-
1.
Does endogenous GLP-1 affect resting energy expenditure and fuel selection in overweight and obese adults?
Poggiogalle, E, Donini, LM, Chiesa, C, Pacifico, L, Lenzi, A, Perna, S, Faliva, M, Naso, M, Rondanelli, M
Journal of endocrinological investigation. 2018;(4):439-445
Abstract
PURPOSE To investigate the association between fasting glucagon-like peptide 1 (GLP-1) levels and resting energy expenditure (REE), and respiratory quotient (RQ) in overweight and obese adults. METHOD Study participants were enrolled at the Dietetic and Metabolic Unit, University of Pavia, Italy. Inclusion criteria were age ≥ 25 and ≤ 45 years, and body mass index (BMI) ≥ 25 and ≤ 35 kg/m2. Diabetic subjects were excluded. Body composition was measured by dual-energy X-ray absorptiometry. REE was evaluated using indirect calorimetry, and RQ was calculated from respiratory gas exchanges. Fasting GLP-1, glucose, insulin and free fatty acid (FFA) levels, and 24-h norepinephrine urinary excretion were measured. Homeostasis model assessments of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) were calculated. RESULTS Thirty-seven participants were included (age 43.4 ± 1.6 years; BMI 30.6 ± 0.5 kg/m2). REE was not associated with fasting GLP-1 levels (p = 0.98) after adjustment for age, sex, fat-free mass (FFM), and fat mass (FM). Similarly, no association was observed between RQ and GLP-1 levels (p = 0.95), after adjustment for age, sex, and body fat. CONCLUSION In adults subjects with increased adiposity fasting, GLP-1 levels do not seem to play a role in the regulation of energy metabolism and in fuel selection.
-
2.
Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect?
Li, Y, Rosenblit, PD
Current cardiology reports. 2018;(11):113
Abstract
PURPOSE OF REVIEW Mimetics and analogs that extend the half-life of native glucagon-like peptide-1 (GLP-1), i.e., glucagon-like peptide-1 receptor agonists (GLP-1 RAs), at therapeutic doses, are indicated as adjuncts to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). In patients with T2DM, GLP-1 RAs not only affect improvements in impaired beta cell and alpha cell function, suppress appetite, and induce weight loss but also possess multiple cardiovascular protective properties that potentially have a beneficial impact on atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality. RECENT FINDINGS Required to demonstrate CV safety, compared to standard-of-care antidiabetic therapies, GLP-1 RAs have revealed statistically significant non-inferiority (p < 0.001), among CV outcome trials (CVOTs) thus far completed. Once-daily liraglutide and once-weekly semaglutide demonstrated significant superiority (p = 0.01 and p = 0.02, respectively), reducing 3-point composite major adverse cardiovascular events (MACE) in extreme risk secondary prevention adults with T2DM. Once-weekly exenatide demonstrated only a non-significant (p = 0.06) favorable trend for CV superiority, possibly due to in-trial mishaps, including placebo drop-ins with other CV protective medications. The short half-life lixisenatide was neutral (p = 0.81) in reducing MACE, most likely due to ineffective once-daily dosing. Structural differences among GLP-1 mimetics and analogs may explain potency differences in both A1C reduction and weight loss that may parallel important cardiovascular protective properties of the GLP-1 RA class. Significant superiority in reducing 3-point composite MACE in adults with T2DM with GLP-1 RAs has been limited to liraglutide and semaglutide. Careful attention to within-trial drop-in of cardioprotective antidiabetic agents assuring equipoise between placebo and investigational product groups might demonstrate significant MACE risk reduction with once-weekly exenatide. Maintenance of 24-h circulating levels, by an alternative administration method, may resurrect lixisenatide as a cardioprotective agent. Before a GLP-1 RA bioequivalence "class effect" claim for composite MACE risk reduction superiority can be fully discussed, we are obliged to wait for the pending results of CVOTs with other GLP-1 RAs, particularly albiglutide and dulaglutide, where steric hindrance may potentially inhibit full mimicry of pharmacologic GLP-1.
