Glucose-dependent Insulinotropic Polypeptide Concentrations Research Articles

Secretion of glucagon, GLP-1 and GIP may be affected by circadian rhythm in healthy males.

Glucagon is secreted from pancreatic alpha cells in response to low blood glucose and increases hepatic glucose production. Furthermore, glucagon enhances hepatic protein and lipid metabolism during a mixed meal. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from gut endocrine cells during meals and control glucose homeostasis by potentiating insulin secretion and inhibiting food intake. Both glucose homeostasis and food intake have been reported to be affected by circadian rhythms and vice versa. In this study, we investigated whether the secretion of glucagon, GLP-1 and GIP was affected by circadian rhythms. A total of 24 healthy men with regular sleep schedules were examined for 24h at the hospital ward with 15h of wakefulness and 9h of sleep. Food intake was standardized, and blood samples were obtained every third hour. Plasma concentrations of glucagon, GLP-1 and GIP were measured, and data were analyzed by rhythmometric statistical methods. Available data on plasma glucose and plasma C-peptide were also included. Plasma concentrations of glucagon, GLP-1, GIP, C-peptide and glucose fluctuated with a diurnal 24-h rhythm, with the highest levels during the day and the lowest levels during the night: glucagon (p < 0.0001, peak time 18:26h), GLP-1 (p < 0.0001, peak time 17:28h), GIP (p < 0.0001, peak time 18:01h), C-peptide (p < 0.0001, peak time 17.59h), and glucose (p < 0.0001, peak time 23:26h). As expected, we found significant correlations between plasma concentrations of C-peptide and GLP-1 and GIP but did not find correlations between glucose concentrations and concentrations of glucagon, GLP-1 and GIP. Our results demonstrate that under meal conditions that are similar to that of many free-living individuals, plasma concentrations of glucagon, GLP-1 and GIP were observed to be higher during daytime and evening than overnight. These findings underpin disturbed circadian rhythm as a potential risk factor for diabetes and obesity. ClinicalTrials.gov Identifier: NCT06166368. Registered 12 December 2023.

Oral glucose has little or no effect on appetite and satiety sensations despite a significant gastrointestinal response.

The effect of oral glucose-induced release of gastrointestinal hormones on satiety and appetite independently of prevailing plasma glucose excursions is unknown. The objective is to investigate the effect of oral glucose on appetite and satiety sensations as compared to isoglycemic IV glucose infusion (IIGI) in healthy volunteers. A crossover study involving two study days for each participant. Nineteen healthy participants (6 women, mean age 55.1 [SD 14.2] years; mean body mass index 26.7 [SD 2.2] kg/m2). Each participant underwent a 3-h 50-g oral glucose tolerance test (OGTT) and, on a subsequent study day, an IIGI mimicking the glucose excursions from the OGTT. On both study days, appetite and satiety were indicated regularly on visual analog scale (VAS), and blood was drawn regularly for measurement of pancreatic and gut hormones. Difference in appetite and satiety sensations during OGTT and IIGI. Circulating concentrations of glucose-dependent insulinotropic polypeptide (P < .0001), glucagon-like peptide 1 (P < .0001), insulin (P < .0001), C-peptide (P < .0001), and neurotensin (P = .003) increased significantly during the OGTT as compared to the IIGI, whereas glucagon responses were similarly suppressed (P = .991). Visual analog scale-assessed ratings of hunger, satiety, fullness, thirst, well-being, and nausea, respectively, were similar during OGTT and IIGI whether assessed as mean 0-3-h values or area under the curves. For both groups, a similar, slow increase in appetite and decrease in satiation were observed. Area under the curve, for prospective food consumption (P = .049) and overall appetite score (P = .044) were slightly lower during OGTT compared to IIGI, whereas mean 0-3-h values were statistically similar for prospective food consumption (P = .053) and overall appetite score (P = .063). Despite eliciting robust responses of appetite-reducing and/or satiety-promoting gut hormones, we found that oral glucose administration has little or no effect on appetite and satiety as compared to an IIGI, not affecting the release of appetite-modulating hormones. ClinicalTrials.gov: NCT01492283 and NCT06064084.

