Receptor Analogues Research Articles

8088 Connecting the Dots: Semaglutide, Constipation, and Diverticulitis - A case report

Abstract Disclosure: K. Tiwari: None. F. Sajid: None. J.G. Karam: None. Introduction: Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes mellitus and weight management. Common side effects, primarily gastrointestinal (>10%), include nausea, vomiting, diarrhea, and constipation. Here, we present a case of acute sigmoid diverticulitis with an adjacent abscess in a patient who was recently initiated on GLP-1 receptor agonist therapy. Case presentation: A 76-year-old female with a medical history of type 2 diabetes mellitus on metformin and empagliflozin, hypertension, chronic kidney disease stage 3A, obesity (BMI: 43), and no known history of diverticulosis was started on semaglutide for additional glycemic, renal, and weight loss benefits, given suboptimal control of her obstructive sleep apnea, blood pressure, and knee arthritis. She received semaglutide subcutaneously at a dose of 0.25 mg weekly for 4 weeks, followed by an increased dosage of 0.5 mg for one week. However, she experienced a slight worsening of underlying constipation as a side effect. On the sixth week of therapy, she started having progressive lower abdominal pain with nausea, chills, and diarrhea, for which she presented to the Emergency Department. She was found to have leukocytosis, and a Computed Tomography (CT) of the abdomen/pelvis revealed peri-colonic fat stranding in the mid-ascending colon, wall thickening in the distal sigmoid colon, and a low-density fluid collection abutting the sigmoid/descending colonic wall, indicative of diverticulitis with a small abscess. She was admitted to the hospital for six days and was treated conservatively with Intravenous (IV) antibiotics, and her diet was slowly advanced as tolerated. Semaglutide was discontinued, and the patient was discharged home with outpatient endocrinology and gastrointestinal follow-up. A post-discharge colonoscopy showed diffuse diverticulosis. Conclusion: Constipation and old age are common risk factors for diverticulitis. While GLP1-1 receptor analogs have proven significant and multiple benefits, more knowledge about associated gastrointestinal complications resulting from slower food transit in the gastrointestinal tract is emerging. Older patients with underlying constipation and/or diverticulosis should particularly be monitored and treated for worsening constipation to avoid complications such as acute diverticulitis. Vigilance and awareness in recognizing and managing this potential complication are crucial with the wider indications and use of GLP-1 receptor analogs. Presentation: 6/3/2024

7672 Ketosis-Prone Diabetes - A Case Series

Abstract Disclosure: T. Ismail: None. A. Farooq: None. G. Acharya: None. J. Snitzer: None. Introduction Ketosis-prone diabetes (KPD) is a syndrome that primarily affects African Americans. It is characterized by ketoacidosis, which is like Type 1 Diabetes Mellitus (T1DM). KPD is unique because it lacks identifiable autoimmunity and has a relative insulin deficiency, resembling Type 2 Diabetes Mellitus (T2DM). Therefore, KPD is informally classified as Type 1.5 Diabetes Mellitus. However, the clinical course and outcomes of KPD are like those of T2DM, and managing blood sugar levels is possible through non-insulin antidiabetic medications and dietary interventions. Case Series: Our study involved six patients who were all of African-American ethnicity. There were an equal number of male and female patients, with ages ranging from 21 to 61 years. One patient had a BMI of 27.2, which is considered overweight, while the rest had a BMI in the obese category ory(BMI>30). Two out of six patients had a pre-existing diagnosis of type 2 diabetes mellitus (T2DM) before the initial diabetic ketoacidosis (DKA) event. One patient had prediabetes. All patients required hospitalization for ketoacidosis and hyperglycemia and were found to have a glycated hemoglobin (HbA1c) level of more than 10% during these DKA events. All patients received intravenous hydration and insulin drip treatment and were discharged with a combination of long and rapid-acting insulin regimens. Following the resolution of the first episode of diabetic ketoacidosis (DKA), all six patients experienced a decrease in their insulin requirements for optimal glycemic control. Currently, four patients have discontinued insulin entirely. Moreover, all six patients tested negative for the presence of GAD-65, insulin, and islet antigen-2 antibodies. Among the patients, only one had a previously established autoimmune disease, i.e., inflammatory bowel disease. None of the patients experienced a repeat episode of diabetic ketoacidosis. Conclusion: It is important to note that not all patients who present with Diabetic ketoacidosis have Type 1 Diabetes Mellitus (T1DM). Hence, checking auto-antibodies for T1DM before making a final diagnosis is crucial. C-peptide levels may not accurately reflect the degree of relative permanent insulin deficiency in this population if measured during or immediately after an episode of diabetic ketoacidosis due to glucose toxicity and other factors. Given its prevalence in obese individuals, weight loss through dietary modifications and GLP-1 receptor analogs may be beneficial. Presentation: 6/3/2024

