Lower Glucagon-like Peptide-1 Research Articles

Fasting GLP-1 Levels and Albuminuria Are Negatively Associated in Patients with Type 2 Diabetes Mellitus.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known for its pivotal role in enhancing insulin secretion and reducing glucagon release from the pancreas. Diabetic nephropathy, which is characterized by albuminuria, represents a significant microvascular complication of diabetes. Most of the previous studies mainly focused on the therapeutic renal protective effect in clinical trials after the administration of GLP-1 receptor agonists (GLP-1 RAs), rather than before administration. Hence, this study aimed to investigate the association between fasting plasma GLP-1 levels and albuminuria before GLP-1 RA administration. A cross-sectional study was designed to evaluate the association between fasting plasma GLP-1 levels and albuminuria in patients with type 2 diabetes mellitus (T2DM). A cohort of 68 participants with T2DM was analyzed using data collected at Wonkwang University Hospital in Iksan, Korea. Logistic regression analysis was employed to determine the odds ratio (OR) and 95% confidence interval (CI) of the incidence of albuminuria between two groups categorized by fasting GLP-1 levels, low (Group L) and high GLP-1 (Group H). The OR (95% CI) for the incidence of albuminuria comparing Group L with Group H of fasting plasma GLP-1 levels was 3.41 (1.16-10.02), p = 0.03 after adjustment for relevant variables including age, gender, fasting plasma glucose, HbA1c, C-peptide, creatinine, and medication use [angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors]. When analyzed as a continuous variable, each 1 pmol/L reduction in fasting plasma GLP-1 levels was associated with an OR (95% CI) of 1.67 (1.17-1.87), p = 0.02, following full adjustment. These results highlight a negative association between fasting plasma GLP-1 levels and the incidence of albuminuria in Korean patients with T2DM, before GLP-1 RA administration. These findings suggest that endogenous GLP-1 may have a beneficial impact in mitigating albuminuria.

Differences in the levels of the appetite peptides ghrelin, peptide tyrosine tyrosine, and glucagon-like peptide-1 between obesity classes and lean controls.

This study was designed to compare basal concentrations of the gastrointestinal appetite modulators ghrelin, peptide tyrosine tyrosine (PYY), and glucagon-like peptide 1 (GLP-1) between obesity classes and obesity classes and controls. The study included 49 healthy controls with body mass index (BMI) between 18.5 and 29.9 kg/m² and 62 individuals with obesity with BMI ≥30 kg/m². Basal ghrelin, PYY, and GLP-1 concentrations of the samples were analyzed by an enzyme-linked immunosorbent assay commercial kit (SunRed Human). Other biochemical parameters were measured by a clinical chemistry autoanalyzer (Beckman Coulter AU 5800) in the biochemistry laboratory. Compared with the control group, ghrelin, PYY, and GLP-1 levels were significantly lower in the obese group (P < .05). The PYY concentration was significantly different between obese groups (P < .05). The PYY and GLP-1 levels were significantly different between obesity class I and obesity class III. In addition, ghrelin levels were significantly different between obesity class II and obesity class III. Correlation analysis revealed a negative correlation between BMI and serum ghrelin, GLP-1, and PYY concentrations. Low basal ghrelin, GLP-1, and PYY hormones in the obese group compared with the control group indicate impaired appetite regulation in this population. The significant difference in PYY levels between obese groups was associated with increasing obesity grade.

Insulin Sensitivity, Islet Cell Function, and Incretin Axis in Pregnant Women With and Without Gestational Diabetes Mellitus.

The aim of this study was to compare insulin sensitivity, islet cell function, and incretin axes in pregnant subjects with GDM and normal healthy controls. Pregnant women at 24 to 28 weeks of gestation were subjected to a 75 g oral glucose tolerance test (OGTT). Samples for glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were collected at 0, 30, 60, and 120 min during the OGTT. The Matsuda index (MI) and insulin secretion and sensitivity index-2 (ISSI-2) were assessed. The glucagon suppression index (GSI) was calculated along with the area under the curve (AUC) for glucose, insulin, glucagon, GLP-1, and GIP. A total of 48 pregnant women (25 GDM and 23 controls) were finally analysed. The MI and ISSI-2 were low in the GDM group [4.31 vs. 5.42; P = 0.04], [1.99 vs. 3.18, P ≤ 0.01] respectively). Total AUCglucagon was higher in the GDM group (7411.7 vs. 6320.1, P = 0.02). GSI30 was significantly lower in the GDM group (-62.6 vs. -24.7, P = 0.03). Fasting GLP-1 levels were low in GDM women (17.3 vs. 22.2, P = 0.04). The total AUCGLP-1 positively correlated with total GSI in the GDM group. Asian-Indian GDM women have high insulin insensitivity, islet cell dysfunction, and low fasting GLP-1. Incretin axis dysfunction plays a potential role in their islet cell dysfunction.