SAT037 Glucagon-like Peptide-1 Receptor Knockout Mice Do Not Compensate For The Lack Of Incretin Action By Increasing Glucose-dependent Insulinotropic Polypeptide Secretion

Abstract Disclosure: K.D. Galsgaard: None. H. Kissow: None. M.M. Smits: None. J.J. Juul: None. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), secreted from the intestinal L-cells and K-cells, respectively, both enhance glucose-stimulated insulin secretion. This enhancement is referred to as the incretin effect. In the pancreatic islets of GIP receptor knockout mice, GLP-1 sensitivity may be increased. Conversely, deletion of the GLP-1 receptor has been shown to be compensated for by increased GIP secretion and action. This suggests a compensatory adaptation to loss of incretin signaling, via increased action/secretion of the remaining incretin hormone. To investigate this further, we subjected GLP-1 receptor knockout (Glp-1r-/-) mice and their wild-type littermates (Glp-1r+/+ mice) to an oral glucose tolerance test (2 g/kg body weight of glucose via oral gavage; OGTT) with subsequent measurement of plasma GIP concentrations. In separate experiments we measured pancreatic insulin, glucagon, somatostatin, and total GLP-1 concentrations in Glp-1r-/- and Glp-1r+/+ mice, and total GLP-1 and GIP concentrations in the duodenum and distal ileum were also measured. During the OGTT, we found a similar GIP secretion (total area under the curve (tAUC0-30min)) in Glp-1r-/- and Glp-1r+/+ mice (15,432±2,148 vs. 13,683±1,316 pg/mL×min, P=0.5, n≥7). Blood glucose concentrations (tAUC0-30min) were increased in Glp-1r-/- mice during the OGTT (523.9±27.4 vs. 429.1±21.2 mmol/L×min, P=0.02, n≥6). Extractable pancreatic hormone concentrations were similar in Glp-1r+/+ and Glp-1r-/- mice; insulin (284.3±11.4 vs. 303.6±32.4 pmol/g tissue, P=0.6, n≥8); glucagon (203.6±24.3 vs. 270.8±36.9 pmol/g tissue, P=0.2, n≥8); somatostatin (299.9±94.97 vs. 321.4±78.79 pmol/g tissue, P=0.9, n≥9); and total GLP-1 (30.9±8.5 vs. 20.2±4.0 pmol/g tissue, P=0.2, n≤8). In the duodenum, extractable GIP (175.0±29.6 vs. 177.3±10.8 pmol/g tissue, P&amp;gt;0.9, n≥8) and GLP-1 (57.5±35.6 vs. 28.9±3.2 pmol/g tissue, P=0.4, n≥9). In the distal ileum, extractable GIP (2.2±0.5 vs. 2.1±0.4 pmol/g tissue, P=0.8, n≥9) and GLP-1 (266.6±57.1 vs. 236.0±43.1, P=0.7, n≥9) concentrations were also similar in Glp-1r+/+ and Glp-1r-/- mice. In conclusion, our results do not support the notion that Glp-1r-/- mice compensate for the lack of GLP-1 receptor signaling by increasing glucose stimulated GIP secretion or by increasing the intestinal GIP content. Presentation: Saturday, June 17, 2023

Impact of dipeptidyl peptidase-4 inhibitors on glucose-dependent insulinotropic polypeptide in type 2 diabetes mellitus: a systematic review and meta-analysis.

Glucose-dependent insulinotropic polypeptide (GIP) confers a variety of metabolic benefits in type 2 diabetes mellitus (T2DM). This meta-analysis was conducted to investigate the impact of dipeptidyl peptidase 4 (DPP4) inhibitors on GIP levels in T2DM patients. Medline (PubMed), CENTER (Cochrane Library), and Embase (Ovid) were searched and randomized controlled trials (RCTs) evaluating the impact of DPP4 inhibitors on fasting and postprandial GIP levels were obtained. For postprandial GIP, only studies with the data of GIP changes reported as the total area under the curve (AUCGIP) using a meal or oral glucose tolerance test were included. A random-effects model was used for data pooling after incorporating heterogeneity. Overall, 14 RCTs with 541 T2DM patients were included. Compared to placebo/no treatment, the use of DPP4 inhibitors significantly increased the fasting GIP level (standard mean difference [SMD]: 0.77, 95% confidence interval [CI]: 0.48-1.05, P<0.001; I2=52%) and postprandial AUCGIP (SMD: 1.33, 95% CI: 1.02-1.64, P<0.001; I2=65%). Influence analysis by excluding one dataset at a time showed consistent results. Sensitivity analyses only including studies with radioimmunoassay showed also consistent results (fasting GIP: SMD: 0.75, 95% CI: 0.51-1.00, P<0.001; I2=0%; and postprandial AUCGIP: SMD: 1.48, 95% CI: 1.18-1.78, P<0.001; I2=54%). Further subgroup analyses demonstrated that the influence of DPP4 inhibitors on fasting and postprandial GIP levels in T2DM patients was not significantly changed by study characteristics such as study design, patient mean age, baseline glycated hemoglobin (HbA1c) concentration, body mass index (BMI), background treatment, treatment duration, or method for postprandial GIP measurement (all P for subgroup effects <0.05). The use of DPP4 inhibitors effectively increases the fasting and postprandial GIP concentrations in T2DM patients. https://www.crd.york.ac.uk/prospero/, identifier CRD42022356716.

