GLP-1/GLP-1RAs: New Options for the Drug Treatment of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a global public health concern. Currently, the cornerstone of NAFLD treatment is lifestyle modification and, if necessary, weight loss. However, compliance is a challenge, and this approach alone may not be sufficient to halt and treat the more serious disease development, so medication is urgently needed. Nevertheless, no medicines are approved to treat NAFLD. Glucagon-like peptide-1 (GLP-1) is an enteropeptide hormone that inhibits glucagon synthesis, promotes insulin secretion, and delays gastric emptying. GLP-1 has been found in recent studies to be beneficial for the management of NAFLD, and the marketed GLP-1 agonist drugs have different degrees of effectiveness for NAFLD while lowering blood glucose. In this article, we review GLP-1 and its physiological roles, the pathogenesis of NAFLD, the correlation between NAFLD and GLP-1 signaling, and potential strategies for GLP-1 treatment of NAFLD.

Gut hormones and appetite regulation.

PURPOSE OF REVIEW: Various gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. This review summarizes the effects of gut hormones on appetite, with a focus on recent research. RECENT FINDINGS: Ghrelin is known as an orexigenic hormone, whereas glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), postprandial peptide YY (PYY), and oxyntomodulin (OXM) are known as anorexigenic hormones. Recent human studies have revealed that gut hormones act differently in various systems, including adipose tissue, beyond appetite and energy intake, and even involve in high-order thinking. Environmental factors including meal schedule, food contents and quality, type of exercise, and sleep deprivation also play a role in the influence of gut hormone on appetite, weight change, and obesity. Recently published studies have shown that retatrutide, a triple-agonist of GLP-1, GIP, and glucagon receptor, and orforglipron, a GLP-1 receptor partial agonist, are effective in weight loss and improving various metabolic parameters associated with obesity. SUMMARY: Various gut hormones influence appetite, and several drugs targeting these receptors have been reported to exert positive effects on weight loss in humans. Given that diverse dietary and environmental factors affect the actions of gut hormones and appetite, there is a need for integrated and largescale long-term studies in this field.

EVOO's Effects on Incretin Production: Is There a Rationale for a Combination in T2DM Therapy?

Type 2 diabetes mellitus (T2DM) is a serious public health concern as it is one of the most common chronic diseases worldwide due to social and economic developments that have led to unhealthy lifestyles, with a considerable impact both in terms of morbidity and mortality. The management of T2DM, before starting specific therapies, includes cornerstones such as healthy eating, regular exercise and weight loss. Strict adherence to the Mediterranean diet (MedDiet) has been related to an inverse association with the risk of T2DM onset, as well as an improvement in glycaemic control; in particular, thanks to the consumption of extra virgin olive oil (EVOO). Agonists of gut-derived glucagon-like peptide-1 (GLP-1), gastrointestinal hormones able to increase insulin secretion in response to hyperglycaemia (incretins), have been recently introduced in T2DM therapy, quickly entering the international guidelines. Recent studies have linked the action of EVOO in reducing postprandial glycaemia to the increase in GLP-1 and the reduction of its inactivating protease, dipeptidyl peptidase-4 (DPP-4). In this review, we explore observations regarding the pathophysiological basis of the existence of an enhanced effect between the action of EVOO and incretins and, consequently, try to understand whether there is a rationale for their use in combination for T2DM therapy.

Gut-Brain Communication in Parkinson's Disease: Enteroendocrine Regulation by GLP-1.

PURPOSE OF REVIEW: Defective gut-brain communication has recently been proposed as a promoter of neurodegeneration, but mechanisms mediating communication remain elusive. In particular, the Parkinson's disease (PD) phenotype has been associated with both dysbiosis of intestinal microbiota and neuroinflammation. Here, we review recent advances in the PD field that connect these two concepts, providing an explanation based on enteroendocrine signaling from the gut to the brain. RECENT FINDINGS: There have been several recent accounts highlighting the importance of the microbiota-gut-brain axis in PD. The objective of this review is to discuss the role of the neuroendocrine system in gut-brain communication as it relates to PD pathogenesis, as this system has not been comprehensively considered in prior reviews. The incretin hormone glucagon-like peptide 1 (GLP-1) is secreted by enteroendocrine cells of the intestinal epithelium, and there is evidence that it is neuroprotective in animal models and human subjects with PD. Agonists of GLP-1 receptors used in diabetes appear to be useful for preventing neurodegeneration. New tools and models have enabled us to study regulation of GLP-1 secretion by intestinal microbiota, to understand how this process may be defective in PD, and to develop methods for therapeutically modifying disease development or progression using the enteroendocrine system. GLP-1 secretion by enteroendocrine cells may be a key mediator of neuroprotection in PD, and new findings in this field may offer unique insights into PD pathogenesis and therapeutic strategies.