Retrospective review of seven patients with obesity simultaneously treated with a combination of a glucagon-like peptide-1 receptor agonist and a meal replacement product

BackgroundThe use of meal replacement products (MRPs) to obtain a caloric deficit while maintaining micro- and macronutrient requirements, has a long tradition in obesity medicine. Limitations include low compliance, variability in efficacy, adverse events (related to acute changes in nutrient intake), and risk of weight regain when discontinued, and their popularity has declined after the emergence of potent GLP-1 receptor analogues (GLP1-RAs). However, GLP-1RAs have limitations, including dose-dependent risk for adverse events (AEs), high cost, as well as weight regain when discontinued. Although concomitant use of MRPs and GLP-1RAs could address some of the limitations, there is a scarcity of data reported on this. Herein we report real world clinical experience of such combined use. MethodsThis retrospective case evaluation involved people with obesity that concomitantly used MRPs (Optifast) and a GLP-1RA and were followed at one of three weight management centers in Australia or South Africa. Parameters collected were gender, age, co-morbidities, height, weight, frequency/amount of MRPs used, dose/type of GLP-1RA used, duration of combined use, and occurrence of AEs. Written informed consent for use of data was obtained from each individual, and the data were managed in an anonymized form and summarized descriptively. ResultA total of seven (5 females) individuals (mean [min, max] age 49 [30,66] years, BMI 44.8 [30.7, 57.9] kg/m2) initiated either semaglutide (n=4) or liraglutide (n=3) concomitantly with daily MRPs (starting number of servings/day 2.7 [1,6]) for a duration of 12 [4, 25] months. Change in weight/BMI/% TBW was -32.0 (-9.6, -77.8) kg/-10.3 (-3.4, -24.5) kg/m2/-24.2 %. Five individuals experienced ≥1 GLP-1RA related AE (nausea, reflux, burping, diarrhea, constipation). One individual discontinued GLP-1RA, whereas two persons discontinued the use of MRPs. ConclusionsMRPs can be initiated concomitantly with a GLP-1 RA for weight management. This might enhance weight-loss effectiveness, with potential additional benefits that should be elucidated in further and larger studies.

48 Dietary functional fiber properties for improved health and disease outcomes in pigs

Abstract In swine production, using feed antibiotics as antimicrobial growth promotants has been reduced; thus, feed alternatives to manage gut health are required. Dietary fiber and similar carbohydrate structures such as resistant starch, oligosaccharides, and exopolysaccharides are nutritional tools that may enhance gut health in pigs. Dietary fiber may have a role to alleviate diarrheal diseases including in pigs post-weaning but can also reduce constipation in sows, but specific functionality depends on fiber properties. Antibiotics are hypothesized to influence gut health via modulation of intestinal microbial profiles; fermentation and intestinal inflammation are considered important mechanisms. Dietary fiber sources differ in a key functional property: fermentability. Rapid fermentation of fiber and oligosaccharides is associated with changes in microbial profiles and increased metabolite production. Recently, microbial composition was hypothesized to be less important and combined output of metabolites should be the focus. Fiber properties may also manipulate retention time and physico-chemical properties of the undigested residue; hence, non-fermentable fiber may prevent constipation in sows. The fiber-like structure resistant starch is not digested and acts as fermentable fiber but has unique properties, because it specifically increases intestinal abundance of bifidobacteria, which are associated with improved gut health. Using crop breeding, feed processing, and feed additives, the structure of fiber and starch can be altered thereby changing its degradation kinetics and affecting its prebiotic activity. Finally, fiber-like structures such as exopolysaccharides from Limosilactobacillus reuteri and unique oligosaccharides may serve as receptor analogues for pathogenic bacteria, e.g., enterotoxigenic Escherichia coli (ETEC). These receptor analogues block lectin domains of bacterial adhesins and thus prevent adherence of pathogens to the gut wall, thereby avoiding initiation of post-weaning diarrhea. In conclusion, dietary fiber and similar structures possess important functional properties that may also provide important solutions to maintain gut health in pigs.

