Higher Glucagon-like Peptide-1 Research Articles

Glucagon-Like Peptide-1 Secretory Function as an Independent Determinant of Blood Pressure: Analysis in the Tanno-Sobetsu Study

AimsRoles of glucagon-like peptide-1 (GLP-1) in extra-pancreatic tissues remain unclear. The aim of this study was to examine determinants of GLP-1 secretory function and possible contribution of GLP-1 to blood pressure (BP) regulation.Methods and ResultsWe recruited 128 subjects who received annual examinations and 75g-oral glucose tolerance tests (OGTT) in the Tanno-Sobetsu cohort. Subjects on regular medications for cardiovascular and/or metabolic diseases were excluded, and data for the remaining 103 subjects were used for the univariate and multivariate analyses. Age, plasma glucose (PG), hemoglobin A1c (HbA1c), plasma insulin, and serum lipids were not selected as independent determinants of fasting GLP-1 level by multiple linear regression analysis. However, age and female sex were selected as independent positive determinants of the area under the curve of GLP-1 level during OGTT (AUCGLP-1), an index of GLP-1 secretory function. Multiple linear regression analysis indicated that AUCGLP-1 was an independent negative predictor of systolic BP (SBP), while AUCGLP-1 was not correlated with fasting PG or HbA1c level. In subgroup analyses using the median of AUCGLP-1 to divide the study subjects into high and low GLP-1 response groups, AUCGLP-1 was significantly correlated with both SBP and diastolic BP (r = 0.40 and 0.28, respectively) in the low GLP-1 response group but not in the high GLP-1 response group.ConclusionsThe results of the present study suggest that GLP-1 secretory function is involved in prevention of BP elevation and that the GLP-1 response to oral glucose rather increases with aging perhaps as an adaptive phenomenon.

Beta and alpha cell function in metabolically healthy but obese subjects: Relationship with entero‐insular axis

Obesity is widely acknowledged as a critical risk factor for metabolic complications. Among obese subjects, there is a phenotype of metabolically healthy but obese (MHO) individuals that shows a favorable cardiometabolic risk profile. We aimed to evaluate the potential mechanisms underlying the metabolic profile of this subset, including alpha and beta cell function and entero-insular axis. One hundred twenty-nine obese and 24 nonobese subjects were studied. Obese participants were defined as MHO or at-risk obese, according to the homeostasis model of assessment-insulin resistance (HOMA-IR) index (MHO: lower tertile of HOMA-IR, n = 43; at-risk: upper tertile of HOMA-IR index, n = 41). Insulin, glucagon, and incretin responses after a 120' oral glucose tolerance test (75-g OGTT) were investigated. During OGTT, MHO individuals showed in comparison with at-risk subjects: lower fasting and afterloads plasma levels of glucose, insulin, and C-peptide; higher disposition index; lower fasting (P = 0.004) and at 30' (P = 0.01) plasma glucose-dependent insulinotropic polypeptide (GIP) levels; lower area under the curve (AUC) (0-30) for GIP (P = 0.008); higher glucagon-like peptide-1 (GLP-1) plasma levels at 90' (P = 0.02) and 120' (P = 0.02); lower glucagon plasma levels at baseline (P = 0.04) and at 30' (P = 0.03); and appropriate glucagon suppression after the oral glucose load. MHO subjects show, as well as normal-weight individuals, a lower diabetogenic profile by virtue of higher disposition index and unaffected entero-insular axis. At-risk obese individuals present increased GIP levels that might play a role in determining increased glucagon secretion and inappropriate glucagon responses after glucose load, thus contributing to impaired glucose homeostasis.

Abstract TP275: Glucagon-Like Peptide-1 Is Increased In Blood Plasma and May Play Neuroprotective Roles After Ischemic Stroke In Human

