GLP-1 RAs in Spain: A Short Narrative Review of Their Use in Real Clinical Practice.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a class of drugs with potent glucose-lowering activity. Additionally, some GLP-1 RAs have demonstrated cardiovascular and renal benefits. Current guidelines recommend their use in patients with type 2 diabetes (T2D) at high risk of or with established cardiovascular disease (CVD), regardless of glycaemic control, with lifestyle modification and metformin. However, several studies have recently highlighted the limited number of patients with T2D benefiting from these medications worldwide. Given the huge burden of CVD among patients with T2D, efforts should be made to bring clinical practice closer to expert guidelines. This review describes the current situation of GLP-1 RA use in Spain and the reasons behind the gap between guidelines and real-world practice and suggests possible solutions. Administrative issues, lack of awareness of the cardiovascular benefits, clinical inertia, rejection of injectable medication and costs could be some of the reasons for the current situation. Possible strategies that could help to close the gap include encouraging a multidisciplinary approach to the treatment of diabetes which involves cardiologists, endocrinologists, nephrologists, primary care providers and pharmacists; improved awareness of comorbidities and earlier evaluation and treatment or risks; and better education of healthcare providers regarding the cardioprotective benefits of these drugs.

The glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a class of drugs that can be beneficial for patients with type 2 diabetes who are at high risk of cardiovascular complications, such as heart attacks. For this reason, the current clinical guidelines strongly recommend their use in these patients. Unfortunately, many patients with type 2 diabetes and high cardiovascular risk still do not benefit from these drugs. This review analyses the reasons for this situation in Spain, and proposes some possible solutions. The reasons for the low use of GLP-1 RAs could be related to doctors not updating a patient's diabetes medicine as often as they should, lack of awareness about the cardiovascular benefits of these drugs, fear of medicines that involve needles, administrative issues, and costs. Some of the possible strategies to improve the use of GLP-1 RAs among patients with type 2 diabetes with high cardiovascular risk could be to foster greater cooperation among specialists, increase awareness of the need to treat cardiovascular risk in patients with diabetes, and better education of doctors regarding the benefits of these drugs.

The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror.

Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon's secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans' islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (ß) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to ß cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.

Effect of intestinal microbiota imbalance associated with chronic hepatitis B virus infection on the expression of microRNA­192 and GLP­1.

It has been reported that hepatitis B virus (HBV) infection has an impact on intestinal microbiota imbalance to induce diabetes mellitus (DM), but the underlying mechanisms still remain to be explored. The present study aimed to investigate the regulatory role of microRNA­192 (miR­192­5p) and glucagon­like peptide­1 (GLP­1) in intestinal microbiota imbalance by recruiting patients with DM infected with HBV. In the present study, patients with HBV infection and different levels of alanine transaminase (ALT) were recruited and divided into three groups. Intestinal microbiota analysis was performed to evaluate the fecal bacterial composition of patients in various groups. Quantitative PCR was performed to explore the differential expression of miR­192­5p and GLP­1 in the feces, peripheral blood and intestinal mucosal tissue samples of each patient. Immunohistochemistry was used to assess the expression of GLP­1 protein in the intestinal mucosal tissue samples. Luciferase assays were performed by cell transfection of miR­192­5p mimics/precursors/inhibitors to study the inhibitory effect of miR­192­5p on GLP­1 expression. Intestinal microbiota imbalance was observed in hepatitis B surface antigen (HBsAg)­positive patients with high ALT. The expression of miR­192­5p was significantly elevated in the feces, peripheral blood and intestinal mucosal tissue samples of HBsAg­positive patients with high ALT along with decreased GLP­1 mRNA and protein expression. Luciferase activity of GLP­1 vector was inhibited by miR­192­5p mimics and promoted by miR­192­5p inhibitors. Transfection of miR­192­5p precursors resulted in upregulation of miR­192­5p and downregulation of GLP­1, while miR­192­5p inhibitors remarkably suppressed the expression of miR­192­5p and notably induced the expression of GLP­1. These results showed a regulatory network involving HBV infection, intestinal microbiota imbalance, and miR­192­5p and GLP­1 expression.