Liraglutide effects on epicardial adipose tissue micro-RNAs and intra-operative glucose control

Background and aimEpicardial adipose tissue (EAT) plays a role in coronary artery disease (CAD). EAT has regional distribution throughout the heart and each location may have a different genetic profile and function. Glucagon like peptide-1 receptor analogs (GLP-1RAs) reduce cardiovascular risk. However, the short-term effects of GLP-1RA on microRNA (miRNA) profile of each EAT location is unknown. Objective was to evaluate if EAT miRNAs were different between coronary (CORO-EAT), left atrial EAT (LA-EAT) and subcutaneous fat (SAT), and liraglutide can modulate EAT miRNAs expression. Methods and resultsThis was a 12-week randomized, double-blind, placebo-controlled study in 38 patients with type 2 diabetes (T2DM) and coronary artery disease (CAD) who were started on either liraglutide or placebo for a minimum of 4 up to 12 weeks prior to coronary artery by-pass grafting (CABG). Fat samples were collected during CABG. miR16, miR155 and miR181a were significantly higher in CORO-EAT and in LA-EAT than SAT (p < 0.01 and p < 0.05) in overall patients. miR16 and miR181-a were significantly higher in CORO-EAT than SAT (p < 0.01), and miR155 and miR181a were higher in LA-EAT than SAT (p < 0.05) in the liraglutide group. Liraglutide-treated patients had better intra-op glucose control than placebo (146 ± 21 vs 160 ± 21 mg/dl, p < 0.01). ConclusionsOur study shows that CORO- and LA-miRNAs profiles were significantly different than SAT miRNAs in overall patients and miRNAs were significantly higher in CORO-EAT and LA-EAT than SAT in the liraglutide group. Pre-op liraglutide was also associated with better intra operative glucose control than placebo independently of weight loss.

Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice.

The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of the MC3R and the melanocortin system in regulating the response to various anorexigenic agents. The genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness to glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor leptin demonstrated that increased sensitivity to anorectic agents was a generalized result of MC3R antagonism. We observed enhanced neuronal activation in multiple hypothalamic nuclei using Fos IHC following low-dose liraglutide in MC3R-KO mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits that control multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r-/- mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may have value in enhancing the dose-response range of obesity therapeutics.

The synergistic potential of GLP-1R agonist dulaglutide and ghrelin receptor analogue anamorelin in ameliorating muscle atrophy

Muscle atrophy represents a multifaceted and intricate syndrome characterized by the reduction in both mass and strength of skeletal muscles, leading to muscle dysfunction and weakness. Its potential causes encompass aging, denervation, disuse, and various diseases. One well-known pharmacological agent for glycemic control in diabetes patients is the glucagon-like peptide-1 receptor (GLP-1R) agonist. Our recent research findings have shown that compounds such as exendin-4 (Ex-4) or dulaglutide can effectively mitigate muscle atrophy in dexamethasone (Dex)-induced cellular and animal models as well as chronic kidney disease (CKD) and rodent sarcopenia models. However, it’s noteworthy that these agents may concurrently induce a decrease in body weight following administration, posing challenges when considering them as potential treatments for muscle atrophy in cachectic and sarcopenic conditions. Ghrelin, being the sole circulating orexigenic hormone known to be associated with growth hormone release, offers a potential solution to counterbalance the appetite-inhibiting effect of GLP-1R agonists. Additionally, ghrelin enhanced muscle anabolism and exerted protective effects for muscle atrophy. Therefore, combination of a GLP-1R agonist and a ghrelin analogue emerges as a synergistic therapeutic approach to effectively combat muscle atrophy.

Evaluation of the safety, biodistribution, dosimetry of [18F]AlF-NOTA-LM3 and head-to-head comparison with [68Ga]Ga-DOTATATE in patients with well-differentiated neuroendocrine tumors: an interim analysis of a prospective trial.

