Active Glucagon-like Peptide-1 Research Articles

Will Tirzepatide become a game-changer in the pharmacological treatment of obesity? - literature review

Introduction and objective: Obesity has become an important public health issue in Poland. Furthermore, it is one of the most common preventable causes of diseases and mortality. Pharmacological methods of treating obesity have been developing significantly in recent years.Tirzepatide is a new dual incretin receptor agonist that activates both GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptors. The aim of this review is to assess the effectiveness of this medication in reducing body weight. Current state of knowledge: According to data from the Central Statistical Office (GUS) in Poland, 65% of men and 49% of women are struggling with the issue of excessive body weight [1]. Obesity in Polish society is steadily increasing in every age group. However, it affects most significantly children aged 7-13 years and adolescents. In 2022, the novel dual GLP and GIP-1 agonist has been registered for the treatment of type 2 diabetes which is not satisfactorily controlled. It can be also used together with diet and physical activity in patients diagnosed with obesity (BMI of 30 kg/m2 or more) or who are overweight (BMI 27-30 kg/m2) and have weight-related health problems such as hypertension, metabolic syndrome, dislipidaemia and diabetes mellitus [2]. Summary: The increasing prevalence of obesity leads to a dynamic search for the most effective pharmacological methods of treating obesity. The combined activation of GLP-1 and GIP receptors by Tirzepatide has been shown to have additional benefits beyond satisfying glucose control. The biological mechanism of action of this medication additionally causes decreased food intake, slowed gastric emptying and enhanced insulin secretion, all of which can contribute to weight reduction.

‘Retatruide’ drug trial: A paradigm shift in Type 2 Diabetes management

Type 2 diabetes mellitus (T2DM) is a chronic medical condition characterised by persistent hyperglycemia caused by insulin resistance and impaired beta cell function. Typically, it occurs in individuals aged 45 and above, but due to the growing prevalence of obesity and sedentary lifestyle, it is increasingly being diagnosed in younger adults and adolescents. A positive family history of T2DM and specific genes such as TCF7L2 and PPARG also play an essential role.[1] Consequently, persistent hyperglycemia in type 2 DM can give rise to a range of microvascular complications such as retinopathy, neuropathy and nephropathy and macrovascular complications such as coronary artery and cerebrovascular diseases. T2DM accounts for 90% of the cases of diabetes, raising concern among the healthcare sector worldwide. In 2017, approximately 462 million individuals were affected by type 2 DM, accounting for 6.28% of the world’s population. By 2030, it is estimated that the global prevalence will rise to 7079 individuals per 100,000.[2] To prevent the complications caused by T2DM, it is essential to prioritize glycemic control. First and foremost, effective dietary control is pivotal. It has been established that obesity in individuals with T2DM is closely associated with insulin resistance and defects in insulin secretions thus managing the calorie intake is mandatory. However, pharmacologic intervention with oral glucose-lowering agents or insulin therapy is necessary when the patient’s blood glucose doesn’t fall within normal limits despite weight reduction, exercise and dietary modifications. The first line pharmacological agent used is Metformin, an oral medication that reduces glucose production in the liver. Additionally, insulin secretagogues such as sulfonylureas and glinides promote insulin release by stimulating beta cells. Thiazolidinediones is another example of an oral agent used to treat diabetes by enhancing glucose uptake by the muscle, liver and adipose tissue.[3] Furthermore, it is crucial to understand that the Incretin effect, responsible for stimulating insulin secretion after meals, is primarily mediated by gut-derived incretin hormones known as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). However, patients with type 2 diabetes (T2DM) commonly exhibit defects in this process. To address this issue, in addition to oral medications, injectable drugs such as RA-GLP1 (Semaglutide, Dulaglutide) are administered to emulate the actions of human GLP-1 effectively. These injectable treatments are vital in reducing postprandial hyperglycemia and have become indispensable in managing T2DM. ---Continue

Novel enzyme-resistant pancreatic polypeptide analogs evoke pancreatic beta-cell rest, enhance islet cell turnover, and inhibit food intake in mice.