235-LB: Incretin-Linked Adipose Tissue Microvascular Blood Flow in Healthy People With and Without a Family History of Type 2 Diabetes

Adipose tissue microvascular blood flow (ATMBF) increases in response to a mixed meal challenge (MMC) to promote nutrient storage. This vascular action is impaired in apparently healthy people with a parent with type 2 diabetes (FH+). The mechanisms for this vascular impairment in FH+ are unknow. We aimed to investigate whether incretins [glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)] are associated with ATMBF responses to a MMC. Thirteen healthy (FH-, no parents or grandparents with type 2 diabetes) and fourteen FH+ underwent a 2-hr MMC after an overnight fast. Age, BMI, fasting and peak postprandial blood glucose and plasma insulin concentrations were similar between FH- and FH+ (Table 1). Baseline ATMBF, assessed by contrast ultrasound, was similar between groups, but was impaired in FH+ in response to the MMC (Table 1). Peak plasma GLP-1 and GIP concentrations, but not their ratio (GLP-1:GIP), were higher in FH+ in response to the MMC (Table 1). GLP-1 and GIP concentrations were not associated with ATMBF, however, GLP-1:GIP was significantly associated with postprandial ATMBF at 1-hr (p=0.025, r=0.46). We conclude that impaired postprandial ATMBF in FH+ is not exclusively linked to incretin levels. However, lower GLP-1:GIP ratios may be linked to impaired ATMBF responses in the postprandial state. Disclosure K. Roberts-thomson: None. L. Parker: None. M. Keske: None.

Bornyl-Containing Derivatives of Benzyloxyphenylpropanoic Acid as FFAR1 Agonists: In Vitro and In Vivo Studies.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide. Several classes of hypoglycemic drugs are used to treat it, but various side effects limit their clinical use. Consequently, the search for new anti-diabetic agents remains an urgent task for modern pharmacology. In this investigation, we examined the hypoglycemic effects of bornyl-containing benzyloxyphenylpropanoic acid derivatives (QS-528 and QS-619) in a diet-induced model of T2DM. Animals were given the tested compounds per os at a dose of 30 mg/kg for 4 weeks. At the end of the experiment, compound QS-619 demonstrated a hypoglycemic effect, while QS-528 showed hepatoprotection. In addition, we performed a number of in vitro and in vivo experiments to study the presumed mechanism of action of the tested agents. Compound QS-619 was determined to activate the free fatty acid receptor-1 (FFAR1) similarly to the reference agonist GW9508 and its structural analogue QS-528. Both agents also increased insulin and glucose-dependent insulinotropic polypeptide concentrations in CD-1 mice. Our results indicate that QS-619 and QS-528 are probably full FFAR1 agonists.

Cytokine Profile and Concentrations of Metabolic Hormones in the Blood of Overweight Men with Coronary Arteriosclerosis.

