Glucose-dependent Insulinotropic Peptide Levels Research Articles

Cannabinoids block fat-induced incretin release via CB1-dependent and CB1-independent pathways in intestinal epithelium

Background and AimsGlucose homeostasis is regulated by a dynamic interplay between hormones along the gastro-insular axis. For example, enteroendocrine L- and K- cells that line the intestine produce the incretins glucagon-like polypeptide-1 (GLP1) and glucose-dependent insulinotropic peptide (GIP), respectively, which are secreted following a meal. Broadly, incretin signaling enhances insulin release from the endocrine pancreas and participates in the control of food intake, and therapeutics that mimic their activity have recently been developed for the treatment of type-2 diabetes and obesity. Notably, genes for cannabinoid subtype-1 receptor (CB1R) are expressed in these cell subpopulations; however, roles for CB1Rs in controlling fat-induced incretin release are unclear. To address this gap in our understanding, we tested the hypothesis that intestinal epithelial CB1Rs control fat-induced incretin secretion. MethodsWe treated mice with conditional deletion of CB1Rs in the intestinal epithelium (IntCB1-/-) or controls (IntCB1+/+) with oil gavage to stimulate incretin release in the presence of the cannabinoid receptor agonists, WIN55,212-2 or Δ9-tetrahydrocannabinol (THC), and the peripherally-restricted CB1R antagonist AM6545. Circulating incretin levels were measured in plasma. ResultsOral gavage of corn oil increased levels of bioactive GLP1 and GIP in IntCB1+/+ mouse plasma. Pretreatment with the WIN55,212-2 or THC blocked this response, which was largely reversed by co-administration with AM6545. WIN55,212-2 failed to inhibit fat-induced GIP release, but not aGLP1, in IntCB1-/- mice. In contrast, THC inhibited the secretion of incretins irrespective of CB1R expression in intestinal epithelial cells. ConclusionsThese results indicate that cannabinoid receptor agonists can differentially inhibit incretin release via mechanisms that include intestinal epithelial CB1R-dependent and CB1R-independent mechanisms.

A Review of Dipeptidyl Peptidase-4 (DPP-4) and its potential synthetic derivatives in the management of Diabetes Mellitus

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a type of oral medication used to treat type 2 diabetes mellitus (T2DM). They have become increasingly popular due to their effectiveness and safety in managing the condition. DPP-4 inhibitors function by inhibiting the enzyme that breaks down the incretin hormones, namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These medicines efficiently raise the levels of active GLP-1 and GIP by blocking DPP-4 activity. As a result, there is an increase in the production of insulin, a decrease in the release of glucagon, and a lowering of glucose levels after a meal. Multiple clinical trials have conclusively shown that DPP-4 inhibitors effectively lower glycated hemoglobin (HbA1c) levels. Certain studies have even proved their equivalent efficacy to other anti-diabetic medications such as metformin or sulfonylureas. Furthermore, DPP-4 inhibitors possess the benefit of being weight-neutral and exhibiting a little risk of hypoglycemia. These qualities render them a compelling option for patients with type 2 diabetes mellitus who are overweight or susceptible to hypoglycemia episodes. In general, DPP-4 inhibitors are a promising therapeutic choice for the management of type 2 diabetes mellitus (T2DM), offering effective regulation of blood sugar levels with a minimal likelihood of adverse effects. Nevertheless, it is important to acknowledge some restrictions and factors to take into account, including the possibility of heightened susceptibility to pancreatitis, nasopharyngitis, and certain drug-drug combinations. Additional investigation is necessary to completely clarify the long-term safety and potential supplementary advantages of DPP-4 inhibitors.

