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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... more
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)
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In persons with type 2 diabetes (T2D), dipeptidyl peptidase 4 (DPP-4) inhibitor treatment improves glycemic control by raising the active levels of the insulinotropic gut hormones glucagon-like peptide 1 and glucose-dependent... more
In persons with type 2 diabetes (T2D), dipeptidyl peptidase 4 (DPP-4) inhibitor treatment improves glycemic control by raising the active levels of the insulinotropic gut hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide (GIP). Using the GIP receptor antagonist GIP(3-30)NH2, we investigated endogenous GIP’s contribution to the insulinotropic effect of DPP-4 inhibition (assessed by insulin secretion rate (ISR) relative to plasma glucose). In a double-blind, placebo-controlled, cross-over study, 12 persons (eight men and four women) with T2D (mean ± SD; BMI 27.4 ± 2.6 kg/m2, HbA1c 7.1 ± 1.4% (54 ± 15 mmol/mol)) underwent two randomized 12-13-day treatment courses with DPP-4 inhibitor (sitagliptin 100 mg once-daily) and placebo, respectively, with an interposed 1-3-week washout period. In the end of each treatment period, two randomized 5-hour liquid mixed-meal tests with infusion of GIP(3-30)NH2 (1,200 pmol/kg/min) or saline (placebo) were performed. During placebo treatment, GIP(3-30)NH2 lowered postprandial serum C-peptide (determined as difference in baseline-subtracted area under curve (ΔbsAUC%) ± SEM: −31 ± 9%, P = 0.005) and increased postprandial plasma glucose excursions (ΔAUC% ± SEM: 7.3 ± 2.8%, P = 0.017) compared to saline. Sitagliptin increased concentrations of active GIP(1-42) (ΔAUC% ± SEM: 153 ± 21%, P < 0.0001) and lowered fasting plasma glucose (mean: 8.7 vs. 7.6 mmol/L, P < 0.0004), whereas postprandial glucose excursions were unchanged compared to placebo treatment. GIP(3-30)NH2 caused a reduction in AUCISR/AUCglucose ratio equivalent to 37 ± 12% of the increments due to sitagliptin. In conclusion, we demonstrate an insulinotropic and glucose-lowering effect of endogenous GIP in persons with T2D and show that endogenous GIP is responsible for more than one third of the improved beta cell function observed during DPP-4 inhibitor treatment. Disclosure S. Stensen: None. L. S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M. M. Rosenkilde: Board Member; Self; Bainan Biotech, Synklino ApS, Board Member; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Consultant; Self; Antag Therapeutics, Bainan Biotech, Synklino ApS, Stock/Shareholder; Self; Antag Therapeutics, Bainan Biotech, Synklino ApS, Stock/Shareholder; Spouse/Partner; Antag Therapeutics, Bainan Biotech. B. Hartmann: None. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. M. B. Christensen: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding European Foundation for the Study of Diabetes/Lilly European Diabetes Research Programme (2018); A.P. Møller Foundation
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The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is released from the small intestine following meal ingestion and potentiates glucose-stimulated insulin secretion. Exogenous GIP has a poor insulinotropic effect in... more
The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is released from the small intestine following meal ingestion and potentiates glucose-stimulated insulin secretion. Exogenous GIP has a poor insulinotropic effect in patients with type 2 diabetes (T2D). We investigated postprandial effects of endogenous GIP in patients with T2D using the GIP receptor antagonist, GIP(3-30)NH2. In a randomized, double-blinded, placebo-controlled, cross-over study, 10 patients with T2D (mean±SD; HbA1c 6.9±3.2%; BMI 32.5±4.8 kg/m2) received 250-minute infusions of GIP(3-30)NH2 (1,200 pmol/kg/min) or placebo (saline) during two separate standardized liquid meal tests. Compared with placebo, GIP(3-30)NH2 infusion caused lower postprandial insulin (Δ%±SD; -19±15%, P=0.010) and C-peptide (-14±21%, P=0.021) responses (area under the curve) but had no effect on plasma glucagon (P=0.580) or glucose excursions (P=0.692). Postprandial inhibition of bone resorption (assessed by carboxy-terminal collagen crosslinks) was ∼50% lower during GIP(3-30)NH2 infusion compared with placebo (P=0.005; Figure 1). In conclusion, endogenous GIP slightly reduced postprandial insulin secretion with no effect on postprandial glucagon or glucose concentrations in patients with T2D. In contrast, endogenous GIP was a major determinant of postprandial suppression of bone resorption in these patients. Disclosure S. Stensen: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. L.S. Krogh: None. A.H. Sparre-Ulrich: Other Relationship; Self; Antag Therapeutics. K. Skov-Jeppesen: None. M. Jensen: Employee; Self; Antag Therapeutics. B. Hartmann: None. T. Vilsbøll: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. M.M. Rosenkilde: Consultant; Self; Antag Therapeutics. M.B. Christensen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. Funding Novo Nordisk Foundation; European Foundation for the Study of Diabetes
