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The present study was aimed at gaining insight into the signalling relationship between glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) in the regulation of glucose metabolism. Further, to assess the role of G-protein-coupled receptor 40 (GPR40) and insulin receptor (INSR) in the pancreas of sheep that were supplemented with calcium salts of long-chain fatty acids (CSFAs). An experiment was carried out over a period of 60 days with eighteen sheep, and they were fed with a standard basal diet. The sheep were divided into three groups: CSFA0 (without CSFAs), while CSFA3 and CSFA5 were supplemented with 3 % and 5 % of CSFAs, respectively. Plasma concentrations of GLP-1, insulin, glucagon, and glucose were assessed every two weeks. At the end of the experiment, sheep were slaughtered, and samples of gastrointestinal tract (GIT) epithelial tissues and pancreas were collected to assess the relative expression of mRNA of GPR40, GLP-1R, and INSR. Postprandial GLP-1 and insulin were increased by 3.7-4.1 and 1.45-1.5 times, respectively, in the CSFAs-supplemented groups compared to CSFA0. Post-feeding, glucagon and glucose levels decreased in CSFA3 and CSFA5 compared to CSFA0. The results indicated that the supplementation of LCFAs increased the expression of GLP-1R in the GIT and pancreas, as well as the mRNA of GPR40 and INSR in the pancreas. Chemosensing of LCFAs by GPR40 in the pancreas triggers signalling transduction, and enhanced GLP-1 and GLP-1R resulted in moderately increased insulin secretion and reduced glucagon levels. These combined effects, along with the glucose-lowering effect of GLP-1, effectively lowered glucose levels in normoglycemic sheep., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The potential of rapeseed-derived peptides (RDPs) in the amelioration of type 2 diabetes mellitus (T2DM) has been hypothesized. However, the mechanisms of the intestinal endocrine hormones activated by RDPs have not been fully understood. This study aimed to explore the amelioration of T2DM and associated hepatic lipid metabolism disorders using RDPs by affecting glucagon-like peptide-1 (GLP-1) secretion. Eight RDPs were prepared by different stepwise enzymatic hydrolysis, wherein RCPP-3 (sequential using alcalase/flavourzyme) and RNPP-1 (sequential using alcalase/trypsin) maintained the normal blood glucose level, significantly increased the body weight (27.17 ± 0.19%) in T2DM mice compared to the positive group ( p < 0.05). Western blotting and immunofluorescence experiments indicated that RCPP-3 and RNPP-1 regulated the intestinal endocrine hormones GLP-1 secretion through the calcium-sensing receptor (CaSR). Additionally, the PI3K-Akt pathway was significantly activated by GLP-1, leading to marked improvements in hepatic lipid parameters (TC, TG, LDL-c, and HDL-c) and mitigated fat accumulation ( p < 0.05). Notably, the stimulating effect of RCPP-3 on GLP-1 was 10.05% ± 0.71% higher than RNPP-1. G2-R3, a fraction separated from RCPP-3, which contained 14 peptides with the best capacity to stimulate GLP-1 secretion, was identified using HPLC-QTOF-MS/MS. This study suggests the potential of RDPs as novel functional food supplements for ameliorating T2DM.

Upon epithelial barrier dysfunction, lipopolysaccharide (LPS) stimulates glucagon-like peptide-1 (GLP-1) secretion from enteroendocrine L cells by activating Toll-like receptor 4 (TLR4). Because GLP-1 accelerates peristalsis in the proximal colon, the present study aimed to explore whether LPS facilitates colonic peristalsis by stimulating L cell-derived GLP-1 release. In isolated segments of rat proximal colon that were serosally perfused with physiological salt solution and luminally perfused with 0.9% saline, peristaltic wall motion was video recorded and converted into spatio-temporal maps. Fluorescence immunohistochemistry was also carried out. Intraluminal administration of LPS (100 or 1 µg mL -1 but not 100 ng mL -1 ) increased the frequency of oro-aboral propagating peristaltic contractions. The LPS-induced acceleration of colonic peristalsis was blocked by TAK-242 (the TLR4 antagonist), exendin-3 (the GLP-1 receptor antagonist) or BIBN4096 (the calcitonin gene-related peptide receptor antagonist). GLP-1-positive epithelial cells co-expressed TLR4 immunoreactivity. In aspirin-pretreated preparations where epithelial barrier function had been impaired, a lower dose of LPS (100 ng mL -1 ) became capable of accelerating peristalsis. By contrast, luminally applied dimethyl sulphoxide, a reactive oxygen species scavenger that protects epithelial integrity, attenuated the prokinetic effects of a higher dose of LPS (100 µg mL -1 ). In colonic segments of a stress rat model leading to a leaky gut, LPS induced more pronounced prokinetic effects. Colonic L cells may well sense luminal LPS via TLR4 triggering the release of GLP-1 that stimulates calcitonin gene-related peptide-containing neurons. The resultant acceleration of peristalsis would facilitate excretion of Gram-negative bacteria from the intestine, and thus L cells may have a protective role against intestinal bacterial infections. KEY POINTS: Colonic epithelial cells form a barrier against bacterial invasion but also may contribute more actively to the exclusion of luminal pathogen by stimulating colonic motility. Luminal lipopolysaccharide (LPS) accelerated colonic peristalsis by stimulating calcitonin gene-related peptide-containing neurons. The prokinetic effect of LPS was mediated by the secretion of glucagon-like peptide-1 from enteroendocrine L cells in which Toll-like receptor 4 was expressed. The LPS-mediated acceleration of peristalsis depended on epithelial barrier integrity. L cells have a defensive role against Gram-negative bacterial infections by facilitating faecal excretion, and could be a potential therapeutic target for gastrointestinal infections., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Background: Diabetic nephropathy (DN), a complication of diabetes, is the most leading cause of end-stage renal disease. Bariatric surgery functions on the remission of diabetes and diabetes-related complications. One anastomosis gastric bypass (OAGB), one of popular bariatric surgery, can improve diabetes and its complications by regulating the glucagon-like peptide-1 (GLP-1) level. Meanwhile, GLP-1 can alleviate renal damage in high-fat-diet-induced obese rats. However, the effect of OAGB on renal injury remains uncertain in DN., Methods: A diabetes model was elicited in rats via HFD feeding and STZ injection. The role and mechanism of OAGB were addressed in DN rats by the body and kidney weight and blood glucose supervision, oral glucose tolerance test (OGTT), enzyme-linked immunosorbent assay (ELISA), biochemistry detection, histopathological analysis, and western blot assays., Results: OAGB surgery reversed the increase in body weight and glucose tolerance indicators in diabetes rats. Also, OAGB operation neutralized the DN-induced average kidney weight, kidney weight/body weight, and renal injury indexes accompanied with reduced glomerular hypertrophy, alleviated mesangial dilation and decreased tubular and periglomerular collagen deposition. In addition, OAGB introduction reduced the DN-induced renal triglyceride and renal cholesterol with the regulation of fatty acids-related proteins expression. Mechanically, OAGB administration rescued the DN-induced expression of Sirt1/AMPK/PGC1α pathway mediated by GLP-1. Pharmacological block of GLP-1 receptor inverted the effect of OAGB operation on body weight, glucose tolerance, renal tissue damage, and fibrosis and lipids accumulation in DN rats., Conclusion: OAGB improved renal damage and fibrosis and lipids accumulation in DN rats by GLP-1-mediated Sirt1/AMPK/PGC1α pathway., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Objectives: Glucagon-like peptide-1 (GLP-1) has a cardiovascular protective effect by preventing abdominal aortic aneurysm (AAA) formation. However, it is unclear at what point the agent should be administered to achieve the optimal effect. In this study, we aimed to determine whether administering the GLP-1 receptor agonist liraglutide during the earlier stages would more efficiently inhibit AAA progression in mice., Methods: Depending on the group, mice were given a daily dose of 300 μg/kg liraglutide for 28 days at 7, 14, and 28 days after aneurysm induction. The morphology of the abdominal aorta was monitored using 7.0 T magnetic resonance imaging (MRI) during the administration of liraglutide. After 28 days of administration, the AAA dilatation ratio was calculated, and histopathological examination was performed. Oxidative stress levels were evaluated by the expression of malondialdehyde (MDA) and matrix metalloproteinases (MMPs). The inflammatory response was also evaluated., Results: Liraglutide treatment led to a decrease in AAA formation, including a reduction in abdominal aorta expansion, elastin degradation in the elastic laminae, and vascular inflammation caused by leukocyte infiltration. The expression of MDA and the activity of MMPs (MMP-2, MMP-9) also decreased. Notably, administering liraglutide during the early stages resulted in a significant reduction in the dilatation rate of the aortic wall, as well as in MDA expression, leukocyte infiltration, and MMP activity in the vascular wall., Conclusions: The GLP-1 receptor agonist liraglutide was found to inhibit AAA progression in mice by exerting anti-inflammatory and antioxidant effects, particularly during the early stages of AAA formation. Therefore, liraglutide may represent a potential pharmacological target for the treatment of AAA., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The widespread adoption of glucagon-like peptide-1 (GLP-1) agonists in treating type 2 diabetes mellitus (T2DM) and obesity has sparked investigations into their impact on hair health, an area characterized by diverse conjectures. Some propose potential risks such as disrupted hair growth cycles or premature androgenetic alopecia (AGA), while others suggest benefits linked to improved insulin sensitivity and enhanced scalp blood circulation. However, despite these theoretical underpinnings, clinical evidence linking GLP-1 agonists to hair loss remains sparse. The necessity for vigilant patient monitoring and collaborative efforts cannot be overstressed in comprehensively addressing any potential consequences of GLP-1 agonist therapy on hair health as their use continues to expand., (© 2024 the International Society of Dermatology.)