Endogenous incretin levels and risk of first incident cancer: a prospective cohort study

Concerns have been raised regarding a potentially increased risk of cancer associated with treatment with glucagon-like peptide-1 (GLP-1) receptor agonists. Here, we explored whether fasting and oral glucose tolerance test post-challenge glucose-dependent insulinotropic peptide (GIP) and GLP-1 levels were associated with incident first cancer. Within the cardiovascular re-examination arm of the population-based Malmö Diet Cancer study (n = 3734), 685 participants with a previous cancer diagnosis were excluded, resulting in 3049 participants (mean age 72.2 ± 5.6 years, 59.5% women), of whom 485 were diagnosed with incident first cancer (median follow-up time 9.9 years). Multivariable Cox-regression and competing risk regression (death as competing risk) were used to explore associations between incretin levels and incident first cancer. Higher levels of fasting GLP-1 (462 incident first cancer cases/2417 controls) showed lower risk of incident first cancer in competing risk regression (sub-hazard ratio 0.90; 95% confidence interval 0.82–0.99; p = 0.022). No association was seen for fasting GIP, post-challenge GIP, or post-challenge GLP-1 and incident first cancer. In this prospective study, none of the fasting and post-challenge levels of GIP and GLP-1 were associated with higher risk of incident first cancer; by contrast, higher levels of fasting GLP-1 were associated with lower risk of incident first cancer.

Glucose-Dependent Insulinotropic Polypeptide Plasma Level Influences the Effect of n-3 PUFA Supplementation

Elevated glucose-dependent insulinotropic peptide (GIP) levels in obesity may predict the metabolic benefits of n-3 PUFA supplementation. This placebo-controlled trial aimed to analyze fasting and postprandial GIP response to 3-month n-3 PUFA supplementation (1.8 g/d; DHA:EPA, 5:1) along with caloric restriction (1200–1500 kcal/d) in obese subjects. Compliance was confirmed by the incorporation of DHA and EPA into red blood cells (RBCs). Blood analyses of glucose, insulin, non-esterified fatty acids (NEFAs), GIP and triglycerides were performed at fasting, and during an oral glucose tolerance test and a high fat mixed-meal tolerance test. Fatty acid composition of RBC was assessed by gas chromatography and total plasma fatty acid content and composition was measured by gas–liquid chromatography. The DHA and EPA content in RBCs significantly increased due to n-3 PUFA supplementation vs. placebo (77% vs. −3%, respectively). N-3 PUFA supplementation improved glucose tolerance and decreased circulating NEFA levels (0.750 vs. 0.615 mmol/L), as well as decreasing plasma saturated (1390 vs. 1001 µg/mL) and monounsaturated (1135 vs. 790 µg/mL) fatty acids in patients with relatively high GIP levels. The effects of n-3 PUFAs were associated with the normalization of fasting (47 vs. 36 pg/mL) and postprandial GIP levels. Obese patients with elevated endogenous GIP could be a target group for n-3 PUFA supplementation in order to achieve effects that obese patients without GIP disturbances can achieve with only caloric restriction.

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.

Segmental reversal of the distal small intestine in a short bowel syndrome model in piglets showed detrimental effect on weight gain

BackgroundTo investigate the effects of a reversed segment of the distal small intestine to improve weight gain in an experimental short bowel syndrome (SBS) model in piglets.MethodsTwenty-four piglets underwent resection of 70% of the distal small intestine. In half of the animals a conventional anastomosis was performed, and in the other half, the distal 25 cm of the remnant jejunum was reversed before the intestinal continuity was recreated. Weight was measured daily until day 28, where the animals were euthanized. Glucagon-Like Peptide-2 (GLP-2) and Glucose-dependent Insulinotropic Peptide (GIP) was measured pre- and postoperatively at day 28.ResultsThe group with reversal of small intestine had a significant lower weight gain at 5.26 ± 3.39 kg (mean ± SD) compared to the control group with 11.14 ± 3.83 kg (p < 0.05). In the control group greater villus height and crypt depth was found distally, and greater muscular thickness was found proximally in the intervention group. GLP-2 and GIP levels increased significantly in the control group.ConclusionsTreatment of short bowel syndrome with a reversed jejunal segment of 25 cm had a detrimental effect on the weight gain.