Plasma FGF21 concentrations are regulated by glucose independently of insulin and GLP-1 in lean, healthy humans.

BACKGROUND: Fibroblast growth factor 21 (FGF21) treatment improves metabolic homeostasis in diverse species, including humans. Physiologically, plasma FGF21 levels increase modestly after glucose ingestion, but it is unclear whether this is mediated by glucose itself or due to a secondary effect of postprandial endocrine responses. A refined understanding of the mechanisms that control FGF21 release in humans may accelerate the development of small-molecule FGF21 secretagogues to treat metabolic disease. This study aimed to determine whether FGF21 secretion is stimulated by elevations in plasma glucose, insulin, or glucagon-like peptide-1 (GLP-1) in humans. METHODS: Three groups of ten healthy participants were included in a parallel-group observational study. Group A underwent a hyperglycemic infusion; Group B underwent a 40 mU/m2/min hyperinsulinemic euglycemic clamp; Group C underwent two pancreatic clamps (to suppress endogenous insulin secretion) with euglycemic and hyperglycemic stages with an infusion of either saline or 0.5 pmol/kg/min GLP-1. Plasma FGF21 concentrations were measured at baseline and during each clamp stage by ELISA. RESULTS: Plasma FGF21 was unaltered during hyperglycemic infusion and hyperinsulinemic euglycemic clamps, compared to baseline. FGF21 was, however, increased by hyperglycemia under pancreatic clamp conditions (P < 0.05), while GLP-1 infusion under pancreatic clamp conditions did not change circulating FGF21 levels. CONCLUSION: Increases in plasma FGF21 are likely driven directly by changes in plasma glucose independent of changes in insulin or GLP-1 secretion. Ecologically valid postprandial investigations are now needed to confirm our observations from basic science infusion models.

Glucagon-like peptide-1: Are its roles as endogenous hormone and therapeutic wizard congruent?

Glucagon-like peptide-1 (GLP-1) is a peptide derived from differential processing of the precursor for the hormone glucagon. It is secreted predominantly by endocrine cells in the gut epithelium in response to nutrient stimulation. Studies from the last 35 years have given us an idea about its physiological functions. On the basis of some of its many actions, it has also been developed into a pharmaceutical agent for the treatment of obesity and type 2 diabetes (T2DM). It is currently positioned as the most effective anti-obesity agent available and is recommended in both national and international guidelines as an effective second-in line treatment for T2DM, in particular in patients with increased cardiovascular risk. In this review, I first discuss whether the processing of proglucagon may also result in GLP-1 formation in the pancreas and in glucagon in the gut. Next, I discuss the relationship between the physiological actions of GLP-1 and the therapeutic effects of the GLP-1 receptor agonists, which are far from being congruent and generally poorly understood. These relationships illustrate both the difficulties and the benefits of bridging results obtained in the laboratory with those emerging from the clinic.

GLP-1 and Underlying Beneficial Actions in Alzheimer's Disease, Hypertension, and NASH.

GLP-1 is derived from intestinal L cells, which takes effect through binding to GLP-1R and is inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). Since its discovery, GLP-1 has emerged as an incretin hormone for its facilitation in insulin release and reduction of insulin resistance (IR). However, GLP-1 possesses broader pharmacological effects including anti-inflammation, neuro-protection, regulating blood pressure (BP), and reducing lipotoxicity. These effects are interconnected to the physiological and pathological processes of Alzheimer's disease (AD), hypertension, and non-alcoholic steatohepatitis (NASH). Currently, the underlying mechanism of these effects is still not fully illustrated and a better understanding of them may help identify promising therapeutic targets of AD, hypertension, and NASH. Therefore, we focus on the biological characteristics of GLP-1, render an overview of the mechanism of GLP-1 effects in diseases, and investigate the potential of GLP-1 analogues for the treatment of related diseases in this review.

Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies.