Some neurodegenerative diseases may be characterized by continuing behavioral and cognitive dysfunction that encompasses memory loss and/or apathy. Alzheimer's disease is the most typical type of such neurodegenerative diseases that are characterized by deficits of cognition and alterations of behavior. Despite the huge efforts against Alzheimer's disease, there has yet been no successful treatment for this disease. Interestingly, several possible risk genes for cognitive dysfunction are frequently expressed within brain cells, which may also be linked to cholesterol metabolism, lipid transport, exosomes, and/or caveolae formation, suggesting that caveolae may be a therapeutic target for cognitive dysfunctions. Interestingly, the modulation of autophagy/mitophagy with the alteration of glucagon-like peptide-1 (GLP-1) and N-methyl-d-aspartate (NMDA) receptor signaling may offer a novel approach to preventing and alleviating cognitive dysfunction. A paradigm showing that both GLP-1 and NMDA receptors at caveolae sites may be promising and crucial targets for the treatment of cognitive dysfunctions has been presented here, which may also be able to modify the progression of Alzheimer's disease. This research direction may create the potential to move clinical care toward disease-modifying treatment strategies with maximal benefits for patients without detrimental adverse events for neurodegenerative diseases.

Processing of proglucagon into glucagon-like peptide-1 (GLP-1) and GLP-2 in intestinal L cells is mediated by the prohormone convertase 1/3 (PC1/3) while PC2 is responsible for the synthesis of glucagon in pancreatic alpha cells. While GLP-1 is also produced by alpha cells, the identity of the convertase involved in its synthesis is still unsettled. It also remains to be determined whether all alpha cells produce the incretin. The aims of this study were first, to elucidate the identity of the proconvertase responsible for GLP-1 production in human alpha cells, and second, to ascertain whether the number of glucagon cells expressing GLP-1 increase during diabetes. To answer these questions, sections of pancreas from donors' non-diabetic controls, type 1 and type 2 diabetes were processed for double-labelled immunostaining of glucagon and GLP-1 and of each hormone and either PC1 or PC2. Stained sections were examined by confocal microscopy. It was found that all alpha cells of islets from those three groups expressed GLP-1 and PC2 but not PC1/3. This observation supports the view that PC2 is the convertase involved in GLP-1 synthesis in all human glucagon cells and suggests that the regulation of its activity may have important clinical application in diabetes.

The combined use of gastrointestinal hormones for treating metabolic diseases is gaining increasing attention. The potential of developing novel dual agonists targeting both cholecystokinin 1 (CCK-1) receptor and glucagon-like peptide 1 (GLP-1) receptor to improve the treatment of type 2 diabetes and obesity have not been fully explored. In this investigation, we reported a series of novel GLP-1/CCK-1 receptor co-agonists constructed by linking the C-terminus of a GLP-1 receptor agonist (bullfrog GLP-1) to the N-terminus of a CCK-1 receptor selective agonist NN9056. In comprehensive in vitro assays, these co-agonists exhibited complete agonistic potency on GLP-1 and CCK-1 receptor. Remarkably, 1f displayed superior hypoglycemic and insulinotropic effects when compared to NN9056 and semaglutide. Evaluation in Kunming and diet-induced obesity (DIO) mice unveiled significant acute and enduring hypoglycemic effects of 1f. Administration of 1f to DIO mice resulted in substantial weight loss, normalized lipid metabolism, and enhanced glucose regulation. These preclinical observations strongly advocate for the therapeutic potential CCK-1 and GLP-1 pathways could be harnessed in a single fusion peptide, yielding a promising combination therapy strategy for treating metabolic disorders., Competing Interests: Declaration of competing interest Authors have no conflict of interest concerning this study and have nothing to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Traditionally known for managing blood sugar, GLP-1, a gut hormone, is emerging as a potential key to both lengthening lifespan and combating age-related ailments. While widely recognized for its role in blood sugar control, GLP-1 is increasingly recognized for its diverse effects on various biological pathways beyond glucose metabolism. Research across organisms and humans suggests that activating GLP-1 receptors significantly impacts cellular processes linked to aging. Its ability to boost mitochondrial function, enhance cellular stress resistance, and quell inflammation hints at its wider influence on aging mechanisms. This intricate interplay between GLP-1 and longevity appears to act through multiple pathways. One key effect is its ability to modulate insulin sensitivity, potentially curbing age-related metabolic issues like type 2 diabetes. Its neuroprotective properties also make it a promising candidate for addressing age-related cognitive decline and neurodegenerative diseases. Furthermore, preclinical studies using GLP-1 analogs or agonists have shown promising results in extending lifespan and improving healthspan in various model organisms. These findings provide a compelling rationale for exploring GLP-1-based interventions in humans to extend healthy aging. However, despite the exciting therapeutic prospects of GLP-1 in promoting longevity, challenges remain. Determining optimal dosages, establishing long-term safety profiles, and investigating potential adverse effects require comprehensive clinical investigations before we can confidently translate these findings to humans. This article emphasises the wide applicability of GLP-1., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Obesity is mediated by the changes in dyslipidemia, oxidative stress, and inflammation, leading to vascular endothelial dysfunction. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 inhibitors prevent the development of endothelial dysfunction. However, the underlying mechanism still remains largely unclear. Long non-coding RNAs (lncRNAs), one class of non-coding small RNAs, have been shown to exert a regulatory impact on the endothelial function in obesity. This study aimed to investigate whether the elevation of GLP-1 by a DPP-4 inhibitor sitagliptin improved vascular endothelial function by modulating lncRNAs in obese mice and to clarify the underlying molecular mechanism., Methods: Male C57BL/6J mice were fed a high-fat diet for 4 months to induce obesity and some obese mice were treated with sitagliptin for the last 1 month. Levels of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and glucagon-like peptide-1 (GLP-1) in plasma were detected by ELISA. LncRNA expression profile was analyzed via microarray. Aortic relaxations were examined by myograph. Protein expressions and phosphorylations were determined using western blot. The differentially expressed lncRNAs were validated using qRT-PCR., Results: Obese mice exhibited increased levels of TC and LDL, decreased concentrations of HDL and GLP-1 in plasma, and impaired aortic endothelium-dependent relaxations; such effects could be reversed by sitagliptin. Moreover, the altered expression profile of lncRNAs in the obese mouse aortae could be modulated by sitagliptin. Consistent with microarray analysis, qRT-PCR also revealed that lncRNA ENSMUST00000213271 was up-regulated in obese mouse aortae and aortic endothelial cells (ECs), which could be down-regulated by sitagliptin. Creb5 silencing reduced lncRNA ENSMUST00000213271 in obese mouse ECs. Knockdown of either Creb5 or lncRNA ENSMUST00000213271 restored the activation of AMPK/eNOS in obese mouse ECs. Furthermore, sitagliptin also suppressed Creb5 and lncRNA ENSMUST00000213271 and increased the phosphorylations of AMPK and eNOS in obese mice., Conclusion: Creb5/lncRNA ENSMUST00000213271 mediated vascular endothelial dysfunction through inhibiting AMPK/eNOS cascade in obesity. Elevation of GLP-1 by sitagliptin possibly improved endothelial function by suppressing Creb5/lncRNA ENSMUST00000213271 and subsequently restoring AMPK/eNOS activation in obese mice. This study will provide new evidence for the benefits of GLP-1 against vasculopathy in obesity., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims/hypothesis: Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes., Methods: Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min., Results: There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given., Conclusions/interpretation: In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control., Trial Registration: www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant., (© 2024. The Author(s).)