The alpha-7 nicotinic acetylcholine receptor agonist GTS-21 engages the glucagon-like peptide-1 incretin hormone axis to lower levels of blood glucose in db/db mice.

To establish if alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a blood glucose-lowering action in db/db mice, and to test if this action requires coordinate α7nAChR and GLP-1 receptor (GLP-1R) stimulation by GTS-21 and endogenous GLP-1, respectively. Blood glucose levels were measured during an oral glucose tolerance test (OGTT) using db/db mice administered intraperitoneal GTS-21. Plasma GLP-1, peptide tyrosine tyrosine 1-36(PYY1-36), glucose-dependent insulinotropic peptide (GIP), glucagon, and insulin levels were measured by ELISA. A GLP-1R-mediated action of GTS-21 that is secondary to α7nAChR stimulation was evaluated using α7nAChR and GLP-1R knockout (KO) mice, or by co-administration of GTS-21 with the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the GLP-1R antagonist, exendin (9-39). Insulin sensitivity was assessed in an insulin tolerance test. Single or multiple dose GTS-21 (0.5-8.0mg/kg) acted in a dose-dependent manner to lower levels of blood glucose in the OGTT using 10-14 week-old male and female db/db mice. This action of GTS-21 was reproduced by the α7nAChR agonist, PNU-282987, was enhanced by sitagliptin, was counteracted by exendin (9-39), and was absent in α7nAChR and GLP-1R KO mice. Plasma GLP-1, PYY1-36, GIP, glucagon, and insulin levels increased in response to GTS-21, but insulin sensitivity, body weight, and food intake were unchanged. α7nAChR agonists improve oral glucose tolerance in db/db mice. This action is contingent to coordinate α7nAChR and GLP-1R stimulation. Thus α7nAChR agonists administered in combination with sitagliptin might serve as a new treatment for type 2 diabetes.

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.

Effects of a new 75 g glucose- and high fat-containing cookie meal test on postprandial glucose and triglyceride excursions in morbidly obese patients.

A new meal tolerance test (MTT) using a 75 g glucose- and high fat-containing meal was applied to classify glucose intolerance in morbidly obese patients. According to the MTT data, the concordance rate of diagnosis was 82.5% compared to the 75 g oral glucose tolerance test (OGTT) in patients with normal glucose tolerance (NGT, n = 40). In the NGT patients, the insulinogenic index (r = 0.833), Matsuda index (r = 0.752), and disposition index (r = 0.845) calculated from the MTT data were each significantly (p < 0.001) correlated with those derived from the OGTT data. However, in patients with impaired glucose tolerance (IGT, n = 23) or diabetes mellitus (DM, n = 17), the postprandial glucose levels post-MTT were significantly lower than those post-OGTT, without increases in the postprandial insulin levels post-MTT. Thus, the severity of glucose intolerance measured by the MTT was milder than that indicated by the OGTT. Plasma levels of both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) were increased at the postprandial state, but only the GIP levels post-MTT were significantly higher than those post-OGTT. The enhancement of glucose disposal rates in patients with NGT or IGT after the MTT was associated with increased GIP levels. The postprandial hypertriglyceridemia induced by the MTT was associated with insulin resistance, but it was not associated with the impaired insulinogenic index or the disposition index. These results indicate that the new MTT is clinically useful to evaluate both abnormal glucose and triglyceride excursions caused by abnormal insulin sensitivity and secretions of insulin and gut hormones in morbidly obese patients.