Introduction: Glucagon-like peptide-1 (GLP-1) is an incretin peptide, which is secreted by intestinal L-cells after food intake and increases the insulin secretion in a glucose-dependent manner. Increasing evidence indicates that GLP-1 may play neuroprotective roles in animal stroke models; however, there have been few reports regarding the relationship between GLP-1 and stroke in human. Hypothesis: GLP-1 is increased in plasma and plays neuroprotective roles after ischemic stroke in human. Methods: We prospectively enrolled 171 patients with ischemic stroke and age- and gender-matched healthy controls. We measured GLP-1 in fasting blood plasma at five time points after the onset (days 0, 3, 7, 14 and 90) and investigated clinical information in the stroke patients. Results: Average GLP-1 values at day 0 were significantly higher in the stroke patients than the controls (2.7 ± 0.4 vs. 1.5 ± 0.2 pmol/L, p = 0.0107). In the patients, GLP-1 values at day 0 tended to be negatively associated with neurological severity as evaluated by National Institute of Health Stroke Scale (NIHSS) on admission (r = - 0.1264, p = 0.0565). Moreover, when the stroke patients were divided into 4 groups (Q1, Q2, Q3 and Q4 from milder to severer) according to the interquartile range of the NIHSS, Q1 (3.6 ± 0.9 pmol/L, p = 0.0014) and Q2 (2.6 ± 0.7 pmol/L, p = 0.0429) groups had significantly higher GLP-1 values than the controls (Figure). GLP-1 continued to be increased until the 90 days after the onset, compared to that of the controls (day 0 (2.7 ± 0.4 pmol/L, p = 0.0107), day 3 (6.0 ± 0.4, p < 0.0001), day7 (7.1 ± 0.6, p < 0.0001), day 14 (8.3 ± 0.8, p < 0.0001), day 90 (8.3 ± 0.7, p < 0.0001)). GLP-1 values tended to be higher in the good outcome group (modified Rankin Scale (mRS) ≤ 1 at 90 day) than the poor outcome group (mRS ≥ 2). Conclusions: GLP-1 is increased in blood plasma after ischemic stroke in human. The increase in the acute phase may be associated with the reduction of neurological severity in ischemic stroke.

Abstract 8993: Protective Effects of Glucagon-like Peptide-1 on Cardiac Microvessels Injury via cAMP/PKA/Rho Dependent Pathway in Diabetic Rats

Introduction: Impaired cardiac microvascular function contributes greatly to diabetes cardiovascular disease. Glucagon-like peptide-1 (GLP-1) was found to have multiple cardioprotective effects besides its glucose lowering properties. Hypothesis: To investigate the protective effects of GLP-1 on cardiac microvessels injury and the underlying mechanism in diabetic rats. Methods: STZ-induced diabetic rats were randomized to 12 weeks of treatment with vehicle, LAF237 or Exenatide. Cardiac function and energetics was examined by echocardiography and 18 F-FDG PET respectively. Lanthanum nitrate perfusion was applied to assess cardiac microvascular barrier function. Cardiac microvascular endothelial cells (CMECs) were cultured in medium alone or medium containing high glucose, GLP-1, high glucose plus GLP-1. Lucigenin-enhanced chemiluminescence assay and DHE staining were used to assess ROS production. The expression of Rho, ROCK, p47 phox and gp91 phox was examined by Western blot. Results: LAF237 or Exetinade treatment improved cardiac function and energetics as well as microvascular barrier function significantly compared with vehicle groups. Compared with vehicle groups, ROS production was markedly decreased in GLP-1 groups. There were also significant reductions in p47 phox and gp91 phox expression. The cAMP/PKA activity was increased and the Rho expression was decreased in high glucose-induced CMECs after treatment with GLP-1, which reproduced the same effects as PKA inhibitor. Conclusions: GLP-1 could protect the cardiac microvessels against oxidative stress injury and the resultant microvascular barrier dysfunction in diabetic rats, which contribute to the improvement of cardiac function. The protective effects of GLP-1 are dependent on downstream inhibition of Rho, which is through cAMP/PKA pathway, resulting in subsequent decreased production of NADPH oxidase.

Absence of the Glucagon-Like Peptide-1 Receptor Does Not Affect the Metabolic Phenotype of Mice with Liver-Specific Gsα Deficiency

The stimulatory G protein α-subunit (G(s)α) couples hormone and other receptors to the generation of intracellular cAMP. We previously showed that mice with liver-specific G(s)α deficiency [liver-specific G(s)α knockout (LGsKO) mice] had reduced adiposity and improved glucose tolerance associated with increased glucose-stimulated insulin secretion, pancreatic islet hyperplasia, and very high serum glucagon and glucagon-like peptide 1 (GLP-1) levels. Because GLP-1 is known to stimulate insulin secretion and to have effects on energy balance, we mated LGsKO mice with germline GLP-1 receptor (GLP-1R) knockout mice (Glp1r(-/-)) and compared LGsKO to double-knockout (LGs/Glp1r(-/-)) mice to determine the contribution of excess GLP-1R signaling to the LGsKO phenotype. Loss of the GLP-1R failed to reverse most of the metabolic features of LGsKO mice, including reduced fat mass, increased glucose tolerance, and second-phase glucose-stimulated insulin secretion, islet cell hyperplasia, and very high glucagon and GLP-1 levels. However, loss of GLP-1R impaired first-phase insulin secretion in mice with or without liver-specific G(s)α deficiency. Thus, excess GLP-1 action (or at least through GLP-1R) does not contribute to the LGsKO metabolic phenotype, and other unknown factors involved in the cross talk between the liver G(s)α/cAMP pathway and pancreatic islet function need to be further elucidated.