Objectives: Co-agonists at the glucagon-like peptide-1 and glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Although most co-agonists to date have been heavily GLP1R-biased, glucagon directly acts on the liver to reduce fat content. The aims of this study were to investigate a GCGR-biased co-agonist as treatment for hepatic steatosis in mice., Methods: Mice with diet-induced obesity (DIO) were treated with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, Semaglutide (GLP1R monoagonist) or food restriction over 24 days, such that their weight loss was matched. Hepatic steatosis, glucose tolerance, hepatic transcriptomics, metabolomics and lipidomics at the end of the study were compared with Vehicle-treated mice., Results: Dicretin lead to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Markers of glucose tolerance and insulin resistance improved in all treatment groups. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice. These include some known targets of glucagon signaling and others with as yet unclear physiological significance., Conclusions: Our study supports the development of GCGR-biased GLP1/GCGR co-agonists for treatment of MASLD and related conditions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TM-MT, JM and SRB declare that they are shareholders in and consultants for Zihipp Ltd., an Imperial College spin-out company that develops gut hormone analogues for the treatment of obesity and associated metabolic disorders., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: In 2021, the International Diabetes Federation reported that 537 million people worldwide are living with diabetes. While glucagon-like peptide-1 agonists provide significant benefits in diabetes management, approximately 40% of patients do not respond well to this therapy. This study aims to enhance treatment outcomes by using machine learning to predict individual response status to glucagon-like peptide-1 therapy., Methods: We analysed a type-2 diabetes mellitus dataset from the Diastrat cohort, recruited at the Northern Ireland Centre for Stratified Medicine. The dataset included individuals prescribed glucagon-like peptide-1 therapy, with response status determined by glycated haemoglobin levels of ≤53 mmol/mol. We identified genomic and proteomic markers and developed machine learning models to predict therapy response., Results: The study found 5 genomic variants and 45 proteomic markers that help differentiate glucagon-like peptide-1 therapy responders from non-responders, achieving 95 % prediction accuracy with a machine learning model., Conclusion: This study demonstrates the potential of machine learning in predicting the response to glucagon-like peptide-1 therapy in individuals with type-2 diabetes mellitus. These findings suggest that integrating genomic and proteomic data can significantly enhance personalized treatment approaches, potentially improving outcomes for patients who might otherwise not respond well to glucagon-like peptide-1 therapy. Further research and validation in larger cohorts are necessary to confirm these results and translate them into clinical practice., Competing Interests: Declaration of competing interest I, Dr. Angelina Thomas Villikudathil, submitting research article, ‘Computational approaches for clinical, genomic and proteomic markers of response to GLP-1 RA therapy in type-2 diabetes mellitus: An exploratory analysis with machine learning algorithms.’ to the Journal Diabetes & Metabolic Syndrome: Clinical Research & Reviews, declare the following potential conflicts of interest: Financial Interests: I have received funding from Ulster University Vice Chancellors Research Scholarship to conduct this research study. I assure the editorial board and readership that I am committed to upholding integrity and objectivity in this submission., (Copyright © 2024 Research Trust of DiabetesIndia (DiabetesIndia) and National Diabetes Obesity and Cholesterol Foundation (N-DOC). Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Declaration of competing interest JS is a consultant for Intuitive Surgical and Enterra Medical. None of these relationships influenced the current study. The other authors declare no competing interests.

Nutritional, endocrine, and neurological signals converge in multiple brain centres to control feeding behaviour and food intake as part of the allostatic regulation of energy balance. Among the several neuroendocrine systems involved, the leptin, glucocorticoid, and glucagon-like peptide 1 (GLP1) systems have been extensively researched. Leptin is at the top hierarchical level since its complete absence is sufficient to trigger severe hyperphagia. Glucocorticoids are key regulators of the energy balance adaptation to stress and their sustained excess leads to excessive adiposity and metabolic perturbations. GLP1 participates in metabolic adaptation to food intake, regulating insulin secretion and satiety by parallel central and peripheral signalling systems. Herein, we review the brain and peripheral targets of these three hormone systems that integrate to regulate food intake, feeding behaviour, and metabolic homeostasis. We examine the functional relationships between leptin, glucocorticoids, and GLP1 at the central and peripheral levels, including the cross-regulation of their circulating levels and their cooperative or antagonistic actions at different brain centres. The pathophysiological roles of these neuroendocrine systems in dysregulated intake are explored in the two extremes of body adiposity - obesity and lipodystrophy - and eating behaviour disorders., (© 2023 Cambridge Philosophical Society.)

Probiotics have garnered increasing attention as a potential therapeutic approach for type 2 diabetes mellitus (T2DM). Previous studies have confirmed that Bifidobacterium animalis subsp. lactis MN-Gup (MN-Gup) could stimulate the secretion of glucagon-like peptide-1 (GLP-1) in NCI-H716 cells, but whether MN-Gup has a hypoglycemic effect on T2DM in vivo remains unclear. In this study, a T2DM mouse model was constructed, with a high-fat diet and streptozotocin in mice, to investigate the effect of MN-Gup on diabetes. Then, different doses of MN-Gup (2 × 10 9 CFU/kg, 1 × 10 10 CFU/kg) were gavaged for 6 weeks to investigate the effect of MN-Gup on glucose metabolism and its potential mechanisms. The results showed that a high-dose of MN-Gup significantly reduced the fasting blood glucose (FBG) levels and homeostasis model assessment-insulin resistance (HOMA-IR) of T2DM mice compared to the other groups. In addition, there were significant increases in the short-chain fatty acids (SCFAs), especially acetate, and GLP-1 levels in the MN-Gup group. MN-Gup increased the relative abundance of Bifidobacterium and decreased the number of Escherichia-Shigella and Staphylococcus . Moreover, the correlation analysis revealed that Bifidobacterium demonstrated a significant positive correlation with GLP-1 and a negative correlation with the incremental AUC. In summary, this study demonstrates that Bifidobacterium animalis subsp. lactis MN-Gup has significant hypoglycemic effects in T2DM mice and can modulate the gut microbiota, promoting the secretion of SCFAs and GLP-1.