New progress in drugs treatment of diabetic kidney disease.

Diabetic kidney disease (DKD) is not only one of the main complications of diabetes, but also the leading cause of the end-stage renal disease (ESRD). The occurrence and development of DKD have always been a serious clinical problem that leads to the increase of morbidity and mortality and the severe damage to the quality of life of human beings. Controlling blood glucose, blood pressure, blood lipids, and improving lifestyle can help slow the progress of DKD. In recent years, with the extensive research on the pathological mechanism and molecular mechanism of DKD, there are more and more new drugs based on this, such as new hypoglycemic drugs sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors with good efficacy in clinical treatment. Besides, there are some newly developed drugs, including protein kinase C (PKC) inhibitors, advanced glycation end product (AGE) inhibitors, aldosterone receptor inhibitors, endothelin receptor (ETR) inhibitors, transforming growth factor-ß (TGF-ß) inhibitors, Rho kinase (ROCK) inhibitors and so on, which show positive effects in animal or clinical trials and bring hope for the treatment of DKD. In this review, we sort out the progress in the treatment of DKD in recent years, the research status of some emerging drugs, and the potential drugs for the treatment of DKD in the future, hoping to provide some directions for clinical treatment of DKD.

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.

GLP-1 agonists for obesity and type 2 diabetes in children: Systematic review and meta-analysis.

Pharmacological options for management of obesity and type 2 diabetes mellitus (T2DM) in children are limited. We aimed to synthesize published randomized controlled trial (RCT) evidence on the efficacy of glucagon-like peptide-1 (GLP-1) agonists in T2DM, pre-diabetes, and obesity in children aged <18 years. Inclusion criteria were RCTs of any GLP-1 agonist, solely or in conjunction with other drugs, for the treatment of obesity, pre-diabetes, and/or T2DM in children aged <18 years old. Nine studies met the inclusion criteria (two for T2DM, one for pre-diabetes, and six for obesity without diabetes). In total, 286 children were allocated to GLP-1 agonist therapy. Compared with controls, GLP-1 agonist therapy reduced HbA1c by -0.30% (95% confidence interval [CI] -0.57, -0.04) with a larger effect in children with (pre-)diabetes (-0.72%; 95% CI -1.17, -0.28; three studies) than in children with obesity (-0.08%; 95% CI -0.13, -0.02; four studies). Conversely, GLP-1 agonist therapy reduced body weight more in children with obesity (-2.74 kg; 95% CI -3.77, -1.70; six studies) than in children with T2DM (-0.97 kg; 95% CI -2.01, 0.08; two studies). Adverse effects included gastrointestinal symptoms and minor hypoglycemic episodes, but not severe hypoglycemia. GLP-1 agonists are efficacious in treating children with obesity and/or T2DM. Effect sizes are comparable with those reported in adults.

Glucagon-like peptide-1 receptor regulation of basal dopamine transporter activity is species-dependent.

INTRODUCTION: A solid body of preclinical evidence shows that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the effects of substance use disorder related behaviors. The mechanisms underlying these effects remain elusive. In the present study, we hypothesized that GLP-1R activation modulates dopaminetransporter (DAT) and thus dopamine (DA) homeostasis in striatum. This was evaluated in three different experiments: two preclinical and one clinical. METHODS: Rat striatal DA uptake, DA clearance and DAT cell surface expression was assessed following GLP-1 (7-36)-amide exposure in vitro. DA uptake in mice was assesed ex vivo following systemic treatment with the GLP-1R agonist exenatide. In addition, DA uptake was measured in GLP-1R knockout mice and compared with DA-uptake in wild type mice. In healthy humans, changes in DAT availability was assessed during infusion of exenatide measured by single-photon emission computed tomography imaging. RESULTS: In rats, GLP-1 (7-36)-amide increased DA uptake, DA clearance and DAT cell surface expression in striatum. In mice, exenatide did not change striatal DA uptake. In GLP-1R knockout mice, DA uptake was similar to what was measured in wildtype mice. In humans, systemic infusion of exenatide did not result in acute changes in striatal DAT availability. CONCLUSIONS: The GLP-1R agonist-induced modulation of striatal DAT activity in vitro in rats could not be replicated ex vivo in mice and in vivo in humans. Therefore, the underlying mechanisms of action for the GLP-1R agonists-induced efficacy in varios addiction-like behavioural models still remain.