Pancreatic polypeptide (PP) is a postprandial hormone secreted from pancreatic islets that activates neuropeptide Y4 receptors (NPY4Rs). PP is known to induce satiety but effects at the level of the endocrine pancreas are less well characterized. In addition, rapid metabolism of PP by dipeptidyl peptidase-4 (DPP-4) limits the investigation of the effects of the native peptide. Therefore, in the present study, five novel amino acid substituted and/or fatty acid derivatized PP analogs were synthesized, namely [P3]PP, [K13Pal]PP, [P3,K13Pal]PP, [N-Pal]PP, and [N-Pal,P3]PP, and their impact on pancreatic beta-cell function, as well as appetite regulation and glucose homeostasis investigated. All PP analogs displayed increased resistance to DPP-4 degradation. In addition, all peptides inhibited alanine-induced insulin secretion from BRIN-BD11 beta cells. Native PP and related analogs (10-8 and 10-6 M), and especially [P3]PP and [K13Pal]PP, significantly protected against cytokine-induced beta-cell apoptosis and promoted cellular proliferation, with effects dependent on the NPY4R for all peptides barring [N-Pal,P3]PP. In mice, all peptides, except [N-Pal]PP and [N-Pal,P3]PP, evoked a dose-dependent (25, 75, and 200 nmol/kg) suppression of appetite, with native PP and [P3]PP further augmenting glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) induced reductions of food intake. The PP peptides had no obvious detrimental effect on glucose tolerance and they did not noticeably impair the glucose-regulatory actions of GLP-1 or CCK. In conclusion, Pro3 amino acid substitution of PP, either alone or together with mid-chain acylation, creates PP analogs with benefits on beta-cell rest, islet cell turnover, and energy regulation that may be applicable to the treatment of diabetes and obesity.

Differential changes in appetite hormones post-prandially based on menstrual cycle phase and oral contraceptive use: A preliminary study

This was a preliminary study that examined whether appetite regulation is altered during the menstrual cycle or with oral contraceptives. Ten naturally cycling females (NON-USERS) and nine tri-phasic oral contraceptive using females (USERS) completed experimental sessions during each menstrual phase (follicular phase: FP; ovulatory phase: OP; luteal phase: LP). Appetite perceptions and blood samples were obtained fasted, 30, 60, and 90 min post-prandial to measure acylated ghrelin, active glucagon-like peptide-1 (GLP-1), and total peptide tyrosine tyrosine (PYY). Changes were considered important if p < 0.100 and the effect size was ≥medium. There appeared to be a three-way (group x phase x time) interaction for acylated ghrelin where concentrations appeared to be greater in USERS versus NON-USERS during the OP 90-min post-prandial and during the LP fasted, and 90-min post-prandial. In USERS, ghrelin appeared to be greater 90-min post-prandial in the OP versus the FP with no other apparent differences between phases. There were no apparent differences between phases in NON-USERS. There appeared to be a three-way interaction for PYY where concentrations appeared to be greater in USERS during the FP 60-min post-prandial and during the OP 30-min post-prandial. In USERS PYY appeared to be greater 60-min post-prandial during the OP versus the LP with no other apparent differences. There were no apparent differences between phases in NON-USERS. There appeared to be no effect of group or phase on GLP-1, or appetite perceptions. These data demonstrate small effects of menstrual cycle phase and oral contraceptive use on the acylated ghrelin and total PYY response to a standardized meal, with no effects on active GLP-1 or perceived appetite, though more work with a large sample size is necessary.

Low- and high-load resistance training exercise to volitional fatigue generate exercise-induced appetite suppression

