Glucose-dependent Insulinotropic Peptide Concentrations Research Articles

Post-prandial secretion of glucagon-like peptide-2 (GLP-2) after carbohydrate-, fat- or protein enriched meals in healthy subjects

Glucagon-like peptide 2 (GLP-2) is an important regulator of intestinal growth and function. In adherable mixed meals the macronutrient composition with the best potential for stimulating GLP-2 secretion is not known. We compared the effect of 3 iso-energetic meals, where approximately 60 % of the energy ratio was provided as either carbohydrate, fat, or protein, respectively, on the post-prandial endogenous GLP-2 secretion. The responses were compared to secretion profiles of peptide YY (PYY), and glucose-dependent insulinotropic peptide (GIP).Ten healthy subjects were admitted on three occasions, at least a week apart, after a night of fasting. In an open-label, crossover design, they were randomized to receive a high carbohydrate (HC), high fat (HF) or high protein (HP) meal. The meals were approximately ∼3.9 MJ. Venous blood was collected for 240 min, and plasma concentrations of GLP-2, GIP and PYY were measured with specific radioimmunoassays.Mean GLP-2 levels peaked already at 30 min for the HC meal, however the HP meal induced the highest mean GLP-2 peaking levels, resulting in significantly higher mean GLP-2 area under the curve (AUC) from baseline of 7279 pmol*min/L, 95 %-CI [6081;8477] compared to the HC meal: 4764 pmol*min/L, 95 %-CI [3498;6029], p = 0.020 and the HF meal: 4796 pmol*min/L, [3385;6207], p = 0.011. Findings were similar for the PYY. The HC meal provided a greater AUC for GIP compared to the HP- and HF meals.The HP meal was most effective with respect to stimulation of the postprandial GLP-2 and PYY secretion, whereas the HC meal was more effective for GIP.

Non-altered incretin secretion in women with impaired fasting plasma glucose in the early stage of pregnancy: a case control study

BackgroundsGlucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) may be involved in pathogenesis of gestational diabetes mellitus (GDM). The aim was to compare GLP-1 and GIP production in fasting state and during 3 h mixed meal tolerance test (MMTT) measured by mean area under the curve (AUC) between pregnant women with normal and impaired fasting glucose in an early phase of pregnancy, and healthy non-pregnant controls.MethodsThis study was undertaken as a case–control study. Repeated measurement of fasting plasma glucose ≥ 5.1 mmol/L and < 7.0 mmol/L during the first trimester of pregnancy and exclusion of overt diabetes according to IADSPG criteria was used to find women with impaired fasting glucose (n = 22). Age-matched controls consisted of healthy pregnant (n = 25) and non-pregnant (n = 24) women. In addition to incretins, anthropometric parameters and markers of insulin resistance and beta-cell function were assessed. Variables were summarized as median (interquartile range).ResultsFasting GLP-1 and GIP concentration or their AUC during MMTT did not significantly differ between pregnant women with impaired fasting plasma glucose [GLP-1AUC 19.0 (53.1) and GIPAUC 302 (100) pg/mL/min] and healthy pregnant women [GLP-1AUC 16.7 (22.3) and GIPAUC 297 (142) pg/mL/min] or non-pregnant controls [GLP-1AUC 16.8 (9.8) and for GIPAUC 313 (98) pg/mL/min]. Although women with impaired fasting glucose were more obese and showed decreased beta-cell function, there were not significant correlations between incretin production and parameters of insulin secretion, insulin resistance, or obesity.ConclusionsWomen with impaired fasting plasma glucose did not show altered incretin production in the first trimester of pregnancy. In contrast to type 2 diabetes, impaired incretin secretion does not seem to play a major role in the early development of GDM.

Effects of whole grain intake on glucagon-like peptide 1 and glucose-dependent insulinotropic peptide: a systematic review and meta-analysis.