A New Hope for Treating Obesity Pandemic

A new class of drugs is transforming obesity treatment in an unprecedented manner. Scientists are amazed by their potency in the treatment of obesity. Glucagon-like peptide 1 (GLP-1) analogs are a class of medications used to treat type 2 diabetes mellitus. These analogs mimic the action of GLP-1, a hormone released by the intestine in response to food intake. GLP-1 analogs have been extensively studied, and scientists have made several important discoveries about their effects and potential therapeutic applications. GLP-1 analogs have shown significant efficacy in improving glycemic control in patients with type 2 diabetes. They stimulate insulin secretion from pancreatic beta cells, suppress glucagon secretion (which reduces hepatic glucose production), and slow down gastric emptying, leading to reduced postprandial glucose levels. Apart from their controlling glycemic index, GLP-1 analogs are shown to offer cardio-protective, reno-protective, and neuroprotective benefits. However, their most surprising and potent effects have been observed in the context of weight loss. Two drugs from this class, semaglutide, and tripeptide, have shown efficacy in recent clinical trials. Tirzepatide was effective in significantly reducing body weight in about half of the participants in a recent clinical trial. In another trial, semaglutide was able to reduce 20% of the body weight of about one-third of the participants. However, not everyone is benefiting from these medications. There are still significant challenges in determining who will benefit from these medications and to what extent. These challenges are currently being addressed. It has been observed that the new drugs work best in people who become hungry in between meals. People with obesity can be classified into four categories; those who need to eat more to reach fullness; those who reach fullness with a regular-sized meal but feel hungry again soon (hungry gut); those who eat to cope with emotions; and those with a relatively slow metabolism. It is not known why people with a ‘hungry gut’ respond most effectively to the new drugs, but one hypothesis suggests that these patients have low levels of GLP-1 hormones, and that’s why they have obesity. When they get a replacement in the form of GLP-1 analogs, they do extremely well. Another study with a GLP-1-mimicking drug called liraglutide found that patients with low GLP-1 levels reduced twice as much weight compared to the general population after using the drug for one year. Both semaglutide and tripeptide are given once weekly, thus increasing treatment compliance. Because of their weekly regimen, the drugs will also help people with erratic schedules and work shifts. Some of the other medications have to be taken at a certain time of day, which can be difficult for those with irregular sleep schedules. Another important question is to find out how long these drugs' weight loss benefits remain. One study concluded that semaglutide’s weight-reducing effects last as long as the patients remain on medication. This means that these drugs will be given chronically to obese patients. Whether ‘chronic’ means ‘life-long’ in this context is still to be determined. Perhaps an even more important question that clinicians face is determining how much weight loss is too much, especially when muscle loss is also involved. More research is needed to find a balance where these drugs are used not only for weight reduction but to treat a person for health, prevent disease, and improve quality of life.

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

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

Role of glucagon-like peptide 1 (GLP-1) and its association with inflammatory markers in the pathogenesis of type 2 diabetes mellitus

Background: Diabetes mellitus is a multifactorial disease associated with hyperglycemia and increased risk of progression of vascular complications. Stimulation of insulin secretion by the incretin hormone glucagon-like peptide 1 (GLP-1) has been found to be diminished in hyperglycemia. We hypothesized that this impairment is due to defect at the receptor level induced by the diabetic state. Inflammatory markers like TNF-α and IL-6 plays a potential role in the pathogenesis of T2DM. Therefore, the present study aims to evaluate whether GLP-1 plays a role in the development of T2DM by modulating the balance between pro and anti-inflammatory markers. Material and methods: A total of 60 subjects were recruited in this study among them 30 were T2DM cases and 30 were healthy controls. m-RNA expression and protein level of GLP-1 receptor, TNF-α and IL-6 in peripheral blood lymphocytes were determined by real time PCR and ELISA respectively. Results: We observed plasma level of GLP-1 was significantly lower in diabetic subjects while serum level of IL-6 and TNF-α were significantly higher level in diabetic subjects (p &lt; 0.05). We found significant down regulation of GLP-1 receptor m-RNA expression in diabetic subjects while expression level of IL-6 and TNF-α were 5.8 and 4 folds respectively higher in diabetic subjects. We found significant negative correlation of m-RNA expression of GLP-1 with protein level while IL-6 and TNF-α showed significant positive correlation. Conclusion: Inflammation plays an important role in the pathogenesis of diabetes mellitus and low GLP-1 levels may promote expression of inflammatory markers due to lack of anti-inflammatory effects of GLP-1

Endogenous GLP-1 levels play an important role in determining the efficacy of DPP-IV Inhibitors in both prediabetes and type 2 diabetes.