Glucagon-like peptide-1(GLP-1) is an incretin hormone secreted primarily from the intestinal L-cells in response to meals. GLP-1 is a key regulator of energy metabolism and food intake. It has been proven that P9 protein from A. muciniphila could increase GLP-1 release and improve glucose homeostasis in HFD-induced mice. To obtain an engineered Lactococcus lactis which produced P9 protein, mature polypeptide chain of P9 was codon-optimized, fused with N-terminal signal peptide Usp45, and expressed in L. lactis NZ9000. Heterologous secretion of P9 by recombinant L. lactis NZP9 were successfully detected by SDS-PAGE and western blotting. Notably, the supernatant of L. lactis NZP9 stimulated GLP-1 production of NCI-H716 cells. The relative expression level of GLP-1 biosynthesis gene GCG and PCSK1 were upregulated by 1.63 and 1.53 folds, respectively. To our knowledge, this is the first report on the secretory expression of carboxyl-terminal processing protease P9 from A. muciniphila in L. lactis. Our results suggest that genetically engineered L. lactis which expressed P9 may have therapeutic potential for the treatment of diabetes, obesity and other metabolic disorders., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Polyphenols are compounds of plant origin with several documented bioactivities related to health promotion. Some polyphenols are hard to be absorbed into the body due to their structural characteristics. This review focuses on the health beneficial effects of polyphenols mediated by intestinal hormones, particularly related to the systemic functions through the secretion of glucagon-like peptide-1 (GLP-1), an enteric hormone that stimulates postprandial insulin secretion. GLP-1 is secreted from L cells in the distal small intestine. Therefore, some poorly absorbed polyphenols are known to have the ability to act on the intestines and promote GLP-1 secretion. It has been reported that it not only reduces hyperglycemia but also prevents obesity by reduction of overeating and improves blood vessel function. This review discusses examples of health effects of polyphenols mediated by GLP-1 secretion., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Glucagon-like peptide-1 (GLP-1), secreted by L cells in the small intestine, assumes a central role in managing type 2 diabetes mellitus (T2DM) and obesity. Its influence on insulin secretion and gastric emptying positions it as a therapeutic linchpin. However, the limited applicability of native GLP-1 stems from its short half-life, primarily due to glomerular filtration and the inactivating effect of dipeptidyl peptidase-IV (DPP-IV). To address this, various structural modification strategies have been developed to extend GLP-1's half-life. Despite the commendable efficacy displayed by current GLP-1 receptor agonists, inherent limitations persist. A paradigm shift emerges with the advent of unimolecular multi-agonists, such as the recently introduced tirzepatide, wherein GLP-1 is ingeniously combined with other gastrointestinal hormones. This novel approach has captured the spotlight within the diabetes and obesity research community. This review summarizes the physiological functions of GLP-1, systematically explores diverse structural modifications, delves into the realm of unimolecular multi-agonists, and provides a nuanced portrayal of the developmental prospects that lie ahead for GLP-1 analogs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Glucagon like peptide-1 (GLP-1) is an effective hypoglycemic drug that can repair the pancreas β cells and promote insulin secretion. However, GLP-1 has poor stability and lacks of target ability, which makes it difficult to reach the site of action to exert its efficacy. Here, GLP-1-expressing plasmids are introduced into the Escherichia coli Nissle 1917 (EcN) and a lipid membrane is formed through simple self-assembly on its surface, resulting in an oral delivery system (LEG) capable of resisting the harsh environment of the gastrointestinal tract. The system utilizes the chemotactic properties of probiotics to achieve efficient enrichment at the pancreatic site, and protects islet β cells from destruction by regulating the balance of immune cells. More interestingly, LEG not only continuously produces GLP-1 to restore pancreatic islet β cell function and secrete insulin to control blood sugar levels, but also regulates the intestinal flora and increases the richness and diversity of probiotics. In mice diabetes models, oral administration of LEG only once every other day has good biosafety and compliance, and achieves long-term control of blood glucose. Therefore, this strategy not only provides an oral delivery platform for pancreatic targeting, but also opens up new avenues for reversing diabetes., (© 2024 Wiley‐VCH GmbH.)

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that arises when the body cannot respond fully to insulin, leading to impaired glucose tolerance. Currently, the treatment embraces non-pharmacological actions (e.g., diet and exercise) co-associated with the administration of antidiabetic drugs. Metformin is the first-line treatment for T2DM; nevertheless, alternative therapeutic strategies involving glucagon-like peptide-1 (GLP-1) analogs have been explored for managing the disease. GLP-1 analogs trigger insulin secretion and suppress glucagon release in a glucose-dependent manner thereby, reducing the risk of hyperglycemia. Additionally, GLP-1 analogs have an extended plasma half-life compared to the endogenous peptide due to their high resistance to degradation by dipeptidyl peptidase-4. However, GLP-1 analogs are mainly administered via subcutaneous route, which can be inconvenient for the patients. Even considering an oral delivery approach, GLP-1 analogs are exposed to the harsh conditions of the gastrointestinal tract (GIT) and the intestinal barriers (mucus and epithelium). Hereupon, there is an unmet need to develop non-invasive oral transmucosal drug delivery strategies, such as the incorporation of GLP-1 analogs into nanoplatforms, to overcome the GIT barriers. Nanotechnology has the potential to shield antidiabetic peptides against the acidic pH and enzymatic activity of the stomach. In addition, the nanoparticles can be coated and/or surface-conjugated with mucodiffusive polymers and target intestinal ligands to improve their transport through the intestinal mucus and epithelium. This review focuses on the main hurdles associated with the oral administration of GLP-1 and GLP-1 analogs, and the nanosystems developed to improve the oral bioavailability of the antidiabetic peptides. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology., (© 2024 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)

Background: Glucagon-like peptide-1 (GLP-1) (7-36) amide, an endogenous active form of GLP-1, has been shown to modulate oxidative stress and neuronal cell survival in various neurological diseases., Objective: This study investigated the potential effects of GLP-1(7-36) on oxidative stress and apoptosis in neuronal cells following traumatic brain injury (TBI) and explored the underlying mechanisms., Methods: Traumatic brain injury (TBI) models were established in male SD rats for in vivo experiments. The extent of cerebral oedema was assessed using wet-to-dry weight ratios following GLP-1(7-36) intervention. Neurological dysfunction and cognitive impairment were evaluated through behavioural experiments. Histopathological changes in the brain were observed using haematoxylin and eosin staining. Oxidative stress levels in hippocampal tissues were measured. TUNEL staining and Western blotting were employed to examine cell apoptosis. In vitro experiments evaluated the extent of oxidative stress and neural apoptosis following ERK5 phosphorylation activation. Immunofluorescence colocalization of p-ERK5 and NeuN was analysed using immunofluorescence cytochemistry., Results: Rats with TBI exhibited neurological deterioration, increased oxidative stress, and enhanced apoptosis, which were ameliorated by GLP-1(7-36) treatment. Notably, GLP-1(7-36) induced ERK5 phosphorylation in TBI rats. However, upon ERK5 inhibition, oxidative stress and neuronal apoptosis levels were elevated, even in the presence of GLP-1(7-36)., Conclusion: In summary, this study suggested that GLP-1(7-36) suppressed oxidative damage and neuronal apoptosis after TBI by activating ERK5/CREB., (© 2024. The Author(s).)