Whole grain intake may control help glycemia and reduce food intake by affecting the secretion of glucagon-like peptide1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). This systematic review and meta-analysis aimed to assess the postprandial and long-term effects of whole grains on GLP-1 and GIP levels. PubMed, Web of Science, and Scopus online databases were searched systematically to identify relevant randomized clinical trials (RCTs) published up to April 2021. RCTs that evaluated the effects of whole grains, compared with refined grains, on the postprandial area under the curve (AUC) value, the postprandial serum concentration of incretins from 0 to 180 minutes, or the fasting level of incretins after at least 14 days of intervention were included. Nineteen studies were included in the meta-analysis. The results showed that acute intake of whole grains could not significantly change the AUC value of GLP-1 or GIP. However, the AUC value of GIP was reduced more significantly in (1) unhealthy participants (standard mean difference [SMD] -1.08; 95%CI, -2.07 to -0.10; I2 = 75.9%) compared with healthy participants, and (2) those with a baseline fasting blood glucose of ≥99 mg/dL (SMD -0.71; 95%CI, -1.30 to -0.11; I2 = 74.4%) compared with those with a baseline value of < 99 mg/dL. On the other hand, the results of time-response evaluation during 0 to 180 minutes after the intake of test meals showed that serum concentrations of GIP decreased significantly from 0 to 30 minutes (coefficient = -44.72; P = 0.005), but increased from 60 to 180 minutes (coefficient = 27.03; P = 0.005). However, long-term studies found no significant effects of whole grains on fasting concentrations of GLP-1 or GIP. Whole grain intake did not affect postprandial levels of GLP-1 but enhanced postprandial levels of GIP from 60 to 180 minutes. Further high-quality trials are required to assess the long-term effects of whole grain intake on serum levels of incretins. PROSPERO registration no. CRD42021256695.

The effect of capromorelin on glycemic control in healthy dogs

Capromorelin is a ghrelin-receptor agonist widely used as an appetite stimulant in dogs. Capromorelin disrupts glucose homeostasis in cats but information regarding its effects on canine glucose homeostasis is lacking. The study objective was to evaluate the effect of capromorelin on glucose homeostatic mechanisms in healthy dogs. Eight clinically healthy client-owned adult dogs were enrolled in this prospective, cross-over, placebo-controlled study. Dogs were randomized to receive capromorelin (Entyce, 3 mg/kg) or placebo, q24h for 3 d. A wk later, treatments were crossed over. Interstitial glucose (IG) concentrations were measured using a flash glucose monitoring system throughout. On d 1 of each treatment, blood glucose (BG), insulin, glucagon, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide-1 (GLP-1) concentrations were measured before drug administration, then before and 30–120 min after feeding a glucose-rich diet (Ensure Plus, 21 kcal/kg). Data were analyzed as a 2-period crossover design using generalized least squares estimation. Capromorelin administration increased mean 48 h IG by10% and mean BG by 20% at 90 and 120 min post-prandially (P < 0.0001). Post-prandially, there was a time-by-treatment effect for insulin (P = 0.03) and GIP (P = 0.0002) because capromorelin doubled geometric mean insulin concentrations at 120 min and increased geometric mean GIP concentrations more rapidly than after placebo. There were no differences in glucagon or GLP-1 concentrations between treatment groups. The increase in post-prandial blood glucose was not the result of overt suppression of incretin hormone secretion. There was also no suppressive effect of capromorelin on insulin.

The gut hormone glucose-dependent insulinotropic polypeptide is downregulated in response to myocardial injury

BackgroundThe gut incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by enteroendocrine cells following food intake leading to insulin secretion and glucose lowering. Beyond its metabolic function GIP has been found to exhibit direct cardio- and atheroprotective effects in mice and to be associated with cardiovascular prognosis in patients with myocardial infarction. The aim of this study was to characterize endogenous GIP levels in patients with acute myocardial infarction.Methods and resultsSerum concentrations of GIP were assessed in 731 patients who presented with clinical indication of coronary angiography. Circulating GIP levels were significantly lower in patients with STEMI (ST-elevation myocardial infarction; n=100) compared to clinically stable patients without myocardial infarction (n=631) (216.82 pg/mL [Q1–Q3: 52.37–443.07] vs. 271.54 pg/mL [Q1–Q3: 70.12–542.41], p = 0.0266). To characterize endogenous GIP levels in patients with acute myocardial injury we enrolled 18 patients scheduled for cardiac surgery with cardiopulmonary bypass and requirement of extracorporeal circulation as a reproducible condition of myocardial injury. Blood samples were drawn directly before surgery (baseline), upon arrival at the intensive care unit (ICU), 6 h post arrival to the ICU and at the morning of the first and second postoperative days. Mean circulating GIP concentrations decreased in response to surgery from 45.3 ± 22.6 pg/mL at baseline to a minimum of 31.9 ± 19.8 pg/mL at the first postoperative day (p = 0.0384) and rose again at the second postoperative day (52.1 ± 28.0 pg/mL).ConclusionsCirculating GIP levels are downregulated in patients with myocardial infarction and following cardiac surgery. These results might suggest nutrition-independent regulation of GIP secretion following myocardial injury in humans.

