Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Metabolism

Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals

  1. Lærke S. Gasbjerg1,2,3,
  2. Mads M. Helsted2,
  3. Bolette Hartmann1,3,
  4. Mette H. Jensen1,4,
  5. Maria B.N. Gabe1,
  6. Alexander H. Sparre-Ulrich1,3,4,
  7. Simon Veedfald1,3,
  8. Signe Stensen2,5,
  9. Amalie R. Lanng2,5,
  10. Natasha C. Bergmann2,5,6,
  11. Mikkel B. Christensen2,5,7,
  12. Tina Vilsbøll2,5,
  13. Jens J. Holst1,3,
  14. Mette M. Rosenkilde1,3⇑ and
  15. Filip K. Knop2,3,5⇑
  1. 1Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  2. 2Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
  3. 3Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  4. 4Antag Therapeutics ApS, Copenhagen, Denmark
  5. 5Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  6. 6Zealand Pharma A/S, Glostrup, Denmark
  7. 7Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
  1. Corresponding author: Filip K. Knop, filip.krag.knop.01{at}regionh.dk, or Mette M. Rosenkilde, rosenkilde{at}sund.ku.dk
Diabetes 2019 May; 68(5): 906-917. https://doi.org/10.2337/db18-1123
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

Abstract

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are secreted postprandially and contribute importantly to postprandial glucose tolerance. In this study, we assessed the individual and combined contributions of endogenous GIP and GLP-1 to the postprandial changes in glucose and glucoregulatory hormones using the novel GIP receptor antagonist GIP(3-30)NH2 and the well-established GLP-1 receptor antagonist exendin(9-39)NH2. During 4-h oral glucose tolerance tests (75 g) combined with an ad libitum meal test, 18 healthy men received on four separate days in randomized, double-blinded order intravenous infusions of A) GIP(3-30)NH2 (800 pmol/kg/min) plus exendin(9-39)NH2 (0–20 min: 1,000 pmol/kg/min; 20–240 min: 450 pmol/kg/min), B) GIP(3-30)NH2, C) exendin(9-39)NH2, and D) saline, respectively. Glucose excursions were significantly higher during A than during B, C, and D, while glucose excursions during B were higher than during C and D. Insulin secretion (assessed by C-peptide/glucose ratio) was reduced by 37 ± 16% (A), 30 ± 17% (B), and 8.6 ± 16% (C) compared with D (mean ± SD). A and C resulted in higher glucagon levels and faster gastric emptying. In conclusion, endogenous GIP affects postprandial plasma glucose excursions and insulin secretion more than endogenous GLP-1, but the hormones contribute additively to postprandial glucose regulation in healthy individuals.

Introduction

Food ingestion leads to secretion of several gut hormones, including the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) (1,2). GIP is secreted from enteroendocrine K cells primarily located in the proximal part of the intestines (duodenum and jejunum), whereas L cells secreting GLP-1 are more prevalent in the distal gut (ileum and colon) (3). GIP and GLP-1 contribute to the so-called incretin effect (i.e., the potentiation of postprandial insulin secretion by gastrointestinal factors) (4). The separate contributions of GIP and GLP-1 to the incretin effect have not been quantified, but, based on exogenous hormone infusions, GIP has been suggested as the predominant incretin hormone in healthy subjects in some (4,5) but not in all studies (2,6). In patients with type 2 diabetes, the incretin effect is diminished, contributing importantly to the postprandial hyperglycemia observed in these patients (7,8).

The physiological effects of GLP-1 have been revealed in studies using the GLP-1 receptor (GLP-1R) antagonist exendin(9-39)NH2 (9,10). Several exendin(9-39)NH2-based studies have confirmed that endogenous GLP-1 delays gastric emptying, stimulates insulin secretion, decreases glucagon secretion, and lowers appetite (10–12). It has not been possible to study the physiological effects of endogenous GIP in a similar way due to lack of a suitable receptor antagonist. Intravenous administration of GIP has shown that GIP effects include glucose-dependent insulin secretion (during high plasma glucose) (13) and glucagon secretion (during low plasma glucose) (14), decreased bone resorption (15), increased deposition of triacylglycerides in the adipose tissue (16), and increased blood flow to the intestines and adipose tissue (16,17).

Recently, we observed that infusions of the naturally occurring GIP fragment GIP(3-30)NH2 act as a GIP receptor (GIPR) antagonist (18–21) able to block effects of exogenous GIP on insulin secretion (18) and on adipose tissue (22) in humans. This antagonist will therefore help to elucidate the effects of endogenous GIP. To investigate the physiological effects of endogenous GIP alone and in combination with endogenous GLP-1 on glucose metabolism and glucose-regulating hormones, we studied healthy men during four separate oral glucose tolerance tests (OGTTs) with concomitant infusions of GIP(3-30)NH2, exendin(9-39)NH2, the combination of the two, and placebo, respectively. We hypothesized that the two incretin hormones equally contribute to postprandial glucose tolerance and that antagonism of the incretin hormone receptors will eliminate the incretin effect and, thus, exert additive effects on postprandial glucose excursions.

Research Design and Methods

Ethics Approval

The protocol was approved by the Scientific-Ethical Committee of the Capital Region of Denmark (identification number H-16033104) and the Danish Data Protection Agency (local number HGH-2018–036; I-Suite number 6508). The study is registered at ClinicalTrials.gov (registration number NCT03133741).

Participants

Eighteen men (Table 1) were included. Inclusion criteria were age 20–70 years, BMI >19.0 kg/m2, hemoglobin A1C <6.5% (48 mmol/mol), and fasting plasma glucose (FPG) <7 mmol/L. Exclusion criteria were use of medication that could not be paused for 12 h, diabetes, first-degree relatives with diabetes, abnormal blood biochemistry (blood hemoglobin and plasma liver enzymes [alanine aminotransferase and ASTs]), plasma creatinine, and urine albumin-to-creatinine ratio. All participants gave written informed consent before inclusion.