Effects of oligofructose on appetite profile, glucagon-like peptide 1 and peptide YY3-36 concentrations and energy intake

In rats, oligofructose has been shown to stimulate satiety hormone secretion, reduce energy intake and promote weight loss. The present study aimed to examine the effect of oligofructose supplementation on appetite profiles, satiety hormone concentrations and energy intake in human subjects. A total of thirty-one healthy subjects (ten men and twenty-one women) aged 28 (SEM 3) years with a BMI of 24·8 (SEM 0·3) kg/m(2) were included in a randomised double-blind, cross-over study. The subjects received 10 g oligofructose, 16 g oligofructose or 16 g placebo (maltodextrin) daily for 13 d, with a 2-week washout period between treatments. Appetite profile, active glucagon-like peptide 1 (GLP-1) and peptide YY3-36 (PYY) concentrations and energy intake were assessed on days 0 and 13 of the treatment period. Time × treatment interaction revealed a trend of reduction in energy intake over days 0-13 by oligofructose (P = 0·068). Energy intake was significantly reduced (11 %) over time on day 13 compared with day 0 with 16 g/d oligofructose (2801 (SEM 301) v. 3217 (SEM 320) kJ, P < 0·05). Moreover, energy intake was significantly lower with 16 g/d oligofructose compared with 10 g/d oligofructose on day 13 (2801 (SEM 301) v. 3177 (SEM 276) kJ, P < 0·05). Area under the curve (AUC) for GLP-1 on day 13 was significantly higher with 16 g/d oligofructose compared with 10 g/d oligofructose (45 (SEM 4) v. 41 (SEM 3) pmol/l × h, P < 0·05). In the morning until lunch, AUC(0-230 min) for PYY on day 13 was significantly higher with 16 g/d oligofructose compared with 10 g/d oligofructose and placebo (409 (SEM 35) v. 222 (SEM 19) and 211 (SEM 20) pg/ml × h, P < 0·01). In conclusion, 16 g/d and not 10 g/d oligofructose may be an effective dose to reduce energy intake, possibly supported by higher GLP-1 and PYY concentrations.

Effects of increasing doses of glucagon-like peptide-1 on insulin-releasing phases during intravenous glucose administration in mice

The increase in insulin secretion caused by glucagon-like peptide-1 (GLP-1) and GLP-1 mimetics observed during an intravenous glucose test (IVGTT) has been reported in both normal and disease animal models, as well as in humans. In this study, a hierarchical population modeling approach is used, together with a previously reported model relating glucose to insulin appearance, to determine quantitative in vivo dose-response relationships between GLP-1 dose level and both first- and second-phase insulin release. Parameters of the insulin kinetic model were estimated from the complete set of glucose and insulin data collected in 219 anesthetized nonfasted NMR-imaged mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03-100 nmol/kg). The resulting dose-response curves indicate a difference in GLP-1 effect on the two release phases, as is also evident from the different ED(50) parameter values (0.107 vs. 6.65 nmol/kg for phase 1 vs. phase 2 insulin release parameters). The first phase of insulin release is gradually augmented with increasing GLP-1 dose, reaching saturation at a dose of ~1 nmol/kg, while the second-phase release changes more abruptly at GLP-1 doses between 3 and 10 nmol/kg and shows a more pronounced 100-fold increase between control and the high GLP-1 dose of 100 nmol/kg Moreover, separate disposition indices calculated for phase 1 and 2 insulin release, show a different pattern of increase with increasing GLP-1 dose.