Relation between glucagon-like peptide 1 (GLP-1), Glucose dependent insulinotropic peptide (GIP) and HOMA index in university students

Introduction. Diabetes mellitus is a disease which affects recently at least 415 million people around the world. Obesity is the main risk factor for the development of this disease. In the development of insulin resistance influences several factors such as carbohydrates metabolism and the secretion of GLP-1 and GIP. Objective. Correlate levels of GLP-1 and GIP with HOMA in students. Methods. A cross-sectional study was performed, we determine glucose levels using dry chemistry and GIP, GLP-1 and insulin levels were quantified by ELISA technique. A Pearson correlation between HOMA. Besides, we stratify in normal weight, overweight and obesity and we did the correlation in the three groups. Results. 78 students in total. GIP increased according to the BMI and show difference between the three groups p=0.01. The GLP-1 did not modify. HOMA index and GIP had a correlation of 0.36 with a significance p=0.002. In the other hand, HOMA index vs GLP-1 r=0.52 (p=0.001); normal weight r=0.94 (p=0.001), overweight r=0.75 (p=0.001), obesity r=0.045 (p=0.001) respectively. Conclusions. GIP and GLP-1 correlate with HOMA. The better correlation was found in GLP-1 which is higher in people with normal weight and decreases in obesity. The correlation between GIP and HOMA was low.

The gut hormone GIP predicts CV prognosis in patients with acute myocardial infarction

Abstract Background The 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 regulatory effects in glucose metabolism activation of the GLP-1 receptor has been found to improve cardiovascular prognosis in patients with diabetes and high cardiovascular risk. The functional relevance of GIP (the other main incretin) in patients with cardiovascular disease is largely unknown. The aim of this study was to assess the predictive capacity of GIP serum levels for cardiovascular outcome in patients with acute myocardial infarction. Methods and results We investigated the predictive value of GIP serum levels at the time of hospital admission for cardiovascular prognosis in a cohort of 852 patients (67±13 years; 73% men) with acute myocardial infarction (34% STEMI, 66% NSTEMI). Kaplan-Meier curves (GIP median; cut-off: 69 pg/mL) and univariable Cox regression analyses showed that lower GIP levels were associated with an increased cardiovascular mortality (HR of logarithmized GIP values: 0.520; 95% CI: 0.30–0.90; p=0.020). After adjustment for age, sex, smoking, hypertension, hypercholesterolemia, diabetes and family history of cardiovascular disease the association between GIP levels and cardiovascular mortality remained significant with similar hazard ratios as in the univariable Cox regression model. Conclusion In summary, we found lower GIP levels to independently predict a poor cardiovascular outcome in high-risk patients with acute myocardial infarction. Future larger studies are needed to foster our understanding of the gut - heart axis as a yet fairly neglected field of system biology and to elucidate whether the GIP system might open novel therapeutic approaches for the treatment of patients with cardiovascular disease. Funding Acknowledgement Type of funding sources: None.

Effects of experimental colitis in rats on incretin levels, inflammatory markers, and enteric neuronal function.

IntroductionThe aim of the study was to assess the effects of chronic inflammation on incretin levels, inflammatory markers, and enteric neuronal function measured in isolated preparations of smooth muscle of rat.Material and methodsWe induced experimental colitis using 2,4-dinitrobenzenesulfonic acid (DNBS) in 17 Albino male Sprague-Dawley rats, while 16 rats were used as a control. They were housed in temperature-controlled rooms in a 12-h light/dark cycle at 22–24°C and 50 to 60% humidity. We evaluated in both inflamed and healthy rats: fasting plasma glucose concentration, fasting plasma insulin, myeloperoxidase, active glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), and GLP-2 levels, adiponectin, and C-reactive protein (CRP). We also evaluated colonic longitudinal smooth muscle contractile activity.ResultsIntrarectal administration of DNBS reduced body weight gain in inflamed rats. We recorded higher levels of fasting plasma glucose, and insulin in inflamed rats. We observed higher levels of myeloperoxidase and CRP, and lower levels of ADN in inflamed rats. We recorded higher levels of GIP, GLP-1, and GLP-2 in inflamed rats compared to the healthy ones. Regarding functional response of colon intestinal smooth muscle after electrical stimulation, we recorded a lower functional response of colon intestinal smooth muscle after electrical stimulation in inflamed rats.ConclusionsWe can conclude that chronic inflammation leads to an increase of incretin levels and to a decrease of functional response of colon intestinal smooth muscle after electrical stimulation.