View this table:
  • View inline
  • View popup
Table 1

Baseline characteristics of the study participants

Peptides

Synthetic human GIP(3-30)NH2 (custom synthesized by Caslo, Lyngby, Denmark) and exendin(9-39)NH2 (catalog number H-8740; Bachem, Bubendorf, Switzerland) were demonstrated to be >95% and >97% pure, respectively, and identical to the natural peptides by high-performance liquid chromatography, mass, and sequence analysis. Exendin(9-39)NH2 was dissolved in sodium chloride (9 mg/mL) with 0.2% human albumin (CSL Behring, Marburg, Germany), and GIP(3-30)NH2 was dissolved in sodium hydrogen carbonate with 0.2% human albumin. After sterile filtration and test for sterility and pyrogens by the Capital Region Pharmacy (Herlev, Denmark), vials were stored at −20°C pending use. On study days, vials were thawed and prepared for infusion under sterile conditions by dilution to a total volume of 250 mL in sodium chloride (9 mg/mL; Fresenius Kabi, Uppsala, Sweden) with 0.2% human albumin. Placebo infusions were 250 mL sodium chloride with 0.2% human albumin.

Study Design

Each participant served as his own control and attended four 75-g OGTTs on four separate study days in a randomized order with infusion of GIP(3-30)NH2 (260 min at a rate of 800 pmol/kg/min), exendin(9-39)NH2 (20 min at 1,000 pmol/kg/min followed by 240 min at 450 pmol/kg/min), GIP(3-30)NH2 and exendin(9-39)NH2, or placebo. An uninvolved laboratory technician dissolved the peptides and/or mixed the placebo infusions; thus, the content was unknown for the participants and investigators.

On each study day, the participant arrived after a 48-h period without alcohol consumption or strenuous physical activity and an overnight fast (∼10 h) including liquids. A cannula was placed in a cubital vein in each arm, one for blood sampling and the other for peptide infusions. The hand and forearm for blood sampling were wrapped in a heating pad (45°C) to arterialize the venous blood. At time −20 min, the peptide infusions were started, and at time 0–5 min, 75 g of glucose (the OGTT) plus 1.5 g of acetaminophen dissolved in 300 mL water was ingested. At time 240–270 min, an ad libitum meal of pasta bolognese was served (energy content per 100 g: 147 kcal, 5.9 g fat, 17 g carbohydrates, and 5.6 g protein) and consumed during continuous infusions.

Data Collection

Blood samples were drawn 30, 15, and 0 min before and 15, 30, 45, 60, 90, 120, 180, and 240 min after initiation of the OGTT. For bedside analysis of plasma glucose, blood was collected in sodium fluoride-coated tubes and immediately centrifuged for 30 s (∼7,500g, room temperature). For analysis of GIP, GLP-1, glucagon, pancreatic polypeptide (PP), GIP(3-30)NH2, and exendin(9-39)NH2, blood was collected into chilled EDTA tubes to which were added a specific dipeptidyl peptidase 4 inhibitor (valine pyrrolidide, 0.01 mmol/L) (gift from Novo Nordisk, Måløv, Denmark). For analysis of insulin and C-peptide, blood was sampled in dry tubes with serum separator gel and clot activator (silica particles) and left at room temperature for 20 min for coagulation. For analysis of acetaminophen (paracetamol), blood was sampled in tubes with lithium and heparin. All tubes were centrifuged for 15 min (2,900g, 4°C). Plasma and serum samples were stored at −20°C until analysis. Questionnaires about hunger, satiety, fullness, potential meal consumption, thirst, comfort, tiredness, and nausea (10-mm visual analog scales [VASs] on paper) were answered every 30 min. The replies (millimeters) were measured with a ruler. The amount of food consumed during the ad libitum meal was determined by weighing meals and leftovers, and the appearance, smell, taste, off-notes, and overall impression of the meal were assessed by VAS.

Laboratory Methods

Plasma glucose was measured by the glucose oxidase method (model 2300 STAT Plus analyzer; YSI Incorporated, Yellow Springs, OH) bedside. Serum insulin and C-peptide were measured with two-sided electrochemiluminescence assays (Roche/Hitachi Modular Analytics; Roche Diagnostics, Mannheim, Germany). Total GLP-1 (23), total GIP (24), PP (25), GIP(3-30)NH2 (18), and exendin(9-39)NH2 (26) were measured in plasma by radioimmunoassays as previously described. Plasma glucagon was measured by ELISA (10–1271–01; Mercodia, Uppsala, Sweden).

Statistical Analyses and Calculations

Results in the text are reported as mean ± SD and in figures mean ± SEM unless otherwise stated. All calculations of the area under curve (AUC) were based on the trapezoidal rule, and AUC values are reported for the period 0–240 min. To assess the postprandial period ended by plasma glucose levels’ return to baseline, baseline-subtracted AUC (bsAUC) is reported for the period 0–180 min. Baselines are calculated as mean of the −30, −15, and 0 min values or, when only available, −30 and 0 min.

Statistical analyses were performed with GraphPad Prism 7.02 (GraphPad Software, San Diego, CA). A two-sided P value <0.05 was used as significance level. One-way repeated-measures ANOVA (rmANOVA) with Greenhouse-Geisser correction and Tukey multiple comparison were used to test for changes and differences among bsAUC, baseline, peak, and time to peak values. Post hoc, the effects of exendin(9-39)NH2 infusions on insulin levels were assessed: bsAUC values for insulin were analyzed in SAS Enterprise Guide 7.15 HF3 (SAS Institute Inc., Cary, NC) by a mixed-model rmANOVA with bsAUC values for insulin as fixed effect and study participant as random effect. Each of the following was subsequently included separately in the model as fixed effect: age, BMI, fat mass, glucagon, GIP, GLP-1, the integrated index of β-cell function, or insulinogenic index.

Insulin secretion rate (ISR) values were based on deconvolution of C-peptide concentrations using age, height, weight, and population-based variables for C-peptide kinetics as previously described (27,28). Insulin/glucose, C-peptide/glucose, and ISR/glucose ratios were calculated for each data point and summarized as a time curve. AUCs for these time curves were calculated as described above. Insulinogenic index was calculated as the change in insulin value from baseline to 30 min divided by the change in glucose for the same period (Δinsulin0–30 min/Δglucose0–30 min) (29). An integrated index of β-cell function throughout the postprandial period was calculated as AUC of ISR divided by AUC of glucose (30). β-Cell glucose sensitivity (30) was calculated as the slope of the linear regression of ISR from 0 min to time of peak value (y values) plotted against the glucose concentrations for the same period (x values).

