Dataset Information

GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models.

ABSTRACT: Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Using single-nuclei RNA sequencing, we identified the cellular phenotypes of AP/NTS cells expressing GIPR and GLP-1R on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in γ-aminobutyric acid-ergic neurons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.

SUBMITTER: Borner T

PROVIDER: S-EPMC8564411 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models.

Borner Tito T Geisler Caroline E CE Fortin Samantha M SM Cosgrove Richard R Alsina-Fernandez Jorge J Dogra Mridula M Doebley Sarah S Sanchez-Navarro Marcos J MJ Leon Rosa M RM Gaisinsky Jane J White Arianna A Bamezai Ankur A Ghidewon Misgana Y MY Grill Harvey J HJ Crist Richard C RC Reiner Benjamin C BC Ai Minrong M Samms Ricardo J RJ De Jonghe Bart C BC Hayes Matthew R MR

Diabetes 20210811 11

Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining re ...[more]

PMID: 34380697

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Project description:BackgroundCombined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism is superior to single GLP1R agonism with respect to glycemic control and weight loss in obese patients with or without type 2 diabetes. As insulin resistance and obesity are strong risk factors for nonalcoholic fatty liver disease (NAFLD), in the current study we investigated the effects of combined GIPR/GLP1R agonism on NAFLD development.MethodsMale APOE∗3-Leiden.CETP mice, a humanized model for diabetic dyslipidemia and NAFLD when fed a high-fat high-cholesterol diet, received subcutaneous injections with either vehicle, a GIPR agonist, a GLP1R agonist, or both agonists combined every other day.FindingsGIPR and GLP1R agonism reduced body weight and additively lowered fasting plasma levels of glucose, triglycerides and total cholesterol. Strikingly, we report an additive reduction in hepatic steatosis as evidenced by lower hepatic lipid content and NAFLD scores. Underlying the lipid-lowering effects were a reduced food intake and intestinal lipid absorption and an increased uptake of glucose and triglyceride-derived fatty acids by energy-combusting brown adipose tissue. Combined GIPR/GLP1R agonism also attenuated hepatic inflammation as evidenced by a decreased number of monocyte-derived Kupffer cells and a reduced expression of inflammatory markers. Together, the reduced hepatic steatosis and inflammation coincided with lowered markers of liver injury.InterpretationWe interpretate that GIPR and GLP1R agonism additively attenuate hepatic steatosis, lower hepatic inflammation, ameliorate liver injury, together preventing NAFLD development in humanized APOE∗3-Leiden.CETP mice. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to attenuate NAFLD progression in humans.FundingThis work was supported by a grant from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences [CVON-GENIUS-II] to P.C.N.R., a Lilly Research Award Program [LRAP] Award to P.C.N.R. and S.K., a Dutch Heart Foundation [2017T016] grant to S.K., and an NWO-VENI grant [09150161910073] to M.R.B.; J.F.D.B. is supported by the Nutrition and Health initiative of the University of Groningen; Z.Y. is supported by a full-time PhD scholarship from the China Scholarship Council (201806850094 to Z.Y.).

Project description:Background and aimsThe pharmacokinetics (PK) and single-dose tolerability of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist being developed for once-weekly treatment of type 2 diabetes (T2D), weight management, and nonalcoholic steatohepatitis, was evaluated in subjects with renal impairment versus healthy subjects with normal renal function.MethodsForty-five subjects, categorized by baseline renal status, i.e. mild (n = 8, estimated glomerular filtration rate [eGFR] 60-89 mL/min/1.73m2), moderate (n = 8, eGFR 30-59 mL/min/1.73m2), severe renal impairment (n = 7, eGFR < 30 mL/min/1.73m2), end-stage renal disease requiring dialysis (n = 8), and normal renal function (n = 14, eGFR ≥ 90 mL/min/1.73m2), received a single subcutaneous dose of tirzepatide 5 mg. Tirzepatide plasma concentrations up to 648 h postdose were measured to compute PK parameters. The primary analysis evaluated the ratios of area under the plasma concentration-time curves (AUCs) and maximum plasma drug concentration (Cmax) of renal impairment versus the normal renal function group (90% confidence interval [CI]). In addition, the relationship between PK parameters and continuous variables of renal function was assessed by linear regression.ResultsTirzepatide exposure was similar across renal impairment groups and healthy subjects. The 90% CI of ratios of AUCs and Cmax comparing each renal impairment group versus normal renal function spanned unity, except for a 25-29% increase in AUCs in the moderate renal impairment group. There was no significant relationship between tirzepatide exposure and eGFR. Few adverse events were reported across the renal impairment and normal renal function groups. The majority were mild in severity and of a gastrointestinal nature in the renal impairment groups.ConclusionThere were no clinically relevant effects of renal impairment on tirzepatide PK. Dose adjustment may not be required for patients with renal impairment.Clinical trial registrationClinicalTrials.gov NCT03482024.