β-Lactoglobulin Is Insulinotropic Compared with Casein and Whey Protein Ingestion during Catabolic Conditions in Men in a Double-Blinded Randomized Crossover Trial.

Muscle loss during acute infectious disease is mainly triggered by inflammation, immobilization, and malnutrition. The objective was to compare muscle protein kinetics and metabolism following ingestion of the dairy protein supplements β-lactoglobulin (BLG), casein (CAS), and whey (WHE) during controlled catabolic conditions. We used a randomized crossover design (registered at clinicaltrials.gov as NCT03319550) to investigate 9 healthy male participants [age: 20-40 y; BMI (in kg/m2) 20-30] who were randomly assigned servings of BLG, CAS, or WHE (0.6g protein/kg, one-third as bolus and two-thirds as sip every 20min) on 3 separate occasions separated by ∼6-8 wk. The participants received an infusion of lipopolysaccharide (1ng/kg) combined with 36h of fasting and bed rest before each study day, mimicking a clinical catabolic condition. The forearm model and isotopic tracer techniques were used to quantify muscle protein kinetics. Muscle biopsy specimens were obtained and intramyocellular signaling investigated using Western blot. BLG, CAS, and WHE improved the net balance of phenylalanine (NBphe) from baseline with ∼75% (P<0.001) with no difference between interventions (primary outcome, P<0.05). No difference in rates of appearance and disappearance of phenylalanine or in intramyocellular signaling activation was found between interventions (secondary outcomes). The incremental AUC for serum insulin was 62% higher following BLG compared with CAS (P <0.001) and 30% higher compared with WHE (P=0.002), as well as 25% higher in WHE compared with CAS (P=0.006). Following BLG consumption, plasma concentrations of glucose-dependent insulinotropic peptide (GIP) increased 70% compared with CAS (P=0.001) and increased 34% compared with WHE (P=0.06). No significant difference was found between WHE and CAS (P=0.12). BLG, WHE, and CAS have similar effects on muscle in young male participants during catabolic conditions. BLG showed specific, possibly GIP-dependent, insulinotropic properties, which may have future clinical implications.

Glucose-Dependent Insulinotropic Peptide in the High-Normal Range Is Associated With Increased Carotid Intima-Media Thickness.

While existing evidence supports beneficial cardiovascular effects of glucagon-like peptide 1 (GLP-1), emerging studies suggest that glucose-dependent insulinotropic peptide (GIP) and/or signaling via the GIP receptor may have untoward cardiovascular effects. Indeed, recent studies show that fasting physiological GIP levels are associated with total mortality and cardiovascular mortality, and it was suggested that GIP plays a role in pathogenesis of coronary artery disease. We investigated the associations between fasting and postchallenge GIP and GLP-1 concentrations and subclinical atherosclerosis as measured by mean intima-media thickness in the common carotid artery (IMTmeanCCA) and maximal intima-media thickness in the carotid bifurcation (IMTmaxBulb). Participants at reexamination within the Malmö Diet and Cancer-Cardiovascular Cohort study (n = 3,734, mean age 72.5 years, 59.3% women, 10.8% subjects with diabetes, fasting GIP available for 3,342 subjects, fasting GLP-1 available for 3,299 subjects) underwent oral glucose tolerance testing and carotid ultrasound. In linear regression analyses, each 1-SD increment of fasting GIP was associated with increased (per mm) IMTmeanCCA (β = 0.010, P = 0.010) and IMTmaxBulb (β = 0.014; P = 0.040) in models adjusted for known risk factors and glucose metabolism. In contrast, each 1-SD increment of fasting GLP-1 was associated with decreased IMTmaxBulb (per mm, β = -0.016, P = 0.014). These associations remained significant when subjects with diabetes were excluded from analyses. In a Swedish elderly population, physiologically elevated levels of fasting GIP are associated with increased IMTmeanCCA, while GLP-1 is associated with decreased IMTmaxBulb, further emphasizing diverging cardiovascular effects of these two incretin hormones.

Glucose-dependent insulinotropic peptide and risk of cardiovascular events and mortality: a prospective study

Aims/hypothesisEvidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk.MethodsGIP concentrations were successfully measured during OGTTs in two independent populations (Malmö Diet Cancer–Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD.ResultsIn meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 × 10−5) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD.Conclusions/interpretationIn two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5–9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.

The Impact of a Large Bolus Dose of l-leucine and l-isoleucine on Enteroendocrine and Pancreatic Hormones, and Glycemia in Healthy, Inactive Adults.