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Background and PurposeGlucagon‐like peptide‐2 (GLP‐2) is secreted postprandially by enteroendocrine L‐cells and stimulates growth of the gut and bone. One GLP‐2 analogue is approved for short bowel syndrome (SBS). To improve therapeutic... more
Background and PurposeGlucagon‐like peptide‐2 (GLP‐2) is secreted postprandially by enteroendocrine L‐cells and stimulates growth of the gut and bone. One GLP‐2 analogue is approved for short bowel syndrome (SBS). To improve therapeutic efficacy, we developed biased GLP‐2 receptor (GLP‐2R) agonists through N‐terminal modifications.Experimental ApproachVariants with Ala and Trp substitutions of the first seven positions of GLP‐2(1‐33) were studied in vitro for affinity, G protein activation (cAMP accumulation), recruitment of β‐arrestin 1 and 2, and internalization of the human and mouse GLP‐2R. The intestinotrophic actions of the most efficacious (cAMP) biased variant were examined in mice.Key ResultsAla substitutions had more profound effects than Trp substitutions. For both, alterations at positions 1, 3 and 6 most severely impaired activity. β‐arrestin recruitment was more affected than cAMP accumulation. Among Ala substitutions, [H1A], [D3A] and [F6A] impaired potency (EC50) for cAMP‐accumulation >20‐fold and efficacy (Emax) to 48%–87%, and were unable to recruit arrestins. The Trp substitutions, [A2W], [D3W] and [G4W] were partial agonists (Emax of 46%–59%) with 1.7–12‐fold decreased potencies in cAMP and diminished β‐arrestin recruitment. The biased variants, [F6A], [F6W] and [S7W] induced less GLP‐2R internalization compared with GLP‐2, which induced internalization in a partly arrestin‐independent manner. In mice, [S7W] enhanced gut trophic actions with increased weight of the small intestine, increased villus height and crypt depth compared with GLP‐2.Conclusion and ImplicationsG protein‐biased GLP‐2R agonists with diminished receptor desensitization have superior intestinotrophic effects and may represent improved treatment of intestinal insufficiency including SBS.
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The gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are known for insulinotropic and glucose-lowering effects. However, their individual roles in postprandial glucose... more
The gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are known for insulinotropic and glucose-lowering effects. However, their individual roles in postprandial glucose homeostasis are unknown. We infused the GIP receptor antagonist GIP(3-30)NH2 and the GLP-1 receptor antagonist exendin(9-39) during a meal to determine the roles of endogenous GIP and GLP-1 on postprandial glucose metabolism. On four separate days, 12 healthy men (age 19-65 years, BMI 20-25 kg/m2) received a liquid mixed meal test with randomized and double-blinded infusions of GIP(3-30)NH2 (800 pmol/kg/min) + Ex(9-39) (450 pmol/kg/min) (A), GIP(3-30)NH2 (B), Ex(9-39) (C), and saline (D). On Day A, B and C, glucose excursions were significantly increased by 85%, 55% and 15%, respectively, compared to D. Day A and B excursions were significantly higher than C (Figure). Glucagon levels at 60 min differed between Day A and B (11.5±1.2 vs. 7.5±0.6 pmol/l, P=0.01), and Day B and C (11.5±1.2 vs. 12.9±1.5 pmol/l, P=0.008). GLP-1 was higher on Day A (P=0.01) and C (P=0.02) than D. No significant effects on insulin, C-peptide, gastric emptying, or GIP were observed. We conclude that endogenous GIP affects postprandial plasma glucose excursions more pronouncedly than GLP-1, and that both hormones additively contribute to control postprandial glycemia in healthy subjects. Disclosure L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M.M. Helsted: None. A.H. Sparre-Ulrich: Employee; Self; Antag Therapeutics ApS. A.R. Lanng: None. S. Stensen: None. M. Jakobsen: None. B. Hartmann: None. M.B. Christensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. M.M. Rosenkilde: Other Relationship; Self; Antag Therapeutics. Advisory Panel; Spouse/Partner; Novo Nordisk A/S. Board Member; Spouse/Partner; Zealand Pharma A/S. Speaker's Bureau; Spouse/Partner; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Spouse/Partner; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Spouse/Partner; Antag Therapeutics. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.