Results

Baseline Characteristics

Eighteen healthy men were included in and completed the study (Table 1). One participant had mild vasovagal reactions to the cannulations on all study days, but it resolved quickly and before infusions were initiated. We observed no reactions to the infusions, and the participants did not report any discomfort.

Infusions

Plasma levels of GIP(3-30)NH2 reached steady state after 20 min of infusion (time 0 min) with mean concentrations of 57 ± 16 nmol/L during the study day with coinfusion of exendin(9-39)NH2 and 59 ± 16 nmol/L during coinfusion with saline (Fig. 1A). Exendin(9-39)NH2 in plasma reached steady state after 50 min (time 30 min) with a mean concentration (time 0–240 min) of 212 ± 117 nmol/L during the coinfusion with GIP(3-30)NH2 and 194 ± 98 nmol/L during the coinfusion with saline (Fig. 1B).

Figure 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1

Plasma levels of GIP(3-30)NH2 and exendin(9-39)NH2. Plasma levels of GIP(3-30)NH2 (A) and exendin(9-39)NH2 (B) during four 75-g OGTTs (initiated at time 0 min [dotted line]), each with concomitant i.v. infusion (time −20 to 240 min) of GIP(3-30)NH2 + exendin(9-39)NH2 (black circles), GIP(3-30)NH2 (white squares), exendin(9-39)NH2 (black triangles), and placebo (white circles, dashed lines), respectively. Data are mean ± SEM.

Glucose

At baseline, infusions with exendin(9-39)NH2 alone as well as combined with GIP(3-30)NH2 caused higher FPG levels than the placebo infusion (Fig. 2 and Table 2). During placebo infusion, the OGTT increased plasma glucose concentrations from 5.3 ± 0.37 mmol/L at baseline to a maximum of 9.3 ± 2.0 mmol/L after 43.3 ± 16 min (Fig. 2). GIP(3-30)NH2 and exendin(9-39)NH2 each had higher peak glucose levels of 10.3 ±2.1 mmol/L (P = 0.0101) and 10.6 ± 2.2 mmol/L (P = 0.0006), respectively, during the separate infusions. An additive effect was observed with the combination of GIP(3-30)NH2 and exendin(9-39)NH2 (11.8 ± 1.9 mmol/L), which was significantly higher than the three other interventions (Fig. 2 and Table 2). The time to peak glucose levels was significantly prolonged by ∼14 min during both infusion with GIP(3-30)NH2 + exendin(9-39)NH2 and infusion with GIP(3-30)NH2 alone, but was not affected by exendin(9-39)NH2 alone (Table 2). bsAUC during exendin(9-39)NH2 was similar to placebo, whereas GIP(3-30)NH2 caused significantly higher glucose excursions (bsAUC) compared with placebo (P = 0.0012). Infusion of GIP(3-30)NH2 + exendin(9-39)NH2 resulted in the highest bsAUC (P < 0.0001 compared with placebo) (Fig. 2B and Table 2) and significantly higher bsAUC than each of the antagonists. Based on fold changes in bsAUC from each participant, GLP-1R antagonism, GIPR antagonism, and the combination increased plasma glucose excursions by 1.9 ± 2.0-, 2.6 ± 3.1-, and 3.6 ± 5.0-fold compared with placebo.

Figure 2
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2

Glucose responses. Plasma levels of glucose (A) and corresponding bsAUC0–180 min (B) during four 75-g OGTTs (initiated at time 0 min) with concomitant i.v. infusion (time −20 to 240 min) of GIP(3-30)NH2 + exendin(9-39)NH2 (black circles), GIP(3-30)NH2 (white squares), exendin(9-39)NH2 (black triangles), or placebo (white circles, dashed lines). Data are presented as mean ± SEM. Data were compared by one-way rmANOVA with Greenhouse-Geisser correction and Tukey multiple comparison: P < 0.0001. Significant differences for the post hoc analyses are marked with asterisks: *P < 0.05; **P ≤ 0.01; ****P ≤ 0.0001.

View this table:
  • View inline
  • View popup
Table 2

Overview of plasma and serum measurements

Insulin, C-Peptide, Glucagon, and PP

No significant differences in baseline values of insulin, C-peptide, glucagon, or PP were observed. During all four interventions, the OGTT stimulated insulin secretion (Fig. 3A–C), but the response was significantly reduced by infusion with GIP(3-30)NH2 (Table 2). In 6 of the 18 participants, infusion of exendin(9-39)NH2 caused significantly higher insulin and C-peptide levels compared with the three other interventions. This phenomenon has been reported in similar studies previously (31–34) and does not seem to be related to age, BMI, fat mass, glucagon, GIP, GLP-1, or the integrated index of β-cell function. However, a significant association was evident for bsAUC of insulin between the insulinogenic index (Fig. 4A and Table 2) calculated from the placebo infusion and the interventions (insulinogenic index × intervention, P = 0.0088) when evaluated by mixed-model ANOVA.

Figure 3
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3

Insulin, C-peptide, glucagon, and PP. Serum levels of insulin (A) and C-peptide (B), bsAUC0–180 min for C-peptide (C), insulin/glucose and C-peptide/glucose ratios (D and E), bsAUC0–180 min for C-peptide/glucose (F) and ISR/glucose (G), and plasma levels of glucagon (H) and PP (I) during four 75-g OGTTs (initiated at time 0 min, dotted line) with concomitant i.v. infusion (time −20 to 240 min) of GIP(3-30)NH2 + exendin(9-39)NH2 (black circles), GIP(3-30)NH2 (white squares), exendin(9-39)NH2 (black triangles), or placebo (white circles, dashed lines). Data are presented as mean ± SEM. Data were compared by one-way rmANOVA with Greenhouse-Geisser correction and Tukey multiple comparison. ANOVAs: P = 0.0025 (C) and P < 0.0001 (F). Significant differences for the post hoc analyses are marked with asterisks: *P < 0.05; **P ≤ 0.01; ****P ≤ 0.0001.

Figure 4
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 4

β-Cell function. Insulinogenic index (A), β-cell glucose sensitivity (B), and the integrated index of β-cell function (C) calculated from the four 75-g OGTTs with concomitant i.v. infusion (time −20 to 240 min) of GIP(3-30)NH2 + exendin(9-39)NH2 (black circles), GIP(3-30)NH2 (white squares), exendin(9-39)NH2 (black triangles), or placebo (white circles). Data were compared by one-way rmANOVA with Greenhouse-Geisser correction and Tukey multiple comparison. ANOVAs: P < 0.0001 (A–C). Significant differences for the post hoc analyses are marked with asterisks: *P < 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001.