Research on exercise-induced appetite suppression often does not include resistance training (RT) exercise and only compared matched volumes. PurposeTo compare the effects of low-load and high-load RT exercise completed to volitional fatigue on appetite-regulation. Methods11 resistance-trained males (24 ± 2 y) completed 3 sessions in a crossover experimental design: 1) control (CTRL); 2) RT exercise at 30% 1-repetition maximum (RM); and 3) RT exercise at 90% 1-RM. RT sessions consisted of 3 sets of 5 exercises completed to volitional fatigue. Acylated ghrelin, active glucagon-like peptide-1 (GLP-1), active peptide tyrosine (PYY), lactate, and subjective appetite perceptions were measured pre-exercise, 0-, 60-, and 120-min post-exercise. Energy intake was recorded the day before, of, and after each session. ResultsLactate was elevated following both 30% (0-, 60-, 120-min post-exercise) and 90% (0-, 60-min post-exercise; P < 0.001, d > 3.92) versus CTRL, with 30% greater than 90% (0-min post-exercise; P = 0.011, d = 1.14). Acylated ghrelin was suppressed by 30% (P < 0.007, d > 1.22) and 90% (P < 0.028, d > 0.096) post-exercise versus CTRL, and 30% suppressed concentrations versus 90% (60-min post-exercise; P = 0.032, d = 0.95). There was no effect on PYY (P > 0.171, ηp2 <0.149) though GLP-1 was greater at 60-min post-exercise in 90% (P = 0.052, d = 0.86) versus CTRL. Overall appetite was suppressed 0-min post-exercise following 30% and 90% versus CTRL (P < 0.013, d > 1.10) with no other differences (P > 0.279, d < 0.56). There were no differences in energy intake (P > 0.101, ηp2 <0.319). ConclusionsRT at low- and high-loads to volitional fatigue induced appetite suppression coinciding with changes in acylated ghrelin though limited effects on anorexigenic hormones or free-living energy intake were present.

Effects of dipeptidyl peptidase-4 inhibition in vivo: Dipeptidyl peptidase-4 inhibitor/gut microbiome crosstalk suggests novel therapeutic options for diabetes management.

Wang etal. report that clinical dipeptidyl peptidase-4 (DPP-4) inhibitors show little effect on microbial DPP-4 produced by Bacteroidesgenus. Furthermore, oral administration of microbial DPP-4 to high-fat diet-fed mice was found to reduce plasma active glucagon-like peptide-1 levels through an increase in extraluminal intestinal tissular DPP-4 activity, resulting in reduced glucose-induced insulin levels and exacerbated glucose tolerance.

A Review of Dipeptidyl Peptidase-4 (DPP-4) and its potential synthetic derivatives in the management of Diabetes Mellitus

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a type of oral medication used to treat type 2 diabetes mellitus (T2DM). They have become increasingly popular due to their effectiveness and safety in managing the condition. DPP-4 inhibitors function by inhibiting the enzyme that breaks down the incretin hormones, namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These medicines efficiently raise the levels of active GLP-1 and GIP by blocking DPP-4 activity. As a result, there is an increase in the production of insulin, a decrease in the release of glucagon, and a lowering of glucose levels after a meal. Multiple clinical trials have conclusively shown that DPP-4 inhibitors effectively lower glycated hemoglobin (HbA1c) levels. Certain studies have even proved their equivalent efficacy to other anti-diabetic medications such as metformin or sulfonylureas. Furthermore, DPP-4 inhibitors possess the benefit of being weight-neutral and exhibiting a little risk of hypoglycemia. These qualities render them a compelling option for patients with type 2 diabetes mellitus who are overweight or susceptible to hypoglycemia episodes. In general, DPP-4 inhibitors are a promising therapeutic choice for the management of type 2 diabetes mellitus (T2DM), offering effective regulation of blood sugar levels with a minimal likelihood of adverse effects. Nevertheless, it is important to acknowledge some restrictions and factors to take into account, including the possibility of heightened susceptibility to pancreatitis, nasopharyngitis, and certain drug-drug combinations. Additional investigation is necessary to completely clarify the long-term safety and potential supplementary advantages of DPP-4 inhibitors.

Systemic inflammation from the brain.

The actions of glucagon-like peptide 1 receptor agonists in the CNS reduce systemic inflammation.

Crosstalk between glucagon-like peptide 1 and gut microbiota in metabolic diseases.