Project description:Background and objectiveTirzepatide, a novel, once-weekly, dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is approved in the US as a treatment for type 2 diabetes and is under development for long-term weight management, heart failure with preserved ejection fraction, and nonalcoholic steatohepatitis. This study evaluated the pharmacokinetics and tolerability of tirzepatide in participants with hepatic impairment (with or without type 2 diabetes) versus healthy participants with normal hepatic function.MethodsParticipants in this parallel, single-dose, open-label study were categorized by hepatic impairment defined by the baseline Child-Pugh (CP) score A (mild impairment; n = 6), B (moderate impairment; n = 6), or C (severe impairment; n = 7) or normal hepatic function (n = 13). All participants received a single subcutaneous 5-mg dose of tirzepatide. Blood samples were collected to determine tirzepatide plasma concentrations to estimate pharmacokinetic parameters. The primary pharmacokinetic parameters of area under the drug concentration-time curve from zero to infinity (AUC0-∞) and maximum observed drug concentration (Cmax) were evaluated using an analysis of covariance. The geometric least-squares means (LSM) and mean ratios for each group, between control and hepatic impairment levels, and the corresponding 90% confidence intervals (CIs) were estimated. The analysis of the time to maximum observed drug concentration was based on a nonparametric method. The relationships between the pharmacokinetic parameters and CP classification parameters (serum albumin level, total bilirubin level, and international normalized ratio) were also assessed. Adverse events were monitored to assess safety and tolerability.ResultsTirzepatide exposure, based on AUC0-∞ and Cmax, was similar across the control and hepatic impairment groups. Statistical analysis showed no difference in the geometric LSM AUC0-∞ or Cmax between participants in the control group and the hepatic impairment groups, with the 90% CI for the ratios of geometric LSM spanning unity (AUC0-∞ ratio of geometric LSM vs control [90% CI 1.08 [0.879, 1.32], 0.960 [0.790, 1.17], and 0.852 [0.699, 1.04] and Cmax ratio of geometric LSM vs control [90% CI]: 0.916 [0.726, 1.16], 1.00 [0.802, 1.25], and 0.972 [0.784, 1.21] for mild, moderate and severe hepatic impairment groups, respectively). There was no change in median time to Cmax of tirzepatide across all groups (time to Cmax median difference vs control [90% CI]: 0 [- 4.00, 12.00], 0 [- 12.00, 12.00], and 0 [- 11.83, 4.17], respectively). There was no significant relationship between the exposure of tirzepatide and the CP score (p > 0.1 for AUC0-∞, Cmax, and apparent total body clearance). Similarly, there was no clinically relevant relationship between the exposure of tirzepatide and serum albumin level, total bilirubin level, or international normalized ratio. The geometric LSM half-life values were also similar across the control and hepatic impairment groups. No notable differences in safety profiles were observed between participants with hepatic impairment and healthy control participants.ConclusionsTirzepatide pharmacokinetics was similar in participants with varying degrees of hepatic impairment compared with healthy participants. Thus, people with hepatic impairment treated with tirzepatide may not require dose adjustments.Clinical trial registrationClinicalTrials.gov identifier number NCT03940742.

Project description:The GLP-1 receptor agonist exendin-4 has recently shown good effects in a phase II clinical trial in Parkinson's disease (PD) patients. Here, a comparison of the new GLP-1/GIP dual receptor agonist DA5-CH and NLY01, a 40 kDa pegylated form of exendin-4, on motor impairments and reducing inflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD mouse model is provided. The drug groups received either DA5-CH or NLY01 (25 nmol/kg) i.p. after daily MPTP intraperitoneal injection. Both drugs showed improvements in motor activity, open field experiments, rotarod tests, and gait analysis, but DA5-CH was more potent. Tyrosine hydroxylase expression in dopaminergic neurons was much reduced by MPTP and improved by DA5-CH, while NLY01 showed weak effects. When analyzing levels of α-synuclein (α-Syn), DA5-CH reduced levels effectively while NLY01 had no effect. When measuring the levels of the inflammation markers Toll-like receptor 4 (TLR4), specific markers of microglia activation (Iba-1), the marker of astrocyte activation glial fibrillary acidic protein (GFAP), nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-α), and transforming growth factor β1 (TGF-β1), DA5-CH was very effective in reducing the chronic inflammation response, while NLY01 did not show significant effects. Levels of key growth factors such as Glial cell-derived neurotrophic factor (GDNF) and Brain-derived neurotrophic factor (BDNF) were much reduced by MPTP, and DA5-CH was able to normalize levels in the brain, while NLY01 showed little effect. The levels of pro-inflammatory cytokines (IL-6 and IL-Iβ) were much reduced by DA5-CH, too, while NLY01 showed no effect. In a separate experiment, we tested the ability of the two drugs to cross the blood-brain barrier. After injecting fluorescin-labelled peptides peripherally, the fluorescence in brain tissue was measured. It was found that the pegylated NLY01 peptide did not cross the BBB in meaningful quantities while exendin-4 and the dual agonist DA5-CH did. The results show that DA5-CH shows promise as a therapeutic drug for PD.

Project description:ContextNovel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide.ObjectiveExplore mechanisms of glucose control by tirzepatide.DesignPost hoc analyses of fasting biomarkers and multiple linear regression analysis.SettingForty-seven sites in 4 countries.Patients or other participantsThree hundred and sixteen subjects with type 2 diabetes.InterventionsTirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo.Main outcome measuresAnalyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks.ResultsHomeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively.ConclusionsTirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.

Dataset Information

GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models.

Publications

GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models.

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