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Objective The insulinotropic effect of exogenous, intravenously infused glucose-dependent insulinotropic polypeptide (GIP) is impaired in patients with type 2 diabetes. We evaluated the effects of endogenous GIP in relation to glucose and... more
Objective The insulinotropic effect of exogenous, intravenously infused glucose-dependent insulinotropic polypeptide (GIP) is impaired in patients with type 2 diabetes. We evaluated the effects of endogenous GIP in relation to glucose and bone metabolism in patients with type 2 diabetes using a selective GIP receptor antagonist and hypothesized that the effects of endogenous GIP were preserved. Design A randomized, double-blinded, placebo-controlled, crossover study. Methods Ten patients with overweight/obesity and type 2 diabetes (mean±s.d.; HbA1c 52 ± 11 mmol/mol; BMI 32.5 ± 4.8 kg/m2) were included. We infused a selective GIP receptor antagonist, GIP(3-30)NH2 (1200 pmol/kg/min), or placebo (saline) during two separate, 230-min, standardized, liquid mixed meal tests followed by a meal ad libitum. Subcutaneous adipose tissue biopsies were analyzed. Results Compared with placebo, GIP(3-30)NH2 reduced postprandial insulin secretion (Δbaseline-subtracted area under the curve (bsAUC)C-peptide% ± s.e.m.; −14 ± 6%, P = 0.021) and peak glucagon (Δ% ± s.e.m.; −11 ± 6%, P = 0.046) but had no effect on plasma glucose (P = 0.692). Suppression of bone resorption (assessed by circulating carboxy-terminal collagen crosslinks (CTX)) was impaired during GIP(3-30)NH2 infusion compared with placebo (ΔbsAUCCTX; ±s.e.m.; −4.9 ± 2 ng/mL × min, P = 0.005) corresponding to a ~50% reduction. Compared with placebo, GIP(3-30)NH2 did not affect plasma lipids, meal consumption ad libitum or adipose tissue triglyceride content. Conclusions Using a selective GIP receptor antagonist during a meal, we show that endogenous GIP increases postprandial insulin secretion with little effect on postprandial glycaemia but is important for postprandial bone homeostasis in patients with type 2 diabetes.
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Tirzepatide is a unimolecular co‐agonist of the glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration... more
Tirzepatide is a unimolecular co‐agonist of the glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor‐activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP‐1 and GIP, their receptors, and previous results of co‐targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP‐1 and GIP receptor activation, tirzepatide...
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Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [438, 437, 32]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically... more
Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [438, 437, 32]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibacterials, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also know...
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Enhanced secretion of glucagon-like peptide-1 (GLP-1) seems to be essential for improved postprandial β-cell function after Roux-en-Y gastric bypass (RYGB) but is less studied after sleeve gastrectomy (SG). Moreover, the role of the other... more
Enhanced secretion of glucagon-like peptide-1 (GLP-1) seems to be essential for improved postprandial β-cell function after Roux-en-Y gastric bypass (RYGB) but is less studied after sleeve gastrectomy (SG). Moreover, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. We studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed meal tests in unoperated (CON), SG-operated, and RYGB-operated people with no history of diabetes. Postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. The effect of GLP-1R versus GIPR blockade differed between groups. GLP-1R blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the surgical groups but had no effect in CON. GIPR block...
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Dipeptidyl peptidase 4 (DPP-4) degrades the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors improve glycemic control in type 2 diabetes, but the importance of... more
Dipeptidyl peptidase 4 (DPP-4) degrades the incretin hormones glucagon-like peptide 1 (GLP-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 to placebo treatment. During placebo treatment, postprandial glucose...
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The incretin effect—the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance—was suspected even before insulin was discovered, and today we know that the effect is... more
The incretin effect—the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance—was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the cham...