Gut microbiota exert influence on gastrointestinal mucosal permeability, bile acid metabolism, short-chain fatty acid synthesis, dietary fiber fermentation, and farnesoid X receptor/Takeda G protein-coupled receptor 5 (TGR5) signal transduction. The incretin glucagon-like peptide 1 (GLP-1) is mainly produced by L cells in the gut and regulates postprandial blood glucose. Changes in gut microbiota composition and function have been observed in obesity and type 2 diabetes (T2D). Meanwhile, the function and rhythm of GLP-1 have also been affected in subjects with obesity or T2D. Therefore, it is necessary to discuss the link between the gut microbiome and GLP-1. In this review, we describe the interaction between GLP-1 and the gut microbiota in metabolic diseases. On the one hand, gut microbiota metabolites stimulate GLP-1 secretion, and gut microbiota affect GLP-1 function and rhythm. On the other hand, the mechanism of action of GLP-1 on gut microbiota involves the inflammatory response. Additionally, we discuss the effects and mechanism of various interventions, such as prebiotics, probiotics, antidiabetic drugs, and bariatric surgery, on the crosstalk between gut microbiota and GLP-1. Finally, we stress that gut microbiota can be used as a target for metabolic diseases, and the clinical application of GLP-1 receptor agonists should be individualized.

The crucial relationship between miRNA-27 and CSE/H2S, and the mechanism of action of GLP-1 in myocardial hypertrophy.

Cardiac hypertrophy is the most prevalent compensatory heart disease that ultimately leads to spontaneous heart failure. Mounting evidence suggests that microRNAs (miRs) and endogenous hydrogen sulfide (H2S) play a crucial role in the regulation of cardiac hypertrophy. In this study, we aimed to investigate whether inhibition of miR-27a could protect against cardiac hypertrophy by modulating H2S signaling. We established a model of cardiac hypertrophy by obtaining hypertrophic tissue from mice subjected to transverse aortic constriction (TAC) and from cells treated with angiotensin-II. Molecular alterations in the myocardium were quantified using quantitative real time PCR (qRT-PCR), Western blotting, and ELISA. Morphological changes were characterized by hematoxylin and eosin (HE) staining and Masson's trichrome staining. Functional myocardial changes were assessed using echocardiography. Our results demonstrated that miR-27a levels were elevated, while H2S levels were reduced in TAC mice and myocardial hypertrophy. Further luciferase and target scan assays confirmed that cystathionine-γ-lyase (CSE) was a direct target of miR-27a and was negatively regulated by it. Notably, enhancement of H2S expression in the heart was observed in mice injected with recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-27a and in cells transfected with a miR-27a inhibitor during cardiac hypertrophy. However, this effect was abolished by co-transfection with CSE siRNA and the miR-27a inhibitor. Conversely, injecting rAAV9-miR-27a yielded opposite results. Interestingly, our findings demonstrated that glucagon-like peptide-1 (GLP-1) agonists could mitigate myocardial damage by down-regulating miR-27a and up-regulating CSE. In summary, our study suggests that inhibition of miR-27a holds therapeutic promise for the treatment of cardiac hypertrophy by increasing H2S levels. Furthermore, our findings unveil a novel mechanism of GLP-1 agonists involving the miR-27a/H2S pathway in the management of cardiac hypertrophy.

Pharmacological and Clinical Studies of Medicinal Plants That Inhibit Dipeptidyl Peptidase-IV.

Dipeptidyl peptidase IV (DPP-IV) is an enzyme responsible for the degradation of the incretin hormone glucagon-like peptide-1 (GLP-1). DPP-IV plays a significant role in regulating blood glucose levels by modulating the activity of GLP-1. In the context of diabetes, DPP-IV inhibitors effectively block the activity of DPP-IV, hence mitigating the degradation of GLP-1. This, in turn, leads to an extension of GLP-1's duration of action, prolongs gastric emptying, enhances insulin sensitivity, and ultimately results in the reduction of blood glucose levels. Nonetheless, reported adverse events of DPP-IV inhibitors on T2DM patients make it essential to understand the activity and mechanism of these drugs, particularly viewed from the perspective of finding the effective and safe add-on medicinal plants, to be implemented in clinical practice. This review is intended to bring forth a thorough overview of plants that work by reducing DPP-IV activity, from computational technique, enzymatic study, animal experiments, and studies in humans. The articles were searched on PubMed using "Plants", "DPP-IV", "DPP-IV inhibitor", "GLP-1", "Type 2 diabetes", "diabetes", "in silico", "in vitro", "in vivo", "studies in human", "clinical study" as the query words, and filtered for ten years of publication period. Eighteen plants showed inhibition against DPP-IV as proven by in silico, in vitro, and in vivo studies; however, only ten plants were reported for efficacy in clinical studies. Several plant-based DPP-IV inhibitors, eg, Allium sativum, Morus Alba, Curcuma longa, Pterocarpus marsupium, and Taraxacum officinale, have established their functional role in inhibiting DPP-IV and have proven their effectiveness through studies in humans earning them a prominent place in therapeutic discovery.