Plasma concentrations of cytokines and metabolic hormones and their association with vulnerable atherosclerotic plaques were studied in 36 overweight men (age 40-77 years; BMI 25.0-29.9 kg/m2) with coronary atherosclerosis who underwent coronary endarterectomy. According to histological analysis, the patients were divided into two groups: with stable (17 (47.2%) men) and vulnerable (19 (52.8%) men) plaques in the coronary arteries. The plasma levels of cytokines and metabolic hormones were measured by multiplex analysis: C-peptide, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1, glucagon, IL-6, insulin, leptin, monocyte chemoattractant protein-1, and TNFα. In overweight patients with vulnerable plaques, the level of glucagon was lower by 4.17 times, GIP - by 2.47 times, and insulin - by 2.1 times. At the same time, the risk of occurrence of a vulnerable plaque increases by 5.4% with a decrease in GIP concentration by 1 pg/ml irrespectively of age, as well as by 3.1% with an increase in insulin concentration by 10 pg/ml, without achieving statistical significance when included in the age model. Overweight men with coronary atherosclerosis and vulnerable plaques have lower levels of insulin, glucagon, and GIP. The levels of GIP and insulin are inversely associated with the risk of having vulnerable atherosclerotic plaque.

The relative importance of Endogenously Secreted incretin hormones, GLP‐1 and GIP for Postprandial Glucose Tolerance and β‐Cell Function After Roux‐en‐Y Gastric Bypass and Sleeve Gastrectomy Surgery

Bariatric surgery procedures, namely Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) is increasingly used worldwide, have been shown to be the most effective strategy to induce and maintain weight loss as well as inducing long-term remission from type 2 diabetes among people with significant obesity. The mechanism for diabetes remission remains unclear and multi-factorial, although increased secretion of endogenous glucagon-like peptide 1 (GLP-1) hormones to improve postprandial β-cell function is widely considered to be the main mechanism for diabetes remission following RYGB. However, recent studies have shown that rate of remission between the two types of bariatric surgery procedures are similar but yet, the mechanism for remission above and beyond weight loss per se following SG is less clear. Beyond GLP-1, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. A study published in Diabetes Care have therefore studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed-meal tests in un-operated (CON), SG-operated, and RYGB-operated people with no history of diabetes. The investigator found that, as expected, 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. Interestingly, blockage of GLP-1R reduced β-cell glucose sensitivity and increased postprandial glucose responses in both surgical groups but had no effect in CON. Blockage of GIPR however reduced β-cell glucose sensitivity and increased postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. This study showed that while GLP-1 is the most important mediator of improved beta cell function after RYGB, both GLP-1 and GIP are equally important after SG. The combine benefits of GLP-1 and GIP following SG is interesting, given the recent emergence of the dual GLP-1 and GIP agonist for the treatment of diabetes and obesity. It would be interesting also to explore the relative role of Glucagon on beta cell function following both procedures.

Stimulatory effect of imeglimin on incretin secretion.

Imeglimin is a new antidiabetic drug structurally related to metformin. Despite this structural similarity, only imeglimin augments glucose-stimulated insulin secretion (GSIS), with the mechanism underlying this effect remaining unclear. Given that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) also enhance GSIS, we examined whether these incretin hormones might contribute to the pharmacological actions of imeglimin. Blood glucose and plasma insulin, GIP, and GLP-1 concentrations were measured during an oral glucose tolerance test (OGTT) performed in C57BL/6JJcl (C57BL/6) or KK-Ay/TaJcl (KK-Ay) mice after administration of a single dose of imeglimin with or without the dipeptidyl peptidase-4 inhibitor sitagliptin or the GLP-1 receptor antagonist exendin-9. The effects of imeglimin, with or without GIP or GLP-1, on GSIS were examined in C57BL/6 mouse islets. Imeglimin lowered blood glucose and increased plasma insulin levels during an OGTT in both C57BL/6 and KK-Ay mice, whereas it also increased the plasma levels of GIP and GLP-1 in KK-Ay mice and the GLP-1 levels in C57BL/6 mice. The combination of imeglimin and sitagliptin increased plasma insulin and GLP-1 levels during the OGTT in KK-Ay mice to a markedly greater extent than did either drug alone. Imeglimin enhanced GSIS in an additive manner with GLP-1, but not with GIP, in mouse islets. Exendin-9 had only a minor inhibitory effect on the glucose-lowering action of imeglimin during the OGTT in KK-Ay mice. Our data suggest that the imeglimin-induced increase in plasma GLP-1 levels likely contributes at least in part to its stimulatory effect on insulin secretion.

The Importance of Endogenously Secreted GLP-1 and GIP for Postprandial Glucose Tolerance and β-Cell Function After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy Surgery.

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 blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. Our results support that GIP is the most important incretin hormone in unoperated people, whereas GLP-1 and GIP are equally important after SG, and GLP-1 is the most important incretin hormone after RYGB.