Patients with dementia are increasing with the aging of the population, and dementia has become a disease with high unmet medical needs. Glucagon-like peptide-1 (GLP-1), a neuropeptide, has been reported to improve learning and memory following intracerebroventricular administration. We focused on intranasal administration, which can deliver drugs noninvasively and efficiently to the brain. Although much of the human nasal mucosa is occupied by respiratory epithelium, many capillaries are present in the paracellular route of respiratory epithelium. Therefore, to incorporate GLP-1 into cells, we created a GLP-1 derivative by adding cell-penetrating peptides (CPP) and penetration accelerating sequences (PAS) to GLP-1. We investigated in vitro and in vivo function of PAS-CPP-GLP-1 to enable the translocation of GLP-1 directly from nose to brain. PAS-CPP-GLP-1 enhanced cellular uptake by macropinocytosis with CPP, efficiently escaped from the endosomes due to PAS, and exited the cells. PAS-CPP-GLP-1 also transited trigeminal nerve cells through axon transport and migrated to the adjacent trigeminal nerve cell. Moreover, PAS-CPP-GLP-1 showed significant improvement in learning memory in mice within 20 min of intranasal administration. These results suggested CPP and PAS may be important for the efficient transfer of GLP-1 to the site of action in the brain following intranasal administration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Alzheimer's disease (AD) is a widespread neurological illness in the elderly, which impacted about 50 million people globally in 2020. Type 2 diabetes has been identified as a risk factor. Insulin and incretins are substances that have various impacts on neurodegenerative processes. Preclinical research has shown that GLP-1 receptor agonists decrease neuroinflammation, tau phosphorylation, amyloid deposition, synaptic function, and memory formation. Phase 2 and 3 studies are now occurring in Alzheimer's disease populations. In this article, we present a detailed assessment of the therapeutic potential of GLP-1 analogues and DPP4 inhibitors in Alzheimer's disease., Aim: This study aimed to gain insight into how GLP-1 analogues and associated antagonists of DPP4 safeguard against AD., Methods: This study uses terms from search engines, such as Scopus, PubMed, and Google Scholar, to explore the role, function, and treatment options of the GLP-1 analogue for AD., Results: The review suggested that GLP-1 analogues may be useful for treating AD because they have been linked to anti-inflammatory, neurotrophic, and neuroprotective characteristics. Throughout this review, we discuss the underlying causes of AD and how GLP signaling functions., Conclusion: With a focus on AD, the molecular and pharmacological effects of a few GLP-1/GIP analogs, both synthetic and natural, as well as DPP4 inhibitors, have been mentioned, which are in the preclinical and clinical studies. This has been demonstrated to improve cognitive function in Alzheimer's patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Diabetes Mellitus develops when the body becomes unable to fuel its cells with glucose, which results in the accumulation of sugar excess in the bloodstream. Because it has diverse pathophysiological impacts on the body, diabetes mellitus represents a significant issue of concern in an attempt to find suitable treatment modalities and medications for afflicted diabetic patients. Glucagon-like peptide 1 (GLP-1) plays a pivotal role in the incretin effect, emerging as a prospective treatment for diabetes mellitus and a promising means of regenerating pancreatic cells, whether directly or through its receptor agonists. It has been shown that GLP-1 efficiently increases insulin production, lowers blood sugar levels in patients with type 2 diabetes mellitus, and decreases appetite, craving, and hunger, therefore amplifying the sensation of fullness and satiety. Moreover, since they are all dependent on GLP-1 effect, intricate signaling pathways share some similarities during specific phases, although the pathways continue to exhibit significant divergence engendered by specific reactions and effects in each organ, which encompasses the rationale behind observed differences. This triggers an expanding range of GLP-1 R agonists, creating new unforeseen research and therapeutic application prospects. This review aims to explain the incretin effect, discuss how GLP-1 regulates blood glucose levels, and how it affects different body organs, as well as how it transmits signals, before introducing selenium's role in the incretin impact., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The diabetic milieu is associated with cascades of pathophysiological pathways that culminate in diabetic complications and tissue injuries. Autophagy is an essential process mandatory for cell survival and tissue homeostasis by degrading damaged organelles and removing injured cells. However, it may turn into a pathological process in an aberrant mode in the diabetic and/or malignant milieu. Moreover, autophagy could serve as a promising therapeutic target for many complications related to tissue injury. Glp-1 mimetics are a class of newer antidiabetic agents that reduce blood glucose through several pathways. However, some evidence suggests that they can provide extra glycemic benefits by modulating autophagy, although there is no complete understanding of this mechanism and its underlying molecular pathways. Hence, in the current review, we aimed to provide new insights on the possible impact of Glp-1 mimetics on autophagy and consequent benefits as well as mediating pathways., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Glucagon-like peptide-1 (GLP-1) has gained much attention in the last decade for the treatment of type 2 diabetes. Accumulating evidence indicates that some metabolites of GLP-1 have biological activities that might contribute to the pleiotropic effects of GLP-1 independent of the GLP-1 receptor. The hypoglycemic and weight-reducing effects of the reported metabolites and modifications still need to be confirmed. In this study, we started from the C-terminal nonapeptide GLP-1(28-36) amide and developed a series of GLP-1(28-36) amide-derived hybrid peptides. Our findings of biological activity evaluation in INS-1 cells, streptozotocin-induced diabetic and diet-induced obesity mice confirmed a novel hybrid peptide, A3, and provided a new perspective in the development of new drugs from peptide metabolites., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study investigated the glucagon-like peptide-1 (GLP-1)-releasing activity of an aqueous extract (ZeinS) from corn zein protein and aimed to identify the active compounds responsible for this activity. Glucagon-like peptide-1-releasing activity was evaluated using a murine enteroendocrine cell line (GLUTag). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed on purified fractions of ZeinS to identify active molecules. ZeinS stimulated more GLP-1 secretion from GLUTag cells compared to zein hydrolysate. Fractions displaying biological activity were determined by solid-phase extraction and high-performance liquid chromatography (HPLC) fractionation. Subsequent LC-MS/MS analysis identified several amino acids in the active fractions of ZeinS. In particular, γ-aminobutyric acid (GABA) exhibited significant GLP-1-releasing activity both alone and synergistically with L-phenylalanine (Phe). Moreover, ZeinS-induced GLP-1 secretion was attenuated by antagonists for the GABA receptor and calcium sensing receptor. These results demonstrate that GABA and Phe identified in ZeinS synergistically stimulate GLP-1 secretion in enteroendocrine cells., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

In recent years, we have witnessed the many beneficial effects of glucagon-like peptide (GLP)-1 receptor agonists, including the reduction in cardiovascular risk in patients with type 2 diabetes, and the reduction of body weight in those with obesity. Increasing evidence suggests that these agents differ considerably from endogenous GLP-1 when it comes to their routes of action, although their clinical effects appear to be the same. Given the limitations of the GLP-1 receptor agonists, could it be useful to develop agents which stimulate GLP-1 release? Here we will discuss the differences and similarities between GLP-1 receptor agonists and endogenous GLP-1, and will detail how endogenous GLP-1-when stimulated appropriately-could have clinically relevant effects., (© 2023 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Objective: Glucagon-like peptide (GLP)-1 is an incretin hormone that acts after food intake to stimulate insulin production, enhance satiety, and promote weight loss. Here we describe the discovery and characterization of ecnoglutide (XW003), a novel GLP-1 analog., Methods: We engineered a series of GLP-1 peptide analogs with an alanine to valine substitution (Ala8Val) and a γGlu-2xAEEA linked C18 diacid fatty acid at various positions. Ecnoglutide was selected and characterized in GLP-1 receptor signaling assays in vitro, as well as in db/db mice and a diet induced obese (DIO) rat model. A Phase 1, double-blind, randomized, placebo-controlled, single (SAD) and multiple ascending dose (MAD) study was conducted to evaluate the safety, tolerability, and pharmacokinetics of subcutaneous ecnoglutide injection in healthy participants. SAD doses ranged from 0.03 to 1.0 mg; MAD doses ranged from 0.2 to 0.6 mg once weekly for 6 weeks (ClinicalTrials.gov Identifier: NCT04389775)., Results: In vitro, ecnoglutide potently induced cAMP (EC 50  = 0.018 nM) but not GLP-1 receptor internalization (EC 50  > 10 μM), suggesting a desirable signaling bias. In rodent models, ecnoglutide significantly reduced blood glucose, promoted insulin induction, and led to more pronounced body weight reduction compared to semaglutide. In a Phase 1 trial, ecnoglutide was generally safe and well tolerated as a once-weekly injection for up to 6 weeks. Adverse events included decreased appetite, nausea, and headache. The half-life at steady state ranged from 124 to 138 h, supporting once-weekly dosing., Conclusions: Ecnoglutide showed a favorable potency, pharmacokinetic, and tolerability profile, as well as a simplified manufacturing process. These results support the continued development of ecnoglutide for the treatment of type 2 diabetes and obesity., Competing Interests: Declaration of competing interest WG, HZ, YL, JF, ZZ, QZ, RZ, BW, YL, SH, HQ, CLJ, EA, LT, MF, WZ, MKJ, SX, and HP are, or were at the time the work was conducted, employees of Sciwind Biosciences., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Dietary peptides potently stimulate glucagon-like peptide-1 (GLP-1) secretion, however, the underlying molecular mechanisms, such as structure-activity relationships and sensing mechanisms are only partly elucidated. In this study, we used a dipeptide library to identify dipeptides that potently stimulate GLP-1 release and to clarify the underlying structure-activity relationship. Murine enteroendocrine GLUTag cells were exposed to 339 dipeptides for 60 min, and the concentration of GLP-1 released into the supernatant was measured. Subsequently, selected dipeptides were examined for their reproducibility and dose responsiveness. In addition, we investigated the role of constituent amino acids in the secretion of GLP-1, and whether tripeptides containing the active dipeptide structures maintained their activity. In a concentration range of 1-5 mg/mL, twelve dipeptides had reproducible and concentration-dependent GLP-1-releasing activity. Among them, nine dipeptides (FY, KF, NI, PM, QL, QY, WF, WN, WY) were novel, with WY exhibiting the most potent activity. The reverse sequences and most free amino acids did not induce GLP-1 secretion, indicating that GLP-1-producing cells recognize the structure of each peptide to induce GLP-1 secretion. However, no apparent similarities were found between the active peptides. A comparison between the six tripeptides composed of F, W, and Y revealed the further potent tripeptides FWY and WYF, than WY. In the present study, a comprehensive analysis revealed nine novel dipeptides with high potential to stimulate GLP-1 secretion. Furthermore, the results indicate that 'WY' is a specific dipeptide sequence that potently stimulates GLP-1 secretion., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tohru Hira reports financial support was provided by Kieikai Research Foundation. Tohru Hira reports financial support was provided by Urakami Foundation for Food and Food Culture Promotion. Tohru Hira reports financial support was provided by The Tojuro Iijima Foundation for Food Science and Technology., (Copyright © 2023 Elsevier Inc. All rights reserved.)