Antihyperglycaemic medication modifies factors of postprandial satiety in type 2 diabetes

Type 2 diabetes is characterized by hyperglycaemia, delayed gastric emptying and a blunted response of gut hormones during feeding that may modulate satiety. We hypothesized that it is associated with more hunger when treated by medication. We studied nine type 2 diabetic men (A1C: 6.7+/-0.3%, waist circumference: 104+/-4 cm) after an overnight fast, during 5 h in response to a 2.88 MJ breakfast, twice, in a crossover design, with or without antihyperglycaemic agents. Satiety ratings, thermic effect of meal, gastric emptying, plasma concentrations of gut peptides, leptin, insulin and substrates and intake from a subsequent buffet were determined. With medication, fasting and postprandial plasma glucose levels were lower but area under the curve (AUC) did not vary vs. without medication. Gastric emptying was shortened, branched chain amino acids (BCAA) AUC and thermic effect were lower, and postprandial glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY3-36) were maintained at higher levels beyond 4 h. Correlations were significant between duration of diabetes and fasting ghrelin (r=0.779, p=0.013) and peak insulin (r=-0.769, p=0.016), 5-h postmeal ghrelin and peak glucose (r=0.822, p=0.007), 5-h glucose and GLP-1 (r=-0.788, p=0.012), and 5-h hunger scores and energy intake at buffet (r=0.828, p=0.006). Without medication, fullness scores correlated with BCAA levels. Visual analogue scale scores, ghrelin and leptin levels did not differ between studies. The decrease in factors associated with postprandial satiety with treatment is counterbalanced by higher GLP-1 and PYY3-36. Medication may normalize the link between perception of hunger and subsequent food intake.

Overview of the Gliptin Class (Dipeptidyl Peptidase-4 Inhibitors) in Clinical Practice

Dipeptidyl peptidase-4 inhibitors (DPP-4s), also commonly called gliptins, are a relatively new class of drugs for the treatment of type 2 diabetes. These agents work in a unique way to improve insulin secretion from the β-cells of the pancreas in response to an increase in blood sugar and simultaneously decrease glucagon output from the α-cells of the pancreas, which results in decreased hepatic glucose output. Specifically, gliptins decrease the breakdown of glucagon-like peptide-1 (GLP-1) such that the circulating levels reach the high normal physiologic GLP-1 range. This results in more prompt and appropriate secretion of insulin and suppression of glucagon in response to a carbohydrate-containing meal or snack. The change in glucagon correlates linearly with improvement in glucose tolerance. Since these drugs improve insulin secretion in response to an increase in blood glucose, it seems appropriate to pair them with drugs that have a different mechanism of action, such as insulin sensitizers or metformin. In fact, improvements in fasting and postprandial glucose levels, improved β-cell function, and improvement in HbA1c levels have been demonstrated in numerous clinical trials using different gliptins as monotherapy and in combination with various type 2 diabetes medications, including insulin. This article reviews data from a number of clinical trials, presentations, and abstracts indicating the importance of the DPP-4 inhibitors sitagliptin, vildagliptin, and alogliptin both alone and in combination with insulin sensitizers in the treatment of type 2 diabetes.

Improvement of high fat-diet-induced insulin resistance in dipeptidyl peptidase IV-deficient Fischer rats

F344/DuCrj rats are genetically deficient in dipeptidyl peptidase IV (DPPIV). This enzyme degrades glucagon-like peptide-1 (GLP-1), which induces glucose-dependent insulin secretion. Glucose tolerance of F344/DuCrj rats is improved as a result of enhanced insulin release induced by high levels of plasma GLP-1. In this study, we fed F344/DuCrj rats and DPPIV-positive F344/Jcl rats, aged five weeks, on a high-fat (HF) diet to examine the effect of DPPIV deficiency on food intake and insulin resistance. F344/Jcl rats gained significantly more body weight and consumed significantly more food than F344/DuCrj rats from Week 4 on either control or HF diet. Glucose excursion in the oral glucose tolerance test (OGTT) was improved in F344/DuCrj rats fed on the control or HF diet at all times examined, compared with F344/Jcl rats. Homeostasis model assessment (HOMA) insulin resistance values of F344/DuCrj and F344/Jcl rats fed on HF diet were higher than those of animals fed on control diet up to Week 6. However, HOMA insulin resistance values of F344/DuCrj rats fed on HF diet became significantly lower than those of F344/Jcl rats on HF diet during Weeks 8–10. The area under the insulin curve in the OGTT at Week 10 showed that the insulin resistance of HF-diet-fed F344/DuCrj rats was greatly ameliorated. Plasma active GLP-1 concentrations of F344/DuCrj rats in the fed state were significantly higher than those of F344/Jcl rats. These observations suggest that DPPIV deficiency results in improved glucose tolerance and ameliorated insulin resistance owing to enhanced insulin release and inhibition of food intake as a result of high active GLP-1 levels.