Background: The ingestion of whey protein and amino acids with carbohydrate (CHO) enhances the release of glucagon-like peptide-1 (GLP-1) and glucose-dependent-insulinotropic peptide (GIP) that promote insulin secretion. It is unknown if L-isoleucine (Ile) and L-leucine (Leu) have this same effect. The purpose of this study was to examine how Ile and Leu influence both GLP-1 and GIP, subsequent pancreatic hormones, and glycemia in healthy, inactive adults. Methods: Twelve adults (6F/6M; age 27.4 ± 2 years; BMI 26.3 ± 2 kg/m2; lean body mass 53.2 ± 5 kg; body fat 34.1 ± 3%) completed four conditions in a randomized, cross-over fashion. Treatments standardized (0.3 g/kg·LBM−1) (1) Leu, (2) Ile, (3) Equal (1:1 g) of Leu + Ile, and (4) placebo (Pla, 3.5 g inert stevia) ingested 30 min prior to an oral glucose tolerance test (OGTT). Samples of plasma glucose, insulin, glucagon, GIPTotal, and GLP-1Active were assessed. Results: A treatment (p = 0.01) effect comparing Ile vs. Leu (p = 0.02) in GIPTotal. Area under the curve showed an increase in GIPTotal from Ile compared to Leu and Pla (p = 0.03). No effect was found on GLP-1. The ingestion of Ile prior to CHO augmented GIP concentration greater than Leu or Pla. No correlation was found between GIP, insulin, and glucose between conditions. Conclusions: Ile impacts GIP concentration, which did not relate to either insulin or glucose concentrations. Neither Ile, nor Leu seem to have an effect on hyperglycemia ingested prior to a CHO drink.

1981-P: The Regulation of Incretin Secretion in Baby Rats in Response to a Lipid Meal

Background: Glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that augment glucose-stimulated insulin secretion, promote pancreatic β-cell proliferation, neogenesis and inhibit β-cell apoptosis. Thus, they are excellent therapeutic targets against type 2 diabetes. Using a lymph fistula rat model, we studied the secretion of incretins into lymph. In adult rats, we found that GIP and GLP-1 concentrations in the fasting lymph were 132 ± 19 pg/ml and 31 ± 8 pM, respectively. After intraduodenal lipid infusion, their concentrations rose to 441 ± 144 pg/ml and 154 ± 23 pM, respectively. Rationale: However, little is known about nutrient-stimulated secretion of GIP and GLP-1 in baby rats, whose gastrointestinal system and pancreatic β-cells are immature compared to adult rats. Methods: Using our well-established lymph fistula model with conscious baby rats, just weaned (21 day after birth) and weighing 50-65 g, we assessed the secretion of GIP and GLP-1 in lymph after an intraduodenal challenge of lipid meal. Results: Fasting GIP and GLP-1 levels were 295.4 ± 48.1 pg/ml and 59.6 ± 16.2 pM, respectively. After lipid infusion, GIP and GLP-1 levels increased to 1052 ± 90.1 pg/ml and 192.0 ± 19.7 pM respectively. Elevated incretin levels in baby rats (relative to adult animals) indicate possible involvement in the maturation of the enteroendocrine system and β-cells. This increase may be also important to ensure the adequate secretion of insulin to regulate blood glucose as the animals shift from a high-fat mother’s milk diet to a chow diet. Further studies are needed to determine the physiological role of the higher incretin levels in baby rats. Conclusions: Lymph fistula baby rats can serve as an excellent model to study regulation of gut hormones by nutrient absorption at their early developmental stage. This model can also be used to study the influence of mother’s milk on the secretion of gut hormones and their impact on glucose and lipid metabolism in the newborn. Disclosure J. Qu: None. Q. Yang: None. C. Ko: None. M. Liu: None. D.D. Black: Advisory Panel; Self; Intercept Pharmaceuticals, Inc. P. Tso: None. Funding National Institutes of Health (DK59630)

Insulin and incretin responses to grazing in insulin-dysregulated and healthy ponies.