18F-labelled somatostatin receptor (SSTR) analogs offer several advantages over 68Ga in terms of yield, cost, spatial resolution and detection rate. This study presents an interim analysis of a prospective trial designed to assess the safety, biodistribution and dosimetry of [18F]AlF-NOTA-LM3, and compare its diagnostic efficacy and clinical management outcomes with [68Ga]Ga-DOTATATE or [68Ga]Ga-NODAGA-LM3 in patients with well-differentiated NETs. Twenty-one patients with histologically confirmed well-differentiated neuroendocrine tumors (G1 and G2) were prospectively recruited. The first eight patients underwent serial PET scans at 5, 15, 30, 45, 60, and 120min after [18F]AlF-NOTA-LM3 injection to assess biodistribution and dosimetry. The remaining patients underwent whole-body PET/CT scans. [18F]AlF-NOTA-LM3 and [68Ga]Ga-DOTATATE PET/CT were done within a week, with a minimum 24-hour interval between the two scans. Focal uptake above the surrounding background activity and could not be explained by physiologic uptake was considered lesions of NETs. Lesion number, tumor uptake, and tumor-to-background ratio (TBR) were compared. In patients with discrepant findings, the size of the smallest lesions (measured on coregistered CT) detected on [68Ga]Ga-DOTATATE and [18F]AlF-NOTA-LM3 was compared. [18F]AlF-NOTA-LM3 was safe and well-tolerated. Physiological uptake of [18F]AlF-NOTA-LM3 was significantly lower than that of [68Ga]Ga-DOTATATE in abdominal organs and bone marrow, but higher in blood pool and lung. The mean effective dose was 0.024 ± 0.014 mSv/MBq. [18F]AlF-NOTA-LM3 detected significantly more liver lesions (457 vs. 291, P = 0.006) and lymph node lesions (30 vs. 22, P = 0.011) compared to [68Ga]Ga-DOTATATE. The tumor uptake was comparable, but TBR was significantly higher with [18F]AlF-NOTA-LM3 for lesions from all sites except for the duodenum. The size of the minimum liver lesions (0.54 ± 0.15 vs. 1.01 ± 0.49, P<0.001) and lymph node lesions (0.50 ± 0.19 vs. 1.26 ± 0.86, P = 0.024) detected on [18F]ALF-NOTA-LM3 were significantly smaller than those detected on [68Ga]Ga-DOTATATE. [18F]AlF-NOTA-LM3 shows favorable biodistribution, higher spatial resolution and superior performance than [68Ga]Ga-DOTATATE in detecting liver and lymph node metastases, with higher TBR. Notably, it is the first SSTR analog to show superiority in detecting lymph node lesions when compared to [68Ga]Ga-DOTATATE. ClinicalTrials.gov identifier NCT06056362.

Efficacious use of GLP-1 receptor analogue in type 1 diabetes complicated by class 3 obesity

Efficacious use of GLP-1 receptor analogue in type 1 diabetes complicated by class 3 obesity

The Application of 68Ga-Somatostatin Analog and 18F-FDG PET/CT for Bone Metastasis from Neuroendocrine Tumors

Introduction: Aims of the study were to assess the differences in the diagnostic efficacy of 68Ga-somatostatin receptor analogs (68Ga-SSAs) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for detecting bone metastases in neuroendocrine neoplasm (NEN) and to analyze the correlation between imaging features and clinical features of BMs. Methods: We retrospectively analyzed the clinical and imaging data of 213 NEN patients who underwent 68Ga-SSA PET/CT and were finally diagnosed as BMs by pathology or follow-up. Of those, 103 patients underwent 18F-FDG PET/CT within 7 days after 68Ga-SSA PET/CT. Result: The BM detection rate of 68Ga-SSA PET/CT was higher than 18F-FDG PET/CT (86.4% vs. 66.0%, p = 0.02) in 103 patients with dual scanning. Meanwhile, the number of positive lesions in 68Ga-SSA PET/CT was significantly more than in 18F-FDG PET/CT (3.37 ± 1.95 vs. 2.23 ± 2.16, t = 4.137, p < 0.001). Most bone metastasis lesions presented as osteogenic change in CT (55.4%, 118/213). Concerning the primary tumor, the most frequent were of pancreatic origin (26.3%, 56/213), followed by rectal origin (22.5%, 48/213), thymic origin in 33 cases (15.5%), pulmonary origin in 29 cases (13.6%), paraganglioma in 20 cases (9.4%). The efficiency of 68Ga-SSA PET/CT to detect BMs was significantly correlated with the primary site (p = 0.02), with thymic carcinoid BMs being the most difficult to detect, and the positive rate was only 60.6% (20/33). However, 18F-FDG PET/CT positive rate was 76.92% (10/13) in thymic carcinoid BMs. In addition, the BMs of 7 patients in this study were detected by 68Ga-SSA PET earlier than CT for 4.57 months (range: 2–10 months). Conclusion: 68Ga-SSA PET/CT has higher sensitivity for detecting the BMs of NEN than 18F-FDG and detects the BM earlier than CT. Moreover, 18F-FDG PET/CT should be a complement for diagnosing the BMs of thymic carcinoids.