The nuclear receptor FXR inhibits Glucagon-Like Peptide-1 secretion in response to microbiota-derived Short-Chain Fatty Acids.

The gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear Farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knock-out (KO) mice, in vitro in GLUTag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in WT and FXR KO mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes.

Suppression of enteroendocrine cell glucagon-like peptide (GLP)-1 release by fat-induced small intestinal ketogenesis: a mechanism targeted by Roux-en-Y gastric bypass surgery but not by preoperative very-low-calorie diet.

OBJECTIVE: Food intake normally stimulates release of satiety and insulin-stimulating intestinal hormones, such as glucagon-like peptide (GLP)-1. This response is blunted in obese insulin resistant subjects, but is rapidly restored following Roux-en-Y gastric bypass (RYGB) surgery. We hypothesised this to be a result of the metabolic changes taking place in the small intestinal mucosa following the anatomical rearrangement after RYGB surgery, and aimed at identifying such mechanisms. DESIGN: Jejunal mucosa biopsies from patients undergoing RYGB surgery were retrieved before and after very-low calorie diet, at time of surgery and 6 months postoperatively. Samples were analysed by global protein expression analysis and Western blotting. Biological functionality of these findings was explored in mice and enteroendocrine cells (EECs) primary mouse jejunal cell cultures. RESULTS: The most prominent change found after RYGB was decreased jejunal expression of the rate-limiting ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHMGCS), corroborated by decreased ketone body levels. In mice, prolonged high-fat feeding induced the expression of mHMGCS and functional ketogenesis in jejunum. The effect of ketone bodies on gut peptide secretion in EECs showed a ∼40% inhibition of GLP-1 release compared with baseline. CONCLUSION: Intestinal ketogenesis is induced by high-fat diet and inhibited by RYGB surgery. In cell culture, ketone bodies inhibited GLP-1 release from EECs. Thus, we suggest that this may be a mechanism by which RYGB can remove the inhibitory effect of ketone bodies on EECs, thereby restituting the responsiveness of EECs resulting in increased meal-stimulated levels of GLP-1 after surgery.

Mechanism of the neuroprotective effect of GLP-1 in a rat model of Parkinson's with pre-existing diabetes.

Several studies have suggested the association between neurodegenerative diseases and diabetes mellitus (DM), DM causes cognitive impairment with age, but its effect is not well known in Parkinson's disease (PD). As a member of the incretin family, Glucagon-like peptide-1 (GLP-1) has glycemic regulation functions. It also exerts many additional effects on different tissues through its receptor's widespread expression. OBJECTIVE: our aim is to investigate the effect of pre-existing diabetes on the severity of PD in male albino rats, and to find out whether GLP-1 could improve PD symptoms in diabetic animals in addition to its hypoglycemic effect, and how it could do that. METHODS: 75 adult male albino rats were equally divided into: Control, Parkinson's, Diabetic Parkinson's, Diabetic Parkinson's + low dose exenatide (GLP-1 receptor agonist), Diabetic Parkinson's + high dose exenatide group. Blood glucose and insulin, striatal dopamine, some striatal oxidative stress and inflammatory markers, and the catalepsy score were measured. RESULTS: Pre-existing of diabetes before initiation of PD raises the severity of PD shown by the more significant increase in catalepsy score, and the more significant decrease in striatal dopamine level. GLP-1 effects extend beyond their hypoglycemic effects only since it has a direct anti-oxidant, and anti-inflammatory neuronal effect with increasing the striatal dopamine and improving the catalepsy score in a dose dependent manner. CONCLUSIONS: Diabetes increases the severity of impairment in PD, and GLP-1 improve it through its direct neuronal effect in addition to its indirect effect through producing hypoglycemia.

The elephant in the room: Why cardiologists should stop ignoring type 2 diabetes.

