Protein- A nd Calcium-Mediated GLP-1 Secretion:A Narrative Review

Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced in the intestine which is secreted in response to nutrient exposure. GLP-1 potentiates glucose-dependent insulin secretion from the pancreatic beta cells and promotes satiety. These important actions on glucose metabolism and appetite have led to widespread interest in GLP-1 receptor agonism. Typically, this involves pharmacological GLP-1 mimetics or targeted inhibition of dipeptidyl peptidase 4 (DPP4), the enzyme responsible for GLP-1 degradation. However, nutritional strategies provide a widely available, cost-effective alternative to pharmacological strategies for enhancing hormone release. Recent advances in nutritional research have implicated the combined ingestion of protein and calcium with enhanced endogenous GLP-1 release, which is likely due to activation of receptors with high affinity and/or sensitivity for amino acids and calcium. Specifically targeting these receptors may enhance gut hormone secretion, thus providing a new therapeutic option. This narrative review provides an overview of the latest research on protein and calcium mediated GLP-1 release with an emphasis on human data, and a perspective on potential mechanisms that link potent GLP-1 release to the co-ingestion of protein and calcium. In light of these recent findings, potential future research directions are also presented

The effect of exercise in a fasted-state on plasma LDL cholesterol concentrations in males and females

Cardiovascular disease (CVD) is the leading cause of death worldwide. Physical activity interventions improve almost all modifiable CVD risk factors, however the effect of physical activity on low density lipoprotein cholesterol (LDL-C) is uncertain. This may be due to lack of research on the feeding status in which the physical activity is performed. The aim of this study is to investigate the effect of fasted versus fed exercise on LDL-C concentrations in males and females. One hundred healthy participants, equal males and females, aged between 25 and 60 years will be recruited and will undergo a home based 12-week exercise intervention. After baseline testing, participants will be randomised to a fasted exercise (exercise after an 8-h fast) or fed exercise (exercise 90-180 min after ingestion of 1 gkg-1 CHO) group and will perform 50 minutes of moderate intensity exercise (e.g. 95 % heart rate of lactate threshold 1) 3 times a week either before or after a high carbohydrate (1 gkg-1) meal. Participants will visit the laboratory again at week 4 and week 12 and measurements taken for body composition, resting blood pressure, fasting blood glucose, lipid profiles and systemic inflammation, lactate threshold and 14-day blood glucose control

Plasma glucagon-like peptide-1 responses to ingestion of protein with increasing doses of milk minerals rich in calcium:Protein, calcium and GLP-1 release

A high dose of whey protein hydrolysate fed with milk minerals rich in calcium (Capolac®) results in enhanced glucagon-like peptide-1 (GLP-1) concentrations in lean individuals; however, the effect of different calcium doses ingested alongside protein is unknown. The present study assessed the dose response of calcium fed alongside 25 g whey protein hydrolysate on GLP-1 concentrations in individuals with overweight/obesity. Eighteen adults (mean ± sd: 8M/10F, 34 ± 18 years, 28·2 ± 2·9 kgm-2) completed four trials in a randomised, double-blind, crossover design. Participants consumed test solutions consisting of 25 g whey protein hydrolysate (CON), supplemented with 3179 mg (LOW), 6363 mg (MED) or 9547 mg (HIGH) Capolac® on different occasions, separated by at least 48 h. The calcium content of test solutions equated to 65, 892, 1719 and 2547 mg, respectively. Arterialised-venous blood was sampled over 180 min to determine plasma concentrations of GLP-1TOTAL, GLP-17-36amide, insulin, glucose, NEFA, and serum concentrations of calcium and albumin. Ad libitum energy intake was measured at 180 min. Time-averaged incremental AUC (iAUC) for GLP-1TOTAL (pmol·l-1·min-1) did not differ between CON (23 ± 4), LOW (25 ± 6), MED (24 ± 5) and HIGH (24 ± 6). Energy intake (kcal) did not differ between CON (940 ± 387), LOW (884 ± 345), MED (920 ± 334) and HIGH (973 ± 390). Co-ingestion of whey protein hydrolysate with Capolac® does not potentiate GLP-1 release in comparison with whey protein hydrolysate alone. The study was registered at clinical trials (NCT03819972).</p

Glucagon-like peptide-1 secretion in people with <i>versus </i>without type 2 diabetes: A systematic review and meta-analysis of cross-sectional studies

Aims/Hypothesis: The aim of this systematic review was to synthesise the study findings on whether GLP-1 secretion in response to a meal tolerance test is affected by the presence of type 2 diabetes (T2D). The influence of putative moderators such as age, sex, meal type, meal form, and assay type were also explored. Methods: A literature search identified 32 relevant studies. The sample mean and SD for fasting GLP-1 TOTAL and GLP-1 TOTAL iAUC were extracted and used to calculate between-group standardised mean differences (SMD), which were meta-analysed using a random-effects model to derive pooled estimates of Hedges' g and 95 % prediction intervals (PI). Results: Pooled across 18 studies, the overall SMD in GLP-1 TOTAL iAUC between individuals with T2D (n = 270, 1047 ± 930 pmol·L −1·min) and individuals without T2D (n = 402, 1204 ± 937 pmol·L −1·min) was very small, not statistically significant and heterogenous across studies (g = −0.15, p = 0.43, PI: −1.53, 1.23). Subgroup analyses demonstrated an effect of assay type whereby Hedges' g for GLP-1 iAUC was greater in individuals with, versus those without T2D when using ELISA or Mesoscale (g = 0.67 [moderate], p = 0.009), but not when using RIA (g = −0.30 [small], p = 0.10). Pooled across 30 studies, the SMD in fasting GLP-1 TOTAL between individuals with T2D (n = 580, 16.2 ± 6.9 pmol·L −1) versus individuals without T2D (n = 1363, 12.4 ± 5.7 pmol·L −1) was small and heterogenous between studies (g = 0.24, p = 0.21, PI: −1.55, 2.02). Conclusions: Differences in fasting GLP-1 TOTAL and GLP-1 TOTAL iAUC between individuals with, versus those without T2D were generally small and inconsistent between studies. Factors influencing study heterogeneity such as small sample sizes and poor matching of groups may help to explain the wide prediction intervals observed. Considerations to improve comparisons of GLP-1 secretion in T2D and potential mediating factors more important than T2D diagnosis per se are outlined. PROSPERO ID: CRD42020195612.</p