Pharmaceutical Management of Secondary Hyperparathyroidism and the Role of Surgery: A 5-Year Retrospective Study.

Background and Objectives: Secondary hyperparathyroidism (SHPT) poses a common condition among patients with chronic kidney disease (CKD) due to the chronic stimulation of the parathyroid glands as a result of persistently low calcium levels. As a first option for medical treatment, vitamin D receptor analogs (VDRAs) and calcimimetic agents are generally used. Apart from cinacalcet, which is orally taken, in recent years, another calcimimetic agent, etelcalcetide, is being administered intravenously during dialysis. Materials and Methods: In a 5-year retrospective study between 2018 and 2023, 52 patients undergoing dialysis were studied. The aim of this study is to highlight the possible effects and/or benefits that intravenously administered calcimimetic agents have on CKD patients. A total of 34 patients (65.4%) received cinacalcet and etelcalcetide while parathormone (PTH) and calcium serum levels were monitored on a monthly basis. Results: A total of 29 out of 33 patients (87.9%) that received treatment with etelcalcetide showed a significant decrease in PTH levels, which rose up to 57% compared to the initial values. None of the included patients needed to undergo parathyroidectomy (PTx) due to either extremely high and persistent PTH levels or severe side effects of the medications. It is generally strongly advised that parathyroidectomies should be performed by an expert surgical team. In recent years, a significant decrease in parathyroidectomies has been recorded globally, a fact that is mainly linked to the constantly wider use of new calcimimetic agents. This decrease in parathyroidectomies has resulted in an important decrease in complications occurring in cervical surgeries (e.g., perioperative hemorrhage and nerve damage). Conslusions: Despite the fact that these surgical complications cannot be easily compared to the pharmaceutical side effects, the recorded decrease in parathyroidectomies is considered to be notable, especially in cases of relapse where a difficult reoperation would be considered based on previously published guidelines.

Anti-adhesive activity peptides against Helicobacter pylori from corn protein: Properties, identification, structural characterization and molecular docking in vitro and in silico

The population infected with Helicobacter pylori (H. pylori) is huge, and it is designated as a class I carcinogen by the World Health Organization (WHO). Inhibiting H. pylori adhesion to gastric mucosal epithelial cells (GES-1 cells) is an effective way to prevent H. pylori infection. In the present study, the properties, identification, structural characterization and mechanism of anti-adhesive activity peptides against H. pylori from corn protein were studied in vitro and in silico. It was found that corn protein-derived peptides prepared by Neutrase could effectively inhibit H. pylori adhesion to GES-1 cells as a receptor analog, and they possessed a low molecular weight distribution (less than 1000 Da accounting for 74.10%) and more hydrophobic amino acids. 241 peptide sequences with potential H. pylori-binding ability were identified and further analyzed for their structural characteristics. Anti-adhesive mechanism studies revealed that Neutrase-CPH inhibited H. pylori adhesion to GES-1 cells by interacting specifically with H. pylori adhesins SabA and BabA, and hydrogen bonds are the main driving forces. In addition, two novel anti-adhesive activity peptides, EFFAEY and VCENPIL, were evaluated in vitro, their anti-adhesive activity was 40.77 ± 1.57% and 34.86 ± 1.36% at 4 mg/mL, respectively. Overall, corn protein-derived anti-adhesive peptides might be applied as a potential functional food ingredient to prevent H. pylori infection, and this study provides theoretical support for the development of anti-adhesive functional food.

Role of fingolimod in acute respiratory distress syndrome.