Effects of calcium salts of palm oil inclusion and ad libitum feeding regimen on growth performance, carcass characteristics, and plasma glucose-dependent insulinotropic polypeptide concentration of feedlot steers.

Sixty Angus × SimAngus-crossbred steers (body weight [BW] 279 ± 16 kg) were used to evaluate the effect of calcium salts of palm oil inclusion (CPO) and the amount of feed offered (AFO) on plasma glucose-dependent insulinotropic polypeptide (GIP) concentration and its association with energy metabolism and marbling score (MS) in feedlot steers. Steers were blocked by BW and gain to feed (G:F) and randomly assigned to individual feedlot pens. Treatments (2 × 2 factorial) consisted of ad libitum-fed steers without (ANF) or with (AWF) the inclusion of CPO or restricted-fed steers (85% of the ad libitum intake of ANF) without (RNF) or with the inclusion of CPO (RWF). After weaning, steers were adapted to individual pens and fed a corn silage-based diet for 30 d and subsequently placed in a ground corn (GC)-based diet. Diets were given ad libitum or at 85% of the ANF intake and with or without CPO. After 59 d on the finishing diet, all steers had ad libitum access to the finishing diet until harvest. Measurements of CO2 emission and O2 consumption to estimate respiratory quotient (RQ) were taken (n = 9/treatment). Correlations between plasma GIP and insulin concentrations and RQ were analyzed. A linear regression was performed to evaluate the association of plasma GIP and MS. All data were analyzed using the PROC MIXED procedure of SAS. During the first 103 d of the trial, there were AFO × CPO interactions (P ≤ 0.01) for BW, dry matter intake (DMI), average daily gain (ADG), and net energy for maintenance (NEm) intake. Ad libitum-fed steers without CPO presented the greatest DMI among dietary treatments and had greater BW and ADG compared with steers in the RWF and RNF treatments. After all steers had ad libitum access to dietary treatments, steers that were previously restricted showed a 30% and 19% increase (P ≤ 0.01) in ADG and G:F, respectively. There was a three-way interaction time × CPO × AFO (P = 0.04) for plasma GIP concentration. There was no correlation (P = 0.96) of GIP with RQ, whereas insulin demonstrated marginal significance for a positive (P = 0.07) and negative (P = 0.08) correlation with plasma GIP and RQ, respectively. There was no association (P = 0.30) between GIP and MS. These data indicate that GIP secretion results from an interaction between CPO and energy intake depending on the time relative to feed intake that GIP might indirectly regulate energy metabolism through insulin secretion, and that GIP does not appear to be associated with MS.

Evaluation of the association between plasma glucose-dependent insulinotropic polypeptide, respiratory quotient, and intramuscular fat deposition in feedlot cattle fed different levels of dry matter intake.

The objectives of this trial were to evaluate the association between different levels of dry matter intake (DMI) on gas exchange, plasma glucose-dependent insulinotropic polypeptide (GIP) concentration, and intramuscular (IM) fat deposition. We used 60 individually fed backgrounded Angus × SimAngus-crossbred steers (n = 30) in a randomized complete block design. Steers (paired by body weight [BW] and gain to feed ratio [G:F]) were randomly allocated to one of the following treatments: ad libitum intake (AI) or restricted intake (RI; the same diet fed at 85% of the AI) of a finishing diet. The diet contained 61% cracked corn, 9% corn silage, 15% distillers’ dried grains with solubles, 5% soyhulls, and 10% of a protein-mineral-vitamin premix. Measurements of CO2 emission and consumption of O2, and respiratory quotient (RQ) were taken using the GreenFeed system (n = 15/treatment). Plasma and gas samples were collected 10 d before slaughter, 1 h before and 2 h after feeding. Plasma glucose, non-esterified fatty acids, GIP, and insulin concentration and gasses (O2, CO2, and RQ) were analyzed using the MIXED procedure of SAS evaluating the fixed effect of treatment, time (repeated measurement) and their interaction, and the random effect of the block. Final BW and carcass characteristics were analyzed with a similar model, without the time statement and its interaction. Compared with RI, AI steers had greater (P < 0.01) DMI and average daily gain (ADG). Steers on AI had greater final BW (P = 0.02), tended to have a greater ribeye area (P = 0.09), and had lower plasma GIP concentration (P = 0.04). There was no treatment effect (P ≥ 0.11) on G:F, subcutaneous backfat (BF), and IM fat, O2 consumption, CO2 emission, and RQ. Plasma glucose concentration of AI steers was greater before and after feeding than RI (P < 0.05). In conclusion, feeding steers ad libitum increased DMI, ADG, and plasma glucose and GIP concentration but does not affect G:F, BF, IM fat, CO2 emission, and O2 consumption. Plasma GIP concentration and RQ are not associated with IM fat deposition.