-
3.
Polyphenol-rich curry made with mixed spices and vegetables increases postprandial plasma GLP-1 concentration in a dose-dependent manner.
Haldar, S, Chia, SC, Henry, CJ
European journal of clinical nutrition. 2018;(2):297-300
Abstract
Glucagon-like peptide-1 (GLP-1) plays an important role in glucose homeostasis. Evidence is emerging that dietary bioactive phytochemicals such as polyphenols can increase GLP-1 concentration in vivo. Spices are rich in polyphenols and have oro-sensory properties, both of which can increase GLP-1 secretion. We therefore investigated the effects of mixed spices intake on postprandial GLP-1 concentration. Using a randomised, controlled, dose-response crossover trial in 20 young, healthy, Chinese men, volunteers were served white rice with 3 doses of curry made with mixed spices and vegetables. These test meals were isocaloric and macronutrient matched. Plasma total GLP-1 concentrations were measured before (baseline) and for up to 3 h after the consumption of test meals. We found a significant dose dependent increase in total AUC of plasma GLP-1 concentrations, adjusted for baseline, with increasing mixed spice doses [adjusted mean (±SEM) of 10568.3 ± 1267.9, 12391.8 ± 1333.94, and 13905.1 ± 1267.6 pg ml-1.min for Dose 0 Control, Dose 1 Curry and Dose 2 Curry respectively (p = 0.019)]. Consumption of polyphenol rich mixed spices and vegetables can therefore increase in vivo GLP-1 concentration.
-
4.
Glucagon like peptide-1 (GLP-1) likes Alzheimer's disease.
Yildirim Simsir, I, Soyaltin, UE, Cetinkalp, S
Diabetes & metabolic syndrome. 2018;(3):469-475
Abstract
Glucagon-like peptide-1 (GLP-1) is a 30 amino acid long peptide hormone derived from the proglucagon gene and secreted in the distal small intestine when food enters the duodenum. GLP-1 is also produced in the central nervous system (CNS), predominantly in the brainstem, and subsequently transported to a large number of regions in the CNS. Neuronal cells in nucleus tractus solitarius (NTS) can synthesize GLP-1 and extends to hypothalamus, some thalamic and cortical areas. A G protein coupled receptor (GPCR) provides the majority of GLP-1 actions. GLP-1 receptor activation triggers some in vivo signaling pathways. GLP-1 receptor agonists (GLP-1 RA) are used in the treatment diabetes and obesity. GLP-1 stimulates insulin secretion, inhibits glucagon secretion, decreases food intake, reduces appetite, delays gastric emptying, provides weight reduction, and protects β cells from apoptosis. Alzheimer's disease (AD) is the most prevalent form of dementia. It is characterized by cognitive insufficiencies and behavioral changes that impact memory and learning abilities, daily functioning and quality of life. Hyperinsulinemia and insulin resistance, which are known as pathophysiological features of the T2DM, have also been demonstrated to have significant impact on cognitive impairment. It is thought that GLP-1 affects neurological and cognitive functions, as well as its regulatory effect on glucose metabolism. The pathophysiological relationship between GLP-1 and AD is discussed in this review.
-
5.
Differences in the Postprandial Release of Appetite-Related Hormones Between Active and Inactive Men.