The profiles of insulin (Fig. 3A), C-peptide (Fig. 3B and C), insulin/glucose ratio (Fig. 3D), and ISR/glucose ratio (Fig. 3G) showed similar changes during the four infusions, but the magnitude of responses was significantly reduced during infusion of GIP(3-30)NH2 alone, and there was no further reduction upon combination with exendin(9-39)NH2 (Fig. 3A–D and Table 2). However, C-peptide/glucose ratios were significantly reduced compared with placebo during exendin(9-39)NH2 and GIP(3-30)NH2, as well as during the two antagonists combined (Fig. 3E and F).

Based on the values of bsAUC for C-peptide/glucose, insulin secretion was reduced by 8.6 ± 16% during exendin(9-39)NH2 infusion (P = 0.0910), by 30 ± 17% during GIP(3-30)NH2 infusion (P = 0.001), and by 37 ± 16% during infusion of exendin(9-39)NH2 + GIP(3-30)NH2 (P = 0.001) compared with placebo.

During placebo infusion, oral glucose induced a decrease in glucagon that was significantly diminished by the infusions of exendin(9-39)NH2 and unaffected by GIP(3-30)NH2 (Fig. 3H and Table 2). PP responses to oral glucose were similar during all four interventions (Fig. 3I and Table 2). As hypoglycemia is a powerful stimulant of PP secretion, the surge in PP after time 180 min was ostensibly due to the decline in plasma glucose, sometimes below fasting levels (35).

β-Cell Function

β-Cell function, assessed by the insulinogenic index (Δinsulin0–30 min/Δglucose0–30 min), appeared to be mainly affected by GIP(3-30)NH2, which caused a significant reduction (Fig. 4A and Table 2). Likewise, the β-cell glucose sensitivity (slope of ISR vs. glucose from 0 min to glucose peak) was significantly reduced by GIP(3-30)NH2 and the combined exendin(9-39)NH2 and GIP(3-30)NH2 infusion compared with placebo (Fig. 4B and Table 2). Infusion with GIP(3-30)NH2 resulted in impaired integrated index of β-cell function during the postprandial period (AUCISR/AUCglucose), which was even more pronounced during coinfusion of GIP(3-30)NH2 + exendin(9-39)NH2 (Fig. 4C and Table 2), indicating individual and additive effects of the two incretin hormones.

GIP and GLP-1

Plasma concentrations of total GIP were similar during all four experiments (Table 2). The postprandial bsAUC for total GIP was slightly increased during infusion with GIP(3-30)NH2 compared with both exendin(9-39)NH2 and placebo infusions (Fig. 5B and Table 2). Infusion with exendin(9-39)NH2 was the only intervention that resulted in a significantly increased peak concentration of total GIP compared with placebo (P = 0.0108) (Fig. 5A). Baseline values of GLP-1 were similar (Table 2), but during infusions with exendin(9-39)NH2 bsAUC as well as peak concentrations of total GLP-1 were clearly and significantly increased (Table 2) as previously reported (31–34).

Figure 5
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 5

GIP and GLP-1. Plasma levels of GIP (A) and GLP-1 (C) and corresponding bsAUC0–180 min (B and D) during four 75-g OGTTs (initiated at time 0 min) with concomitant i.v. infusion (time −20 to 240 min) of GIP(3-30)NH2 + exendin(9-39)NH2 (black circles), GIP(3-30)NH2 (white squares), exendin(9-39)NH2 (black triangles), or placebo (white circles, dashed lines). Data are presented as mean ± SEM. Data were compared by one-way rmANOVA with Greenhouse-Geisser correction and Tukey multiple comparison. ANOVAs: P = 0.0400 (B) and P = 0.0005 (D). Significant differences for the post hoc analyses are marked with asterisks: *P < 0.05; ***P ≤ 0.001.

Acetaminophen Absorption and Appetite

Acetaminophen was undetectable in all baseline samples. Infusions with exendin(9-39)NH2 accelerated gastric emptying, resulting in ∼11 min earlier and significantly higher peak values (Fig. 6A and Table 2).

Figure 6
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 6

Acetaminophen absorption and appetite measurements. Plasma levels of acetaminophen (A), amount of ingested food during the ad libitum meal (B), VAS of hunger (C), satiety (D), fullness (E), prospective food consumption (F), comfort (G), nausea (H), and thirst (I) during four 75-g OGTTs (initiated at time 0 min), each with concomitant i.v. infusion (time −20 to 240 min) of GIP(3-30)NH2 + exendin(9-39)NH2 (black circles), GIP(3-30)NH2 (white squares), exendin(9-39)NH2 (black triangles), or placebo (white circles, dashed lines). Data are presented as mean ± SEM. Data were compared by one-way rmANOVA with Greenhouse-Geisser correction and Tukey multiple comparison.

The ad libitum meal was evaluated by VAS (0–100 mm) with a mean score for appearance of 73 ± 21 mm, smell 76 ± 15 mm, taste 78 ± 2.0 mm, off-taste 10 ± 16 mm, and overall impression 76 ± 16 mm (n = 17). One study participant refused to consume the ad libitum meal due to the choice of dish. Infusion with exendin(9-39)NH2 increased the bsAUC for hunger significantly (Fig. 6C), but the amount of food consumed or VAS for satiety, fullness, prospective food consumption, comfort, nausea, or thirst was similar during the four interventions (Fig. 6B and D–I).

Discussion

In the current study, the separate and combined effects of endogenous GIP and GLP-1 during an OGTT were evaluated by infusions of specific antagonists of the GIPR and GLP-1R, respectively, and we find that the two incretin hormones have additive insulinotropic effects. Furthermore, the data indicate that endogenous GIP may be responsible for a greater proportion of the insulin response to oral glucose than endogenous GLP-1 in healthy men.