Expression of the GCG gene and secretion of active glucagon-like peptide-1 varies along the length of intestinal tract in horses.

Active glucagon-like peptide-1 (aGLP-1) has been implicated in the pathogenesis of equine insulin dysregulation (ID), but its role is unclear. Cleavage of proglucagon (coded by the GCG gene) produces aGLP-1 in enteral L cells. The aim in vivo was to examine the sequence of the exons of GCG in horses with and without ID, where aGLP-1 was higher in the group with ID. The aims in vitro were to identify and quantify the expression of GCG in the equine intestine (as a marker of L cells) and determine intestinal secretion of aGLP-1. Genomic studies were case-control studies. Expression and secretion studies in vitro were cross-sectional. The GCG gene sequence of the exons was determined using a hybridisation capture protocol. Expression and quantification of GCG in samples of stomach duodenum, jejunum, ileum, caecum and ascending and descending colon was achieved with droplet digital PCR. For secretory studies tissue explants were incubated with 12 mM glucose and aGLP-1 secretion was measured with an ELISA. Although the median [IQR] post-prandial aGLP-1 concentrations were higher (p = 0.03) in animals with ID (10.2 [8.79-15.5]), compared with healthy animals (8.47 [6.12-11.7]), there was 100% pairwise identity of the exons of the GCG sequence for the cohort. The mRNA concentrations of GCG and secretion of aGLP-1 differed (p < 0.001) throughout the intestine. Only the exons of the GCG gene were sequenced and breeds were not compared. The horses used for the study in vitro were not assessed for ID and different horses were used for the small, and large, intestinal studies. Differences in post-prandial aGLP-1 concentration were not due to a variant in the exons of the GCG gene sequence in this cohort. Both the large and small intestine are sites of GLP-1 secretion.

Melatonin-mediated IGF-1/GLP-1 activation in experimental OCD rats: Evidence from CSF, blood plasma, brain and in-silico investigations

Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition characterized by intrusive, repetitive thoughts and behaviors. Our study uses a validated 8-OH-DPAT-induced experimental model of OCD in rodents. We focus on the modulatory effects of Insulin-like growth factor-1 (IGF-1) and glucagon-like peptide-1 (GLP-1), which are linked to neurodevelopment and survival. Current research investigates melatonin, a molecule with neuroprotective properties and multiple functions. Melatonin has beneficial effects on various illnesses, including Alzheimer's, Parkinson's, and depression, indicating its potential efficacy in treating OCD. In the present study, we employed two doses of melatonin, 5 mg/kg and 10 mg/kg, demonstrating a dose-dependent effect on 8-OH-DPAT-induced rat changes. In addition, the melatonin antagonist luzindole 5 mg/kg was utilized to compare and validate the efficacy of melatonin. In-silico studies alsocontribute to understanding the activation of IGF-1/GLP-1 pathways by melatonin. Current research indicates restoring neurochemical measurements on various biological samples (brain homogenates, CSF, and blood plasma) and morphological and histological analyses. In addition, the current research seeks to increase understanding of OCD and investigate potential new treatment strategies. Therefore, it is evident from the aforementioned research that the protective effect of melatonin can serve as a strong basis for developing a new OCD treatment by upregulating IGF-1 and GLP-1 levels. The primary focus of current study revolves around the examination of melatonin as an activator of IGF-1/GLP-1, with the aim of potentially mitigating behavioral, neurochemical, and histopathological abnormalities in an experimental model of obsessive–compulsive disorder caused by 8-OH-DPAT in adult Wistar rats.