Type 2 Diabetes (T2D) is a growing public health threat that is evolving into a global pandemic with debilitating, expensive and often lethal complications. Even when hemoglobin A1c (HbA1C) levels are well controlled, and concomitant cardiovascular (CV) risk factors are effectively treated, two out of every three patients with T2D are destined to die from CV complications. Several large randomized controlled trials (RCT) indicate that two classes of glucose-lowering medications, oral sodium-glucose cotransporter type 2 inhibitors (SGLT2-i) and injectable glucagon-like peptide-1 receptor agonists (GLP-1RA), confer significant CV benefits, including reductions in: hospitalizations for heart failure (HF), progression of diabetic kidney disease, atherosclerotic CV events, and (with some agents) CV death. These CV benefits appear to be independent of the glucose-lowering effects of these agents. These compelling findings are triggering a fundamental paradigm shift in T2D management whereby the focus is no longer on HbA1c alone, but instead on implementing a comprehensive CV risk reduction strategy prioritizing the use of these evidence-based therapies (along with other evidence-based treatment strategies) with the objective of reducing the risk of morbid complications, and improving the quantity and quality of life of patients with T2D. Cardiologists are uniquely positioned to become more involved in the management of T2D and established CV disease, which at this time should include initiation (either by prescribing or by making recommendations) of agents proven to reduce CV risk. Specifically, SGLT2-is and/or GLP-1RA have now been shown to have a favorable risk-benefit balance, and are being increasingly emphasized by the practice guidelines as preferable treatment options in vulnerable patients with T2D. The cardiology community should collaborate with other care providers to ensure that when and where appropriate these new T2D therapies are used along with other evidence-based therapies to improve patient outcomes.

Mechanistic insights regarding the role of SGLT2 inhibitors and GLP1 agonist drugs on cardiovascular disease in diabetes.

The treatment landscape for patients with established or at high risk for cardiovascular disease and type 2 diabetes mellitus has entirely changed over the past decade, with the introduction of several anti-hyperglycemic agents. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are two anti-hyperglycemic classes which have been of special interest after multiple large cardiovascular disease (CVD) outcomes studies have demonstrated superiority of these agents compared to placebo for major adverse CVD events and in some cases, hospitalization for heart failure. Despite the dramatic results of these trials, only recently have we began to understand the mechanisms underlying these CVD benefits. Here we review the underlying mechanisms which have the greatest plausibility for both of these agents including the impact of ventricular loading conditions, direct effects on cardiac structure and function, myocardial energetics and sodium/hydrogen exchange for SGLT2 inhibitors, and the anti-atherosclerotic, anti-inflammatory, and modulation of endothelial function for GLP-1 agonists.

Cardiovascular outcome trials of the newer anti-diabetic medications.

Concerns of elevated cardiovascular disease (CVD) risk with some anti-diabetic medications warranted phase 4 clinical trials to demonstrate CVD safety of newly marketed anti-diabetic drugs. Although initially designed to evaluate safety, some of these CVD outcome trials (CVOTs) have in fact shown CVD benefits. New medication classes, like glucagon-like peptide 1 (GLP-1) analogues and sodium-glucose co-transporter 2 (SGLT2) inhibitors, have shown reductions in the risk of major adverse cardiovascular events (MACE) including, myocardial infarction, stroke, CV death, and heart failure (HF). Perhaps more importantly, SGLT2 inhibitors demonstrated reduction in the risk of HF hospitalizations, being the first class of anti-diabetic drugs to do so. Conversely, dipeptidyl peptidase 4 (DPP-4) inhibitors did not significantly affect atherosclerotic CVD end-points and some actually increased the risk of HF hospitalizations. Further, the adverse/beneficial CVD effects of these medications may not be class specific. This review focuses on the main results of these CVOTs while highlighting the heterogeneity of CVD end-points within each class and discusses important mechanistic insights and adverse effect profiles.

Liraglutide Inhibits Endothelial-to-Mesenchymal Transition and Attenuates Neointima Formation after Endovascular Injury in Streptozotocin-Induced Diabetic Mice.