BackgroundIn contrast to Western population, glucagon-like peptide-1 (GLP-1) levels are preserved in some East Asian population with type 2 diabetes (T2D), explaining why dipeptidyl peptidase-IV (DPP-IV) inhibitors are more effective in East Asians. We assessed whether differences in endogenous GLP-1 levels resulted in different treatment responses to DPP-IV inhibitors in prediabetes and T2D.MethodsA prospective 12-week study using linagliptin 5mg once daily in 50 subjects (28 prediabetes and 22 T2D) who were stratified into high versus low fasting GLP-1 groups. A 75-g oral glucose tolerance test (OGTT) was performed at week 0 and 12. Primary outcomes were changes in HbA1c, fasting and post-OGTT glucose after 12 weeks. Secondary outcomes included changes in insulin resistance and beta cell function indices.ResultsThere was a greater HbA1c reduction in subjects with high GLP-1 compared to low GLP-1 levels in both the prediabetes and T2D populations [least-squares mean (LS-mean) change of -0.33% vs. -0.11% and -1.48% vs. -0.90% respectively)]. Linagliptin significantly reduced glucose excursion by 18% in high GLP-1 compared with 8% in low GLP-1 prediabetes groups. The reduction in glucose excursion was greater in high GLP-1 compared to low GLP-1 T2D by 30% and 21% respectively. There were significant LS-mean between-group differences in fasting glucose (-0.95 mmol/L), 2-hour glucose post-OGTT (-2.4 mmol/L) in the high GLP-1 T2D group. Improvement in insulin resistance indices were seen in the high GLP-1 T2D group while high GLP-1 prediabetes group demonstrated improvement in beta cell function indices. No incidence of hypoglycemia was reported.ConclusionsLinagliptin resulted in a greater HbA1c reduction in the high GLP-1 prediabetes and T2D compared to low GLP-1 groups. Endogenous GLP-1 level play an important role in determining the efficacy of DPP-IV inhibitors irrespective of the abnormal glucose tolerance states.

341-OR: Enhanced Responsiveness of ß- and α-Cells to Glucagon-Like Peptide-1 (GLP-1) in Youth vs. Adults with Impaired Glucose Tolerance (IGT) or Drug-Naïve Type 2 Diabetes (T2D)

In the Restoring Insulin Secretion (RISE) Study, youth (Y) compared to adults (A) had enhanced β-cell (greater incremental C-peptide [CP] responses) and α-cell responsiveness (greater glucagon [GG] suppression) . As GLP-1 increases CP and decreases GG, we measured GLP-1 (Mercodia) during a 3-h oral glucose tolerance test (OGTT) in 65 Y (age: 14.2 y) and 65 A (51.0 y) to determine if greater GLP-1 release explained age-related differences in CP and GG responses. Groups were matched for sex (71% female) , race/ethnicity (29% white, 22% black, 37% Hispanic) and IGT/drug naïve T2D (80/20%) status and did not differ by BMI (36.7±6.0 vs. 35.3±4.1 kg/m2) . We calculated fasting, early (0-to-30 mins; ∆) and incremental area under the curve (iAUC) responses for G, CP and GLP-1, and decrements in GG (d∆; dAUC) . Y and A did not differ in fasting or OGTT glycemic responses, but Y had greater fasting CP, ∆CP and iAUC CP, more d∆GG suppression, and a trend for more diGG suppression, than A (Table) . Fasting GLP-1 was not different in Y vs. A, but stimulated GLP-1 was lower in Y throughout the OGTT. In conclusion, in Y higher CP and lower GG during an OGTT, paired with lower GLP-1 concentrations, suggest that the enhanced β- and α-cell responsiveness to GLP-1 could be due to increased sensitivity of the islet cells to the incretin, rather than a primary increase in GLP-1 release. Disclosure K.J.Nadeau: None. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck &amp; Co., Inc., Novo Nordisk, Pfizer Inc. T.Consortium: None. A.H.Tjaden: None. D.A.Ehrmann: None. S.A.Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk. S.Caprio: None. S.Edelstein: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. K.A.Temple: None. A.Xiang: None. Funding American Diabetes Association (1-20-RISE-01) ; NIDDK, Department of Veterans Affairs, and Kaiser Permanente Southern California

The metabolite GLP-1 (9-36) is neuroprotective and anti-inflammatory in cellular models of neurodegeneration.