The Incretin Effect

The incretin effect is usually estimated by comparing the insulin responses of an OGTT and an isoglycemic i.v. glucose infusion (36). By infusing GIPR and GLP-1R antagonists, we can now confirm that endogenous GIP and GLP-1 increase the insulin secretion in healthy individuals additively and contribute by at least 40% to the total insulin response to a 75-g OGTT. Furthermore, assessment of the effect of endogenous GIP and GLP-1 during OGTT on plasma glucose (bsAUC of glucose) was estimated to be at least 57 ± 15% (bsAUCboth antagonists/bsAUCplacebo as percent of placebo), reflecting that 57 ± 15% of the glucose disposal during an OGTT seems to be a result of the incretin hormones GIP and GLP-1.

The contributions of the two hormones to the incretin effect have previously been estimated in studies applying i.v. administration of GIP and GLP-1. Depending on the protocol, data have suggested that the two hormones contribute about equally or that either GIP or GLP-1 explains the majority of the incretin effect in healthy subjects (2,5,6). Based on the current data, it seems that endogenous GIP lowers postprandial glucose levels to a greater extent than endogenous GLP-1 and that, while GIPR antagonism affects glycemic levels during the whole postprandial period, GLP-1R antagonism primarily affects the glucose excursions in the early postprandial phase. Thus, during the exendin(9-39)NH2 infusions, plasma glucose responses showed increased and significantly delayed peak glucose concentrations (by >10 min and 1.3 mmol/L), but the overall glucose excursion (as assessed by bsAUC) equaled that seen with placebo. In contrast, during the infusion of GIP(3-30)NH2, the bsAUC for glucose was significantly higher than during placebo [and exendin(9-39)NH2] infusion, but there was no delay in time to peak of glucose, and the increase in peak concentration of glucose was only 1.0 mmol/L (P = 0.0101 compared with placebo). Combined with the accelerated absorption of acetaminophen during exendin(9-39)NH2 infusions, these results would support that GLP-1 antagonism primarily affected gastric emptying and secondarily the insulin secretion (4,37).

Because the effects of the receptor antagonists are highly dependent on the degree of receptor blockage, we chose doses that previously resulted in high plasma concentrations (18,31,34). GIP(3-30)NH2 is pharmacologically well characterized (18–21) and has a Kd value of 3.4 nmol/L (19); the plasma concentrations reached in this study were >15-fold higher. Exendin(9-39)NH2 has been extensively used as a tool for studying the effects of endogenous GLP-1. Its affinity for the GLP-1R is high and almost similar to that of GLP-1 (9). The plasma concentrations obtained in this study exceed the plasma concentrations of endogenous GLP-1 ∼1,000-fold. Thus, the GLP-1Rs are theoretically fully blocked, whereas the GIPRs are at least 80% blocked (18). However, the mechanism of action of endogenous GLP-1 is complex and possibly involves activation of afferent sensory neurons in the gut and liver, which locally may be exposed to considerably higher GLP-1 concentrations. Furthermore, GLP-1 acts in a paracrine manner within the pancreatic islets (38), and this means that completeness of GLP-1R blockade cannot be estimated from infusion experiments. For GIP, a similar neural signaling mechanism is not known to exist.

The incretin effect is severely reduced in patients with type 2 diabetes (39), most likely due to diminished insulinotropic effect of GIP in these patients (40). GIP(3-30)NH2 may represent an important tool to delineate this pathophysiological phenomenon and evaluate its contribution to the hyperglycemic state of type 2 diabetes.

Appetite

GLP-1 reduces energy intake via peripheral and central neuronal pathways (41), and in obese individuals, exendin(9-39)NH2 has been shown to increase food intake (42). In the current study, we did not observe any difference in amount of food ingested (ad libitum meal) during the different infusions. Nevertheless, in contrast to the infusions with GIP(3-30)NH2 and exendin(9-39)NH2 + GIP(3-30)NH2, respectively, the infusion with exendin(9-39)NH2 alone did increase hunger (Fig. 6C). This effect might be disturbed by GIPR antagonism or depleted by the higher plasma glucose levels during the infusion of exendin(9-39)NH2 + GIP(3-30)NH2. A lack of effect of exendin(9-39)NH2 on food consumption has been reported in previous studies (42,43) and could be due to simultaneously increased levels of peptide YY (10,30,34,37), stimulating satiety (44). A role for endogenous GIP in the regulation of appetite sensations and food intake has not been identified previously and has not been suspected because of absent effects of exogenous GIP (45–48). Our results show that blockage of the GIPR using GIP(3-30)NH2 for a period of ∼4.5 h had no effect on appetite sensations (as assessed by VAS) or the amount of food consumed during an ad libitum meal, in agreement with data from previous GIP infusion studies (46,48).

Exendin(9-39)NH2 as a Study Tool

Administration of exendin(9-39)NH2 to humans may have several effects including changes in gastric emptying, glucose levels, and glucagon levels (10,49,50). We found a paradoxically increased insulin secretion (serum insulin and C-peptide levels) not accompanied by correspondingly decreased glucose levels. Interestingly, we found a significant association with the insulinogenic index of each study participant, indicating that paradoxically high insulin levels are related to low insulin sensitivity. This phenomenon has been reported previously, primarily in healthy subjects undergoing OGTT or mixed-meal test (31–34), and is not present when glucose is administered intraduodenally (51). When evaluating insulin secretion from C-peptide/glucose or insulin/glucose ratios (describing insulin secretion in relation to prevailing glucose concentrations), the stimulation largely disappeared (Fig. 3D–F). This indicates that the increased insulin secretion could be a response to the hyperglycemia arising from exendin(9-39)NH2–induced stimulation of glucagon secretion and acceleration of gastric emptying. The increased GLP-1 release from the enteroendocrine L cells occurring during exendin(9-39)NH2 administration is most likely a result of a disturbed feedback loop involving somatostatin-secreting cells (52) and may also involve exendin(9-39)NH2–induced acceleration of gastric emptying, but is unlikely to play a role in the increased insulin secretion observed during exendin(9-39)NH2 infusion as GLP-1Rs on the β-cells are blocked. Nevertheless, other changes occurring during GLP-1R antagonism, including peptide YY secretion from L cells and GIP secretion from K cells (a weak response was actually observed in the present experiments [Fig. 5A and Table 2]), may contribute to explain the lack of effect of exendin(9-39)NH2 on typical GLP-1 effects such as food intake and insulin secretion as previously described (31,43,48).

Conclusion

In healthy men, endogenous GIP and GLP-1 additively contribute to OGTT-induced insulin secretion and glucose tolerance, with GIP apparently having the greatest effect.

