GLP-1 programs the neurovascular landscape.

Readily available nutrient-rich foods exploit our inherent drive to overconsume, creating an environment of overnutrition. This transformative setting has led to persistent health issues, such as obesity and metabolic syndrome. The development of glucagon-like peptide-1 receptor (GLP-1R) agonists reveals our ability to pharmacologically manage weight and address metabolic conditions. Obesity is directly linked to chronic low-grade inflammation, connecting our metabolic environment to neurodegenerative diseases. GLP-1R agonism in curbing obesity, achieved by impacting appetite and addressing associated metabolic defects, is revealing additional benefits extending beyond weight loss. Whether GLP-1R agonism directly impacts brain health or does so indirectly through improved metabolic health remains to be elucidated. In exploring the intricate connection between obesity and neurological conditions, recent literature suggests that GLP-1R agonism may have the capacity to shape the neurovascular landscape. Thus, GLP-1R agonism emerges as a promising strategy for addressing the complex interplay between metabolic health and cognitive well-being.

iGlarLixi effectively reduces residual hyperglycaemia in Chinese people with type 2 diabetes on basal insulin: A post hoc analysis of the LixiLan-L-CN study.

AIM: To compare the effects of iGlarLixi versus insulin glargine 100 U/mL (iGlar) on residual hyperglycaemia in Chinese people with uncontrolled type 2 diabetes (T2D) on prior basal insulin (BI) therapy ± oral antidiabetic drugs in the LixiLan-L-CN study (NCT03798080). MATERIALS AND METHODS: In this post hoc analysis, residual hyperglycaemia (i.e. HbA1c ≥ 7.0% [≥ 53 mmol/mol] and fasting plasma glucose [FPG] < 7.0 mmol/L) were assessed over 30 weeks. Outcomes were assessed at week 30 in participants with baseline residual hyperglycaemia, including changes from baseline in HbA1c, FPG, 2-hour postprandial glucose (PPG) and daily BI dose, the proportion of participants with HbA1c less than 7.0% (< 53 mmol/mol) and FPG less than 7.0 mmol/L and the incidence of hypoglycaemia. RESULTS: Of 421 participants, 124 (29.5%) had baseline residual hyperglycaemia (iGlarLixi, n = 64 [31.7%]; iGlar, n = 60 [29.1%]). At week 30, the residual hyperglycaemia rate decreased to 7.0% with iGlarLixi and increased to 43.3% with iGlar. Among participants with baseline residual hyperglycaemia, a greater proportion achieved both HbA1c and FPG targets at week 30 with iGlarLixi versus iGlar (43.8% vs. 16.7%), and iGlarLixi provided greater reductions in HbA1c (least squares mean [LSM] difference, -0.9% [-9.4 mmol/mol]) and 2-hour PPG (LSM difference, -4.7 mmol/L; both P < .001). Daily BI dose and incidence of hypoglycaemia were similar in the two groups. CONCLUSIONS: The findings of this post hoc analysis suggest that iGlarLixi had greater benefits than iGlar in reducing the rate of residual hyperglycaemia over 30 weeks in Chinese people with suboptimally controlled T2D on prior BI-based therapy.

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists: Exploring Their Impact on Diabetes, Obesity, and Cardiovascular Health Through a Comprehensive Literature Review.