Glucagon-like peptide-1 (GLP-1) is best known for its insulinotropic action following food intake. Its metabolite, GLP-1 (9-36), was assumed biologically inactive because of low GLP-1 receptor (GLP-1R) affinity and non-insulinotropic properties; however, recent studies contradict this assumption. Increased use of FDA approved GLP-1 analogues for treating metabolic disorders and neurodegenerative diseases raises interest in GLP-1 (9-36)'s biological role. We use human SH-SY5Y neuroblastoma cells and a GLP-1R over-expressing variety (#9), in both undifferentiated and differentiated states, to evaluate the neurotrophic/neuroprotective effects of GLP-1 (9-36) against toxic glutamate exposure and other oxidative stress models (via the MTS, LDH or ROS assays). In addition, we examine GLP-1 (9-36)'s signaling pathways, including cyclic-adenosine monophosphate (cAMP), protein kinase-A (PKA), and 5' adenosine monophosphate-activated protein kinase (AMPK) via the use of ELISA, pharmacological inhibitors, or GLP-1R antagonist. Human HMC3 and mouse IMG microglial cell lines were used to study the anti-inflammatory effects of GLP-1 (9-36) against lipopolysaccharide (LPS) (via ELISA). Finally, we applied GLP-1 (9-36) to primary dissociation cultures challenged with α-synuclein or amyloid-β and assessed survival and morphology via immunochemistry. We demonstrate evidence of GLP-1R, cAMP, PKA, and AMPK-mediated neurotrophic and neuroprotective effects of GLP-1 (9-36). The metabolite significantly reduced IL-6 and TNF-α levels in HMC3 and IMG microglial cells, respectively. Lastly, we show mild but significant effects of GLP-1 (9-36) in primary neuron cultures challenged with α-synuclein or amyloid-β. These studies enhance understanding of GLP-1 (9-36)'s effects on the nervous system and its potential as a primary or complementary treatment in pathological contexts.

516 UROCORTIN 3 EXPRESSION IN HUMAN ENTEROENDOCRINE CELLS AND CORRELATION WITH PLASMA GLP1 LEVELS IN HUMAN OBESITY

Introduction Enteroendocrine cells (EECs) are hormone secretory cells sparsely distributed throughout the GI tract, and implicated in obesity. Intestinal L-type EECs secrete Glucagon-Like peptide 1(GLP-1) in response to a meal to promote satiety and maintain glucose homeostasis. Abnormal post prandial satiety (APS) is a phenotypic subset of obesity characterized by blunted post-prandial levels of GLP-1. Intestinal D-type EECs release somatostatin (SST) to inhibit GLP-1 release from L cells via the STT-receptor. In the pancreas, somatostatin release from delta cell is stimulated by pancreatic urocortin-3 from the beta cells. It is unknown whether urocortin-3 is expressed in intestinal EEC cells. Thus, we aimed to study the role of UCN3 in intestinal L, and D- type EECs, and its association with GLP-1 secretion in human obesity. Methods We studied a total of 34 participants, 17 healthy controls (age 38±13y, BMI 23±2kg/m2, 59% female), and 17 with obesity (age 39±9y, BMI 37±5kg/m2, 65% female). Obesity was sub-grouped into: Abnormal postprandial satiety (APS, low postprandial GLP-1, n=6) and normal post prandial satiety (NPS, normal postprandial GLP-1, n=11). Human colonic biopsies from participants were obtained by sigmoidoscopy and preserved for scRNA-seq (CryoStorCS10), gene expression (RNAlater), or microscopy studies (10%NBF). Single-cell transcriptomics was completed using the Chromium 10X Genomics platform followed by Illumina HiSeq4000 sequencing. Blood was collected from participants at fasting, and postprandial at 15, 45, and 90 minutes. Immunofluorescence (IF) confocal microscopy was used to detect protein expression of UCN3 in L-type EECs in the gut mucosa. UCN3 mRNA expression was determined by RT-qPCR. Blood GLP-1 levels were determined by ELISA. Results Our transcriptomic investigation of EECs in human obesity revealed expression of UCN3 in Chromogranin A-positive EECs, and GLP-1 positive L-type EECs, previously not known to be expressed in EECs (Fig1A). Protein expression of UCN3 in GLP-1 positive EEC was confirmed using immunofluorescence in human ileum and colon (Fig 1B). Colonic UCN3 mRNA expression was positively associated with BMI (r=0.43, p Conclusions These findings suggest that intestinal UCN3 is overexpressed in obesity, and further overexpressed in APS obesity phenotype. This study introduces a new pathophysiological underpinning of obesity where negative feedback mechanisms of SST-mediated GLP-1 inhibition are exaggerated, and may potentially promote blunted postprandial GLP-1 levels and decreased satiety in obesity. Download : Download high-res image (100KB) Download : Download full-size image Figure 1 . Expression of Urocortin 3 (UCN3) in human enteroendocrine cells (EECs). (A) Ratio of cell population clusters of the human colonic mucosa in either all EECs or just GCG-expressing L-Type EECs, expressing UCN3 of 10 patients (n=4 lean, n=6 obesityall). (B) Double immunoflurescent staining of the human intestinal mucosa demonstrating expression of UCN3 (Red) in a subset of GLP-1 (Green) L-type EECs. Red bar indicates 20µm. Download : Download high-res image (95KB) Download : Download full-size image Figure 2 . Urocortin 3 (UCN3) Associations with BMI and GLP-1 Release. (A) Association of colonic UCN3 mRNA expression (A) to BMI (kg/m2). Relative Human colonic mucosal mRNA expression of UCN3 comparing (B) lean and all-obesity; and (C) lean and obesity with and without APS. Association of intestinal UCN3 expression with (D) plasma concentrations of GLP-1 measured 45 and (C) resulting association of GLP-1 area under the curve (AUC). Significance testing used a linear regression for A,D, E, and a two-tailed student t-test compared between all groupings; # p