Article Information

Acknowledgments. The authors thank the study participants for loyalty and commitment and Sisse Marie Schmidt and Inass Al Nachar (both from Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark), and Lene Albæk (Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark) for laboratory assistance.

Funding. The clinical studies were conducted at Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen (Gentofte Hospital, Denmark) and supported by the European Foundation for the Study of Diabetes, the Novo Nordisk Foundation, and the Hørslev Foundation.

Duality of Interest. GIP(3-30)NH2 as a therapeutic agent is protected by intellectual property rights owned by University of Copenhagen (PCT/DK2015/050266). L.S.G., M.B.N.G., and M.B.C. are minority shareholders of Antag Therapeutics. B.H. is a minority shareholder in Bainan Biotech. M.H.J. is an industrial PhD student employed by Antag Therapeutics ApS. A.H.S.-U. is a shareholder in and Chief Executive Officer employed by Antag Therapeutics ApS. N.C.B. is an industrial PhD student employed by Zealand Pharma A/S. J.J.H. is a minority shareholder and board member of Antag Therapeutics and has been a consultant for, served on scientific advisory panels of, and been given speaker honoraria for Novo Nordisk and Merck Sharp & Dohme/Merck. M.M.R. is a minority shareholder in and consultant for Antag Therapeutics, minority shareholder and chair of the board of Bainan Biotech, and consultant for Synklino. F.K.K. has served on scientific advisory panels, been part of speakers’ bureaus for, served as a consultant to, and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly and Company, Gubra, MedImmune, Merck Sharp & Dohme/Merck, Norgine, Novo Nordisk, Sanofi, SNIPR Biome, and Zealand Pharma and is a minority shareholder in Antag Therapeutics. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. L.S.G., M.M.H., S.S., and A.R.L. performed the study. L.S.G., B.H., M.H.J., M.B.N.G., and S.V. performed the radioimmunoassay and ELISA measurements. L.S.G., B.H., A.H.S.-U., M.B.C., J.J.H., M.M.R., and F.K.K. performed the data analysis. L.S.G., A.H.S.-U., N.C.B., M.B.C., T.V., J.J.H., M.M.R., and F.K.K. designed the study and wrote the study protocol. L.S.G. and F.K.K. wrote the manuscript. L.S.G., M.M.H., B.H., M.H.J., M.B.N.G., A.H.S.-U., S.V., S.S., A.R.L., N.C.B., M.B.C., T.V., J.J.H., M.M.R., and F.K.K. critically edited the manuscript and approved the final version. L.S.G. and F.K.K. are the guarantors of this work and, as such, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Footnotes

  • Clinical trial reg. no. NCT03133741, clinicaltrials.gov

  • See accompanying article, p. 897.

  • Received October 16, 2018.
  • Accepted January 5, 2019.
  • © 2019 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