Glucagon-like peptide-1 secretion in people with <i>versus </i>without type 2 diabetes: A systematic review and meta-analysis of cross-sectional studies

Aims/Hypothesis: The aim of this systematic review was to synthesise the study findings on whether GLP-1 secretion in response to a meal tolerance test is affected by the presence of type 2 diabetes (T2D). The influence of putative moderators such as age, sex, meal type, meal form, and assay type were also explored. Methods: A literature search identified 32 relevant studies. The sample mean and SD for fasting GLP-1 TOTAL and GLP-1 TOTAL iAUC were extracted and used to calculate between-group standardised mean differences (SMD), which were meta-analysed using a random-effects model to derive pooled estimates of Hedges' g and 95 % prediction intervals (PI). Results: Pooled across 18 studies, the overall SMD in GLP-1 TOTAL iAUC between individuals with T2D (n = 270, 1047 ± 930 pmol·L −1·min) and individuals without T2D (n = 402, 1204 ± 937 pmol·L −1·min) was very small, not statistically significant and heterogenous across studies (g = −0.15, p = 0.43, PI: −1.53, 1.23). Subgroup analyses demonstrated an effect of assay type whereby Hedges' g for GLP-1 iAUC was greater in individuals with, versus those without T2D when using ELISA or Mesoscale (g = 0.67 [moderate], p = 0.009), but not when using RIA (g = −0.30 [small], p = 0.10). Pooled across 30 studies, the SMD in fasting GLP-1 TOTAL between individuals with T2D (n = 580, 16.2 ± 6.9 pmol·L −1) versus individuals without T2D (n = 1363, 12.4 ± 5.7 pmol·L −1) was small and heterogenous between studies (g = 0.24, p = 0.21, PI: −1.55, 2.02). Conclusions: Differences in fasting GLP-1 TOTAL and GLP-1 TOTAL iAUC between individuals with, versus those without T2D were generally small and inconsistent between studies. Factors influencing study heterogeneity such as small sample sizes and poor matching of groups may help to explain the wide prediction intervals observed. Considerations to improve comparisons of GLP-1 secretion in T2D and potential mediating factors more important than T2D diagnosis per se are outlined. PROSPERO ID: CRD42020195612.</p

Insulin regulates Rab3-Noc2 complex dissociation to promote GLUT4 translocation in rat adipocytes.

AIMS/HYPOTHESIS: The glucose transporter GLUT4 is present mainly in insulin-responsive tissues of fat, heart and skeletal muscle and is translocated from intracellular membrane compartments to the plasma membrane (PM) upon insulin stimulation. The transit of GLUT4 to the PM is known to be dependent on a series of Rab proteins. However, the extent to which the activity of these Rabs is regulated by the action of insulin action is still unknown. We sought to identify insulin-activated Rab proteins and Rab effectors that facilitate GLUT4 translocation. METHODS: We developed a new photoaffinity reagent (Bio-ATB-GTP) that allows GTP-binding proteomes to be explored. Using this approach we screened for insulin-responsive GTP loading of Rabs in primary rat adipocytes. RESULTS: We identified Rab3B as a new candidate insulin-stimulated G-protein in adipocytes. Using constitutively active and dominant negative mutants and Rab3 knockdown we provide evidence that Rab3 isoforms are key regulators of GLUT4 translocation in adipocytes. Insulin-stimulated Rab3 GTP binding is associated with disruption of the interaction between Rab3 and its negative effector Noc2. Disruption of the Rab3-Noc2 complex leads to displacement of Noc2 from the PM. This relieves the inhibitory effect of Noc2, facilitating GLUT4 translocation. CONCLUSIONS/INTERPRETATION: The discovery of the involvement of Rab3 and Noc2 in an insulin-regulated step in GLUT4 translocation suggests that the control of this translocation process is unexpectedly similar to regulated secretion and particularly pancreatic insulin-vesicle release

The impact of long-term physical inactivity on adipose tissue immunometabolism

CONTEXT: Adipose tissue and physical inactivity both influence metabolic health and systemic inflammation, but how adipose tissue responds to chronic physical inactivity is unknown. OBJECTIVE: This work aimed to characterize the impact of chronic physical inactivity on adipose tissue in healthy, young males. METHODS: We collected subcutaneous adipose tissue from 20 healthy, young men before and after 60 days of complete bed rest with energy intake reduced to maintain energy balance and fat mass. We used RNA sequencing, flow cytometry, ex vivo tissue culture, and targeted protein analyses to examine adipose tissue phenotype. RESULTS: Our results indicate that the adipose tissue transcriptome, stromal cellular compartment, and insulin signaling protein abundance are largely unaffected by bed rest when fat mass is kept stable. However, there was an increase in the circulating concentration of several adipokines, including plasma leptin, which was associated with inactivity-induced increases in plasma insulin and absent from adipose tissue cultured ex vivo under standardized culture conditions. CONCLUSION: Physical inactivity–induced disturbances to adipokine concentrations such as leptin, without changes to fat mass, could have profound metabolic implications outside a clinical facility when energy intake is not tightly controlled