Bøhler, L, Coutinho, SR, Rehfeld, JF, Morgan, L, Martins, C
International journal of sport nutrition and exercise metabolism. 2018;(6):602-610
Abstract
Active, as opposed to inactive, individuals are able to adjust their energy intake after preloads of different energy contents. The mechanisms responsible for this remain unknown. This study examined differences in plasma concentration of appetite-related hormones in response to breakfasts of different energy contents, between active and inactive men. Sixteen healthy nonobese (body mass index = 18.5-27 kg/m2) adult males (nine active and seven inactive) participated in this study. Participants were given a high-energy (570 kcal) or a low-energy (205 kcal) breakfast in a random order. Subjective feelings of appetite and plasma concentrations of active ghrelin, active glucagon-like peptide-1, total peptide YY (PYY), cholecystokinin, and insulin were measured in fasting and every 30 min up to 2.5 hr, in response to both breakfasts. Mixed analysis of variance (fat mass [in percentage] as a covariate) revealed a higher concentration of active ghrelin and lower concentration of glucagon-like peptide-1, and cholecystokinin after the low-energy breakfast (p < .001 for all). Postprandial concentration of PYY was greater after the high energy compared with the low energy, but for inactive participants only (p = .014). Active participants had lower postprandial concentrations of insulin than inactive participants (p < .001). Differences in postprandial insulin between breakfasts were significantly lower in active compared with inactive participants (p < .001). Physical activity seems to modulate the postprandial plasma concentration of insulin and PYY after the intake of breakfasts of different energy contents, and that may contribute, at least partially, to the differences in short-term appetite control between active and inactive individuals.
-
6.
Incretins and Lipid Metabolism.
Tsimihodimos, V, Elisaf, M
Current medicinal chemistry. 2018;(18):2133-2139
Abstract
BACKGROUND Recent findings indicate that incretin hormones and incretin-based therapies may affect the metabolism of lipoproteins, although the corresponding mechanisms are not clearly defined. OBJECTIVE To summarize the available data on the mechanisms linking incretins with the characteristics of serum lipoproteins and discuss the clinical implications of these relationships. METHODS PubMed was searched using the terms "incretins", "GLP-1", "GIP" and "lipids", "dyslipidemia", "triglycerides", "apolipoprotein B48". All articles published in the English language until June 2016 were assessed and the relevant information is presented here. RESULTS GLP-1, and therapies that increase its activity, exert a beneficial effect on lipoprotein metabolism that is translated in a reduction in the fasting and postprandial concentration of triglycerides and a small improvement in the concentration and function of HDLs. In addition, a shift towards larger, less atherogenic particles usually follows the administration of GLP-1 receptor agonists. The mechanisms that underlie these changes involve a direct effect of GLP- 1 on the hepatic and intestinal production of triglyceride-rich lipoproteins, the GLP-1 induced increase in the production and function of insulin, the activation of specific areas of central nervous system as well as the increase in the peripheral utilization of triglycerides for energy production. On the other hand, GLP-2 increases the absorption of dietary fat and the production of triglyceride-rich lipoproteins while the role of GIP on lipid metabolism remains indeterminate. CONCLUSION GLP-1 and incretin-based therapies favorably affect lipid metabolism. These effects may contribute to the beneficial effects of incretin-based therapies on atherosclerosis and fatty liver disease.
-
7.
Acute effect of smoking and smoking abstinence on energy intake and appetite-related hormones blood concentrations.
Yannakoulia, M, Anastasiou, CA, Zachari, K, Sidiropoulou, M, Katsaounou, P, Tenta, R
Physiology & behavior. 2018;:78-82
Abstract
The effect of smoking on energy balance and the underlying mechanisms are not fully understood. The aim of the present study is to examine the acute effect of smoking and its abstinence on energy intake, subjective feelings of appetite and related hormones. Fourteen healthy smokers participated in a randomized, crossover study consisting of two trials: the Cigarette trial (participants smoked two cigarettes of their brand within 15min) and the Sham trial (they were asked to hold the cigarette as smoking, but without lighting it). After 45min the participants were offered an ad libitum variety of snacks, and their intake was recorded. Blood samples were taken at fasting, before the ad libitum meal and 1h after and were analyzed for obestatin, ghrelin, glucagon-like peptide-1, cholecystokinin and insulin levels. Subjective feelings of hunger, satiety and desired to eat, as well as smoking craving were evaluated by visual analog scales. Mean energy intake at the ad libitum meal was 825±310kcal in the Sham trial and 673±245kcal in the Cigarette trial (p=0.010). No significant intervention effects were observed for the reported appetite feelings or the appetite-related hormones levels. In conclusion, smoking was found to have an acute effect on dietary intake; this was not explained by changes in the hormonal levels that were evaluated. More research is needed to confirm these results in more prolonged periods of abstinence and explore other pathways through which smoking and its abstinence affect energy balance.