Objective: Sphingosine 1 Phosphate (S1P) is a key regulator of inflammation, angiogenesis, vessel permeability, and immune processes, acting through S1P receptors. Fingolimod (FTY720), an S1P receptor analog Fingolimod, was initially approved for multiple sclerosis treatment and has shown potential for application in infectious and inflammatory disorders, including COVID-19. Study Design: Comprehensive Literature Review. Setting: Northwest School of Medicine. Period: 1st March 2023 to 3rd July 2023. Methods: Examining S1P pathways, S1P receptor analogs, and their potential in treating inflammatory and infectious disorders, particularly COVID-19, utilizing Fingolimod. Results: S1P analogs have demonstrated therapeutic benefits in autoimmune diseases. In COVID-19, these analogs modulate the inflammatory response, reduce tissue damage, and promote viral clearance. Fingolimod, in particular, affects S1PR1, S1PR4, and S1PR5, blunting the inflammatory response and mitigating lung tissue injury. Early administration may prevent excessive inflammation without interfering with viral clearance. Potential risks include disturbance of cytokine homeostasis and delayed administration. Limited human studies and concerns about off-target effects need addressing. Conclusion: Fingolimod shows promise in treating COVID-19 by reducing inflammation and lung damage. Further research is needed to address limitations and ensure safety for clinical application. Sphingosine 1 Phosphate (S1P) plays a key role in regulating inflammation and immune responses, with Fingolimod being a potential treatment option.

Decreased Risk of Readmission and Complications With Preoperative GLP-1 Analog Use in Patients Undergoing Primary Total Joint Arthroplasty

BackgroundThere has been considerable interest in the use of GLP-1 receptor analogs (GLP-1 RAs) for weight optimization in patients undergoing elective arthroplasty. As there is limited data regarding the implications of their use, our study aimed to evaluate the association between preoperative GLP-1 RA use and postoperative outcomes in patients undergoing primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). MethodsThe TrinetX research network was queried to identify all patients undergoing primary THA or TKA between May 2005 and December 2023 across 84 health care organizations. Patients were stratified based on preoperative GLP-1 RA use. Propensity score matching (1:1) was performed to account for baseline differences in demographics, laboratory investigations, and comorbidities. Subsequently, risk ratios were evaluated for postoperative outcomes. ResultsA total of 268,504 and 386,356 patients underwent THA and TKA, of which 1,044 and 2,095 used preoperative GLP-1 RAs. After matching, GLP-1 RA use was associated with a decreased 90-day risk of periprosthetic joint infection (2.1 versus 3.6%, RR = 0.58, P = .042) and readmission (1.1 versus 2.0%, RR = 0.53, P = .017) following THA and TKA, respectively. There was no difference in the risk of all other outcomes between comparison groups. ConclusionsPreoperative GLP-1 RA use is associated with a 42% decreased risk of periprosthetic joint infection and 47% decreased risk of readmission in the 90-day postoperative period following THA and TKA, respectively, with no difference in other risks, including aspiration. Our findings indicate that GLP-1 RAs may be safe to use in patients undergoing elective arthroplasty; however, further studies are warranted to inform the routine use of GLP-1 RAs for weight management in THA and TKA patients.

Unacylated Ghrelin Protects Against Muscle Wasting, Mitochondrial Dysfunction, and Neuromuscular Junction Disruption in Tumor Bearing Mice

Background: Cancer cachexia is a complex metabolic syndrome that severely impacts mobility, treatment strategies, and life quality of the patients. However, no treatments are available to mitigate the debilitating consequences of cancer cachexia. Ghrelin is a hormone released from the stomach that increases appetite upon acylation by binding to GHSR1a receptors in the brain. Because of its orexigenic effects and increases in body weight, ghrelin GHSR1a receptor analogs were tested as clinical trials to mitigate muscle wasting and loss of strength in cancer patients in several countries. The analogs (i.e., Anamorelin) increased body weight of the non-small lung cancer patients in European countries and Japan, but failed to increase strength, which is the critical component in cancer cachexia. Mainly due to the lack of improvement in strength and patients’ quality of life, Anamorelin was not approved for clinical use in Europe. While the lack of increases in strength is, at least in part, associated with the adipogenic effects of acylated ghrelin, unacylated ghrelin directly improves satellite cell renewal, muscle growth, and mitochondrial function independent of GHSR1a receptor activation and increases in appetite. Unacylated ghrelin is the predominant population in circulation comprising proximately 90-95% of total ghrelin in humans and rodents. Hypothesis: Unacylated ghrelin projects against muscle wasting, loss of strength, and metabolic dysfunction of tumor bearing mice. Methods and Results: Supplementing the cancer cell conditioned medium (CM) with unacylated ghrelin preserved myotube size. Unacylated ghrelin also diminished the cancer cell CM-induced upregulation of MuRF-1, muscle specific ubiquitin ligase. Interestingly, unacylated ghrelin normalized transcriptional upregulation of denervation markers (i.e., sarcolipin, Runx1, GADD45a) in myotubes treated with CM. To further investigate the therapeutic effects of unacylated ghrelin in vivo, we inoculated lung cancer cell line (LL2, ATCC®) in the flank of 4 months old male mice. Two weeks after the injection prior to development of cachexia, mice were provided with unacylated ghrelin containing drinking water or untreated water as control. Tumor bearing (TB) mice treated with unacylated ghrelin showed 30-40% increases in gastrocnemius and quadriceps weights, while soleus muscle mass was unchanged. In addition to the muscle quantity, unacylated ghrelin increased force generating capacity was also improved by unacylated ghrelin. Notably, unacylated ghrelin increased mitochondrial oxygen consumption rate and protected against neuromuscular junction disruption and denervation in TB control mice. Conclusion: Unacylated ghrelin protects against cancer cachexia by targeting multiple risk factors in skeletal muscle wasting, including protein balance, metabolic alterations, and neuromuscular junction disruption. Our findings show protective effects of unacylated ghrelin against cachexia and neuromuscular impairment in tumor bearing mice, indicating its therapeutic potential in cancer patients. NIA R00 064143 to Ahn B. Pilot funds from the Center for Redox Biology in Medicine, and Cancer Genetics and Metabolism program at the Wake Forest Baptist Comprehensive Cancer Center. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Diagnosis, Management, and Associated Comorbidities of Polycystic Ovary Syndrome: A Narrative Review.