Exogenous GLP-1 stimulates TCA cycle and suppresses gluconeogenesis and ketogenesis in late-fasted northern elephant seals pups

The post-weaning fast of northern elephant seal pups is characterized by a lipid-dependent metabolism and associated with a decrease in plasma glucagon-like peptide-1 (GLP-1), insulin, and glucose and increased gluconeogenesis (GNG) and ketogenesis. We have also demonstrated that exogenous GLP-1 infusion increased plasma insulin despite simultaneous increases in cortisol and glucagon, which collectively present contradictory regulatory stimuli of GNG, ketogenesis, and glycolysis. To assess the effects of GLP-1 on metabolism using primary carbon metabolite profiles in late-fasted seal pups, we dose-dependently infused late-fasted seals with low (LDG; 10 pM/kg; n=3) or high (HDG; 100 pM/kg; n=4) GLP-1 immediately following a glucose bolus (0.5g/kg), using glucose without GLP-1 as control (n=5). Infusions were performed in similarly aged animals 6-8 weeks into their post-weaning fast. The plasma metabolome was measured from samples collected at 5 time points just prior to and during the infusions, and network maps constructed to robustly evaluate the effects of GLP-1 on primary carbon metabolism. HDG increased key tricarboxylic acid (TCA) cycle metabolites, and decreased phosphoenolpyruvate and acetoacetate (P<0.05) suggesting that elevated levels of GLP-1 promote glycolysis and suppress GNG and ketogenesis, which collectively increase glucose clearance. These GLP-1-mediated effects on cellular metabolism help to explain why plasma GLP-1 concentrations decrease naturally in fasting pups as an evolved mechanism to help conserve glucose during the late-fasting period.

Incretin dysfunction and hyperglycemia in cystic fibrosis: Role of acyl-ghrelin

BackgroundInsulin secretion is insufficient in cystic fibrosis (CF), even before diabetes is present, though the mechanisms involved remain unclear. Acyl-ghrelin (AG) can diminish insulin secretion and is elevated in humans with CF. MethodsWe tested the hypothesis that elevated AG contributes to reduced insulin secretion and hyperglycemia in CF ferrets. ResultsFasting AG was elevated in CF versus non-CF ferrets. Similar to its effects in other species, AG administration in non-CF ferrets acutely reduced insulin, increased growth hormone, and induced hyperglycemia. During oral glucose tolerance testing, non-CF ferrets had responsive insulin, glucagon like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels and maintained normal glucose levels, whereas CF ferrets had insufficient responses and became hyperglycemic. Interestingly in wild-type ferrets, the acyl-ghrelin receptor antagonist [D-Lys3]-GHRP-6 impaired glucose tolerance, and abolished insulin, GLP-1, and GIP responses during glucose tolerance testing. By contrast, in CF ferrets [D-Lys3]-GHRP-6 improved glucose tolerance, enhanced the insulin-to-glucose ratio, but did not impact the already low GLP-1 and GIP levels. ConclusionsThese results suggest a mechanism by which elevated AG contributes to CF hyperglycemia through inhibition of insulin secretion, an effect magnified by low GLP-1 and GIP. Interventions that lower ghrelin, ghrelin action, and/or raise GLP-1 or GIP might improve glycemia in CF.

Glucagon-Like Peptide-1 Is a Marker of Systemic Inflammation in Patients Treated with High-Dose Chemotherapy and Autologous Stem Cell Transplantation.