Hyperglycaemia causes endothelial dysfunction, which is the initial process in the development of diabetic vascular complications. Upon injury, endothelial cells undergo an endothelial-to-mesenchymal transition (EndMT), lose their specific marker, and gain mesenchymal phenotypes. This study investigated the effect of liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, on EndMT inhibition and neointima formation in diabetic mice induced by streptozotocin. The diabetic mice with a wire-induced vascular injury in the right carotid artery were treated with or without liraglutide for four weeks. The degree of neointima formation and re-endothelialisation was evaluated by histological assessments. Endothelial fate tracing revealed that endothelium-derived cells contribute to neointima formation through EndMT in vivo. In the diabetic mouse model, liraglutide attenuated wire injury-induced neointima formation and accelerated re-endothelialisation. In vitro, a high glucose condition (30 mmol/L) triggered morphological changes and mesenchymal marker expression in human umbilical vein endothelial cells (HUVECs), which were attenuated by liraglutide or Activin receptor-like 5 (ALK5) inhibitor SB431542. The inhibition of AMP-activated protein kinase (AMPK) signaling by Compound C diminished the liraglutide-mediated inhibitory effect on EndMT. Collectively, liraglutide was found to attenuate neointima formation in diabetic mice partially through EndMT inhibition, extending the potential therapeutic role of liraglutide.

Intestinal electrical stimulation attenuates hyperglycemia and prevents loss of pancreatic ß cells in type 2 diabetic Goto-Kakizaki rats.

BACKGROUND/OBJECTIVE: Recently, intestinal electrical stimulation (IES) has been reported to result in weight loss; however, it is unclear whether it has a therapeutic potential for diabetes. The aim of the present study was to explore the potential hypoglycemic effects of IES and its possible mechanisms involving ß cells in diabetic rats. SUBJECTS/METHODS: Diabetic Goto-Kakizaki (GK) rats were chronically implanted with one pair of electrodes in the duodenum. The oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed with or without IES, and plasma glucagon-like peptide-1 (GLP-1) and insulin level were measured. In the other two OGTT sessions, rats were treated with either Exendin (9-39) (GLP-1 antagonist) or Exendin (9-39) plus IES to investigate the underlying mechanism involving GLP-1. Gastric emptying and small intestinal transit were also measured with or without IES. In a chronic study, GK rats were treated with IES or Sham-IES for 8 weeks. Blood glucose, plasma GLP-1 and insulin level, body weight, and food intake were measured. Pancreas weight, islet ß-cell apoptosis, and proliferation were also analyzed. RESULTS: Acute IES reduced blood glucose level from 60 to 120 min during OGTT by 16-20% (all p < 0.05, vs. Sham-IES). GLP-1 antagonist significantly blocked the inhibitory effect of IES on hyperglycemia from 15 to 120 min (all p < 0.05). IES accelerated the small intestinal transit by 15% (p = 0.004). After 8 weeks of chronic stimulation, IES significantly reduced blood glucose (p < 0.05) and body weight (p = 0.02) and increased the plasma GLP-1 concentration (p < 0.05). Furthermore, we observed that chronic IES reduced pancreatic ß-cell apoptosis (p = 0.045), but showed no effects on ß-cell proliferation. CONCLUSIONS: Our study firstly proved the hypoglycemic effect of IES in a rodent model of type 2 diabetes, possibly attributed to the increasing GLP-1 secretion and improvement in ß-cell functions.

GI Dysfunctions in Diabetic Gastroenteropathy, Their Relationships With Symptoms, and Effects of a GLP-1 Antagonist.

