipoprotein metabolism and frames the emerging therapeutic benefits of GLP-1 analogs and GLP-1-based multiagonists as add-on treatment options for diabetes associated dyslipidemia.

UNGAL - An early marker for kidney injury in patients with type I diabetes mellitus

Derangements in triglyceride and cholesterol metabolism (dyslipidemia) are major risk factors for the development of cardiovascular diseases in obese and type-2 diabetic (T2D) patients. An emerging class of glucagon-like peptide-1 (GLP-1) analogues and next generation peptide dual-agonists such as GLP-1/glucagon or GLP-1/GIP could provide effective therapeutic options for T2D patients. In addition to their role in glucose and energy homeostasis, GLP-1, GIP and glucagon serve as regulators of lipid metabolism. This review summarizes the current knowledge in GLP-1, glucagon and GIP effects on lipid and lipoprotein metabolism and frames the emerging therapeutic benefits of GLP-1 analogs and GLP-1-based multiagonists as add-on treatment options for diabetes associated dyslipidemia.

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.

Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism

ObjectiveStructurally-improved GIP analogs were developed to determine precisely whether GIP receptor (GIPR) agonism or antagonism lowers body weight in obese mice. MethodsA series of peptide-based GIP analogs, including structurally diverse agonists and a long-acting antagonist, were generated and characterized in vitro using functional assays in cell systems overexpressing human and mouse derived receptors. These analogs were characterized in vivo in DIO mice following acute dosing for effects on glycemic control, and following chronic dosing for effects on body weight and food intake. Pair-feeding studies and indirect calorimetry were used to survey the mechanism for body weight lowering. Congenital Gipr−/− and Glp1r−/− DIO mice were used to investigate the selectivity of the agonists and to ascribe the pharmacology to effects mediated by the GIPR. ResultsNon-acylated, Aib2 substituted analogs derived from human GIP sequence showed full in vitro potency at human GIPR and subtly reduced in vitro potency at mouse GIPR without cross-reactivity at GLP-1R. These GIPR agonists lowered acute blood glucose in wild-type and Glp1r−/− mice, and this effect was absent in Gipr−/− mice, which confirmed selectivity towards GIPR. Chronic treatment of DIO mice resulted in modest yet consistent, dose-dependent decreased body weight across many studies with diverse analogs. The mechanism for body weight lowering is due to reductions in food intake, not energy expenditure, as suggested by pair-feeding studies and indirect calorimetry assessment. The weight lowering effect was preserved in DIO Glp-1r−/− mice and absent in DIO Gipr−/− mice. The body weight lowering efficacy of GIPR agonists was enhanced with analogs that exhibit higher mouse GIPR potency, with increased frequency of administration, and with fatty-acylated peptides of extended duration of action. Additionally, a fatty-acylated, N-terminally truncated GIP analog was shown to have high in vitro antagonism potency for human and mouse GIPR without cross-reactive activity at mouse GLP-1R or mouse glucagon receptor (GcgR). This acylated antagonist sufficiently inhibited the acute effects of GIP to improve glucose tolerance in DIO mice. Chronic treatment of DIO mice with high doses of this acylated GIPR antagonist did not result in body weight change. Further, co-treatment of this acylated GIPR antagonist with liraglutide, an acylated GLP-1R agonist, to DIO mice did not result in increased body weight lowering relative to liraglutide-treated mice. Enhanced body weight lowering in DIO mice was evident however following co-treatment of long-acting selective individual agonists for GLP-1R and GIPR, consistent with previous data. ConclusionsWe conclude that peptide-based GIPR agonists, not peptide-based GIPR antagonists, that are suitably optimized for receptor selectivity, cross-species activity, and duration of action consistently lower body weight in DIO mice, although with moderate efficacy relative to GLP-1R agonists. These preclinical rodent pharmacology results, in accordance with recent clinical results, provide definitive proof that systemic GIPR agonism, not antagonism, is beneficial for body weight loss.

The role of single nucleotide polymorphisms in GIPR gene in the changes of secretion in hormones and adipokines in patients with obesity with type 2 diabetes

The relationship between the rs2302382, rs8111428 and Glu354Gln (rs1800437) polymorphisms in GIPR (glucosedependent insulinotropic polypeptide receptor) gene and plasma levels of mediators involved in the regulation of carbohydrate metabolism in obese patients with type 2 diabetes (before and after a test breakfast) was investigated. The contribution of polymorphic variants of rs2302382, rs8111428 in GIPR gene in the predisposition to type 2 diabetes in individuals belonging to the Slavic population of Russia was found. Polymorphisms rs2302382 and rs8111428 in the GIPR gene were characterized by the nonequilibrium cohesion. The decrease in the level of expression of the GIPR gene in adipose tissue of the small intestine mesentery in the carriers of the CC genotype rs2302382 and AA rs8111428 was associated with the increase in the plasma leptin level, whereas during normal expression, the plasma content of insulin, and GIP (in persons with the genotype of the polymorphism rs2302382 and AG polymorphism rs8111428), resistin and ghrelin (in individuals with the genotype of the polymorphism rs2302382) increased. We propose the stimulating effect of GIP on the secretion of resistin, leptin and ghrelin, with an increase in insulin production in obese patients with type 2 diabetes.