Type 2 diabetes (T2D) is characterized by chronic hyperglycemia secondary to the decline of functional beta-cells and is usually accompanied by a reduced sensitivity to insulin. Whereas altered beta-cell function plays a key role in T2D onset, a decreased beta-cell mass was also reported to contribute to the pathophysiology of this metabolic disease. The decreased beta-cell mass in T2D is, at least in part, attributed to beta-cell apoptosis that is triggered by diabetogenic situations such as amyloid deposits, lipotoxicity and glucotoxicity. In this review, we discussed the molecular mechanisms involved in pancreatic beta-cell apoptosis under such diabetes-prone situations. Finally, we considered the molecular signaling pathways recruited by glucagon-like peptide-1-based therapies to potentially protect beta-cells from death under diabetogenic situations.

Ghrelin and Glucagon-Like Peptide-1: A Gut-Brain Axis Battle for Food Reward.

Eating behaviors are influenced by the reinforcing properties of foods that can favor decisions driven by reward incentives over metabolic needs. These food reward-motivated behaviors are modulated by gut-derived peptides such as ghrelin and glucagon-like peptide-1 (GLP-1) that are well-established to promote or reduce energy intake, respectively. In this review we highlight the antagonizing actions of ghrelin and GLP-1 on various behavioral constructs related to food reward/reinforcement, including reactivity to food cues, conditioned meal anticipation, effort-based food-motivated behaviors, and flavor-nutrient preference and aversion learning. We integrate physiological and behavioral neuroscience studies conducted in both rodents and human to illustrate translational findings of interest for the treatment of obesity or metabolic impairments. Collectively, the literature discussed herein highlights a model where ghrelin and GLP-1 regulate food reward-motivated behaviors via both competing and independent neurobiological and behavioral mechanisms.

Effect of GLP-1/GLP-1R on the Polarization of Macrophages in the Occurrence and Development of Atherosclerosis.

AIMS: To investigate the effect of GLP-1/GLP-1R on the polarization of macrophages in the occurrence and development of atherosclerosis. METHODS: Totally, 49 patients with coronary heart disease (CHD) and 52 cases of health control (HC) were recruited, all subjects accept coronary angiography gold standard inspection. One or more major coronary arteries (LM, LAD, LCx, and RCA) stenosis degree in 50% of patients as CHD group; the rest of the stenosis less than 50% or not seen obvious stenosis are assigned to the HC group. Flow cytometry were used to detect the percentage of (CD14+) M macrophages, (CD14+CD80+) M1 macrophages, (CD14+CD206+) M2 macrophages, and their surface GLP-1R expression differences in the two groups, using BD cytokine kit to detect the levels of IL-8, IL-1ß, IL-6, IL-10, TNF, and IL-12p70. RESULTS: GLP-1R expression on the surface of total macrophages and M2 macrophages was different between the CHD group and the HC group (P < 0.05). There was no difference in the percentage of total, M1 or M2 macrophages (P > 0.05). Concentration of IL-8 in the HC group was higher than that in the CHD group (P < 0.05). There is no significant difference in the cytokine IL-1ß, IL-6, IL-10, TNF, and IL-12p70 in the two groups (P > 0.05). After controlling for potential confounders including age, gender, smoking status (S.S.), drinking status (D.S.), HR, SBP, DBP, PP, TC, TG, HDL-C, LDL-C, GHbA1c, M, M1, M2, GLP-1R_M, GLP-1R_M1, GLP-1R_M2, IL-8, IL-1ß, IL-6, IL-10, TNF, and IL-12p70 by multiple linear regression, decreasing Gensini Score was significantly associated with increased percentage of M1 macrophage. CONCLUSION: GLP-1R agonist is independent of the hypoglycemic effect of T2DM and has protective effect on cardiovascular system. GLP-1R may regulate the polarization of macrophages toward M2, thus playing a protective role in the progression of coronary atherosclerosis.

The Role of Incretins on Insulin Function and Glucose Homeostasis.

The incretin effect-the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance-was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the champion. When the action of both incretins is prevented, glucose tolerance is pathologically impaired. Thus, after 100 years of research, we now know that insulinotropic hormones from the gut are indispensable for normal glucose tolerance. The loss of the incretin effect in type 2 diabetes, therefore, contributes greatly to the impaired postprandial glucose control.

Evidence for the existence and potential roles of intra-islet glucagon-like peptide-1.