BackgroundSupraphysiological insulin and incretin responses to a cereal‐based diet have been described in horses and ponies with insulin dysregulation (ID). However, the hormonal responses to grazing have not yet been described.ObjectivesTo determine if there is a difference in the insulin and incretin responses to grazing pasture between insulin‐dysregulated and healthy ponies.AnimalsA cohort of 16 ponies comprising 5 with normal insulin regulation (NIR), 6 with moderate ID (MID), and 5 with severe ID (SID).MethodsIn this case‐control study, an oral glucose test (OGT) was used to determine the insulin responsiveness of each pony to PO carbohydrate before grazing pasture (4 hours) for 3 consecutive days. Serial blood samples collected during grazing were analyzed for glucose, insulin, glucose‐dependent insulinotropic peptide (GIP) and active glucagon‐like peptide‐1 (aGLP‐1), and compared among pony groups and day of pasture access.ResultsThe area under the insulin curve when grazing increased with ID severity (P < .03). The median (range) maximal insulin concentration was greater in the MID (72.5 [129] μIU/mL) and SID (255 [338.5] μIU/mL) groups, compared to the NIR (11.7 [24.9] μIU/mL) group (P < .03) and occurred within 2‐4 hours of grazing. Postprandial OGT insulin concentration was positively correlated with 2 hours post‐grazing insulin across all 3 grazing days (P ≤ .03). The aGLP‐1 and GIP concentrations increased in response to grazing but did not differ among groups.Conclusions and Clinical ImportanceGrazing pasture provoked an increased insulin and incretin response in insulin‐dysregulated ponies within 4 hours of grazing. The pasture and OGT insulin concentrations were correlated.

Early Serum Gut Hormone Concentrations Associated With Time to Full Enteral Feedings in Preterm Infants.

The primary objective of this study was to evaluate early postnatal serum gut hormone concentrations in preterm infants as predictors of time to full enteral feedings. The secondary objective was to identify infant characteristics and nutritional factors that modulate serum gut hormone concentrations and time to full enteral feedings. Sixty-four preterm infants less than 30 weeks of gestation were included in this retrospective cohort study. Serum gut hormone concentrations at postnatal days 0 and 7 were measured using enzyme-linked immunosorbent assays. Linear regression and mediation analyses were performed. Median (interquartile range) serum concentrations of glucose-dependent insulinotropic peptide (GIP) and peptide YY (PYY) on postnatal day 7 were 31.3 pg/mL (18.2, 52.3) and 1181.7 pg/mL (859.0, 1650.2), respectively. GIP and PYY concentrations on day 7 were associated with days to full enteral feedings after adjustment for confounders (β = -1.1, P = 0.03; and β = -0.002, P = 0.02, respectively). Nutritional intake was correlated with serum concentrations of GIP and PYY on postnatal day 7 and time to full enteral feedings. Mediation analysis revealed that the effect of serum gut hormone concentrations on time to full enteral feedings was not fully explained by nutritional intake. Intrauterine growth restriction, mechanical ventilation on postnatal day 7, and patent ductus arteriosus treated with indomethacin were associated with longer time to full enteral feedings. Serum concentrations of GIP and PYY on postnatal 7 are independently associated with time to full enteral feedings. The link between serum gut hormone concentrations and time to full enteral feedings is not fully mediated by nutritional factors, suggesting an independent mechanism underlying the influence of gut hormones on feeding tolerance and time to full enteral feedings.

Lean Subjects with Fatty Liver Show Decreased GLP-1 and GIP Response during OGTT

Subjects with nonalcoholic fatty liver disease (NAFLD) are at high risk of type 2 diabetes even if they are not obese and recent studies have indicated that liver fat (LF)&amp;gt;2.5% was already associated with alteration in glucose and insulin metabolism. Our aim was to investigate if having LF as low as 2.5% was associated to impairment in insulin sensitivity, secretion (ISR) and/or incretin hormones glucagon-like peptide (GLP) 1 and glucose-dependent insulinotropic peptide (GIP) released during an oral glucose tolerance test (OGTT). We studied 49 nondiabetic non-obese subjects (age 52±4; BMI 24.2±0.4 kg/m2). All subjects underwent a 2 h OGTT with plasma insulin, C-peptide, GLP-1, and GIP concentrations were measured every 15-30 min and ISR was quantitated by C-peptide deconvolution. Insulin sensitivity was quantified by HOMA and Matsuda index. Liver fat (LF) accumulation was quantified by magnetic resonance spectroscopy (MRS). In this group of non-obese subjects the great majority were non-NAFLD (31 had LF&amp;lt;2.5%), while 18 had NAFLD (9 had LF 2.5-5% and 9 had LF&amp;gt;5%). Age, BMI, HOMA (1.4±0.2 vs. 1.1±0.2), Matsuda index (7.3±0.7 vs. 10.6±1.3), fasting glucose (5.2±0.1 vs. 5.2±0.1 mmol/l), insulin (6.1±0.7 vs. 4.7±0.7 mU/l), ALT (20±1 vs. 19±1 U/l) and TG (96±22 vs. 88±6 mg/dl) were similar in NAFLD and non-NAFLD. Subjects with LF&amp;gt;2.5% had lower GLP-1 [GLP-1_AUC0-120 was 2.8±0.3 vs. 3.7±0.3, p=0.03], insulin secretion [ISR_AUC60-120 was 61±5 vs. 78±5 nmol, p=0.03] and insulin clearance [MCRI0-120 69±6 vs. 91±7 ml/kg/min, p=0.01] but not GIP [GIP_AUC0-120 was 4.6±0.3 vs. 5.3±0.3, p=ns] response compared to NAFLD; glucose and insulin concentrations during OGTT were similar [Glu0-120 6.7±0.3 vs. 7.3±0.3 mmol/l; Ins0-120 39.9±3.7 vs. 37.5±3.3 mU/l]. Conclusions: Liver fat accumulation (LF&amp;gt;2.5%) is associated with reduced GLP-1, ISR and MCRI; this can help to explain the increased risk of T2D of subjects with NAFLD. Disclosure A. Gastaldelli: Advisory Panel; Self; Gilead Sciences, Inc.. Other Relationship; Self; European Foundation for the Study of Diabetes. Consultant; Self; INVENTIVA SA. J. Garduno-Garcia: Speaker's Bureau; Self; Sanofi-Aventis, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., AstraZeneca. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. N. Musi: None.