Evaluating the In Situ Insulinotropic Effects of Pea Protein Hydrolysates Mediated by Active GLP-1 via a 2D and Dual-Layered Coculture Cell Model.

The aim of this study was to evaluate the in situ insulinotropic effects of pea protein hydrolysates (PPHs) mediated by active glucagon-like peptide-17-36 (active GLP-1) using a 2D and dual-layered coculture cell model. Following this model, a mixed Caco-2 and NCI-H716 cell monolayer was differentiated on the apical side to study the effects of PPHs on active GLP-1 levels; meanwhile, the beta-TC-6 cells were seeded on the basolateral side to investigate the insulin responses induced by active GLP-1. The in situ DPP-4 half-maximal inhibitory concentration (IC50) of PPHs, PPHs-120G, and PPHs-120I was 2.94, 3.43, and 2.26 mg/mL, respectively. They directly stimulated active GLP-1 secretion in NCI-H716 cells by 3.03 ± 0.21, 1.99 ± 0.03, and 2.24 ± 0.02 times, respectively. Insulin release in beta-TC-6 cells was directly stimulated by PPHs but not by PPHs-120G and PPHs-120I. Interestingly, PPHs-120G and PPHs-120I indirectly stimulated insulin release in this coculture cell model by enhancing active GLP-1 concentrations. More importantly, PPHs, PPHs-120G, and PPHs-120I increase active GLP-1 levels by their dual function of stimulating active GLP-1 secretion and DPP-4 inhibition. This study suggests that the 2D and dual-layered coculture cell model supports a more comprehensive assessment of in situ insulinotropic effects of protein hydrolysates mediated by active GLP-1.

Evaluation of postprandial total triglycerides within the TIGG model for characterizing postprandial response of glucose, insulin, and GLP-1.

The TIGG model is the first model to integrate glucose and insulin regulation, incretin effect, and triglyceride (TG) response in the lipoprotein subclasses of chylomicrons and VLDL-V6. This model described the response following a high-fat meal in individuals who are lean, obese, and very obese and provided insights into the possible regulation of glucose homeostasis in the extended period following a meal. Often, total TGs are analyzed within clinical studies, instead of lipoprotein subclasses. We extended the existing TIGG model to capture the observed total TGs and determined if this model could be used to predict the postprandial TG response of chylomicron and VLDL-V6 when only total TGs are available. To assess if the lipoprotein distinction was important for the model, a second model (tTIGG) was developed using only the postprandial response in total TGs, instead of postprandial TG response in chylomicrons and VLDL-V6. The two models were compared on their predictability to characterize the postprandial response of glucose, insulin, and active GLP-1. Both models were able to characterize the postprandial TG response in individuals who are lean, obese, or very obese following a high-fat meal. The extended TIGG model resulted in a better model fit of the glucose data compared to the tTIGG model, indicating that chylomicron and VLDL-V6 provided additional information compared to total TGs. Furthermore, the expanded TIGG model was able to predict the postprandial TG response of chylomicrons and VLDL-V6 using the total TGs and could therefore be used in studies where only total TGs were collected.

Denosumab Improves Glycaemic Parameters in Postmenopausal Osteoporosis Patients with Combined Type 2 Diabetes Mellitus.