Glucagon-Like Peptide-1 (GLP-1) is an important peptide hormone secreted by L-cells in the gastrointestinal tract in response to nutrients. It is produced by the differential cleavage of the proglucagon peptide. GLP-1 elicits a wide variety of physiological responses in many tissues that contribute to metabolic homeostasis. For these reasons, therapies designed to either increase endogenous GLP-1 levels or introduce exogenous peptide mimetics are now widely used in the management of diabetes. In addition to GLP-1 production from L-cells, recent reports suggest that pancreatic islet alpha cells may also synthesize and secrete GLP-1. Intra-islet GLP-1 may therefore play an unappreciated role in islet health and glucose regulation, suggesting a potential functional paracrine role for islet-derived GLP-1. In this review, we assess the current literature from an islet-centric point-of-view to better understand the production, degradation, and actions of GLP-1 within the endocrine pancreas in rodents and humans. The relevance of intra-islet GLP-1 in human physiology is discussed regarding the potential role of intra-islet GLP-1 in islet health and dysfunction.

Central and peripheral GLP-1 systems independently suppress eating.

The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which, respectively, define the peripheral and central GLP-1 systems. PPG neurons in the nucleus tractus solitarii (NTS) are widely assumed to link the peripheral and central GLP-1 systems in a unified gut-brain satiation circuit. However, direct evidence for this hypothesis is lacking, and the necessary circuitry remains to be demonstrated. Here we show that PPGNTS neurons encode satiation in mice, consistent with vagal signalling of gastrointestinal distension. However, PPGNTS neurons predominantly receive vagal input from oxytocin-receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. PPGNTS neurons are not necessary for eating suppression by GLP-1 receptor agonists, and concurrent PPGNTS neuron activation suppresses eating more potently than semaglutide alone. We conclude that central and peripheral GLP-1 systems suppress eating via independent gut-brain circuits, providing a rationale for pharmacological activation of PPGNTS neurons in combination with GLP-1 receptor agonists as an obesity treatment strategy.

The role of GLP-1 in the postprandial effects of acarbose in type 2 diabetes.

AIMS: The alpha-glucosidase inhibitor acarbose is believed to reduce plasma glucose by delaying hydrolysis of carbohydrates. Acarbose-induced transfer of carbohydrates to the distal parts of the intestine increases circulating glucagon-like peptide 1 (GLP-1). Using the GLP-1 receptor antagonist exendin(9-39)NH2, we investigated the effect of acarbose-induced GLP-1 secretion on postprandial glucose metabolism in patients with type 2 diabetes. METHODS: In a double-blinded, placebo-controlled, randomized, crossover study, 15 participants with metformin-treated type 2 diabetes (age: 57-85 years, HbA1c: 40-74 mmol/mol) were subjected to two 14-day treatment periods with acarbose or placebo, respectively, separated by a 6-week wash-out period. At the end of each period, two randomized 4-h liquid mixed meal tests with concomitant infusion of exendin(9-39)NH2 and saline, respectively, were performed. RESULTS: Compared to placebo, acarbose increased postprandial GLP-1 concentrations and decreased postprandial glucose. We observed no absolute difference in the exendin(9-39)NH2-induced increase in postprandial glucose excursions between placebo and acarbose periods, but relatively, postprandial glucose was increased by 119 ± 116% (mean ± s.d.) during exendin(9-39)NH2 infusion in the acarbose period vs a 39 ± 27% increase during the placebo period (P = 0.0163). CONCLUSIONS: We confirm that acarbose treatment stimulates postprandial GLP-1 secretion in patients with type 2 diabetes. Using exendin(9-39)NH2, we did not see an impact of acarbose-induced GLP-1 secretion on absolute measures of postprandial glucose tolerance, but relatively, the effect of exendin(9-39)NH2 was most pronounced during acarbose treatment.

Metabolic Messengers: glucagon-like peptide 1.

Glucagon like peptide-1 (GLP-1), a peptide hormone from the intestinal tract, plays a central role in the coordination of postprandial glucose homeostasis through actions on insulin secretion, food intake and gut motility. GLP-1 forms the basis for a variety of current drugs for the treatment of type 2 diabetes and obesity, as well as new agents currently being developed. Here, we provide a concise overview of the core physiology of GLP-1 secretion and action, and the role of the peptide in human health, disease and therapeutics.

Congenital Glucagon-like Peptide-1 Deficiency in the Pathogenesis of Protracted Diarrhea in Mitchell-Riley Syndrome.