The incretin hormone GIP is upregulated in patients with atherosclerosis and stabilizes plaques in ApoE−/− mice by blocking monocyte/macrophage activation

ObjectiveThe incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by the gut after food intake leading to pancreatic insulin secretion and glucose lowering. Beyond its role in glucose control, GLP-1 was found in mice and men to beneficially modulate the process of atherosclerosis, which has been linked to improved cardiovascular outcome of patients with diabetes at high cardiovascular risk treated with GLP-1 receptor agonists. However, little is known on the role of the other main incretin in the cardiovascular system. The aim of this study was to characterize GIP in atherosclerotic cardiovascular disease. Methods and resultsSerum concentrations of GIP were assessed in 731 patients who presented for elective coronary angiography at the University Hospital Aachen. While GIP concentrations were not associated with coronary artery disease (CAD), we found 97 patients with PAD (peripheral artery disease) vs. 634 without PAD to have higher circulating GIP levels (413.0 ± 315.3 vs. 332.7 ± 292.5 pg/mL, p = 0.0165). GIP levels were independently related to PAD after multivariable adjustment for CAD, age, sex, BMI, hypertension, diabetes, CRP, WBC, and smoking. To investigate the functional relevance of elevated GIP levels in human atherosclerotic disease, we overexpressed GIP (1–42) in ApoE−/− mice fed a Western diet for 12 weeks using an adeno-associated viral vector system. GIP overexpression led to reduced atherosclerotic plaque macrophage infiltration and increased collagen content compared to control (LacZ) with no change in overall lesion size, suggesting improved plaque stability. Mechanistically, we found GIP treatment to reduce MCP-1-induced monocyte migration under In vitro conditions. Additionally, GIP prevented proinflammatory macrophage activation leading to reduced LPS-induced IL-6 secretion and inhibition of MMP-9 activity, which was attributable to GIP dependent inhibition of NfκB, JNK-, ERK, and p38 in endotoxin activated macrophages. ConclusionElevated concentrations of the incretin hormone GIP are found in patients with atherosclerotic cardiovascular disease, while GIP treatment attenuates atherosclerotic plaque inflammation in mice and abrogates inflammatory macrophage activation in vitro. These observations identified GIP as a counterregulatory vasoprotective peptide, which might open new therapeutic avenues for the treatment of patients with high cardiovascular risk.