Glucagon-like peptide-1 receptor agonists (GLP-1-RAs) are a novel class of medications promising for treating type 2 diabetes mellitus (T2DM) and obesity-related conditions such as cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). This comprehensive literature review examines available research on these medications, focusing on their mechanisms of action, clinical effectiveness, safety profiles, and socioeconomic implications. A comprehensive search was performed using the PubMed, EMBASE, and Cochrane Library databases. Although initially developed for glucose management, these drugs have also demonstrated efficacy in promoting weight loss and reducing the risk of CVD. GLP-1-RAs function similarly to naturally occurring incretins. They stimulate insulin secretion in response to glucose levels, inhibit glucagon release, delay stomach emptying, and generate a sense of fullness via brain pathways. Head-to-head clinical studies have indicated that GLP-1-RAs outperform conventional antidiabetic medicines in terms of glycemic management and weight reduction. According to cardiovascular outcome studies, various drugs in this category have been found to reduce the frequency of severe adverse cardiovascular events. A common side effect is gastrointestinal toxicity, which can be mitigated by gradually increasing the dose. Personalized treatment is likely because the effectiveness, safety, and dose regimens of currently available GLP-1-RAs differ. GLP-1-RAs are a superior choice for patients with T2DM, especially those who already have CVD or require weight-control support. The high cost of these drugs creates hurdles to access and fair healthcare. Current research mainly focuses on increasing therapeutic uses and producing orally delivered medicines with greater potency and bioavailability. Integrating GLP-1-RAs into clinical practice can enhance patient outcomes and reduce the community burden of cardiometabolic disease.

N-acyl glycines produced by commensal bacteria potentiate GLP-1 secretion as GPCR ligands.

Commensal microbiota is crucial for nutrient digestion and production of biologically active molecules, many of which mimic endogenous ligands of human GPCRs. Bacteroides spp. are among the most abundant bacteria residing in the human gut and their absence has been positively correlated with metabolic disorders. In the present study, we focused on N-acylated glycines (NAGlys) as products of Bacteroides spp. and potential GPCR ligands modulating GLP-1 secretion. Representative strains of the most abundant commensal Bacteroides were cultured in either yeast- or animal-based nutrient broths. The broths post-culture were investigated in terms of the contents of NAGlys and stimulatory effects towards GLP-1 production in GLUTag and NCI-H716 cell lines. Pure preparations of the detected NAGlys were further studied to evaluate stimulation of GLP-1 production and related cellular signalling evoked. The most potent NAGlys were also tested as ligands of key lipid GPCRs involved in the regulation of carbohydrate metabolism: GPR40/FFAR1, GPR55, GPR119, and GPR120/FFAR4. We found that Bacteroides potentiate GLP-1 production, depending on the strain and provided nutrient mix. Long-chain unsaturated oleoyl and arachidonoyl glycines, produced by B. thetaiotaomicron and B. intestinalis in the animal-based broth, were particularly effective in stimulation of GLP-1 secretion. They served as agonists of all the receptors under study expressed in GLP-1-producing cells. The obtained results broaden the knowledge of microbial signalling molecules and their role in regulation of carbohydrate homeostasis. They also emphasise the importance of balanced diet as a source of building blocks for commensal bacteria to produce efficient agonists of lipid GPCRs.

Fam3a-mediated prohormone convertase switch in α-cells regulates pancreatic GLP-1 production in an Nr4a2-Foxa2-dependent manner.