CONTEXT: Mitchell-Riley syndrome due to RFX6 gene mutations is characterized by neonatal diabetes and protracted diarrhea. The RFX6 gene encodes a transcription factor involved in enteroendocrine cell differentiation required for beta-cell maturation. In contrast to the pathway by which RFX6 mutations leads to diabetes, the mechanisms underlying protracted diarrhea are unknown. OBJECTIVE: To assess whether glucagon-like peptide-1 (GLP-1) was involved in the pathogenesis of Mitchell-Riley syndrome protracted diarrhea. METHODS: Two case report descriptions. in a tertiary pediatric hospital. "Off-label" treatment with liraglutide. We describe 2 children diagnosed with Mitchell-Riley syndrome, presenting neonatal diabetes and protracted diarrhea. Both patients had nearly undetectable GLP-1 plasma levels and absence of GLP-1 immunostaining in distal intestine and rectum. The main outcome was to evaluate whether GLP-1 analogue therapy could improve Mitchell-Riley syndrome protracted diarrhea. RESULTS: "Off-label" liraglutide treatment, licensed for type 2 diabetes treatment in children, was started as rescue therapy for protracted intractable diarrhea resulting in rapid improvement during the course of 12 months. CONCLUSION: Congenital GLP-1 deficiency was identified in patients with Mitchell-Riley syndrome. The favorable response to liraglutide further supports GLP-1 involvement in the pathogenesis of protracted diarrhea and its potential therapeutic use.

Hyper-Activation of Endogenous GLP-1 System to Gram-negative Sepsis Is Associated With Early Innate Immune Response and Modulated by Diabetes.

BACKGROUND: Culture-positive gram-negative sepsis induces greater magnitude of early innate immunity /inflammatory response compared with culture-negative sepsis. We previously demonstrated increased activation of anti-inflammatory Glucagon Like Peptide-1 (GLP-1) hormone in initial phase of sepsis more pronounced in diabetes patients. However, whether GLP-1 system is hyperactivated during the early innate immune response to gram-negative sepsis and modulated by diabetes remains unknown. OBJECTIVES: Total and active GLP-1, soluble Dipeptidyl peptidase 4 (sDPP-4) enzyme, and innate immunity markers presepsin (sCD14) and procalcitonin (PCT) in plasma were determined by ELISA on admission and after 2 to 4 days in 37 adult patients with and without type 2 diabetes and gram-negative or culture-negative sepsis of different severity. RESULTS: Severe but not non-severe sepsis was associated with markedly increased GLP-1 system response, which correlated with PCT and the organ dysfunction marker lactate. Culture-positive gram-negative bacteria but not culture-negative sepsis induced hyper-activation of GLP-1 system, which correlated with increased innate immune markers sCD14, PCT, and lactate. GLP-1 inhibitory enzyme sDPP-4 was down regulated by sepsis and correlated negatively with sCD14 in gram-negative sepsis. Diabetic patients demonstrated increased GLP-1 response but significantly weaker innate immune response to severe and gram-negative sepsis. CONCLUSIONS: Early stage of gram-negative sepsis is characterized by endogenous GLP-1 system hyperactivity associated with over activation of innate immune response and organ dysfunction, which are modulated by diabetes. Total GLP-1 may be novel marker for rapid diagnosis of gram-negative sepsis and its severity.

Functional interaction between Ghrelin and GLP-1 regulates feeding through the vagal afferent system.

The gastrointestinal tract transmits feeding-regulatory signals to the brain via neuronal and hormonal pathways. Here we studied the interaction between the orexigenic gastric peptide, ghrelin, and the anorectic intestinal peptide, glucagon-like peptide 1 (GLP-1), in terms of feeding regulation via the vagal afferents. GLP-1 preadministration 30 min before ghrelin administration to rats and mice abolished ghrelin-induced food intake, while ghrelin preadministration abolished the anorectic effect of GLP-1. Ghrelin preadministration suppressed GLP-1-induced Fos expression in the nodose ganglia (NG). Electrophysiological assessment confirmed that the initially administered peptide abolished the vagal afferent electrical alteration induced by the subsequently administered peptide. Both the growth hormone secretagogue receptor (GHSR) and the GLP-1 receptor (GLP-1R) are co-localised in a major proportion of NG neurons that innervate the stomach. In these Ghsr+Glp1r+ neurons, ghrelin preadministration abolished the GLP-1-induced calcium response. Ghrelin generated a hyperpolarising current and GLP-1 generated a depolarising current in isolated NG neurons in a patch-clamp experiment. Ghrelin and GLP-1 potently influenced each other in terms of vagally mediated feeding regulation. This peptidergic interaction allows for fine control of the electrophysiological properties of NG neurons.