Older Subjects With β-Cell Dysfunction Have an Accentuated Incretin Release

Insulin secretion (IS) declines with age, which increases the risk of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in older adults. IS is regulated by the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Here we tested the hypotheses that incretin release is lower in older adults and that this decline is associated with β-cell dysfunction. A total of 40 young (25 ± 3 years) and 53 older (74 ± 7 years) lean nondiabetic subjects underwent a 2-hour oral glucose tolerance test (OGTT). Based on the OGTT, subjects were divided into three groups: young subjects with normal glucose tolerance (Y-NGT; n = 40), older subjects with normal glucose tolerance (O-NGT; n = 32), and older subjects with IGT (O-IGT; n = 21). Plasma insulin, C-peptide, GLP-1, and GIP concentrations were measured every 15 to 30 minutes. We quantitated insulin sensitivity (Matsuda index) and insulin secretory rate (ISR) by deconvolution of C-peptide with the calculation of β-cell glucose sensitivity. Matsuda index, early phase ISR (0 to 30 minutes), and parameters of β-cell function were lower in O-IGT than in Y-NGT subjects but not in O-NGT subjects. GLP-1 concentrations were elevated in both older groups [GLP-1 area under the curve (AUC)0-120 was 2.8 ± 0.1 in Y-NGT, 3.8 ± 0.5 in O-NGT, and 3.7 ± 0.4 nmol/L∙120 minutes in O-IGT subjects; P < 0.05], whereas GIP secretion was higher in O-NGT than in Y-NGT subjects (GIP AUC0-120 was 4.7 ± 0.3 in Y-NGT, 6.0 ± 0.4 in O-NGT, and 4.8 ± 0.3 nmol/L∙120 minutes in O-IGT subjects; P < 0.05). Aging is associated with an exaggerated GLP-1 secretory response. However, it was not sufficient to increase insulin first-phase release in O-IGT and overcome insulin resistance.

Genetic determinants of circulating GIP and GLP-1 concentrations.

The secretion of insulin and glucagon from the pancreas and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) from the gastrointestinal tract is essential for glucose homeostasis. Several novel treatment strategies for type 2 diabetes (T2D) mimic GLP-1 actions or inhibit incretin degradation (DPP4 inhibitors), but none is thus far aimed at increasing the secretion of endogenous incretins. In order to identify new potential therapeutic targets for treatment of T2D, we performed a meta-analysis of a GWAS and an exome-wide association study of circulating insulin, glucagon, GIP, and GLP-1 concentrations measured during an oral glucose tolerance test in up to 7,828 individuals. We identified 6 genome-wide significant functional loci associated with plasma incretin concentrations in or near the SLC5A1 (encoding SGLT1), GIPR, ABO, GLP2R, F13A1, and HOXD1 genes and studied the effect of these variants on mRNA expression in pancreatic islet and on metabolic phenotypes. Immunohistochemistry showed expression of GIPR, ABO, and HOXD1 in human enteroendocrine cells and expression of ABO in pancreatic islets, supporting a role in hormone secretion. This study thus provides candidate genes and insight into mechanisms by which secretion and breakdown of GIP and GLP-1 are regulated.

The effect of diet, adiposity, and weight loss on the secretion of incretin hormones in cats

Degree of adiposity and dietary macronutrient composition affect incretin hormone secretion in humans and mice, but little is known about their effect in cats. In this study, 7 overweight cats were fed a maintenance diet (MD) for at least 2 wk followed by a reduced calorie diet (RCD), which was lower in fat and higher in carbohydrates and fiber. Cats were fed ad libitum initially, and then, food was restricted to achieve 1%–2% loss of body weight weekly (11 wk). When lean, cats were fed MD for 2 wk. A standardized meal test (SMT) using a third diet was performed after at least 7 d on each diet, before and after weight loss (four SMT's total). Glucose, insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) concentrations were measured immediately before and over 6 h after feeding the SMT. Area under the curve (AUC) was compared for GLP-1, GIP, and insulin concentrations using 2-way analysis of variance. Leaner cats had increased GIPAUC compared to obese cats (P = 0.025). There was a trend toward increased GIPAUC on RCD compared to the MD (P = 0.085). There was a moderate negative correlation between body fat percentage and GLP-1AUC (r = −0.45; P = 0.05). There was no effect of diet on GLP-1AUC. In conclusion, degree of adiposity and dietary macronutrient content could be important in determining GIP responses not only acutely but also on a long-term basis. Further investigation of GIP responses in cats should take both diet and degree of adiposity into account.

Lower plasma levels of glucose-dependent insulinotropic peptide (GIP) and pancreatic polypeptide (PP) in patients with ductal adenocarcinoma of the pancreas and their relation to the presence of impaired glucoregulation and weight loss