The Effect of Melatonin on Incretin Hormones: Results From Experimental and Randomized Clinical Studies.

Glucose homeostasis is under circadian control through both endocrine and intracellular mechanisms, with several lines of evidence suggesting that melatonin affects glucose homeostasis. To evaluate the acute in vivo and in situ effects of melatonin on secretion of the incretin hormones, glucagon-like-peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), and their impact on β-cell insulin secretion. A human randomized, double-blinded, placebo-controlled crossover study combined with a confirmatory in situ study of perfused rat intestines. Aarhus University Hospital. Fifteen healthy male participants were examined 2 × 2 times: an oral glucose tolerance test (OGTT) was performed on day 1 and an isoglycemic IV glucose infusion replicating the blood glucose profile of the OGTT day was performed on day 2. These pairs of study days were repeated on treatment with melatonin and placebo, respectively. For the in situ study, 6 rat intestines and 4 rat pancreases were perfused arterially with perfusion buffer ± melatonin. The intestines were concomitantly perfused with glucose through the luminal compartment. In humans, melatonin treatment resulted in reduced GIP secretion compared with placebo (ANOVA P = 0.003), an effect also observed in the perfused rat intestines (ANOVA P = 0.003), in which GLP-1 secretion also was impaired by arterial melatonin infusion (ANOVA P < 0.001). Despite a decrease in GIP levels, the in vivo glucose-stimulated insulin secretion was unaffected by melatonin (P = 0.78). Melatonin reduced GIP secretion during an oral glucose challenge in healthy young men but did not affect insulin secretion. Reduced GIP secretion was confirmed in an in situ model of the rat intestine.

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.

Dipeptidyl peptidase-4 activity, lipopolysaccharide, C-reactive protein, glucose metabolism, and gut peptides 3 months after bariatric surgery.

Bariatric surgery induces weight loss, but changes in glucose metabolism, gut peptides, and inflammatory biomarkers still have conflicting results. University hospital. We investigated glucose metabolism, gut hormones, and inflammatory profile after bariatric surgery and medical treatment. Forty patients with obesity were recruited and were subjected to Roux-en-Y gastric bypass (n = 15; Bariatric Surgery Group - BSG) or received medical care (n = 20; MG). Sleeve gastrectomy was performed in five patients who were excluded from analysis. Glucose, insulin, homeostatic model for the assessment of insulin resistance (HOMA-IR), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), glucagon, ghrelin, dipeptidyl peptidase-4 (DPP-4) activity, circulating lipopolysaccharide (LPS), LPS-binding protein (LPB) and high-sensitivity C-reactive protein (hs-CRP) were evaluated before and three months after each treatment. Except for HOMA-IR, hs-CRP, and LBP, all variables were assessed at fasting and 30- and 60-minutes after a standard meal. After 3 months, both groups lost weight. However, BSG had a more extensive reduction than MG (respectively, 17.6% vs. 4.25%; P < 0.01). Except for LPS levels, higher on BSG than MG (1.38 ± 0.96 vs. 0.83 ± 0.60 EU/ml, P < 0.01), groups were similar before treatment. In respect to metabolic/hormonal changes, the BSG showed higher glucose, insulin, GLP-1, and GIP levels at 30-min and also GLP-1 at 30- and 60-minutes. DPP-4 activity, HOMA-IR, and fasting LBP did not change. LPS levels at 60-minutes decreased after surgery in the BSG. hs-CRP decreased on BSG compared to MG. Bariatric surgery resulted in more extensive effects on glucose metabolism, gut hormones, and inflammation.