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The endogenous chemokines CCL19 and CCL21 signal via their common receptor CCR7. CCL21 is the main lymph node homing chemokine, but a weak chemo-attractant compared to CCL19. Here we show that the 41-amino acid positively charged peptide,... more
The endogenous chemokines CCL19 and CCL21 signal via their common receptor CCR7. CCL21 is the main lymph node homing chemokine, but a weak chemo-attractant compared to CCL19. Here we show that the 41-amino acid positively charged peptide, released through C-terminal cleavage of CCL21, C21TP, boosts the immune cell recruiting activity of CCL21 by up to 25-fold and the signaling activity via CCR7 by ~ 100-fold. Such boosting is unprecedented. Despite the presence of multiple basic glycosaminoglycan (GAG) binding motifs, C21TP boosting of CCL21 signaling does not involve interference with GAG mediated cell-surface retention. Instead, boosting is directly dependent on O-glycosylations in the CCR7 N-terminus. As dictated by the two-step binding model, the initial chemokine binding involves interaction of the chemokine fold with the receptor N-terminus, followed by insertion of the chemokine N-terminus deep into the receptor binding pocket. Our data suggest that apart from a role in initi...
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Context Inhibitors of the protease neprilysin (NEP) are used for treating heart failure, but are also linked to improvements in metabolism. NEP may cleave proglucagon-derived peptides, including the glucose and amino acid (AA)-regulating... more
Context Inhibitors of the protease neprilysin (NEP) are used for treating heart failure, but are also linked to improvements in metabolism. NEP may cleave proglucagon-derived peptides, including the glucose and amino acid (AA)-regulating hormone glucagon. Studies investigating NEP inhibition on glucagon metabolism are warranted. Objective This work aims to investigate whether NEP inhibition increases glucagon levels. Methods Plasma concentrations of glucagon and AAs were measured in eight healthy men during a mixed meal with and without a single dose of the NEP inhibitor/angiotensin II type 1 receptor antagonist, sacubitril/valsartan (194 mg/206 mg). Long-term effects of sacubitril/valsartan (8 weeks) were investigated in individuals with obesity (n = 7). Mass spectrometry was used to investigate NEP-induced glucagon degradation, and the derived glucagon fragments were tested pharmacologically in cells transfected with the glucagon receptor (GCGR). Genetic deletion or pharmacologica...
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Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [431, 430, 32]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically... more
Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [431, 430, 32]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known a...
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The glucose-dependent insulinotropic polypeptide (GIP) is a 42-residue metabolic hormone that is actively being targeted for its regulatory role of glycemia and energy balance. Rational design of ligands, however, has been tedious with no... more
The glucose-dependent insulinotropic polypeptide (GIP) is a 42-residue metabolic hormone that is actively being targeted for its regulatory role of glycemia and energy balance. Rational design of ligands, however, has been tedious with no structural data of the GIP receptor available. This study investigates structure and function of the GIP receptor (GIPR), using a homology model based on the GLP-1 receptor. Molecular dynamics combined with in vitro mutational data were used to pinpoint residues that play a role in ligand binding and/or receptor activation. Significant differences in binding mode were identified for the naturally occurring agonists GIP(1-30)NH2 and GIP(1-42) compared to high potency antagonists GIP(3-30)NH2 and GIP(5-30)NH2. Residues R1832.60, R1902.67 and R3005.40 are shown to play a key role in the activation of the GIPR and evidence suggests that a disruption of the K293ECL2 – E362ECL3 salt bridge by GIPR antagonists strongly reduces GIPR activation. These findings improve the basis for rational design of ligands targeting the GIPR.
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Reactivation of human cytomegalovirus (HCMV) in transplant recipients can cause life-threatening disease. Consequently, for transplant recipients, killing latently infected cells could have far-reaching clinical benefits. In vivo, myeloid... more
Reactivation of human cytomegalovirus (HCMV) in transplant recipients can cause life-threatening disease. Consequently, for transplant recipients, killing latently infected cells could have far-reaching clinical benefits. In vivo, myeloid cells and their progenitors are an important site of HCMV latency, and one viral gene expressed by latently infected myeloid cells is US28. This viral gene encodes a cell surface G protein-coupled receptor (GPCR) that binds chemokines, triggering its endocytosis. We show that the expression of US28 on the surface of latently infected cells allows monocytes and their progenitor CD34+ cells to be targeted and killed by F49A-FTP, a highly specific fusion toxin protein that binds this viral GPCR. As expected, this specific targeting of latently infected cells by F49A-FTP also robustly reduces virus reactivation in vitro. Consequently, such specific fusion toxin proteins could form the basis of a therapeutic strategy for eliminating latently infected ce...