-
8.
Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes.
Bahne, E, Sun, EWL, Young, RL, Hansen, M, Sonne, DP, Hansen, JS, Rohde, U, Liou, AP, Jackson, ML, de Fontgalland, D, et al
JCI insight. 2018;(23)
Abstract
BACKGROUND Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose-lowering effect and mode of action. TRIAL REGISTRATION NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074). FUNDING This study received grants from the A.P. Møller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc.
-
9.
Altered glucose metabolism after bariatric surgery: What's GLP-1 got to do with it?
Smith, EP, Polanco, G, Yaqub, A, Salehi, M
Metabolism: clinical and experimental. 2018;:159-166
Abstract
Bariatric surgery is an effective treatment for obesity. The two widely performed weight-loss procedures, Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG), alter postprandial glucose pattern and enhance gut hormone secretion immediately after surgery before significant weight loss. This weight-loss independent glycemic effects of GB has been attributed to an accelerated nutrient transit from stomach pouch to the gut and enhanced secretion of insulinotropic gut factors; in particular, glucagon-like peptide-1 (GLP-1). Meal-induced GLP-1 secretion is as much as tenfold higher in patients after GB compared to non-surgical individuals and inhibition of GLP-1 action during meals reduces postprandial hyperinsulinemia after GB two to three times more than that in persons without surgery. Moreover, in a subgroup of patients with the late complication of postprandial hyperinsulinemic hypoglycemia after GB, GLP1R blockade reverses hypoglycemia by reducing meal stimulated insulin secretion. The role of enteroinsular axis activity after SG, an increasingly popular alternative to GB, is less understood but, similar to GB, SG accelerates nutrient delivery to the intestine, improves glucose tolerance, and increases postprandial GLP-1 secretion. This review will focus on the current evidence for and against the role of GLP-1 on glycemic effects of GB and will also highlight differences between GB and SG.
-
10.
Incretin hormones: Their role in health and disease.
Nauck, MA, Meier, JJ
Diabetes, obesity & metabolism. 2018;:5-21
Abstract
Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycaemia. GIP (glucose-dependent insulinotropic polypeptide) und GLP-1 (glucagon-like peptide-1) are the known incretin hormones from the upper (GIP, K cells) and lower (GLP-1, L cells) gut. Together, they are responsible for the incretin effect: a two- to three-fold higher insulin secretory response to oral as compared to intravenous glucose administration. In subjects with type 2 diabetes, this incretin effect is diminished or no longer present. This is the consequence of a substantially reduced effectiveness of GIP on the diabetic endocrine pancreas, and of the negligible physiological role of GLP-1 in mediating the incretin effect even in healthy subjects. However, the insulinotropic and glucagonostatic effects of GLP-1 are preserved in subjects with type 2 diabetes to the degree that pharmacological stimulation of GLP-1 receptors significantly reduces plasma glucose and improves glycaemic control. Thus, it has become a parent compound of incretin-based glucose-lowering medications (GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 or DPP-4). GLP-1, in addition, has multiple effects on various organ systems. Most relevant are a reduction in appetite and food intake, leading to weight loss in the long term. Since GLP-1 secretion from the gut seems to be impaired in obese subjects, this may even indicate a role in the pathophysiology of obesity. Along these lines, an increased secretion of GLP-1 induced by delivering nutrients to lower parts of the small intestines (rich in L cells) may be one factor (among others like peptide YY) explaining weight loss and improvements in glycaemic control after bariatric surgery (e.g., Roux-en-Y gastric bypass). GIP and GLP-1, originally characterized as incretin hormones, have additional effects in adipose cells, bone, and the cardiovascular system. Especially, the latter have received attention based on recent findings that GLP-1 receptor agonists such as liraglutide reduce cardiovascular events and prolong life in high-risk patients with type 2 diabetes. Thus, incretin hormones have an important role physiologically, namely they are involved in the pathophysiology of obesity and type 2 diabetes, and they have therapeutic potential that can be traced to well-characterized physiological effects.