BACKGROUND: Fam3a has been demonstrated to regulate pancreatic ß-cell function and glucose homeostasis. However, the role and mechanism of Fam3a in regulating α-cell function remains unexplored. METHODS: Glucagon and glucagon-like peptide-1 (GLP-1) levels in pancreas and plasma were measured in global Fam3a knockout (Fam3a-/-) mice. Human islet single-cell RNA sequencing (scRNA-seq) datasets were utilized to analyze gene expression correlations between FAM3A and PCSK1 (encoding PC1/3, which processes proglucagon into GLP-1). Mouse pancreatic α-cell line αTC1.9 cells were transfected with Fam3a siRNA or plasmid for Fam3a knockdown or overexpression to explore the effects of Fam3a on PC1/3 expression and GLP-1 production. The downstream mediator (including Nr4a2) was identified by transcriptomic analysis, and its role was confirmed by Fam3a knockdown or overexpression in αTC1.9 cells. Based on the interacted protein of Nr4a2 and the direct binding to Pcsk1 promoter, the transcription factor Foxa2 was selected for further verification. Nuclear translocation assay and dual-luciferase reporter assay were used to clarify the involvement of Fam3a-Nr4a2-Foxa2 pathway in PC1/3 expression and GLP-1 production. Moreover, α-cell-specific Fam3a knockout (Fam3aα-/-) mice were constructed to evaluate the metabolic variables and hormone levels under normoglycemic, high-fat diet (HFD)-fed and streptozotocin (STZ)-induced diabetic conditions. Exendin 9-39 (Ex9), a GLP-1 receptor antagonist, was used to investigate GLP-1 paracrine effects in Fam3aα-/- mice and in their primary islets. RESULTS: Compared with wild-type mice, pancreatic and plasma active GLP-1 levels were increased in Fam3a-/- mice. Analysis of human islet scRNA-seq datasets showed a significant negative correction between FAM3A and PCSK1 in α-cells. Fam3a knockdown upregulated PC1/3 expression and GLP-1 production in αTC1.9 cells, while Fam3a overexpression displayed inverse effects. Transcriptomic analysis identified Nr4a2 as a key downstream mediator of Fam3a, and Nr4a2 expression in αTC1.9 cells was downregulated and upregulated by Fam3a knockdown and overexpression, respectively. Nr4a2 silencing increased PC1/3 expression, albeit Nr4a2 did not directly bind to Pcsk1 promoter. Instead, Nr4a2 formed a complex with Foxa2 to facilitate Fam3a-mediated Foxa2 nuclear translocation. Foxa2 negatively regulated PC1/3 expression and GLP-1 production. Besides, Foxa2 inhibited the transcriptional activity of Pcsk1 promoter at specific binding sites 10 and 6, and this inhibition was intensified by Nr4a2 in αTC1.9 cells. Compared with Flox/cre littermates, improved glucose tolerance, increased active GLP-1 level in pancreas and plasma, upregulated plasma insulin level in response to glucose, and decreased plasma glucagon level were observed in Fam3aα-/- mice. Primary islets isolated from Fam3aα-/- mice also showed an increase in active GLP-1 and insulin release. In addition, the insulinotropic effect of intra-islet GLP-1 were blocked by Ex9 in Fam3aα-/- mice and in their primary islets. Similarly, HFD-fed Fam3aα-/- mice also exhibited an improved glucose tolerance. Both HFD-fed and STZ-induced diabetic Fam3aα-/- mice showed an increased pancreatic active GLP-1 level, an elevated plasma insulin level and a reduced plasma glucagon level. CONCLUSIONS: Fam3a deficiency in α-cells enhances pancreatic GLP-1 production to improve ß-cell function via paracrine signaling in an Nr4a2-Foxa2-PC1/3-dependent manner. Our study unveils a novel strategy for reprogramming α-cell proglucagon processing output from glucagon to GLP-1 and deepen the understanding of crosstalk between α-cells and ß-cells.

Acute Pancreatitis Likely Due to Semaglutide.

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA) that has gained recent popularity in its effective management of type 2 diabetes mellitus (T2DM) and obesity. Minimal evidence has reported the link between Semaglutide use and acute pancreatitis. In this case report, we discuss the case of a 36-year-old female presenting to the Emergency Department with sudden-onset epigastric pain, subsequently diagnosed with acute pancreatitis. Moreover, she had recently started subcutaneous semaglutide injections for weight loss, which she had procured from one of her acquaintances without seeking medical advice. Semaglutide was thus stopped and her lipase levels normalized with significant improvement of her symptoms, making semaglutide the likely causative factor for her acute pancreatitis. Given the increased use of GLP-1RA, we aim to increase awareness among patients taking this medication whether prescribed or not and increase clinician awareness when prescribing this medication.

PIONEER REAL UK: A Multi-Centre, Prospective, Real-World Study of Once-Daily Oral Semaglutide Use in Adults with Type 2 Diabetes.