Research Interests: Stem Cells, Biology, Virology, Medicine, Multidisciplinary, and 15 moreChemokines and chemokine receptors, Humans, Endocytosis, Journal Article, Cell Death, Cytomegalovirus, Monocytes, DDC, Chemokines, Antivirals, Nature Communications, Herpes Virus, Viral Load, Hematopoietic Stem Cell Transplantation, and Human Cytomegalovirus
BACKGROUND AND PURPOSE The majority of small molecule compounds targeting chemokine receptors share a similar pharmacophore with a centrally located aliphatic positive charge and flanking aromatic moieties. Here we describe a novel... more
BACKGROUND AND PURPOSE The majority of small molecule compounds targeting chemokine receptors share a similar pharmacophore with a centrally located aliphatic positive charge and flanking aromatic moieties. Here we describe a novel piperidine‐based compound with structural similarity to previously described CCR8‐specific agonists, but containing a unique phenyl‐tetrazol moiety which, in addition to activity at CCR8 was also active at CCR1.EXPERIMENTAL APPROACH Single point mutations were introduced in CCR1 and CCR8, and their effect on small molecule ligand‐induced receptor activation was examined through inositol trisphosphate (IP3) accumulation. The molecular interaction profile of the agonist was verified by molecular modeling.KEY RESULTS The chemokine receptor conserved glutamic acid in TM‐VII served as a common anchor for the positively charged amine in the piperidine ring. However, whereas the phenyl‐tetrazol group interacted with TyrIV:24 (Tyr172) and TyrIII:09 (Tyr114) in th...
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The pervasive human cytomegalovirus (HCMV) causes significant morbidity in immunocompromised individuals. Treatment using the current standard-of-care (SOC) is limited by severe toxic adverse effects and anti-viral resistance development.... more
The pervasive human cytomegalovirus (HCMV) causes significant morbidity in immunocompromised individuals. Treatment using the current standard-of-care (SOC) is limited by severe toxic adverse effects and anti-viral resistance development. Furthermore, they only affect HCMV in its lytic phase, meaning viral disease is not preventable as latent infection cannot be treated and the viral reservoirs persist. The viral chemokine receptor (vCKR) US28 encoded by HCMV has received much attention in recent years. This broad-spectrum receptor has proven to be a desirable target for development of novel therapeutics through exploitation of its ability to internalize and its role in maintaining latency. Importantly, it is expressed on the surface of infected cells during both lytic and latent infection. US28-targeting small molecules, single-domain antibodies, and fusion toxin proteins have been developed for different treatment strategies, e.g. forcing reactivation of latent virus or using inte...
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Context Impact of lost GLP-1 receptor function in human physiology. Objective Identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations. Methods We sequenced... more
Context Impact of lost GLP-1 receptor function in human physiology. Objective Identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations. Methods We sequenced GLP1R in 8,642 Danish individuals with type 2 diabetes or normal glucose tolerance and examined the ability of nonsynonymous variants to bind GLP-1 and to signal in transfected cells via cAMP formation and beta-arrestin recruitment. We performed a cross-sectional study between the burden of loss-of-signalling (LoS) variants and cardiometabolic phenotypes in 2,930 patients with type 2 diabetes and 5,712 participants in a population-based cohort. Furthermore, we studied the association between cardiometabolic phenotypes and the burden of the LoS variants and 60 partly overlapping predicted loss-of-function (pLoF) GLP1R variants found in 330,566 unrelated Caucasian exome-sequenced participants in the UK Biobank cohort. Results We identified 36 nonsynon...
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Selective modification of peptides is often exploited to improve pharmaceutically relevant properties of bioactive peptides like stability, circulation time, and potency. In Nature, natural products belonging to the class of ribosomally... more
Selective modification of peptides is often exploited to improve pharmaceutically relevant properties of bioactive peptides like stability, circulation time, and potency. In Nature, natural products belonging to the class of ribosomally synthesized and post-translationally modified peptides (RiPPs) are known to install a number of highly attractive modifications with high selectivity. These modifications are installed by enzymes guided to the peptide by corresponding leader peptides removed as the last step of biosynthesis. Here, we exploit leader peptides and their matching enzymes to investigate the installment of D-Ala post-translationally in a critical position in the hormones, glucagon-like peptides (GLP) 1 and 2. We also offer insight into how precursor peptide design can modulate the modification pattern achieved.