Polycystic ovary syndrome (PCOS) is the most widespread and diverse endocrine health issue affecting many adolescent-aged women globally. It is the most frequent illness in reproductive-aged women. According to the Rotterdam criteria, two out of three elements: oligo-anovulation, hyperandrogenism, and polycystic ovaries (defined as having at least one ovary with an ovarian volume > 10 mL and/or 12 or more follicles measuring 2 to 9 mm in diameter) are present in PCOS. Conducted studies show epigenetics, environmental toxins, stress, and food as external factors as well as inflammation, oxidative stress, hyperandrogenism, insulin resistance, and obesity as internal factors related to PCOS. Although a portion of the mechanism associated with the occurrence of PCOS has been identified, there is still much to learn about the exact etiology and pathophysiology. The main debate covers the best ways to diagnose and treat this disease in adolescents. Early detection is crucial because of the disease's long-term effects on metabolic and reproductive health. Before beginning treatment for this group of young women, a firm diagnosis may not be made. Various criteria are used to diagnose PCOS patients. A person with PCOS has a chance of developing several comorbidities and health effects. PCOS patients are at risk of cardiac diseases, metabolic syndromes, resistance to insulin, infertility, and many more. There are numerous medications available for PCOS therapy that need a methodical approach. However, changing one's lifestyle should come first. There is proof in the support of the usage of several medications for PCOS, including mucolytic agents, Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, gliptins (oral diabetic medication), glucose-like peptide-1 receptor analogues, glitazones, and sodium-glucose cotransporter protein-2 (SGLT2) inhibitors. A comprehensive, systematic, schematic therapy approach is crucial for the treatment of PCOS.

Time to unshackle the medical treatment of obesity in the NHS

Obesity affects one in four people in the United Kingdom and costs the National Health Service (NHS) ∼£6.5 billion annually. The glucagon-like peptide-1 (GLP-1) receptor analogues, such as once-daily subcutaneous Liraglutide 3.0 mg (Saxenda®) and once-weekly subcutaneous Semaglutide 2.4 mg (Wegovy®), were approved by the National Institute of Health and Care Excellence (NICE) as a treatment for obesity and funded by the NHS for 2 years. Our local data shows that Saxenda is effective at reducing body weight and glycaemia in people with obesity and diabetes; however, the supply issues of GLP-1 receptor analogues have contributed to the unavailability of Saxenda and Wegovy in our service. Our patients are devastated that they cannot access NICE-approved GLP-1 receptor analogues for obesity. The 2-year GLP-1 receptor analogue treatment limit for obesity alongside a lack of funded NHS services and supply issues represent barriers to treatment for people living with obesity who have clear medical indications.

Recent advances and future challenges in the diagnosis of neuroendocrine neoplasms.