Glucagon-like peptide-1 agonist therapy in patients with diabetes mellitus and obesity

Due to the high efficiency of glucagon-like peptide-1 (GLP-1) receptor agonists therapy in only a part of patients, the search for predictors of response to the treatment is a relevant problem. Purpose. The purpose is to compare the efficacy of liraglutide and exenatide therapy in obese patients with type 2 diabetes mellitus (T2DM) and to evaluate the predictors of response to glycated hemoglobin (HbA1c), weight and lipids reduction. Material and methods. The study included 47 patients with type 2 diabetes and obesity who received GLP-1 receptor agonists therapy. 26 patients were treated with liraglutide, 21 patients were treated with exenatide. We measured the parameters of carbohydrate and lipid metabolism, the levels of hormones involved in glucose and lipids metabolism and in appetite regulation. Blood pressure was measured. These parameters were evaluated at baseline and after 24 weeks of treatment. Results. Patients receiving exenatide therapy showed a tendency towards more frequent HbA1c level reduction by 1% or more (60% versus 30.4%, p = 0.07). The effects of liraglutide and exenatide on weight and waist circumference were comparable. When assessing the predictors of response to the therapy, a more pronounced decrease in HbA1c level (by 1% or more) was in the patients with a higher initial HbA1c level (8.7 (8.2; 9.7) versus 8.2 (6.9; 8.7)%, p = 0.04), as well as with a higher initial GLP-1 level (0.12 (0.05; 0.17) versus 0.040 (0.01; 0.09) ng/ml.) A more significant decrease in the triglycerides (TG) level was detected in patients with a higher level of glucose-dependent insulinotropic peptide (GIP) before therapy (409 (316.0; 431.4) pg/ml in patients who reduced TG level by 30% or more and 331.5 (324.9; 367.1) pg/ml in patients with a lower decrease in TG level). Among the studied parameters, no predictors of body mass reduction were revealed. Conclusion. Measurement of HbA1c, GLP-1, GIP level may be useful to predict the efficacy of GLP-1 receptor agonists therapy.

Interrelations of components of metabolic syndrome with the level of the hormones involved in regulation of adipose tissue metabolism

Background . Metabolic syndrome (MS) is a pathological condition characterized by abdominal obesity, insulin resistance, arterial hypertension (HTN) and dyslipidemia. MS contributes to type 2 diabetes mellitus, coronary heart disease, stroke and other cardiovascular events. Currently, much attention is paid to the study of the underlying factors, including hormones involved in fat metabolism. The changes in the level of hormones affecting the metabolism of adipose tissue in MS, as well as the relationship of these changes with various MS components, should be studied for the development of effective treatment approaches. Objective . To study the relationship of various MS components with the level of hormones affecting the metabolism of adipose tissue in patients with MS. Design and methods . The study included 88 obese patients (26 males; 62 females), average age 42,0 ± 11,2 years, average body weight 109,7 ± 25,1 kg, body mass index (BMI) 37,9 ± 6,2 kg/m 2 . Dyslipidemia was detected in 60 patients, carbohydrate metabolism disturbance (impaired glucose tolerance) was recorded in 12 patients, and HTN — in 22 patients. All patients underwent an assessment of the level of hormones involved in the regulation of fat metabolism (glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), ghrelin, leptin, adiponectin), lipid profiles (cholesterol, high-density lipoprotein, low density lipoprotein, triglyceride), fasting venous plasma glucose, insulin. The HOMA-IR index was calculated. Results . Levels of leptin and GLP-1 were increased in MS compared with healthy people, and levels of ghrelin, adiponectin, and GIP were reduced. Women showed a more significant increase in leptin and a less pronounced decrease in ghrelin than in men. BMI positively correlated with the level of insulin, leptin, the HOMA-IR index and negatively with the level of ghrelin. Waist circumference correlated positively with insulin levels and the HOMA-IR index and negatively with ghrelin and adiponectin levels. Ghrelin was associated with glucose level and diastolic blood pressure correlated with the GIP level. Conclusions . Our study confirms the previously established relationships between BMI and waist circumference with the severity of insulin resistance (increased insulin levels and the HOMA-IR index), leptin resistance (increased leptin levels) and the development of adiponectin deficiency. The dynamics of adiponectin and ghrelin were more closely related to the visceral type of obesity. The established relationships between the levels of GIP and ghrelin and relationship of GIP with diastolic blood pressure require further investigation.