This study aimed to determine whether RANKL inhibitors in postmenopausal osteoporosis patients with combined type 2 diabetes mellitus (T2DM) could improve their glucose metabolism index. First of all, 84 patients affected with postmenopausal osteoporosis with combined T2DM attending the Department of Endocrinology at the Third Hospital of Hebei Medical University were selected and randomized into two groups of 42 patients each. One group was given Denosumab 60 mg once every six months (denosumab group, D.G.), and the other group was given 2 mg ibandronate once every three months (ibandronate group, I.G.). Blood glucose parameters were compared before and after treatment in both groups and serum active GLP-1 levels and DPP-4 levels were also assessed. After treatment, there was no significant difference in fasting glucose between the two groups, but there was a significant decrease in fasting glucose in the Denosumab Group (D.G.) compared to before treatment. There was a significant difference in 2-hour postprandial glucose (2hPG) between the two groups after treatment, with the D.G. being lower than the ibandronate group (I.G.). Glycosylated haemoglobin (HbA1c) was lower in the D.G. than in the I.G. after treatment, but the difference between them was insignificant. In the D.G., serum active GLP-1 levels increased after treatment, and serum DPP-4 levels decreased. Serum GLP-1 and DPP-4 levels in the I.G. did not change compared with those before treatment. In conclusion, In the clinical management of postmenopausal osteoporosis patients with combined T2DM, the choice of RANKL inhibitors as anti-osteoporosis therapy may benefit their glycaemic parameters by elevating serum active GLP-1 levels and decreasing serum DPP-4 levels.

Implications of Ozempic and Other Semaglutide Medications for Facial Plastic Surgeons.

Obesity is a growing global health concern, leading to various health issues, including diabetes. Semaglutide-based medications, such as Ozempic, Wegovy, and Rybelsus, have emerged as potential treatments. These medications, belonging to the glucagon-like peptide-1 (GLP-1) receptor agonist class, mimic the action of GLP-1, regulating appetite and promoting weight loss. Clinical trials have shown their effectiveness in reducing body weight and improving metabolic parameters. Ozempic, though Food and Drug Administration-approved for diabetes, is also used off-label for weight loss alone. Rapid weight and fat loss with Ozempic can lead to the characteristic "Ozempic face," where facial volume and fat are depleted, resulting in wrinkles and sagging skin. Providers prescribing Ozempic seldom counsel patients about the potential impact on the face. As a result, the plastic surgery community faces a challenge in managing facial changes associated with rapid weight loss. Dermal fillers, skin tightening techniques, and surgical interventions are useful for both restoration of facial volume and to manage excess skin. Discontinuation of Ozempic should be considered prior to general anesthesia due to gastrointestinal side effects including delayed gastric emptying. As the popularity of Ozempic grows, facial plastic surgeons must be aware of both the impact on facial appearance and perioperative considerations.

Transepithelial Transport of the Bifunctional Peptide IPYWTY Indirectly Induced Insulin Release Mediated by Active GLP-1.

There is currently no appropriate cell model suitable for evaluating the insulinotropic effects of DPP-4 inhibitory peptides (DPP-4IPs) mediated by active glucagon-like peptide-17-36 (active GLP-1). The study aims to evaluate the transepithelial transport of IPYWTY on its in situ insulinotropic effects by using a 2D and dual-layered coculture cell model that consists of Caco-2 and NCI-H716 cells on the apical (AP) side and β-TC-6 cells on the basolateral (BL) side. During transportation, IPYWTY was absorbed in its intact form through PepT1 and paracellular transport. Meanwhile, it was degraded to several peptide fragments, including PYWTY, YWTY, WTY, and IPY, which decreased its in situ DPP-4 inhibitory activity. IPYWTY does not directly stimulate insulin release in β-TC-6 cells, while it increased the active GLP-1 level from 76.57 ± 15.16 to 95.63 ± 1.99 pM (1.25 times) in NCI-H716 cells. Interestingly, IPYWTY indirectly increased insulin levels from 426.91 ± 6.07 to 573.94 ± 2.97 μIU/mL (1.34 times) in the 2D and dual-layered coculture cell model for its dual function of stimulating active GLP-1 secretion and DPP-4 inhibition. These results suggested that the 2D and dual-layered coculture cell model is an alternative strategy for effectively evaluating the insulinotropic effects of DPP-4IPs mediated by active GLP-1.

Interleukin-6 is not involved in appetite regulation following moderate-intensity exercise in males with normal weight and obesity.