Incretins modulate progesterone biosynthesis by regulating bone morphogenetic protein activity in rat granulosa cells

The effects of incretins on ovarian steroidogenesis have not been clarified. In this study, we investigated the effects of incretins, including GIP and GLP-1, on ovarian steroidogenesis using rat primary granulosa cells. Treatment with incretins significantly suppressed progesterone synthesis in the presence of FSH, and the effect of GIP was more potent than that of GLP-1. In contrast, incretins had no significant effect on estrogen synthesis by rat granulosa cells. In accordance with the effects of incretins on steroidogenesis, GIP and GLP-1 suppressed the expression of progesterogenic factors and enzymes, including StAR, P450scc, 3βHSD, but not P450arom, and cellular cAMP synthesis induced by FSH. In addition, incretins moderately increased FSHR mRNA expression in granulosa cells. Of note, treatment with GIP, but not treatment with GLP-1, augmented Smad1/5/8 phosphorylation and transcription of the BMP target gene Id-1 induced by BMP-6 stimulation, suggesting that GIP upregulates BMP receptor signaling that can inhibit FSH-induced progesterone synthesis in rat granulosa cells. On the other hand, BMP-6 treatment suppressed the expression of GIP receptor but not that of GLP-1 receptor. Expression of the BMP type-I receptor ALK-3 was upregulated by treatment with GIP and GLP-1 and that of ALK-6 was also increased by GIP, while inhibitory Smad6 expression was impaired by GIP and GLP-1 in rat granulosa cells. Collectively, the results indicate that incretins, particularly GIP, impair FSH-induced progesterone production, at least in part, by upregulating BMP signaling in rat granulosa cells. The modulatory effects of incretins on endogenous BMP activity may be applicable to treatment of dysregulated steroidogenesis such as polycystic ovary syndrome.

Suppressive Effects of Glucose-Dependent Insulinotropic Polypeptide on Cardiac Hypertrophy and Fibrosis in Angiotensin II-Infused Mouse Models.

Activation of glucose-dependent insulinotropic polypeptide receptor (GIPR) has been shown to be protective against atherosclerosis. However, effects of GIP on the heart have remained unclear. To address this question, in vitro and in vivo experiments were conducted. In isolated mouse cardiomyocytes, GIPR mRNA was detected by reverse transcription-polymerase chain reaction, and GIP stimulation increased adenosine 3',5'-cyclic monophosphate production. In apolipoprotein E-knockout mice, infusion of angiotensin II (AngII; 2,000 ng·kg(-1)·min(-1)) significantly increased the heart weights, and co-administration of GIP (25 nmol·kg(-1)·day(-1)) reversed this increase (both P<0.01). In the left ventricular walls, GIP suppressed AngII-induced cardiomyocyte hypertrophy by 34%, apoptosis by 77%, and interstitial fibrosis by 79% (all P<0.01). Furthermore, GIP reduced AngII-induced expression of transforming growth factor-β1 (TGF-β1) and hypoxia inducible factor-1α. In wild-type mice, cardiac hypertrophy was induced by AngII to a lesser extent, and prevented by GIP. In contrast, GIP did not show any cardioprotective effect against AngII-induced cardiac hypertrophy in GIPR-knockout mice. In an in vitro experiment using mouse cardiomyocytes, GIP suppressed AngII-induced mRNA expression of B-type natriuretic peptide and TGF-β1. It was demonstrated that cardiomyocytes represent a direct target of GIP action in vitro, and that GIP ameliorated AngII-induced cardiac hypertrophy via suppression of cardiomyocyte enlargement, apoptosis, and fibrosis in vivo. (Circ J 2016; 80: 1988-1997).