Interrupting Prolonged Sitting with Intermittent Walking Increases Postprandial Gut Hormone Responses.

Continuous exercise can increase postprandial gut hormone such as glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) responses, but it is unknown whether interrupting prolonged sitting with intermittent walking elicits this effect. Ten participants with central overweight/obesity (7 men and 3 postmenopausal women, 51 ± 5 yr; mean ± SD) completed a randomized crossover study in which they consumed breakfast and lunch in the laboratory while either sitting continuously for the entire 5.5-h period (SIT) or the prolonged sitting interrupted every 20 min by walking briskly (6.4 km·h-1) for 2 min (BREAKS). Blood samples were collected at regular intervals to examine postprandial plasma GLP-1, PYY, and glucose-dependent insulinotropic polypeptide concentrations. Adipose tissue samples were collected at baseline and at the end of the trials to examine changes in net dipeptidyl peptidase 4 secretion from primary explants. Mean (95% confidence interval) postprandial GLP-1 and PYY incremental area under curve values were elevated by 26% and 31% in the BREAKS trial versus SIT (8.4 [0.7, 16.1] vs 6.7 [-0.8, 14.2], P = 0.001, and 26.9 [8.1, 45.6] vs 20.4 [5.1, 35.8] nmol·330 min·L-1, P = 0.024, respectively) but without any such effect on glucose-dependent insulinotropic polypeptide (P = 0.076) or net adipose tissue dipeptidyl peptidase 4 secretion (P > 0.05). Interrupting prolonged sitting with regular short bouts of brisk walking increases postprandial GLP-1 and PYY concentrations in healthy middle-age men and women with central adiposity.

Administration of Jerusalem artichoke reduces the postprandial plasma glucose and glucose-dependent insulinotropic polypeptide (GIP) concentrations in humans

BackgroundThe consumption of Jerusalem artichoke has multiple beneficial effects against diabetes and obesity.ObjectiveThe aim of this study was to determine the effect of a single administration of Jerusalem artichoke tubers on postprandial glycemia and the concentrations of incretin hormones in humans.MethodGrated Jerusalem artichoke was administered prior to a meal (Trial 1; white rice for prediabetic participants, n = 10). Dose-dependent effect of Jerusalem artichoke (Trial 2; white rice for prediabetic participants, n = 4) and effect prior to the fat-rich meal were also investigated (Trial 3; healthy participants, n = 5) in this pilot study. Circulating glucose, insulin, triglyceride, glucagon, active glucagon-like peptide-1 (GLP-1), and active glucose-dependent insulinotropic polypeptide (GIP) concentrations were subsequently measured in all the trials.ResultsJerusalem artichoke significantly reduced the glucose and GIP concentrations after the consumption of either meal in Trial 1 and Trial 3, whereas there were no differences in the insulin, glucagon, and active GLP-1 concentrations. Also, there was no significant difference in the triglyceride concentration after the ingestion of the fat-rich meal in Trial 3. The glucose and GIP-lowering effects were dose-dependent, and the consumption of at least 100 g of Jerusalem artichoke was required to have these effects in Trial 2.ConclusionThis study demonstrates that a single administration of Jerusalem artichoke tubers reduces postprandial glucose and active GIP concentrations in prediabetic and healthy individuals.

Associations between Postprandial Gut Hormones and Markers of Bone Remodeling.