CONTEXT: Delayed gastric emptying (GE) is common but often asymptomatic in diabetes. The relationship between symptoms, glycemia, and neurohormonal functions, including glucagonlike peptide 1 (GLP-1), are unclear. OBJECTIVES: To assess whether GE disturbances, symptoms during a GE study, and symptoms during enteral lipid infusion explain daily symptoms and whether GLP-1 mediates symptoms during enteral lipid infusion. DESIGN: In this randomized controlled trial, GE, enteral lipid infusion, gastrointestinal (GI) symptoms during these assessments, autonomic functions, glycosylated hemoglobin (HbA1c), and daily GI symptoms (2-week Gastroparesis Cardinal Symptom Index diary) were evaluated. During enteral lipid infusion, participants received the GLP-1 antagonist exendin 9-39 or placebo. SETTING: Single tertiary referral center. PARTICIPANTS: 24 healthy controls and 40 patients with diabetic gastroenteropathy. MAIN OUTCOME MEASURES: GE, symptoms during enteral lipid infusion, and the effect of exendin 9-39 on the latter. RESULTS: In patients, GE was normal (55%), delayed (33%), or rapid (12%). During lipid infusion, GI symptoms tended to be greater (P = 0.06) in patients with diabetes mellitus (DM) than controls; exendin 9-39 did not affect symptoms. The HbA1c was inversely correlated with the mean symptom score during the GE study (r = -0.46, P = 0.003) and lipid infusion (r = -0.47, P < 0.01). GE and symptoms during GE study accounted for 40% and 32%, respectively, of the variance in daily symptom severity and quality of life. CONCLUSIONS: In DM gastroenteropathy, GE and symptoms during a GE study explain daily symptoms. Symptoms during enteral lipid infusion were borderline increased but not reduced by a GLP-1 antagonist.

Accumbal ghrelin and glucagon-like peptide 1 signaling in alcohol reward in female rats.

The present study investigated the relationship between accumbal ghrelin and glucagon-like peptide 1 (GLP-1) signaling in alcohol reward in female rats. Animals with guide cannulae targeting the nucleus accumbens core (NAcC) and shell (NAcS) were habituated to alcohol for 12 weeks through a two-bottle intermittent access paradigm. JMV2959, a ghrelin antagonist, and exendin-4 (Ex-4), a GLP-1 agonist, were microinjected at the onset of the nocturnal cycle. Alcohol, food, water, and total fluid intake were measured 2, 6, and 24 h postinjection. Results indicated that JMV2959 reduced alcohol consumption when injected into both the NAcC and NAcS. Ex-4 administration as well as combined JMV2959 and Ex-4 treatment reduced intake when injected into the NAcS, but not the NAcC. These effects were time-dependent. JMV2959 had no effect on food intake when administered into either the NAcC or the NAcS, whereas Ex-4 decreased food intake when injected separately into both structures. The combination of JMV2959 and Ex-4 decreased food intake when administered only into the NAcC. These effects were also time-dependent. No estrous-related effects on alcohol or food intake were found. However, water and total fluid intake were increased during the metestrus and diestruses phases of the estrous cycle compared with the proestrus and estrus phases. Overall, these findings demonstrate the importance of accumbal ghrelin and GLP-1 signaling in alcohol reward and appetitive motivation.

Treatment of 'Diabesity': Beyond Pharmacotherapy.

Obesity is a prominent risk factor for type 2 diabetes. Management of type 2 diabetes requires weight management in addition to glycemic parameters. For obese type 2 diabetes patients, metformin, Sodium-glucose co-transporter-2 inhibitors or Glucagon-Like Peptide-1 Receptor Agonists should be prescribed as the first priority for controlling both hyperglycemia and body weight or fat distribution. The combination of these drugs with sulfonylureas, thiazolidinediones, and insulin may also be required in chronic cases. These drugs cause weight gain. Fortunately, many phytochemicals having a beneficial effect on diabetes and obesity, have minimum side-effects as compared to synthetic drugs. This review discusses the treatment strategies for controlling glycemia and weight management, with the focus on anti-diabetic drugs and phytochemicals. Glucagonostatic role, activation of Adenosine monophosphate-activated protein kinase and adipocyte targeting potential of anti-diabetic drugs and phytochemicals are also discussed.

Targeting incretin hormones and the ASK-1 pathway as therapeutic options in the treatment of non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is currently one of the leading forms of chronic liver disease, and its rising frequency worldwide has reached epidemic proportions. NAFLD, particularly its progressive variant NASH (non-alcoholic steatohepatitis), can lead to advanced fibrosis, cirrhosis, and HCC. The pathophysiologic mechanisms that contribute to the development and progression of NAFLD and NASH are complex, and as such myriad therapies are under investigation targeting different pathophysiological mechanisms. Incretin-based therapies, including GLP-1RAs and DPP-4 inhibitors and the inhibition of ASK1 pathway have provided two such novel mechanisms in the management of this disease, and will remain focus of this review.