BackgroundThe changes in gastrointestinal hormones associated with pancreatic ductal adenocarcinoma (PDAC) in patients with impaired glucoregulation have yet to be evaluated. The aim of this study was to determine plasma concentrations of selected gastrointestinal hormones in PDAC patients with and without diabetes and to compare them with levels found in Type 2 diabetic patients without cancer. MethodsIn this study we examined plasma concentrations of glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide 1 (GLP-1), pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY), and cytokines leptin and adiponectin in 94 patients with histologically confirmed PDAC. Thirty-nine patients with Type 2 diabetes without PDAC and 29 healthy individuals with no evidence of acute or chronic diseases were examined as controls. ResultsSignificantly lower plasma concentrations of GIP were found in PDAC patients with new-onset diabetes/prediabetes (n = 76), or in those with normal glucose regulation (n = 18), compared to patients with Type 2 diabetes without PDAC and controls (15.5 (3.7–64.5) or 6.5 (1.7–24.5) vs. 39.8 (15.1–104.7) and 28.8 (7.4–112.2) ng/L, p < 0.001); the same relationship was observed for PP (38.9 (10.2–147.9) or 28.1 (7.9–100.0) vs 89.1 (38.0–208.9) and 75.8 (30.1–190.6) ng/L, p < 0.01), respectively. The lowest levels of GIP and PP concentrations were found in PDAC patients with new-onset diabetes/prediabetes and weight loss > 2 kg (p < 0.001). ConclusionsWe conclude that GIP and PP plasma concentrations are lower in pancreatic cancer irrespective of the degree of glucose intolerance as compared to Type 2 diabetic patients and healthy controls. In new onset diabetes especially if associated with weight loss, these changes may represent a new clue for the diagnosis of PDAC.

The effect of 8 days of strict bed rest on the incretin effect in healthy volunteers.

Bed rest and physical inactivity are the consequences of hospital admission for many patients. Physical inactivity induces changes in glucose metabolism, but its effect on the incretin effect, which is reduced in, e.g., Type 2 diabetes, is unknown. To investigate how 8 days of strict bed rest affects the incretin effect, 10 healthy nonobese male volunteers underwent 8 days of strict bed rest. Before and after the intervention, all volunteers underwent an oral glucose tolerance test (OGTT) followed by an intravenous glucose infusion (IVGI) on the following day to mimic the blood glucose profile from the OGTT. Blood glucose, serum insulin, serum C-peptide, plasma incretin hormones [glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic peptide (GIP)], and serum glucagon were measured serially during both the OGTT and the IVGI. The incretin effect is calculated as the relative difference between the area under the curve for the insulin response during the OGTT and that of the corresponding IVGI, respectively. Concentrations of glucose, insulin, C-peptide, and GIP measured during the OGTT were higher after the bed rest intervention (all P < 0.05), whereas there was no difference in the levels of GLP-1 and Glucagon. Bed rest led to a mean loss of 2.4 kg of fat-free mass, and induced insulin resistance evaluated by the Matsuda index, but did not affect the incretin effect (P = 0.6). In conclusion, 8 days of bed rest induces insulin resistance, but we did not see evidence of an associated change in the incretin effect.

Circulating concentrations of glucagon-like peptide 1, glucose-dependent insulinotropic peptide, peptide YY, and insulin in client-owned lean, overweight, and diabetic cats

Our objectives were to measure plasma concentrations of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) in client-owned newly diagnosed diabetic cats and nondiabetic lean or overweight cats and to determine whether circulating concentrations of these hormones differed between study groups and if they increased postprandially as seen in other species. A total of 31 cats were recruited and placed into 1 of 3 study groups: lean (body condition score 4–5 on a scale of 1–9; n = 10), overweight (body condition score 6–8; n = 11), or diabetic (n = 10). Diabetics were newly diagnosed and had not had prior insulin therapy. Preprandial (fasting) and postprandial (60 min after meal) plasma hormone and glucose concentrations were measured at baseline and 2 and 4 wk. All cats were exclusively fed a commercially available high-protein and low-carbohydrate diet commonly prescribed to feline diabetic patients for 2 wk before the 2-wk assessment and continued through the 4-wk assessment. Results showed that plasma concentrations of GLP-1, GIP, PYY, and insulin increased in general after a meal in all study groups. Plasma PYY concentrations did not differ (P > 0.10) between study groups. Diabetics had greater plasma concentrations of GLP-1 and GIP compared with the other study groups at baseline (P < 0.05), and greater preprandial and postprandial GLP-1 concentrations than lean cats at 2 and 4 wk (P < 0.05). Preprandial plasma GIP concentrations were greater in diabetics than obese and lean (P < 0.05) cats at week 4. Postprandial plasma GIP concentrations in diabetics were greater than lean (P < 0.05) at week 2 and obese and lean cats (P < 0.05) at week 4. Together, our findings suggest that diabetic status is an important determinant of circulating concentrations of GLP-1 and GIP, but not PYY, in cats. The role of GLP-1, GIP, and PYY in the pathophysiology of feline obesity and diabetes remains to be determined.