By binding to its receptor, glucagon-like peptide-1 (GLP-1) plays various physiological roles, including activating glucose-dependent insulin secretion, inhibiting gastric emptying, and reducing appetite. This suite of activities makes GLP-1 and its analogs an attractive choice for treating type 2 diabetes mellitus in the context of overweight or obesity. This study used different types and lengths of fatty acids to design dual fatty acid side chains for GLP-1 receptor agonists including decanoic, dodecanoic, tetradecanoic, hexadecanoic, dodecanedioic, tetradecanedioic, hexadecanedioic, and octadecanedioic acids. Sixteen GLP-1 receptor agonists (conjugates 13-28) with dual fatty acid side chains were obtained by liquid-phase synthesis. After structural confirmation using high-resolution mass spectrometry, peptide mapping, and circular dichroism, the biological activities of the conjugates were screened. First, the conjugates were screened for albumin binding and activity in GLP-1R-CRE-bla CHO-K1 cells. Albumin binding results suggested a synergistic effect between the two fatty acids in the conjugates. Next, conjugates 18, 19, and 21 selected after primary screening were assessed for receptor affinity, activity in INS-1 cells, plasma stability across different species, and efficacy and pharmacokinetics in normal and db/db mice. One candidate (conjugate 19) was found to have albumin binding of >99 %, good receptor affinity, activities of INS-1 cells, and plasma stability. We found that cellular activities in GLP-1R-CRE-bla CHO-K1 cells and pharmacodynamics and pharmacokinetics in normal and db/db mice for conjugate 19 were superior to those of semaglutide., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Protein intake potently increases body temperature and energy expenditure, but the underlying mechanism thereof remains incompletely understood. Simultaneously, protein intake potently stimulates glucagon-like peptide-1 (GLP-1) secretion. Here, we examined the involvement of GLP-1 in the thermic effects of dietary proteins in rodents by measuring rectal temperature and energy expenditure and modulating GLP-1 signaling. Rectal temperature of rats or mice fasted for 4 or 5 hours were measured using a thermocouple thermometer before and after an oral administration of nutrients. Oxygen consumption after oral protein administration was also measured in rats. Rectal temperature measurements in rats confirmed an increase in core body temperature after refeeding, and the thermic effect of the oral administration of protein was greater than that of a representative carbohydrate or lipid. Among the five dietary proteins examined (casein, whey, rice, egg, and soy), soy protein had the highest thermic effect. The thermic effect of soy protein was also demonstrated by increased oxygen consumption. Studies using a nonselective β-adrenergic receptor antagonist and thermal camera suggested that brown adipose tissue did not contribute to soy protein-induced increase in rectal temperature. Furthermore, the thermic effect of soy protein was completely abolished by antagonism and knockout of the GLP-1 receptor, yet potentiated via augmentation of intact GLP-1 levels through inhibition of dipeptidyl peptidase-4 activity. These results indicate that GLP-1 signaling is essential for the thermic effects of dietary proteins in rats and mice, and extend the metabolic actions of GLP-1 ensuing from nutrient ingestion to encompass the thermic response to ingested protein., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Glucagon-like peptide-1 (GLP-1), a gut-derived incretin hormone, plays a pivotal role in glucose-induced insulin secretion. Currently, the role of incretin hormones in the pathogenesis of cirrhosis is not clearly defined. This study aimed to investigate circulating levels of GLP-1 in liver cirrhosis and its association with the severity of liver disease., Methods: A total of 80 participants including 39 patients with a definite diagnosis of liver cirrhosis and 41 healthy controls recruited in this cross-sectional study. Circulating levels of GLP-1 were determined using the ELISA method. The severity of liver cirrhosis was assessed according to the Child-Pugh, MELD (i), MELD-Na, MELD New, and UK end-stage liver disease score (UKELD) criteria., Results: The mean age of patients and healthy subjects was 42.51 ± 12.80 and 42.07 ± 10.92 years, respectively ( p value = .869). The mean MELD (i), MELD-Na, MELD New, UKELD, and Child-Pugh scores were 14.36 ± 4.26, 15.26 ± 4.81, 14.74 ± 4.66, 52.33 ± 3.82, and 7.28 ± 1.50, respectively. In this study, circulating levels of GLP-1 were statistically lower in cirrhotic patients compared with healthy controls (95.26 ± 17.15 vs 111.84 ± 38.14 pg/mL; p value = .017)., Conclusion: Larger prospective studies are needed to explore the incretin effect in cirrhosis patients compared with healthy individuals.