In obesogenic states and after exercise, interleukin (IL)-6 elevations are established, and IL-6 is speculated to be an appetite-regulating mechanism. This study examined the role of IL-6 on exercise-induced appetite regulation in sedentary normal weight (NW) males and those with obesity (OB). Nine NW participants and eight participants with OB completed one non-exercise control (CTRL) and one moderate-intensity continuous training (MICT; 60 minutes, 65% V̇O2max ) session. IL-6, acylated ghrelin, active peptide tyrosine-tyrosine3-36 , active glucagon-like peptide-1, and overall appetite perceptions were measured fasted, pre exercise, and 30, 90, and 150 minutespost exercise. Fasted IL-6 concentrations were elevated in OB (p = 0.005, = 0.419); however, increases following exercise were similar between groups (p = 0.934, = 0.000). Acylated ghrelin was lower in OB versus NW (p < 0.017, d > 0.84), and OB did not respond to MICT (p > 0.512, d < 0.44) although NW had a decrease versus CTRL (p < 0.034, d > 0.61). IL-6 did not moderate/mediate acylated ghrelin release after exercise (p > 0.251). There were no observable effects of MICT on tyrosine-tyrosine3-36 , glucagon-like peptide-1, or overall appetite (p > 0.334, < 0.062). These results suggest that IL-6 is not involved in exercise-induced appetite suppression. Despite blunted appetite-regulatory peptide responses to MICT in participants with OB, NW participants exhibited decreased acylated ghrelin; however, no differences in appetite perceptions existed between CTRL and MICT or NW and OB.

A New Hope for Treating Obesity Pandemic

A new class of drugs is transforming obesity treatment in an unprecedented manner. Scientists are amazed by their potency in the treatment of obesity. Glucagon-like peptide 1 (GLP-1) analogs are a class of medications used to treat type 2 diabetes mellitus. These analogs mimic the action of GLP-1, a hormone released by the intestine in response to food intake. GLP-1 analogs have been extensively studied, and scientists have made several important discoveries about their effects and potential therapeutic applications. GLP-1 analogs have shown significant efficacy in improving glycemic control in patients with type 2 diabetes. They stimulate insulin secretion from pancreatic beta cells, suppress glucagon secretion (which reduces hepatic glucose production), and slow down gastric emptying, leading to reduced postprandial glucose levels. Apart from their controlling glycemic index, GLP-1 analogs are shown to offer cardio-protective, reno-protective, and neuroprotective benefits. However, their most surprising and potent effects have been observed in the context of weight loss. Two drugs from this class, semaglutide, and tripeptide, have shown efficacy in recent clinical trials. Tirzepatide was effective in significantly reducing body weight in about half of the participants in a recent clinical trial. In another trial, semaglutide was able to reduce 20% of the body weight of about one-third of the participants. However, not everyone is benefiting from these medications. There are still significant challenges in determining who will benefit from these medications and to what extent. These challenges are currently being addressed. It has been observed that the new drugs work best in people who become hungry in between meals. People with obesity can be classified into four categories; those who need to eat more to reach fullness; those who reach fullness with a regular-sized meal but feel hungry again soon (hungry gut); those who eat to cope with emotions; and those with a relatively slow metabolism. It is not known why people with a ‘hungry gut’ respond most effectively to the new drugs, but one hypothesis suggests that these patients have low levels of GLP-1 hormones, and that’s why they have obesity. When they get a replacement in the form of GLP-1 analogs, they do extremely well. Another study with a GLP-1-mimicking drug called liraglutide found that patients with low GLP-1 levels reduced twice as much weight compared to the general population after using the drug for one year. Both semaglutide and tripeptide are given once weekly, thus increasing treatment compliance. Because of their weekly regimen, the drugs will also help people with erratic schedules and work shifts. Some of the other medications have to be taken at a certain time of day, which can be difficult for those with irregular sleep schedules. Another important question is to find out how long these drugs' weight loss benefits remain. One study concluded that semaglutide’s weight-reducing effects last as long as the patients remain on medication. This means that these drugs will be given chronically to obese patients. Whether ‘chronic’ means ‘life-long’ in this context is still to be determined. Perhaps an even more important question that clinicians face is determining how much weight loss is too much, especially when muscle loss is also involved. More research is needed to find a balance where these drugs are used not only for weight reduction but to treat a person for health, prevent disease, and improve quality of life.