Neuroendocrine neoplasms (NEN) are a heterogeneous group of malignancies with increasing incidence, whose diagnosis is usually delayed, negatively impacting on patients' prognosis. The latest advances in pathological classifications, biomarker identification and imaging techniques may provide early detection, leading to personalized treatment strategies. In this narrative review the recent developments in diagnosis of NEN are discussed including progresses in pathological classifications, biomarker and imaging. Furthermore, the challenges that lie ahead are investigated. By discussing the limitations of current approaches and addressing potential roadblocks, we hope to guide future research directions in this field. This article is proposed as a valuable resource for clinicians and researchers involved in the management of NEN. Update of pathological classifications and the availability of standardized templates in pathology and radiology represent a substantially improvement in diagnosis and communication among clinicians. Additional immunohistochemistry markers may now enrich pathological classifications, as well as miRNA profiling. New and multi-analytical circulating biomarkers, as liquid biopsy and NETest, are being proposed for diagnosis but their validation and availability should be improved. Radiological imaging strives for precise, non-invasive and less harmful technique to improve safety and quality of life in NEN patient. Nuclear medicine may benefit of somatostatin receptors' antagonists and membrane receptor analogues. Diagnosis in NEN still represents a challenge due to their complex biology and variable presentation. Further advancements are necessary to obtain early and minimally invasive diagnosis to improve patients' outcomes.

Meta-analysis on GLP-1 mediated modulation of autophagy in islet β-cells: Prospectus for improved wound healing in type 2 diabetes.

Type 2 diabetes mellitus refers to a significantly challenging health disease due to its high prevalence and risk of other chronic diseases across the world. Notably, GLP-1 has been recognized to enhance the treatment of T2DM, along with this, GLP-1 is also involved in autophagy modulation. However, ineffectiveness of few analogue types can limit the efficacy of this treatment. This study particularly aims to elucidate the influence of GLP-1 receptor analogues on wound infection and patients with type 2 diabetes. To conduct the meta-analysis, an expansive literature survey was conducted to unveil the studies and research conducted on T2DM patients that revealed whether the adoption of any GLP-1 analogue in the form of specific interventions impacts the type 2 diabetes mellitus. The literature was searched using multiple search terms, screened and data were extracted to conduct the meta-analysis and it was conducted using metabin function of R package meta. A total of 800 patients consisting of the both intervention and control groups were employed to carry out the meta-analysis to analyse and evaluate the impact of GLP-1 mediated modulation to improve wound healing in the T2DM patients. The results revealed that GLP-1 mediated modulation considering one type of analogue was an effective intervention to patients suffering from T2DM. The variations in these results depicted insignificant outcomes with the values (risk ratio [RR]: 1.03, 95% confidence interval [CI]: 0.90-1.18, p > 0.05) and enlightened the fact that adopting different GLP-1 analogues may significantly improve the efficacy of wound healing in T2DM patients. Hence, interventions of GLP-1 mediated modulation must be utilized in the clinical practice to reduce the incidence of T2DM patients.

Altered biodistribution of [68Ga]Ga-DOTA-TOC during somatostatin analogue treatment.

The need for an interval between the administration of long-acting Somatostatin Receptor Analogues (SSA) and the [68Ga]Ga-DOTA-TATE PET has been questioned based on recent literature in the new EANM guidelines. Here an earlier studies showed that SSA injection immediately before SSTR PET had minimal effect on normal organ and tumor uptake (1). However, data are scarce and there are (small) differences between [68Ga]Ga-DOTA-TATE and [68Ga]Ga-DOTA-TOC binding affinity, and it remains unknown whether these findings can be directly translated to scans with [68Ga]Ga-DOTA-TOC as well. The purpose of this study was to assess the effect of SSA use on the biodistribution in a subsequent [68Ga]Ga-DOTA-TOC PET/CT and compare this intra-individually across several cycles of SSA treatments. Retrospectively, 35 patients with NENs were included. [68Ga]Ga-DOTA-TOC PET at staging and after the 1st and 2nd cycle of SSA were included. SUVmean and SUVmax of blood, visceral organs, primary tumor and two metastases were determined. Also, the interval between SSA therapy and the PET scan was registered. Treatment with SSA resulted in a significantly higher bloodpool activity and lower visceral tracer uptake. This effect was maintained after a 2nd cycle of SSA therapy. Furthermore, there was an inverse relationship between bloodpool tracer availability and visceral tracer binding and a positive correlation between bloodpool tracer availability and primary tumor tracer uptake. With an interval of up to 5days, there was a significantly higher bloodpool activity than at longer intervals. Absolute comparison of the SUV on [68Ga]Ga-DOTA-TOC PET should be done with caution as the altered biodistribution of the tracer after SSA treatment should be taken into account. We recommend not to perform a scan within the first 5days after the injection of lanreotide.