Autologous stem cell transplantation (ASCT) is challenged by side effects that may be propagated by chemotherapy-induced mucositis, resulting in bacterial translocation and systemic inflammation. Because gastrointestinal damage appears as an early event in this cascade of reactions, we hypothesized that markers reflecting damage to the intestinal barrier could serve as early predictive markers of toxicity. Glucagon-like peptide-1 (GLP-1), a well-known regulator of blood glucose, has been found to promote intestinal growth and repair in animal studies. We investigated fasting GLP-1 plasma levels in 66 adults undergoing ASCT for lymphoma and multiple myeloma. GLP-1 increased significantly after chemotherapy, reaching peak levels at day +7 post-transplant (median, 8 pmol/L [interquartile range, 4 to 12] before conditioning versus 10 pmol/L [interquartile range, 6 to 17] at day +7; P = .007). The magnitude of the GLP-1 increase was related to the intensity of conditioning. GLP-1 at the day of transplantation (day 0) was positively associated with peak C-reactive protein (CRP) levels (46 mg/L per GLP-1 doubling, P < .001) and increase in days with fever (32% per GLP-1 doubling, P = .0058). Patients with GLP-1 above the median at day 0 had higher CRP levels from days +3 to +10 post-transplant than patients with lower GLP-1 (P ≤ .041) with peak values of 238 versus 129 mg/L, respectively. This study, which represents the first clinical investigation of fasting GLP-1 in relation to high-dose chemotherapy, provides evidence that GLP-1 plays a role in regulation of mucosal defenses. Fasting GLP-1 levels may serve as an early predictor of systemic inflammation and fever in patients receiving high-dose chemotherapy.

Correlation between the level of glucagon like peptide-1 and the extent of coronary lesions in patients with coronary heart disease at different glucose tolerance state

Objective To explore the correlation between the level of glucagon like peptide-1(GLP-1)and the extent of coronary lesions in coronary heart disease(CHD). Methods One hundred and ninety-two CHD patients included in the study were divided into simple CHD group(n=60), CHD accompanied with impaired glucose tolerance(IGT)group(n=67), and CHD accompanied with type 2 diabetes mellitus(T2DM)group(n=65). 48 subjects were used as controls. The levels of GLP-1 in all the patients were analyzed by ELISA. Oral glucose tolerance test (OGTT) was performed. Blood glucose, insulin, and C-peptide levels were measured. The area under curves of insulin(AUCINS), C-peptide (AUCC-P), glucose (AUCGlu), and GLP-1 (AUCGLP-1) were calculated. All the patients underwent coronary angiography and the extent of coronary lesions was analyzed by total amount of coronary narrow degree integral. The association of GLP-1 level with coronary narrow degree was analyzed by correlation analysis and multivariate linear stepwise regression analysis. Results The levels of blood glucose and AUCGlu during OGTT in CHD accompanied with T2DM group were significantly higher than those in CHD with IGT group (P<0.01), while the levels of insulin and C-peptide, AUCINS, and AUCC-P were decreased (P<0.05). The levels of blood glucose, insulin, C-peptide, AUCGlu, AUCINS, and AUCC-P in CHD accompanied with IGT group were significantly higher than those in control group and simple CHD group (P<0.01). Compared with simple CHD group and CHD accompanied with IGT group, GLP-1 level in CHD accompanied with T2DM group was markedly decreased(P<0.01) while coronary artery narrow degree was raised(P<0.05). Compared with simple CHD group, CHD accompanied with IGT group showed lower GLP-1 level and higher coronary artery narrow degree(P<0.01). Correlation analysis revealed that GLP-1 level was negatively correlated with the coronary artery narrow degree in CHD patients(P<0.01). Multivariate linear regression analysis showed that systolic blood pressure, high density lipoprotein-cholesterol, fasting C-peptide and GLP-1 had a predictive effect on the coronary narrow degree integral in CHD patients. Conclusion The level of GLP-1 is closely correlated with the coronary artery narrow degree in CHD patients, especially in patients accompanied by hyperglycemia. Key words: Coronary heart disease; Glucagon like peptide-1; Coronary narrow degree integral

Reduced GLP-1 Secretion at 30 Minutes After a 75-g Oral Glucose Load Is Observed in Gestational Diabetes Mellitus: A Prospective Cohort Study.