INTRODUCTION: Oral semaglutide provides an alternative to injectable glucagon-like peptide-1 receptor agonists (GLP-1RAs) for treatment of type 2 diabetes (T2D). The PIONEER REAL studies evaluate clinical outcomes of oral semaglutide treatment of T2D in a real-world setting. PIONEER REAL UK focused on adults living with T2D in the UK. METHODS: The multi-centre, prospective and non-interventional single-arm study enrolled 333 participants and followed them for 34-44 weeks. Participants were treated as part of routine clinical practice and had not been previously treated with injectable glucose-lowering medication. The primary endpoint was change in glycated haemoglobin (HbA1C) from baseline to end of study (EOS). Secondary endpoints included change in body weight, proportion of participants with HbA1C < 7% (53 mmol/mol) at EOS and proportion of participants with ≥ 1%-point HbA1C reduction and body weight reduction of ≥ 3% or ≥ 5% at EOS. Treatment satisfaction was assessed by Diabetes Treatment Satisfaction Questionnaire (DTSQ) status and change. RESULTS: Of 333 participants, 299 completed the study and 227 were on treatment at EOS. People treated with oral semaglutide experienced significantly reduced HbA1C by an estimated change of - 1.1%-points (95% CI - 1.27 to - 0.96; P < 0.0001) or - 12.2 mmol/mol (CI - 13.87 to - 10.47; P < 0.0001). Estimated change in body weight was - 4.8 kg (CI - 5.47 to - 4.12; P < 0.0001). At EOS, an HbA1C level < 7% (53 mmol/mol) was recorded in 46.3% of participants. A ≥ 1%-point reduction in HbA1C combined with a ≥ 3% reduction in body weight was observed in 36.4% of participants, and 27.1% had a ≥ 1%-point reduction in HbA1C and a ≥ 5% body weight reduction. Treatment satisfaction improved significantly during the study. No new safety concerns or cases of severe hypoglycaemia were reported. CONCLUSION: People living with T2D in the UK experienced a meaningful decrease in HbA1C and body weight after initiation of oral semaglutide treatment. No new safety issues were observed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04862923. Graphical plain language summary available for this article.

PIONEER REAL UK investigated the use of a tablet form of the medicine semaglutide in people living with type 2 diabetes in the UK. The purpose was to determine how well the tablet works for blood sugar control and weight loss in everyday clinical practice. The study followed 333 participants whose doctors had given them semaglutide tablets. Their blood sugar levels and body weight were measured before and after taking the semaglutide tablet for 34­44 weeks. The participants were also asked to fill out questionnaires about their treatment satisfaction and how it changed when taking the semaglutide tablet. The participants' blood sugar levels dropped a lot, and body weight was lowered by an average of 4.8 kg during the 34­44 weeks of the study. The participants were also more satisfied with their treatment at the end of the study than before taking the semaglutide tablet. Doctors treating the participants found the treatment to be a success in more than two-thirds of participants. The study also found that the semaglutide tablet was not associated with cases of too low blood sugar and was generally well tolerated. In summary, the semaglutide tablet is a good option for people living with type 2 diabetes who need better blood sugar control and would benefit from weight loss. The treatment is generally well tolerated, and people are very satisfied with it.

Comparative Effects of GLP-1 Agonists, Sleeve Gastrectomy and Roux-en-Y Gastric Bypass on Diabetes Mellitus Outcomes.

PURPOSE OF REVIEW: The purpose of this review is to assess the effects of glucagon-like peptide-1 (GLP-1) agonists, sleeve gastrectomy (SG), and Roux-en-Y gastric bypass (RYGB) on type 2 diabetes mellitus (T2DM) remission. This review explores the efficacy, safety, and durability of these surgical and medical modalities of diabetes management. RECENT FINDINGS: Studies have shown that GLP-1 agonists achieve higher rates of T2DM remission compared to standard glucose-lowering medications and lifestyle changes. In addition to weight loss, bariatric surgery has been found to be highly effective in treating and inducing remission of T2DM. Studies suggest that post-surgical patients see enhanced glycemic control. Both surgical interventions and GLP1 agonists are effective in achieving T2DM remission. Long-term follow-up and randomized controlled trials comparing bariatric surgery and GLP-1 agonists are necessary to evaluate their relative effectiveness in T2DM control. Further research is also needed to assess the combined effects of these treatment modalities.