Glucagon-like peptide-1 (GLP-1) receptor agonists currently occupy a privileged place in the management of type-2 diabetes (T2D). Dual glucose-dependent insulinotropic polypeptides (GIP/GLP-1) have been recently developed. Tirzepatide is the most advanced unimolecular dual GIP/GLP-1 receptor agonist to be used as once weekly subcutaneous injection in T2D and recently received approval by the European Medicines Agency. Because of the complementarity of action of the two incretins, tirzepatide showed better dose-dependent (5, 10 and 15mg) efficacy (greater reduction in HbA1c and body weight) than placebo, basal insulin or two GLP-1 analogues (dulaglutide and semaglutide) in the SURPASS program. Its cardiovascular protective effect is currently being assessed versus dulaglutide in the SURPASS-CVOT study. Finally, studies for the treatment of obesity (SURMOUNT program) and metabolic-associated fatty liver disease (MAFLD) are also ongoing. Gastrointestinal tolerance of tirzepatide appears comparable to that of GLP-1 analogues, except for higher incidence of diarrhea. Other original molecules have been built, including triple GIP/GLP-1/glucagon receptor agonists. The risk/benefit ratio will decide whether dual (or triple) receptor agonists should replace pure GLP-1 receptor agonists for the management of T2D in the near future, with a significant role in the pharmacotherapy of obesity., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Eating and drinking co-occur and many of the same mechanisms that control one are involved in the control of the other, making it difficult to isolate specific mechanisms for the control of fluid intake. Glucagon-like peptide-1 (GLP-1) is a peptide that seems to be involved in the endogenous control of both ingestive behaviors, but we lack a thorough understanding of how and where GLP-1 is acting to control fluid intake. Vasopressin-deficient Brattleboro rats are a model of hereditary hypothalamic diabetes insipidus that have been used extensively for the study of vasopressin actions in behavior and physiology. Here, we propose that these rats, that eat normally but drink excessively, provide a useful model to dissociate central controls of food and fluid intakes. As an initial step toward establishing this model for these purposes, we focused on GLP-1. Similar to the effect observed after treatment with a GLP-1 receptor (GLP-1R) agonist, the intake difference between wildtype and Brattleboro rats was largely a function in the number of licking bursts, indicating differences in post-ingestive feedback (e.g., satiation). When given central injections of a GLP-1R agonist, the effect on feeding was comparable between wildtype and Brattleboro rats, but the effect of drug on fluid intake was markedly exaggerated in Brattleboro rats. Additionally, Brattleboro rats did not respond to GLP-1R antagonism, whereas wildtype rats did. Taken together, these results suggest that Brattleboro rats exhibit a selective disruption to GLP-1's control of water intake. Overall, these experiments provide foundational studies of the ingestive behavior of Brattleboro rats and demonstrate the potential to use these rats to disentangle the effects of GLP-1 on food and fluid intakes., Competing Interests: Declaration of Competing Interest The authors have no competing interests and no conflicts nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Context: Whole grain intake may control help glycemia and reduce food intake by affecting the secretion of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)., Objective: This systematic review and meta-analysis aimed to assess the postprandial and long-term effects of whole grains on GLP-1 and GIP levels., Data Sources: PubMed, Web of Science, and Scopus online databases were searched systematically to identify relevant randomized clinical trials (RCTs) published up to April 2021., Study Selection: RCTs that evaluated the effects of whole grains, compared with refined grains, on the postprandial area under the curve (AUC) value, the postprandial serum concentration of incretins from 0 to 180 minutes, or the fasting level of incretins after at least 14 days of intervention were included., Results: Nineteen studies were included in the meta-analysis. The results showed that acute intake of whole grains could not significantly change the AUC value of GLP-1 or GIP. However, the AUC value of GIP was reduced more significantly in (1) unhealthy participants (standard mean difference [SMD] -1.08; 95%CI, -2.07 to -0.10; I2 = 75.9%) compared with healthy participants, and (2) those with a baseline fasting blood glucose of ≥99 mg/dL (SMD -0.71; 95%CI, -1.30 to -0.11; I2 = 74.4%) compared with those with a baseline value of < 99 mg/dL. On the other hand, the results of time-response evaluation during 0 to 180 minutes after the intake of test meals showed that serum concentrations of GIP decreased significantly from 0 to 30 minutes (coefficient = -44.72; P = 0.005), but increased from 60 to 180 minutes (coefficient = 27.03; P = 0.005). However, long-term studies found no significant effects of whole grains on fasting concentrations of GLP-1 or GIP., Conclusion: Whole grain intake did not affect postprandial levels of GLP-1 but enhanced postprandial levels of GIP from 60 to 180 minutes. Further high-quality trials are required to assess the long-term effects of whole grain intake on serum levels of incretins., Systematic Review Registration: PROSPERO registration no. CRD42021256695., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although exocytosis can be categorized into several forms based on docking dynamics, temporal regulatory mechanisms of the exocytotic forms are unclear. We explored the dynamics of glucagon-like peptide-1 (GLP-1) exocytosis in murine GLUTag cells (GLP-1-secreting enteroendocrine L-cells) upon stimulation with deoxycholic acid (DCA) or high K + to elucidate the mechanisms regulating the balance between the different types of exocytotic forms (pre-docked with the plasma membrane before stimulation; docked after stimulation and subsequently fused; or rapidly recruited and fused after stimulation, without stable docking). GLP-1 exocytosis showed a biphasic pattern, and we found that most exocytosis was from the pre-docked granules with the plasma membrane before stimulation, or granules rapidly fused to the plasma membrane without docking after stimulation. In contrast, granules docked with the plasma membrane after stimuli and eventually fused were predominant thereafter. Inhibition of actin polymerization suppressed exocytosis of the pre-docked granules. These results suggest that the docking dynamics of GLP-1 granules shows a time-dependent biphasic shift, which is determined by interaction with F-actin., (© 2023 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Aims/introduction: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important incretin hormones. They are released from the gut after meal ingestion and potentiate glucose-stimulated insulin secretion. Their release after meal ingestion and oral glucose are well established and have been characterized previously. During recent years, knowledge of other regulatory aspects that potentially may affect GIP and GLP-1 secretion after meal ingestion have also begun to emerge. Here, the results of human studies on these novel aspects of meal- and nutrient-stimulated incretin hormone secretion are reviewed., Materials and Methods: The human literature was revisited by identifying articles in PubMed using key words GIP, GLP-1, secretion, meal, and nutrients., Results: The results show that all macronutrients individually stimulate GIP and GLP-1 secretion. However, there was no synergistic action when given in combination. A pre-load 30 min before a meal augments the GIP and GLP-1 response. GIP and GLP-1 secretion have a diurnal variation with a higher response to an identical meal in the morning than in the afternoon. There is no difference in GIP and GLP-1 secretion whether a meal is ingested slowly or rapidly. GIP and GLP-1 secretion after dinner are the same whether or not breakfast and lunch have been ingested. The temperature of the food may be of importance for the incretin hormone response., Conclusions: These novel findings have increased our knowledge on the regulation of the complexity of the incretin system and are also important knowledge when designing future studies., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

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., Competing Interests: Declaration of competing interest JW has received research funding as part of their PhD studentship from Arla Foods Ingredients (DK). SC, and GA have no conflicts of interest. JJH is a member of the advisory board to Novo Nordisk. FK is supported by MRC (UK) funding (MR/P002927/1). JAB is an investigator on research grants funded by BBSRC, MRC, British Heart Foundation, Rare Disease Foundation, EU Hydration Institute, GlaxoSmithKline, Nestlé, Lucozade Ribena Suntory, ARLA foods, Kennis Centrum Suiker and Salus Optima (L3M Technologies Ltd); has completed paid consultancy for PepsiCo, Kellogg's, SVGC and Salus Optima (L3M Technologies Ltd); is Company Director of Metabolic Solutions Ltd.; receives an annual honorarium as a member of the academic advisory board for the International Olympic Committee Diploma in Sports Nutrition; and receives an annual stipend as Editor-in Chief of International Journal of Sport Nutrition & Exercise Metabolism. J.T.G. is an investigator on research grants funded by BBSRC, MRC, British Heart Foundation, The Rank Prize Funds, The European Society for Clinical Nutrition and Metabolism (ESPEN), Lucozade Ribena Suntory, ARLA Foods Ingredients, Kenniscentrum Suiker and Voeding and Clasado Biosciences; and has completed paid consultancy for PepsiCo and SVGC., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Bitter taste receptors (TAS2Rs) are G protein-coupled receptors localized in the taste buds of the tongue. They may also be present in non-lingual organs, including the brain, lung, kidney, and gastrointestinal (GI) tract. Recent studies on bitter taste receptor functions have suggested TAS2Rs as potential therapeutic targets. The human bitter taste receptor subtype hTAS2R50 responds to its agonist isosinensetin (ISS). Here, we demonstrated that, unlike other TAS2R agonists, isosinensetin activated hTAS2R50 as well as increased Glucagon-like peptide 1 (GLP-1) secretion through the G βγ -mediated pathway in NCI-H716 cells. To confirm this mechanism, we showed that ISS increased intracellular Ca 2+ and was suppressed by the IP 3 R inhibitor 2-APB as well as the PLC inhibitor U73122, suggesting that TAS2Rs alters the physiological state of enteroendocrine L cells in a PLC-dependent manner. Furthermore, we demonstrated that ISS upregulated proglucagon mRNA and stimulated GLP-1 secretion. ISS-mediated GLP-1 secretion was suppressed in response to small interfering RNA-mediated silencing of G α -gust and hTAS2R50 as well as 2-APB and U73122. Our findings improved the understanding of how ISS modulates GLP-1 secretion and indicates the possibility of using ISS as a therapeutic agent in the treatment of diabetes mellitus.

The postoperative increase in glucagon-like peptide-1 (GLP-1) is the main factor to improve glucose metabolism following sleeve gastrectomy (SG) in obese patients with type 2 diabetes. We investigated whether the β-cell responsiveness to an injection of exogenous GLP-1 in the preoperative period could determine the postoperative glucose tolerance in 18 patients underwent SG. In the preoperative period, a regular oral glucose tolerance test (OGTT) and an exenatide-challenge during OGTT (Ex-OGTT) were performed to evaluate the β-cell function and its responsiveness to GLP-1. The postoperative glucose tolerance was evaluated by another regular OGTT performed at 3 months after SG. The significant decrease in glucose levels with enhanced secretions of insulin and GLP-1 was observed in OGTT at 3 months after SG. The area under the curve of glucose from 0 to 120 minutes (AUC glucose 0-120 min ) and the insulinogenic index (I.I.) in OGTT at 3 months post-SG were significantly improved compared to those in preoperative period, but comparable with those in Ex-OGTT. AUC glucose 0-120 min and I.I. in OGTT at 3 months post-SG were significantly correlated with not only those in Ex-OGTT, but also those in the preoperative regular OGTT. Conversely, the correlations calculated by the Spearman's ρ were stronger in the latter than the former. This exenatide-challenge protocol might be useful to estimate glucose tolerance and insulin secretion after SG, however, it may be insufficient to improve predictability of a patient who is likely to achieve a significant benefit on glucose metabolism from receiving SG.