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The seven transmembrane G protein-coupled receptor EBV-induced gene 2 (EBI2), also known as GPR183, is expressed in particular in immune cells. Activated by its endogenous ligands, which are a group of oxysterols, it functions as a... more
The seven transmembrane G protein-coupled receptor EBV-induced gene 2 (EBI2), also known as GPR183, is expressed in particular in immune cells. Activated by its endogenous ligands, which are a group of oxysterols, it functions as a chemo-attractant receptor, mediating cell migration. In coordination with other receptors, EBI2 plays important roles in controlling the migration of immune cells during the course of a T-dependent Ab response in the spleen. In recent years, it has become clear that EBI2 also has other roles to play in the immune system. Thus, EBI2 seems to be involved in innate immune responses, such as those mediated by TLR signaling, and it has been implicated in regional immune responses, including immune responses in the CNS. In this review, we describe the functions of EBI2 in B cells, T cells, and dendritic cells during the course of a T-dependent Ab response in the spleen. Furthermore, we review the existing evidence supporting a role for EBI2 in local immune resp...
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The intestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is involved in important physiological functions, including postprandial blood glucose homeostasis, bone remodeling, and lipid metabolism. While mutations leading... more
The intestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is involved in important physiological functions, including postprandial blood glucose homeostasis, bone remodeling, and lipid metabolism. While mutations leading to physiological changes can be identified in large-scale sequencing, no systematic investigation of GIP missense variants has been performed. Here, we identified 168 naturally occurring missense variants in the human GIP genes from three independent cohorts comprising ~720,000 individuals. We examined amino acid changing variants scattered across the pre-pro-GIP peptide using in silico effect predictions, which revealed that the sequence of the fully processed GIP hormone is more protected against mutations than the rest of the precursor protein. Thus, we observed a highly species-orthologous and population-specific conservation of the GIP peptide sequence, suggestive of evolutionary constraints to preserve the GIP peptide sequence. Elucidating th...
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Islets of Langerhans stained with probes specific for <i>Bacillus subtilis</i> dihydrodipicolinate reductase (<i>DapB</i>) mRNA (negative control) and <i>Mus musculus </i>Insulin 1... more
Islets of Langerhans stained with probes specific for <i>Bacillus subtilis</i> dihydrodipicolinate reductase (<i>DapB</i>) mRNA (negative control) and <i>Mus musculus </i>Insulin 1 (<i>Ins1</i>) mRNA (positive control). Countertained with DAPI. Bar=100µm. n=3.
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Infection of immunosuppressed transplant patients with the human γ-herpesvirus Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease (PTLD), an often fatal complication. Immunosuppressed miniature pigs... more
Infection of immunosuppressed transplant patients with the human γ-herpesvirus Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease (PTLD), an often fatal complication. Immunosuppressed miniature pigs infected with γ-herpesvirus porcine lymphotropic herpesvirus 1 (PLHV1) develop a similar disease, identifying pigs as a potential preclinical model for PTLD in humans. BILF1 is a G protein-coupled receptor (GPCR) encoded by EBV with constitutive activity linked to tumorigenesis and immunoevasive function downregulating MHC-I. In the present study, we compared BILF1-orthologues encoded by the three known PLHVs (PLHV1-3) with EBV-BILF1 to determine pharmacological suitability of BILF1 orthologues as model system to study EBV-BILF1 druggability. Cell surface localization, constitutive internalization, and MHC-I downregulation as well as membrane proximal constitutive Gαi signaling patterns were conserved across all BILFs. Only subtle differences between ...