Incretin hormones, insulin, glucagon and advanced glycation end products in relation to cognitive function in older people with and without diabetes, a population‐based study

The aim of this observational study was to investigate relationships between physiological levels of glucometabolic biomarkers and cognitive test results in a population-based setting. Cross-sectional data were obtained from the Swedish population-based Malmö Diet and Cancer Study Re-examination 2007-2012 comprising 3001 older people (mean age 72years). Through oral glucose tolerance testing (OGTT), fasting and post-load levels of serum insulin, plasma glucagon, serum glucose-dependent insulinotropic peptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) were measured. Insulin resistance and insulin sensitivity levels were calculated. In 454 participants, advanced glycation end products (AGEs) were estimated through skin autofluorescence. Associations between biomarkers and two cognitive tests, the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT) respectively, were explored in multiple regression analyses. Positive associations following adjustments for known prognostic factors were found between MMSE scores and insulin sensitivity (B=0.822, P=0.004), 2-h plasma glucagon (B=0.596, P=0.026), 2-h serum GIP (B=0.581, P=0.040) and 2-h plasma GLP-1 (B=0.585, P=0.038), whereas negative associations were found between MMSE scores and insulin resistance (B=-0.734, P=0.006), fasting plasma GLP-1 (B=-0.544, P=0.033) and AGEs (B=-1.459, P=0.030) were found. Higher levels of insulin sensitivity, GIP and GLP-1 were associated with better cognitive outcomes, but AGEs were associated with worse outcomes, supporting evidence from preclinical studies. Glucagon was linked to better outcomes, which could possibly reflect neuroprotective properties similar to the related biomarker GLP-1 which has similar intracellular properties. Longitudinal and interventional studies are needed to further evaluate neuromodulating effects of these biomarkers. Abstract presented at the European Association for the Study of Diabetes (EASD) 2019, Barcelona, Spain.

Oxyntomodulin May Distinguish New-Onset Diabetes After Acute Pancreatitis From Type 2 Diabetes.

OBJECTIVE:New-onset diabetes is an important sequela of acute pancreatitis, but there are no biomarkers to differentiate it from the much more common type 2 diabetes. The objective was to investigate whether postprandial circulating levels of gut hormones can serve this purpose.METHODS:This was a case-control study nested into a prospective longitudinal cohort study that included 42 insulin-naive cases with new-onset prediabetes/diabetes after acute pancreatitis (NODAP) and prediabetes/diabetes followed by acute pancreatitis (T2D-AP), sex matched with 21 healthy controls. All individuals underwent a standardized mixed-meal test, and blood samples were assayed for gut hormones (glucose-dependent insulinotropic peptide, glucagon-like peptide-1, oxyntomodulin, and peptide YY). Analysis of variance and linear regression analysis were conducted in unadjusted and adjusted models (accounting for age, homeostatic model assessment of β-cell function, and magnetic resonance imaging–derived body fat composition).RESULTS:Oxyntomodulin levels were significantly lower in NODAP compared with T2D-AP and healthy controls (P = 0.027 and P = 0.001, respectively, in the most adjusted model). Glucagon-like peptide-1 and peptide YY were significantly lower in NODAP compared with T2D-AP (P = 0.001 and P = 0.014, respectively, in the most adjusted model) but not compared with healthy controls (P = 1.000 and P = 0.265, respectively, in the most adjusted model). Glucose-dependent insulinotropic peptide levels were not significantly different between NODAP and T2D-AP.DISCUSSION:Oxyntomodulin is a promising biomarker to guide the differential diagnosis of new-onset diabetes after acute pancreatitis. However, external validation studies are warranted before it can be recommended for routine use in clinical practice.

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.