Glucose-Dependent Insulinotropic Polypeptide May Enhance Fatty Acid Re-esterification in Subcutaneous Abdominal Adipose Tissue in Lean Humans

OBJECTIVEGlucose-dependent insulinotropic polypeptide (GIP) has been implicated in lipid metabolism in animals. In humans, however, there is no clear evidence of GIP effecting lipid metabolism. The present experiments were performed in order to elucidate the effects of GIP on regional adipose tissue metabolism.RESEARCH DESIGN AND METHODSEight healthy subjects were studied on four different occasions. Abdominal subcutaneous adipose tissue metabolism was assessed by measuring arterio-venous concentration differences and regional adipose tissue blood flow during GIP (1.5 pmol/kg/min) or saline infused intravenously alone or in combination with a hyperinsulinemic-hyperglycemic (HI-HG) clamp.RESULTSDuring GIP and HI-HG clamp, abdominal subcutaneous adipose tissue blood flow, hydrolysis of circulating triacylglycerol (TAG) (P = 0.009), and glucose uptake (P = 0.03) increased significantly while free fatty acid (FFA) output (P = 0.04) and FFA/glycerol release ratio (P = 0.02) decreased compared with saline and HI-HG clamp.CONCLUSIONSIn conclusion, GIP in combination with hyperinsulinemia and slight hyperglycemia increased adipose tissue blood flow, glucose uptake, and FFA re-esterification, thus resulting in increased TAG deposition in abdominal subcutaneous adipose tissue.

The direct effects of GLP-1 and GIP, alone or in combination, on human pancreatic islets

GLP-1 and GIP are incretins known to affect beta-cell function and turnover. However, information on the direct actions of these hormones on human islet cells is limited. We tested the effects of acute (45 min) or prolonged (2 days) exposure to GLP-1 or GIP, alone or in combination, on the function and some molecular features of human islets isolated from non-diabetic and type 2 diabetic multiorgan donors. Acutely, both GLP-1 and, more markedly so, GIP, significantly potentiated glucose-stimulated insulin release, with no apparent synergic action. Some of these effects were observed with type 2 diabetic islets as well. Following prolonged exposure to the incretins, improved insulin secretion was observed, and transcription of insulin, PDX-1 and Bcl-2 was increased in both non-diabetic and diabetic islets, with the combination of GLP-1 and GIP showing more significant effects. Although it is still unclear at what extent these beta-cell direct actions of individual or combined incretins occur in-vivo in humans, nevertheless the results of the present study suggest that enhancing the exposure of pancreatic islets to circulating levels of both incretins may be useful for therapeutical purposes.

DPP-4 inhibitors enhance GIP and attenuate GLP-1 incretin effects during IVGTT in Wistar rats

Aims: DPP-4 (dipeptidyl peptidase-4) inhibition has been reported to increase incretin effects of GIP as well as GLP-1 by prolonging their half life. DPP-4 cleaves GIP into dipeptide and the GIP metabolite GIP (3–42), whereas the GLP-1 (7–36) amide is cleaved to GLP-1 (9–36) amide. Based on studies in man, pig and rat, these peptides are involved in various glucoregulatory processes. We have recently developed a test to differentiate the insulinotropic effects of both peptides in rats. In the present study, we compared the insulinotropic effects of the intact GIP and the GLP-1 (7–36) amide during IVGTT following DPP4 inhibitor administration.

The glucose-dependent insulinotropic polypeptide and glucose-stimulated insulin response to exercise training and diet in obesity

Aging and obesity are characterized by decreased beta-cell sensitivity and defects in the potentiation of nutrient-stimulated insulin secretion by GIP. Exercise and diet are known to improve glucose metabolism and the pancreatic insulin response to glucose, and this effect may be mediated through the incretin effect of GIP. The purpose of this study was to assess the effects of a 12-wk exercise training intervention (5 days/wk, 60 min/day, 75% Vo(2 max)) combined with a eucaloric (EX, n = 10) or hypocaloric (EX-HYPO, pre: 1,945 +/- 190, post: 1,269 +/- 70, kcal/day; n = 9) diet on the GIP response to glucose in older (66.8 +/- 1.5 yr), obese (34.4 +/- 1.7 kg/m(2)) adults with impaired glucose tolerance. In addition to GIP, plasma PYY(3-36), insulin, and glucose responses were measured during a 3-h, 75-g oral glucose tolerance test. Both interventions led to a significant improvement in Vo(2 max) (P < 0.05). Weight loss (kg) was significant in both groups but was greater after EX-HYPO (-8.3 +/- 1.1 vs. -2.8 +/- 0.5, P = 0.002). The glucose-stimulated insulin response was reduced after EX-HYPO (P = 0.02), as was the glucose-stimulated GIP response (P < 0.05). Furthermore, after the intervention, changes in insulin (DeltaI(0-30)/DeltaG(0-30)) and GIP (Delta(0-30)) secretion were correlated (r = 0.69, P = 0.05). The PYY(3-36) (Delta(0-30)) response to glucose was increased after both interventions (P < 0.05). We conclude that 1) a combination of caloric restriction and exercise reduces the GIP response to ingested glucose, 2) GIP may mediate the attenuated glucose-stimulated insulin response after exercise/diet interventions, and 3) the increased PYY(3-36) response represents an improved capacity to regulate satiety and potentially body weight in older, obese, insulin-resistant adults.