Improved Glucose Tolerance via Enhanced Glucose-Dependent Insulin Secretion in Dipeptidyl Peptidase IV-Deficient Fischer Rats

Glucagon-like peptide-1 (GLP-1) is an incretin, which induces glucose-dependent insulin secretion. GLP-1 is rapidly degraded by dipeptidyl peptidase IV (DPPIV) after its release. We investigated whether DPPIV-deficient F344/DuCrj rats show improved glucose tolerance when compared with DPPIV-positive F344/Jcl rats. Oral glucose tolerance test indicated improved glucose tolerance in F344/DuCrj rats, but blood glucose levels of the two strains were almost the same 120 min after the glucose bolus. Valine-pyrrolidide, a DPPIV inhibitor, had no effect on the glucose tolerance of F344/DuCrj rats, but improved that of F344/Jcl rats. Enhanced insulin secretion and high plasma active GLP-1 levels were detected in an intraduodenal glucose tolerance test. Glucose tolerance is improved in DPPIV-deficient F344/DuCrj rats via enhanced insulin release mediated by high active GLP-1 levels. Our results suggest that DPPIV inhibition is a rational strategy to treat diabetic patients by improving glucose tolerance with low risk of hypoglycemia.

Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor.

Truncated forms of glucagon-like peptide-1 are the most potent endogenous stimuli of insulin secretion and have powerful antidiabetogenic effects. To determine the structure and coupling mechanisms of the human GLP-1 receptor we have isolated two pancreatic islet cDNAs, encoding the 463 amino acid receptor and differing mainly in their 3' untranslated regions. The deduced amino acid sequence is 90% homologous with the rat GLP-1 receptor. Northern blot analysis shows expression of a single 2.7 kb transcript in pancreatic tissue. When expressed in COS-7 cells the recombinant receptor conferred specific, high affinity GLP-1(7-37) binding. GLP-1(7-37) increased intracellular cAMP in a concentration dependent manner and caused an increase in the free cytosolic calcium ([Ca2+]i) from an intracellular pool, characteristic of phospholipase C (PLC) activation. Thus, like the structurally related glucagon and parathyroid hormone receptors, the human GLP-1 receptor can activate multiple intracellular signaling pathways including adenylyl cyclase and PLC. Knowledge of the GLP-1 receptor structure will facilitate the development of receptor agonists and elucidation of the important role of GLP-1 in normal physiology and disease states.

Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor

Truncated forms of glucagon-like peptide-1 are the most potent endogenous stimuli of insulin secretion and have powerful antidiabetogenic effects. To determine the structure and coupling mechanisms of the human GLP-1 receptor we have isolated two pancreatic islet cDNAs, encoding the 463 amino acid receptor and differing mainly in their 3' untranslated regions. The deduced amino acid sequence is 90% homologous with the rat GLP-1 receptor. Northern blot analysis shows expression of a single 2.7 kb transcript in pancreatic tissue. When expressed in COS-7 cells the recombinant receptor conferred specific, high affinity GLP-1(7-37) binding. GLP-1(7-37) increased intracellular cAMP in a concentration dependent manner and caused an increase in the free cytosolic calcium ([Ca2+]i) from an intracellular pool, characteristic of phospholipase C (PLC) activation. Thus, like the structurally related glucagon and parathyroid hormone receptors, the human GLP-1 receptor can activate multiple intracellular signaling pathways including adenylyl cyclase and PLC. Knowledge of the GLP-1 receptor structure will facilitate the development of receptor agonists and elucidation of the important role of GLP-1 in normal physiology and disease states.

Postprandial release of glucagon-like peptide-1, pancreatic glucagon, and insulin after esophageal resection.

Postprandial concentrations of glucose and the immunoreactivity of insulin, glucagon-like peptide-1 (GLP-1), and pancreatic glucagon were measured in 10 patients who had undergone esophageal resection (ER) and replacement by the stomach. Emptying of the esophageal substitute was assessed by scintigraphy using a 99Tc-labeled solid test meal. The data were compared with measurements performed in 14 controls, in 7 of whom gastric emptying was measured. The gastric emptying half time was 6.8 +/- 6.2 min (median 144 s) in ER cases, significantly shorter than in controls: 70 +/- 29 min (median 51 min). The early integrated (first 30 min) and total integrated insulin and GLP-1 concentrations were significantly higher than in controls. In 3 of 10 esophagectomy patients the blood glucose concentration fell below 3.8 mmol/l postprandially. High GLP-1 concentrations in the first 30 min were associated with low serum glucose during the 2nd h postprandially when all the hypoglycemic episodes occurred. It is concluded that rapid emptying of the esophageal substitute induces the exaggerated GLP-1 response, which is a main factor for reactive hypoglycemia.