Gut-derived hormones have been suggested to play a role in bone homeostasis following food intake, although the associations are highly complex and not fully understood. In a randomized, two-day cross-over study on 14 healthy individuals, we performed postprandial time-course studies to examine the associations of the bone remodeling markers carboxyl-terminal collagen type I crosslinks (CTX) and procollagen type 1 N-terminal propeptide (P1NP) with the gut hormones glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) using two different meal types—a standardized mixed meal (498 kcal) or a granola bar (260 kcal). Plasma concentrations of total GIP, total GLP-1, total PYY, CTX, and P1NP were measured up to 240 min after meal intake, and the incremental area under the curve (iAUC) for each marker was calculated. The iAUC of CTX and P1NP were used to assess associations with the iAUC of GIP, GLP-1, and PYY in linear mixed effect models adjusted for meal type. CTX was positively associated with GIP and GLP-1, and it was inversely associated with PYY (all p < 0.001). No associations of P1NP with GIP or GLP-1 and PYY were found. In conclusion, the postprandial responses of the gut hormones GIP, GLP-1, and PYY are associated with the bone resorption marker CTX, supporting a link between gut hormones and bone homeostasis following food intake.

85-LB: Glucose-Dependent Insulinotropic Polypeptide (GIP) Contributes Substantially to the Improved Beta-Cell Function during Sitagliptin Treatment in Persons with Type 2 Diabetes

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 &amp;lt; 0.0001) and lowered fasting plasma glucose (mean: 8.7 vs. 7.6 mmol/L, P &amp;lt; 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 &amp; 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

Co-ingestion of NUTRALYS® pea protein and a high-carbohydrate beverage influences the glycaemic, insulinaemic, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) responses: preliminary results of a randomised controlled trial.

Plant-based proteins may have the potential to improve glycaemic and gastrointestinal hormone responses to foods and beverages. The aim of this study was to investigate the effect of two doses of pea protein on postprandial glycaemic, insulinaemic, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) response following a high-carbohydrate beverage intake in healthy individuals. In a single-blind, randomised, controlled, repeat measure, crossover design trial, thirty-one participants were randomly assigned to ingest 50g glucose (Control), 50g glucose with 25g pea protein (Test 1) and 50g glucose with 50g pea protein (Test 2) on three separate days. Capillary blood samples (blood glucose and plasma insulin measurements) and venous blood samples (GIP and GLP-1 concentrations) were taken before each test and at fixed intervals for 180min. The data were compared using repeated-measures ANOVA or the Friedman test. Glucose incremental Area under the Curve (iAUC180) was significantly lower (p < 0.001) after Test 2 compared with Control (- 53%), after Test 1 compared with Control (- 31%) and after Test 2 compared with Test 1 (-32%). Insulin iAUC 180 was significantly higher (p < 0.001) for Test 1 (+ 28%) and Test 2 (+ 40%) compared with Control and for Test 2 (+ 17%) compared with Test 1 (p = 0.003). GIP and GLP-1 release showed no clear difference between Control and Pea protein drinks. The consumption of pea protein reduced postprandial glycaemia and stimulated insulin release in healthy adults with a dose-response effect, supporting its role in regulating glycaemic and insulinaemic responses.

Metabolic, hormonal and performance effects of isomaltulose ingestion before prolonged aerobic exercise: a double-blind, randomised, cross-over trial