The γ-herpesvirus Epstein–Barr Virus (EBV) establishes lifelong infections in approximately 90% of adults worldwide. Up to 1,000,000 people yearly are estimated to suffer from health conditions attributed to the infection with this virus,... more
The γ-herpesvirus Epstein–Barr Virus (EBV) establishes lifelong infections in approximately 90% of adults worldwide. Up to 1,000,000 people yearly are estimated to suffer from health conditions attributed to the infection with this virus, such as nasopharyngeal and gastric carcinomas as well as several forms of B, T and NK cell lymphoma. To date, no EBV-specific therapeutic option has reached the market, greatly reducing the survival prognoses of affected patients. Similar to other herpesviruses, EBV encodes for a G protein–coupled receptor (GPCR), BILF1, affecting a multitude of cellular signaling pathways. BILF1 has been identified to promote immune evasion and tumorigenesis, effectively ensuring a life-long persistence of EBV in, and driving detrimental health conditions to its host. This review summarizes the epidemiology of EBV-associated malignancies, their current standard-of-care, EBV-specific therapeutics in development, GPCRs and their druggability, and most importantly co...
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Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised patients. The UL146 gene exists as 14 diverse genotypes among clinical isolates, which encode 14 different CXC chemokines. One genotype (vCXCL1GT1) is a known agonist... more
Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised patients. The UL146 gene exists as 14 diverse genotypes among clinical isolates, which encode 14 different CXC chemokines. One genotype (vCXCL1GT1) is a known agonist for CXCR1 and CXCR2, while two others (vCXCL1GT5 and vCXCL1GT6) lack the ELR motif considered crucial for CXCR1 and CXCR2 binding, thus suggesting another receptor targeting profile. To determine the receptor target for vCXCL1GT5, the chemokine was probed in a G protein signaling assay on all 18 classical human chemokine receptors, where CXCR2 was the only receptor being activated. In addition, vCXCL1GT5 recruited β-arrestin in a BRET-based assay and induced migration in a chemotaxis assay through CXCR2, but not CXCR1. In contrast, vCXCL1GT1 stimulated G protein signaling, recruited β-arrestin and induced migration through both CXCR1 and CXCR2. Both vCXCL1GT1 and vCXCL1GT5 induced equally potent and efficacious migration of neutrophils, and ELR vCXCL...
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This review paper highlights the major advances investigating the roles of glucose dependent insulinotropic polypeptide and its receptors in glucose metabolism and their potential use in management of type 2 diabetes mellitus. It also... more
This review paper highlights the major advances investigating the roles of glucose dependent insulinotropic polypeptide and its receptors in glucose metabolism and their potential use in management of type 2 diabetes mellitus. It also focusses on the role of dipeptidyl peptidase-4 inhibitors in the treatment of this disease. This study discussed the recent therapeutic development which have occurred in this field, and also covering the evolvement of the potential treatments for diabetes which can be discovered and implemented in the near future to design an effective therapy for diabetes and prediabetes.
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The intestinal G protein-coupled receptor GPR119 is a novel metabolic target involving glucagon-like peptide-1 (GLP-1)-derived insulin-regulated glucose homeostasis. Endogenous and diet-derived lipids, including N-acylethanolamines and... more
The intestinal G protein-coupled receptor GPR119 is a novel metabolic target involving glucagon-like peptide-1 (GLP-1)-derived insulin-regulated glucose homeostasis. Endogenous and diet-derived lipids, including N-acylethanolamines and 2-monoacylglycerols (2-MAG) activate GPR119. The purpose of this work is to evaluate whether 2-oleoyl glycerol (2-OG) improves glucose tolerance through GPR119, using wild type (WT) and GPR 119 knock out (KO) mice. We here show that GPR119 is essential for 2-OG-mediated release of GLP-1 and CCK from GLUTag cells, since a GPR119 specific antagonist completely abolished the hormone release. Similarly, in isolated primary colonic crypt cultures from WT mice, GPR119 was required for 2-OG-stimulated GLP-1 release while there was no response in crypts from KO mice. In vivo, gavage with 2-oleyl glyceryl ether ((2-OG ether), a stable 2-OG analog with a potency of 5.3 µM for GPR119 with respect to cAMP formation as compared to 2.3 µM for 2-OG), significantly (P < 0.05) improved glucose clearance in WT littermates, but not in GPR119 KO mice. Finally, deletion of GPR119 in mice resulted in lower glucagon levels, whereas the levels of insulin and GIP were unchanged. In the present study we show that 2-OG stimulates GLP-1 secretion through GPR119 activation in vitro, and that fat-derived 2-MAGs are potent candidates for mediating fat-induced GLP-1 release through GPR119 in vivo. © 2016 BioFactors, 42(6):665-673, 2016.