Glucagon-like peptide 1 (GLP-1) levels may be reduced in type 2 diabetes, but whether a similar impairment exists in gestational diabetes mellitus (GDM) has not been established. We studied this in a prospective cohort study of pregnant women (n = 144) during oral glucose tolerance test (OGTT). GLP-1, glucose, and insulin were sampled at 30-min intervals during a 2-h 75-g OGTT, and indices of insulin secretion and sensitivity were calculated. In a nested case-control study, women with GDM (n = 19) had 12% lower total GLP-1 secretion area under the curve (AUC) compared with control subjects matched for age, ethnicity, and gestational age (n = 19), selected from within the lowest quartile of glucose120 min values in our cohort. GDM had lower GLP-1 response in the first 30 min (19% lower GLP-130 min and 17% lower AUC0-30 min) after adjustment for possible confounders. Their glucose levels began to diverge at 30 min of the OGTT with increasing insulin levels, and by 120 min, their insulin levels were three times higher. In a secondary cohort of 57 women that included "high-normal" glucose120 min values, low GLP-1 AUC0-30 min was independently associated with lower indices of insulin secretion and sensitivity. In conclusion, we have observed that women with GDM have lower GLP-1 response at 30 min of an OGTT and hyperglycemia at 120 min despite significant hyperinsulinemia.

Low glucagon-like peptide-1 (GLP-1) concentration in serum is indicative of mild cognitive impairment in type 2 diabetes patients

ObjectivesTo reveal potential association between glucagon-like peptide 1 (GLP-1) concentration in serum and mild cognitive function impairment (MCI) in type 2 diabetes mellitus (T2DM) patients. Patients and MethodsA total of 106 T2DM patients and 47 normal controls were recruited in this study. Montreal Cognitive Assessment (MoCA) was performed in all subjects. Among the 106 patients, 52 presented with MCI. Fasting blood glucose (FBG), total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C), triglyceride (TG), uric acid (UA) and GLP-1 levels were also assessed in all subjects. ResultsPatients with MCI had higher serum concentrations of FBG and TC and lower concentrations of GLP-1 and HDL-C than controls. Bivariate correlation analysis showed that MCI in T2DM patients closely correlated with FBG, HDL-C, and GLP-1 levels. Moreover, ordinal regression analysis showed that GLP-1 concentration in serum was protective for MCI in T2DM patients (OR = 0.025; 95%CI: 0.005–3.934). ConclusionsOur results indicated that low concentration of GLP-1 may play a role in the pathogenesis of MCI in T2DM patients.

High DPP-4 Concentrations in Adolescents Are Associated With Low Intact GLP-1.

Dipeptidyl peptidase 4 (DPP-4) metabolizes glucagon-like peptide-1 (GLP-1), and increased DPP4 levels are associated with obesity and visceral adiposity in adults. Investigating DPP-4 levels in adolescents and their association with (1) circulating intact GLP-1 levels and glucose tolerance; (2) body mass index (BMI); and (3) visceral, subcutaneous, and liver fat compartments. Cross-sectional study, July 2012 to April 2015. Pediatric obesity clinic, Uppsala University Hospital. Children and adolescents with obesity (n = 59) and lean controls (n = 21) aged 8 to 18 years. BMI SD score, fasting plasma concentrations of DPP-4, total and intact GLP-1, fasting and oral glucose tolerance test (OGTT) concentrations of glucose, and visceral adipose tissue (VAT) and subcutaneous adipose tissue volumes and liver fat fraction. Plasma DPP-4 levels decreased with age in both obese (41 ng/mL per year) and lean subjects (48 ng/mL per year). Plasma DPP-4 levels were higher in males in both the obesity and lean groups. With adjustments for age and sex, plasma DPP-4 level was negatively associated with intact GLP-1 at fasting (β = -12.3; 95% CI: -22.9, -1.8) and during OGTT (β = -12.1; 95% CI: -22.5, -1.7). No associations were found between DPP-4 and plasma glucose levels measured at fasting or after a 2-hour OGTT. Plasma DPP-4 level was 19% higher in obese subjects. Among adipose tissue compartments, the strongest association was with VAT (β = 0.05; 95% CI: -0.02, 0.12). In adolescents, high plasma DPP-4 concentrations were associated with low proportions of intact GLP-1, high BMI, young age, and male sex. The observed associations are compatible with increased metabolism of GLP-1 in childhood obesity.

Strong Association between Plasma Dipeptidyl Peptidase-4 Activity and Impaired Cognitive Function in Elderly Population with Normal Glucose Tolerance.