Objective: Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) and reduces bodyweight by increasing energy expenditure and reducing energy intake in humans. Here we describe the pharmacological profile of the novel glucagon receptor (GCGR)/GLP-1 receptor (GLP-1R) dual agonist BI 456906., Methods: BI 456906 was characterized using cell-based in vitro assays to determine functional agonism. In vivo pharmacological studies were performed using acute and subchronic dosing regimens to demonstrate target engagement for the GCGR and GLP-1R, and weight lowering efficacy., Results: BI 456906 is a potent, acylated peptide containing a C18 fatty acid as a half-life extending principle to support once-weekly dosing in humans. Pharmacological doses of BI 456906 provided greater bodyweight reductions in mice compared with maximally effective doses of the GLP-1R agonist semaglutide. BI 456906's superior efficacy is the consequence of increased energy expenditure and reduced food intake. Engagement of both receptors in vivo was demonstrated via glucose tolerance, food intake, and gastric emptying tests for the GLP-1R, and liver nicotinamide N-methyltransferase mRNA expression and circulating biomarkers (amino acids, fibroblast growth factor-21) for the GCGR. The dual activity of BI 456906 at the GLP-1R and GCGR was supported using GLP-1R knockout and transgenic reporter mice, and an ex vivo bioactivity assay., Conclusions: BI 456906 is a potent GCGR/GLP-1R dual agonist with robust anti-obesity efficacy achieved by increasing energy expenditure and decreasing food intake., (Copyright © 2022 Boehringer Ingelheim Pharma GmbH & CoKG. Published by Elsevier GmbH.. All rights reserved.)

Peptide dual agonists toward both glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus (T2DM) patients with obesity. Our previous work identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13, which showed decent hypoglycemic and body weight lowering activity. However, the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life. Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins, we rationally designed a panel of O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/ GCGR dual agonists. One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays. As expected, O-GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo. Importantly, chronic administration of 1f potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, and normalized lipid metabolism and adiposity in both db/db and diet induced obesity (DIO) mice models. These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs., (Copyright © 2022 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Growing evidence suggests that the glucagon-like peptide-1 (GLP-1) system modulates alcohol seeking and consumption, and GLP-1 analogues may represent novel pharmacotherapies for alcohol use disorder (AUD). Accordingly, it is important to understand the potential effects of alcohol on the endogenous GLP-1 system. In a series of secondary analyses of previous human laboratory experiments, we first examined the effects of alcohol administration, with different doses and routes of administration, on peripheral active GLP-1 concentrations in heavy-drinking individuals with AUD enrolled in placebo-controlled pharmacological studies (only placebo conditions were analysed here). Alcohol administration resulted in a significant reduction of GLP-1 levels across the four experiments (oral alcohol, variable dose: F 3,28  = 6.52, p = 0.002; oral alcohol, fixed dose: F 7,75.94  = 5.08, p < 0.001; intravenous alcohol, variable dose: F 4,37.03  = 20.72, p < 0.001; intravenous alcohol, fixed dose: F 4,13.92  = 10.44, p < 0.001). Next, central expression of the GLP-1 receptor (GLP-1R) in post-mortem brain tissues (amygdala, ventral tegmental area, nucleus accumbens, hippocampus and prefrontal cortex) was compared between individuals with AUD and controls. Fold change of GLP-1R mRNA in the hippocampus was significantly higher in individuals with AUD, compared to controls (F 1,21  = 6.80, p = 0.01). A trend-level effect with the same direction was also found in the prefrontal cortex (F 1,20  = 3.07, p = 0.09). Exploratory analyses showed that GLP-1R gene expression levels were correlated with behavioural measures of alcohol drinking (hippocampus) and cigarette smoking (hippocampus and prefrontal cortex). Collectively, these data provide novel information on the crosstalk between alcohol and GLP-1 in a clinically relevant sample. Further studies are needed to understand the underlying mechanisms of this link., (© 2022 Society for the Study of Addiction. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Obesity is a prevalent disease, but effective treatments remain limited. Agonists of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) promote negative energy balance in mice, but these effects are not well-studied in rats. We tested the hypothesis that the α7nAChR agonist GTS-21 would decrease food intake and body weight in adult male Sprague Dawley rats. Contrary to our hypothesis, acute systemic administration of GTS-21 produced no significant effects on chow or high-fat diet (HFD) intake. Acute intracerebroventricular (ICV) GTS-21 also had no impact on chow intake, and actually increased body weight at the highest dose tested. Previous studies suggest that GTS-21 engages the food intake-suppressive glucagon-like peptide-1 (GLP-1) system in mice. As there are known species differences in GLP-1 physiology between mice and rats, we tested the ability of GTS-21 to elicit GLP-1 secretion in rats. Our results showed that plasma levels of total GLP-1 in rats were not significantly altered by peripheral GTS-21 injection. These results represent an advance in understanding how α7nAChR activation impacts energy balance control in rodents and suggest that there may be important differences between rats and mice in the ability of GTS-21/α7nAChR activation to increase secretion of GLP-1., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study aims to investigate whether stabilization of glucagon-like peptide-1 (GLP-1) level reduces angiotensin II (Ang II)-induced cardiac fibrosis and -elevated blood pressure accompanying with inhibition of NADPH oxidase (NOX) expression and preservation of mitochondrial integrity. The study was performed in Sprague-Dawley rat model of Ang II infusion (500 ng/kg/min) using osmotic minipumps for 4 weeks. GLP-1 receptor agonist liraglutide (0.3 mg/kg, injected subcutaneously twice daily) and dipeptidyl peptides-4 inhibitor, linagliptin (8 mg/kg, administered via oral gavage) were selected to preserve GLP-1 level. Blood pressure was measured noninvasively. Heart and aorta were saved for histological analysis. Relative to the animals with Ang II infusion, in the heart, liraglutide and linagliptin comparatively reduced the protein levels of NOX4 and TGFβ1 and expression of monocyte chemoattractant protein 1, and attenuated the proliferation of myofibroblasts (15 ± 4 and 13 ± 3 vs. 42 ± 22/HPF in Ang II group). The number of distorted mitochondria in both groups was significantly reduced (8 ± 4 and 10 ± 6 vs. 27 ± 13/HPF in Ang II group), in company with a significant reduction in cardiac fibrosis. In the aorta, treatment with liraglutide and linagliptin significantly downregulated the expression of NOX4 and intercellular adhesion molecule 1, and enhanced endothelial NOS expression. Aortic wall thickness was reduced comparatively (267 ± 22 and 286 ± 25 vs. 339 ± 40 μm in Ang II group). The area of fibrotic aorta was also reduced (13 ± 6 and 14 ± 5 vs. 38 ± 24 mm 2 in Ang II group), respectively, in coincidence with a significant reduction in mean blood pressure. Taken together, these results suggest that the conservation of GLP-1 level with exogenous supply of liraglutide or the prevention of endogenous degradation of GLP-1 with linagliptin protects against Ang II-induced injury in the heart and aorta, potentially associated with inhibition of NOX4 expression and preservation of mitochondrial integrity., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Live-cell imaging with fluorescent proteins (FPs) is a powerful tool for investigating the exocytosis processes of hormones. However, the secretion process of glucagon-like peptide-1 (GLP-1) has not been visualized by FPs, which might be because tagging FPs inhibits GLP-1 synthesis through the post-translational processing from proglucagon. Here, we have developed FP-tagged GLP-1 by inserting FPs into the middle of GLP-1 and adding the proglucagon signal peptide. Confocal imaging confirmed that GLP-1 fused to FPs with high folding efficiency showed granular structure, in which secretory vesicle markers colocalized. The fluorescence intensity of FP in the culture supernatant from cells treated with KCl or forskolin was significantly increased compared with those from untreated cells. Furthermore, FP-tagged GLP-1 enables direct visualization of stimulation-dependent exocytosis of GLP-1 at a single granule resolution with total internal reflection fluorescence microscopy. FP-tagged GLP-1 might facilitate the screening of GLP-1 secretagogues and the discovery of new antidiabetic drugs., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)