BackgroundIsomaltulose has been discussed as a low glycaemic carbohydrate but evidence concerning performance benefits and physiological responses has produced varying results. Therefore, we primarily aimed to investigate the effects of isomaltulose ingestion compared to glucose and maltodextrin on fat and carbohydrate oxidation rates, blood glucose levels and serum hormone concentrations of insulin and glucose-dependent insulinotropic polypeptide (GIP). As secondary aims, we assessed running performance and gastrointestinal discomfort.MethodsTwenty-one male recreational endurance runners performed a 70-min constant load trial at 70% maximal running speed (Vmax), followed by a time to exhaustion (TTE) test at 85% Vmax after ingesting either 50 g isomaltulose, maltodextrin or glucose. Fat and carbohydrate oxidation rates were calculated from spiroergometric data. Venous blood samples for measurement of GIP and insulin were drawn before, after the constant load trial and after the TTE. Capillary blood samples for glucose concentrations and subjective feeling of gastrointestinal discomfort were collected every 10 min during the constant load trial.ResultsNo between-condition differences were observed in the area under the curve analysis of fat (p = 0.576) and carbohydrate oxidation rates (p = 0.887). Isomaltulose ingestion led to lower baseline postprandial concentrations of blood glucose compared to maltodextrin (percent change [95% confidence interval], − 16.7% [− 21.8,-11.6], p < 0.001) and glucose (− 11.5% [− 17.3,-5.7], p = 0.001). Similarly, insulin and GIP concentrations were also lower following isomaltulose ingestion compared to maltodextrin (− 40.3% [− 50.5,-30.0], p = 0.001 and − 69.1% [− 74.3,-63.8], p < 0.001, respectively) and glucose (− 32.6% [− 43.9,-21.2], p = 0.012 and − 55.8% [− 70.7,-40.9], p < 0.001, respectively). Furthermore, glucose fluctuation was lower after isomaltulose ingestion compared to maltodextrin (− 26.0% [− 34.2,-17.8], p < 0.001) and glucose (− 17.4% [− 29.1,-5.6], p < 0.001). However, during and after exercise, no between-condition differences for glucose (p = 0.872), insulin (p = 0.503) and GIP (p = 0.244) were observed. No between-condition differences were found for TTE (p = 0.876) or gastrointestinal discomfort (p = 0.119).ConclusionIsomaltulose ingestion led to lower baseline postprandial concentrations of glucose, insulin and GIP compared to maltodextrin and glucose. Consequently, blood glucose fluctuations were lower during treadmill running after isomaltulose ingestion, while no between-condition differences were observed for CHO and fat oxidation rates, treadmill running performance and gastrointestinal discomfort. Further research is required to provide specific guidelines on supplementing isomaltulose in performance and health settings.

Dose-dependent efficacy of the glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist GIP(3-30)NH2 on GIP actions in humans.

The glucose-dependent insulinotropic polypeptide (GIP) fragment GIP(3-30)NH2 is a selective, competitive GIP receptor antagonist, and doses of 800 to 1200 pmol/kg/min inhibit GIP-induced potentiation of glucose-stimulated insulin secretion by >80% in humans. We evaluated the effects of GIP(3-30)NH2 across a wider dose range in eight healthy men undergoing six separate and randomized 10-mmol/L hyperglycaemic clamps (A-F) with concomitant intravenous infusion of GIP (1.5 pmol/kg/min; A-E) or saline (F). Clamps A to E involved double-blinded, infusions of saline (A) and GIP(3-30)NH2 at four rates: 2 (B), 20 (C), 200 (D) and 2000 pmol/kg/min (E), respectively. Mean plasma concentrations of glucose (A-F) and GIP (A-E) were similar. GIP-induced potentiation of glucose-stimulated insulin secretion was reduced by 44 ± 10% and 84 ± 10% during clamps D and E, respectively. Correspondingly, the amounts of glucose required to maintain the clamp during D and E were not different from F. GIP-induced suppression of bone resorption and increase in heart rate were lowered by clamps D and E. In conclusion, GIP(3-30)NH2 provides extensive, dose-dependent inhibition of the GIP receptor in humans, with most pronounced effects of the doses 200 to 2000 pmol/kg/min within the tested range.

Establishment of novel specific assay for short-form glucose-dependent insulinotropic polypeptide and evaluation of its secretion in nondiabetic subjects.

The short‐form glucose‐dependent insulinotropic polypeptide (GIP) (1–30) is released from islet alpha cells and promotes insulin secretion in a paracrine manner in vitro. However, it is not well elucidated how GIP (1–30) is involved in glucose metabolism in vivo, since a specific assay system for GIP (1–30) has not yet been established. We first developed a sandwich enzyme‐linked immunosorbent assay (ELISA) specific for GIP (1–30) by combining a novel antibody specific to the GIP (1–30) C terminus with the common antibody against GIP N terminus. Then, we explored cross‐reactivities with incretins and glucagon‐related peptides in this ELISA. GIP (1–30) amide, but not GIP (1–42), GLP‐1, or glucagon increased absorbance in a dose‐dependent manner. We next measured plasma GIP (1–30) concentrations in nondiabetic participants (ND) during a 75‐g oral glucose tolerance test or cookie meal test (carbohydrates 75 g, lipids 28.5 g, proteins 8.5 g). Both glucose and cookie load increased GIP (1–30) concentrations in ND, but the increases were much lower than those of GIP (1–42). Furthermore, the DPP‐4 inhibitor significantly increased GIP (1–30) concentrations similarly to GIP (1–42) in ND. In conclusion, we for the first time developed an ELISA specific for GIP (1–30) and revealed its secretion in ND.