References

  1. ↵
    1. Dupre J,
    2. Ross SA,
    3. Watson D,
    4. Brown JC
    . Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab 1973;37:826–828pmid:4749457
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    1. Kreymann B,
    2. Williams G,
    3. Ghatei MA,
    4. Bloom SR
    . Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 1987;2:1300–1304pmid:2890903
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    1. Jorsal T,
    2. Rhee NA,
    3. Pedersen J, et al
    . Enteroendocrine K and L cells in healthy and type 2 diabetic individuals. Diabetologia 2018;61:284–294pmid:28956082
    OpenUrlPubMed
  4. ↵
    1. Nauck MA,
    2. Meier JJ
    . The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol 2016;4:525–536pmid:26876794
    OpenUrlPubMed
  5. ↵
    1. Nauck MA,
    2. Bartels E,
    3. Ørskov C,
    4. Ebert R,
    5. Creutzfeldt W
    . Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab 1993;76:912–917pmid:8473405
    OpenUrlCrossRefPubMedWeb of Science
  6. ↵
    1. Vilsbøll T,
    2. Krarup T,
    3. Madsbad S,
    4. Holst JJ
    . Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept 2003;114:115–121pmid:12832099
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Bagger JI,
    2. Knop FK,
    3. Lund A,
    4. Vestergaard H,
    5. Holst JJ,
    6. Vilsbøll T
    . Impaired regulation of the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab 2011;96:737–745pmid:21252240
    OpenUrlCrossRefPubMedWeb of Science
  8. ↵
    1. Muscelli E,
    2. Mari A,
    3. Casolaro A, et al
    . Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes 2008;57:1340–1348pmid:18162504
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Göke R,
    2. Fehmann HC,
    3. Linn T, et al
    . Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J Biol Chem 1993;268:19650–19655pmid:8396143
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Schirra J,
    2. Sturm K,
    3. Leicht P,
    4. Arnold R,
    5. Göke B,
    6. Katschinski M
    . Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J Clin Invest 1998;101:1421–1430pmid:9525985
    OpenUrlCrossRefPubMedWeb of Science
    1. van Bloemendaal L,
    2. IJzerman RG,
    3. Ten Kulve JS, et al
    . GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes 2014;63:4186–4196pmid:25071023
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Salehi M,
    2. Prigeon RL,
    3. D’Alessio DA
    . Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans. Diabetes 2011;60:2308–2314pmid:21868791
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Creutzfeldt W
    . The incretin concept today. Diabetologia 1979;16:75–85pmid:32119
    OpenUrlCrossRefPubMedWeb of Science
  13. ↵
    1. Christensen M,
    2. Vedtofte L,
    3. Holst JJ,
    4. Vilsbøll T,
    5. Knop FK
    . Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes 2011;60:3103–3109pmid:21984584
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Nissen A,
    2. Christensen M,
    3. Knop FK,
    4. Vilsbøll T,
    5. Holst JJ,
    6. Hartmann B
    . Glucose-dependent insulinotropic polypeptide inhibits bone resorption in humans. J Clin Endocrinol Metab 2014;99:E2325–E2329pmid:25144635
    OpenUrlCrossRefPubMed
  15. ↵
    1. Asmar M,
    2. Simonsen L,
    3. Madsbad S,
    4. Stallknecht B,
    5. Holst JJ,
    6. Bülow J
    . Glucose-dependent insulinotropic polypeptide may enhance fatty acid re-esterification in subcutaneous abdominal adipose tissue in lean humans. Diabetes 2010;59:2160–2163pmid:20547981
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Koffert J,
    2. Honka H,
    3. Teuho J, et al
    . Effects of meal and incretins in the regulation of splanchnic blood flow. Endocr Connect 2017;6:179–187pmid:28258126
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Gasbjerg LS,
    2. Christensen MB,
    3. Hartmann B, et al
    . GIP(3-30)NH2 is an efficacious GIP receptor antagonist in humans: a randomised, double-blinded, placebo-controlled, crossover study. Diabetologia 2018;61:413–423pmid:28948296
    OpenUrlPubMed
  18. ↵
    1. Hansen LS,
    2. Sparre-Ulrich AH,
    3. Christensen M, et al
    . N-terminally and C-terminally truncated forms of glucose-dependent insulinotropic polypeptide are high-affinity competitive antagonists of the human GIP receptor. Br J Pharmacol 2016;173:826–838pmid:26572091
    OpenUrlPubMed
    1. Sparre-Ulrich AH,
    2. Gabe MN,
    3. Gasbjerg LS, et al
    . GIP(3-30)NH2 is a potent competitive antagonist of the GIP receptor and effectively inhibits GIP-mediated insulin, glucagon, and somatostatin release. Biochem Pharmacol 2017;131:78–88pmid:28237651
    OpenUrlPubMed
  19. ↵
    1. Gabe MBN,
    2. Sparre-Ulrich AH,
    3. Pedersen MF, et al
    . Human GIP(3-30)NH2 inhibits G protein-dependent as well as G protein-independent signaling and is selective for the GIP receptor with high-affinity binding to primate but not rodent GIP receptors. Biochem Pharmacol 2018;150:97–107pmid:29378179
    OpenUrlPubMed
  20. ↵
    1. Asmar M,
    2. Asmar A,
    3. Simonsen L, et al
    . The gluco- and liporegulatory and vasodilatory effects of glucose-dependent insulinotropic polypeptide (GIP) are abolished by an antagonist of the human GIP receptor. Diabetes 2017;66:2363–2371pmid:28667118
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Ørskov C,
    2. Rabenhøj L,
    3. Wettergren A,
    4. Kofod H,
    5. Holst JJ
    . Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes 1994;43:535–539pmid:8138058
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Lindgren O,
    2. Carr RD,
    3. Deacon CF, et al
    . Incretin hormone and insulin responses to oral versus intravenous lipid administration in humans. J Clin Endocrinol Metab 2011;96:2519–2524pmid:21593115
    OpenUrlCrossRefPubMedWeb of Science
  23. ↵
    1. Dirksen C,
    2. Jørgensen NB,
    3. Bojsen-Møller KN, et al
    . Gut hormones, early dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass. Int J Obes 2013;37:1452–1459pmid:23419600
    OpenUrlCrossRefPubMed
  24. ↵
    1. Jørgensen NB,
    2. Dirksen C,
    3. Bojsen-Møller KN, et al
    . Exaggerated glucagon-like peptide 1 response is important for improved β-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes. Diabetes 2013;62:3044–3052pmid:23649520
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Hovorka R,
    2. Soons PA,
    3. Young MA
    . ISEC: a program to calculate insulin secretion. Comput Methods Programs Biomed 1996;50:253–264pmid:8894385
    OpenUrlCrossRefPubMedWeb of Science
  26. ↵
    1. Kjems LL,
    2. Christiansen E,
    3. Vølund A,
    4. Bergman RN,
    5. Madsbad S
    . Validation of methods for measurement of insulin secretion in humans in vivo. Diabetes 2000;49:580–588
    OpenUrlAbstract
  27. ↵
    1. Pacini G,
    2. Andrea T,
    3. Winzer C,
    4. Kautzky-Willer A
    . The insulinogenic index is a valid marker of beta cell function in different metabolic categories (Abstract). Diabetes 2005;54:A370
    OpenUrl
  28. ↵
    1. Svane MS,
    2. Bojsen-Moller KN,
    3. Nielsen S, et al.
    Effects of endogenous GLP-1 and GIP on glucose tolerance after Roux-en-Y gastric bypass surgery. Am J Physiol Endocrinol Metab 2016;310:E505–E514
    OpenUrlCrossRefPubMed
  29. ↵
    1. Edwards CM,
    2. Todd JF,
    3. Mahmoudi M, et al
    . Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. Diabetes 1999;48:86–93pmid:9892226
    OpenUrlAbstract
    1. Schirra J,
    2. Nicolaus M,
    3. Woerle HJ,
    4. Struckmeier C,
    5. Katschinski M,
    6. Göke B
    . GLP-1 regulates gastroduodenal motility involving cholinergic pathways. Neurogastroenterol Motil 2009;21:609–618, e21–e22pmid:19220754
    OpenUrlCrossRefPubMed
    1. D’Alessio DA,
    2. Vogel R,
    3. Prigeon R, et al
    . Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons. J Clin Invest 1996;97:133–138pmid:8550824
    OpenUrlCrossRefPubMedWeb of Science
  30. ↵
    1. Nauck MA,
    2. Kind J,
    3. Köthe LD, et al
    . Quantification of the contribution of GLP-1 to mediating insulinotropic effects of DPP-4 inhibition with vildagliptin in healthy subjects and patients with type 2 diabetes using exendin [9-39] as a GLP-1 receptor antagonist. Diabetes 2016;65:2440–2447pmid:27207543
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Schwartz TW,
    2. Holst JJ,
    3. Fahrenkrug J, et al
    . Vagal, cholinergic regulation of pancreatic polypeptide secretion. J Clin Invest 1978;61:781–789pmid:641155
    OpenUrlCrossRefPubMedWeb of Science
  32. ↵
    1. Nauck MA,
    2. Homberger E,
    3. Siegel EG, et al
    . Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 1986;63:492–498pmid:3522621
    OpenUrlCrossRefPubMedWeb of Science
  33. ↵
    1. Wettergren A,
    2. Schjoldager B,
    3. Mortensen PE,
    4. Myhre J,
    5. Christiansen J,
    6. Holst JJ
    . Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci 1993;38:665–673pmid:8462365
    OpenUrlCrossRefPubMedWeb of Science
  34. ↵
    1. Yabe D,
    2. Seino Y,
    3. Seino Y
    . Incretin concept revised: the origin of the insulinotropic function of glucagon-like peptide-1 - the gut, the islets or both? J Diabetes Investig 2018;9:21–24
    OpenUrl
  35. ↵
    1. Nauck M,
    2. Stöckmann F,
    3. Ebert R,
    4. Creutzfeldt W
    . Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986;29:46–52pmid:3514343
    OpenUrlCrossRefPubMedWeb of Science
  36. ↵
    1. Vilsbøll T,
    2. Knop FK,
    3. Krarup T, et al
    . The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype. J Clin Endocrinol Metab 2003;88:4897–4903pmid:14557471
    OpenUrlCrossRefPubMedWeb of Science
  37. ↵
    1. Muscogiuri G,
    2. DeFronzo RA,
    3. Gastaldelli A,
    4. Holst JJ
    . Glucagon-like peptide-1 and the central/peripheral nervous system: crosstalk in diabetes. Trends Endocrinol Metab 2017;28:88–103pmid:27871675
    OpenUrlPubMed
  38. ↵
    1. Svane MS,
    2. Jørgensen NB,
    3. Bojsen-Møller KN, et al
    . Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery. Int J Obes 2016;40:1699–1706pmid:27434221
    OpenUrlPubMed
  39. ↵
    1. Steinert RE,
    2. Feinle-Bisset C,
    3. Asarian L,
    4. Horowitz M,
    5. Beglinger C,
    6. Geary N
    . Ghrelin, CCK, GLP-1, and PYY(3-36): secretory controls and physiological roles in eating and glycemia in health, obesity, and after RYGB. Physiol Rev 2017;97:411–463pmid:28003328
    OpenUrlCrossRefPubMed
  40. ↵
    1. Batterham RL,
    2. Cohen MA,
    3. Ellis SM, et al
    . Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 2003;349:941–948pmid:12954742
    OpenUrlCrossRefPubMedWeb of Science
  41. ↵
    1. Asmar M,
    2. Tangaa W,
    3. Madsbad S, et al
    . On the role of glucose-dependent insulintropic polypeptide in postprandial metabolism in humans. Am J Physiol Endocrinol Metab 2010;298:E614–E621pmid:19996386
    OpenUrlCrossRefPubMedWeb of Science
  42. ↵
    1. Daousi C,
    2. Wilding JPH,
    3. Aditya S, et al
    . Effects of peripheral administration of synthetic human glucose-dependent insulinotropic peptide (GIP) on energy expenditure and subjective appetite sensations in healthy normal weight subjects and obese patients with type 2 diabetes. Clin Endocrinol (Oxf) 2009;71:195–201pmid:19178509
    OpenUrlCrossRefPubMed
    1. Edholm T,
    2. Degerblad M,
    3. Grybäck P, et al
    . Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis. Neurogastroenterol Motil 2010;22:1191–1200, e315pmid:20584260
    OpenUrlCrossRefPubMed
  43. ↵
    1. Bergmann NC,
    2. Lund A,
    3. Gasbjerg LS, et al
    . The effects of GIP/GLP-1 receptor co-activation on appetite and food intake in overweight/obese subjects. Diabetologia 2017;60:S5
    OpenUrl
  44. ↵
    1. Woerle HJ,
    2. Carneiro L,
    3. Derani A,
    4. Göke B,
    5. Schirra J
    . The role of endogenous incretin secretion as amplifier of glucose-stimulated insulin secretion in healthy subjects and patients with type 2 diabetes. Diabetes 2012;61:2349–2358pmid:22721966
    OpenUrlAbstract/FREE Full Text
  45. ↵
    1. Shah M,
    2. Law JH,
    3. Micheletto F, et al
    . Contribution of endogenous glucagon-like peptide 1 to glucose metabolism after Roux-en-Y gastric bypass. Diabetes 2014;63:483–493pmid:24089513
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. Steinert RE,
    2. Schirra J,
    3. Meyer-Gerspach AC, et al
    . Effect of glucagon-like peptide-1 receptor antagonism on appetite and food intake in healthy men. Am J Clin Nutr 2014;100:514–523pmid:24965303
    OpenUrlAbstract/FREE Full Text
  47. ↵
    1. Hansen L,
    2. Hartmann B,
    3. Bisgaard T,
    4. Mineo H,
    5. Jørgensen PN,
    6. Holst JJ
    . Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum. Am J Physiol Endocrinol Metab 2000;278:E1010–E1018pmid:10827002
    OpenUrlPubMedWeb of Science
PreviousNext
Back to top
Diabetes: 68 (5)