Objective: Inflammation, oxidative stress, and decreased glucagon-like peptide-1 (GLP-1) are risk factors for cognitive impairment. Dipeptidyl peptidase-4 (DPP4) was identified as a novel adipokine capable of enhancing these risk factors. Hence, we investigated the relationship between plasma DPP4 activity and impaired cognitive function in elderly Chinese population with normal glucose tolerance (NGT).Methods: We performed a cross-sectional study using data from 1229 elderly participants (60 years or older) in Guilin. Plasma DPP4 activity, oxidative stress parameters, fasting active GLP-1, and inflammatory markers were measured in all participants. Impaired cognitive function was diagnosed according to the National Institute on Aging-Alzheimer’s Association workgroups criteria.Results: Participants in the upper quartile of plasma DPP4 activity had higher C-reactive protein (CRP), interleukin-6 (IL-6), 8-iso-PGF2a, nitrotyrosine, and lower GLP-1 and Montreal Cognitive Assessment (MoCA) scores compared with those in the lowest quartile (P < 0.001). The odds ratios (ORs) for increased CRP, IL-6, 8-iso-PGF2a, nitrotyrosine, and decreased active GLP-1 were higher with increasing DPP4 quartiles after adjustment for confounders (all P < 0.001). In the highest DPP4 quartile, impaired cognitive function risk was higher (OR, 2.26; 95% confidence interval, 1.36–3.76) than in the lowest quartile after adjustment for potential confounders. The risk for impaired cognitive function increased more with higher levels of DPP4 activity, nitrotyrosine and 8-iso-PGF2a (P < 0.05), but not with higher IL-6, CRP or lower GLP-1.Conclusion: Plasma DPP4 activity is significantly and independently associated with impaired cognitive function, mainly executive, in elderly Chinese population with NGT. The underlying mechanisms for this association may be partly attributed to the effect of DPP4 on oxidative stress. Plasma DPP4 activity might serve as a risk biomarker or therapeutic target for the prevention and treatment of impaired cognitive function.

Anti-obesogenic effects of calcium prevent changes in the GLP-1 profile in adult rats primed by early weaning.

Gut peptides regulate appetite and adipogenesis. Early weaning (EW) leads to later development of obesity that can be prevented by calcium supplementation. We evaluated gut peptides that may have a role in the establishment of this dysfunction. At birth, lactating Wistar rats were separated in: EW, lactating rats involved with a bandage interrupting the lactation during the last 4 days of standard lactation, and C (control) dams whose pups had free access to milk during throughout lactation. At 120 days old, half of EW group received calcium supplementation (EWCa); EW and C received standard diet. At 21 days old, EW presented higher glucagon-like peptide 1 (GLP-1) in plasma and glucagon-like peptide 1 receptor (GLP1-R) in adipose tissue and hypothalamus, but lower GLP-1 and GLP1-R in the gut. At 180 days old, GLP-1 response to food intake was blunted in EW and restored by calcium. GLP-1 in the gut was lower in EW and its receptor was lower in adipose tissue, and GLP1-R was higher in the gut of calcium EW group. Thus, EW had short- and long-term effects upon GLP-1 profile, which may have contributed to obesity development, hyperphagia, and insulin resistance due to its adipogenic and appetite control roles. Calcium supplementation was able to prevent most of the changes in GLP-1 caused by EW.

Association of low GLP-1 with oxidative stress is related to cardiac disease and outcome in patients with type 2 diabetes mellitus: A pilot study

Oxidative stress (OS) contributes to cardiovascular damage in type 2 diabetes mellitus (T2DM). The peptide glucagon-like peptide-1 (GLP-1) inhibits OS and exerts cardiovascular protective actions. Our aim was to investigate whether cardiac remodeling (CR) and cardiovascular events (CVE) are associated with circulating GLP-1 and biomarkers of OS in T2DM patients. We also studied GLP-1 antioxidant effects in a model of cardiomyocyte lipotoxicity. We examined 72 T2DM patients with no coronary or valve heart disease and 14 nondiabetic subjects. A median of 6 years follow-up information was obtained in 60 patients. Circulating GLP-1, dipeptidyl peptidase-4 activity, and biomarkers of OS were quantified. In T2DM patients, circulating GLP-1 decreased and OS biomarkers increased, compared with nondiabetics. Plasma GLP-1 was inversely correlated with serum 3-nitrotyrosine in T2DM patients. Patients showing high circulating 3-nitrotyrosine and low GLP-1 levels exhibited CR and higher risk for CVE, compared to the remaining patients. In palmitate-stimulated HL-1 cardiomyocytes, GLP-1 reduced cytosolic and mitochondrial oxidative stress, increased mitochondrial ATP synthase expression, partially restored mitochondrial membrane permeability and cytochrome c oxidase activity, blunted leakage of creatine to the extracellular medium, and inhibited oxidative damage in total and mitochondrial DNA. These results suggest that T2DM patients with reduced circulating GLP-1 and exacerbated OS may exhibit CR and be at higher risk for CVE. In addition, GLP-1 exerts antioxidant effects in HL-1 palmitate-overloaded cardiomyocytes. It is proposed that therapies aimed to increase GLP-1 may counteract OS, protect from CR, and prevent CVE in patients with T2DM.