In this Issue

May 2019, 68(5)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by Author
  • Masthead (PDF)
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals
(Your Name) has forwarded a page to you from Diabetes
(Your Name) thought you would like to see this page from the Diabetes web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals
Lærke S. Gasbjerg, Mads M. Helsted, Bolette Hartmann, Mette H. Jensen, Maria B.N. Gabe, Alexander H. Sparre-Ulrich, Simon Veedfald, Signe Stensen, Amalie R. Lanng, Natasha C. Bergmann, Mikkel B. Christensen, Tina Vilsbøll, Jens J. Holst, Mette M. Rosenkilde, Filip K. Knop
Diabetes May 2019, 68 (5) 906-917; DOI: 10.2337/db18-1123

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals
Lærke S. Gasbjerg, Mads M. Helsted, Bolette Hartmann, Mette H. Jensen, Maria B.N. Gabe, Alexander H. Sparre-Ulrich, Simon Veedfald, Signe Stensen, Amalie R. Lanng, Natasha C. Bergmann, Mikkel B. Christensen, Tina Vilsbøll, Jens J. Holst, Mette M. Rosenkilde, Filip K. Knop
Diabetes May 2019, 68 (5) 906-917; DOI: 10.2337/db18-1123
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Research Design and Methods
    • Results
    • Discussion
    • Article Information
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Ncor2/PPARα-Dependent Upregulation of MCUb in the Type 2 Diabetic Heart Impacts Cardiac Metabolic Flexibility and Function
  • Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance
  • Heme Oxygenase-1 Regulates Ferrous Iron and Foxo1 in Control of Hepatic Gluconeogenesis
Show more Metabolism

Similar Articles

Subjects

  • Integrated Physiology-Insulin Secretion In Vivo

Navigate

  • Current Issue
  • Online Ahead of Print
  • Scientific Sessions Abstracts
  • Collections
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes Care
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.