Search Results (107)

Background: Type 2 diabetes is projected to affect millions of people annually as the number of cases rises year on year. This includes children. Treating diabetes and its related comorbidities has a huge economic impact and puts pressure on healthcare providers. Understanding the disease at a molecular level is key for developing better therapeutics. The protein Islet Amyloid Polypeptide (IAPP) or amylin is important for glucose regulation; however, it is also instrumental in type 2 diabetes pathology. Human IAPP can misfold into oligomers and amyloid fibrillar aggregates within pancreatic islets, promoting β-cell dysfunction and death, contributing to progressive insulin deficiency and worsening hyperglycaemia. Methods: Based on previous studies on mutations at residues 18, 28 and 31,we have designed three novel IAPP analogues (two double and one triple mutant) to assess whether the combined amino acid substitutions impact fibril formation, solubility and toxicity. Results: All three of our analogues show a reduced propensity to aggregate and are more soluble than wild type IAPP. Compared with pramlintide, a clinically prescribed synthetic analogue of human amylin, all of our analogues appeared to have similarly reduced toxicity and improved solubility relative to human IAPP. Additionally, two of our analogues exhibited a markedly slower rate of fibril formation. Conclusions: Our results highlight the importance of targeting multiple residues as a promising strategy for developing improved diabetes therapeutics in the future. Full article

Background/Objectives: Drug development and delivery remain critical areas of research for addressing modern bioanalytical challenges. Understanding drug biodistribution, stability, and metabolism within biological systems is essential for optimising therapeutic efficacy. This study focuses on synthesising and characterising a novel fluorescent conjugate derived from commercially available rapid-acting insulin glulisine (Apidra^®) and fluorescein isothiocyanate (FITC). The objective was to produce a mono-labelled FITC-insulin glulisine conjugate without employing complex protective group strategies or multi-step processes. Methods: The conjugation was optimised by varying molar ratios (1:1 to 3:1) and reaction times (18–24 h) at pH 7. Results: The desired B1 mono-labelled conjugate was successfully achieved at a 2:1 molar ratio, pH 7, and 18 h reaction time. MALDI-TOF mass spectrometry confirmed the molecular weight and conjugation site, with fragmentation analysis identifying FITC attachment at phenylalanine (B1) on the β-chain (m/z = 537.11). Western blots performed on C2C12 skeletal cell lysates stimulated with the FITC–insulin glulisine conjugate showed Akt and IRS-1 activity similar to that of cells treated with native commercial insulin glulisine. Confocal imaging also demonstrated translocation of GLUT4 in FITC–insulin glulisine conjugate-treated C2C12 cells similar to that of commercial native insulin glulisine. Octanol-water partitioning studies assessed the physicochemical properties of the conjugate. Conclusions: This approach demonstrates an efficient method for fluorescent labelling of insulin analogues, enabling future applications in imaging, biodistribution studies, and pharmacokinetic profiling. Full article

Background: Long-acting insulin analogues have been widely used in patients with type 2 diabetes with reduced insulin secretion. In these patients, hypoglycemia may occur during the night when they do not consume food. We have already reported that anti-insulin antibodies developed at a fairly high frequency in patients with type 2 diabetes treated with insulin analogues. Therefore, clinical factors associated with nocturnal hypoglycemia, including anti-insulin antibodies, were searched in patients with type 2 diabetes treated with insulin analogues. Methods: The subjects consisted of 55 patients with type 2 diabetes with relatively stable glucose control treated with long-acting insulin analogues and 15 non-diabetic subjects. Using a continuous glucose monitoring, glucose fluctuation was observed for 10 days. Hypoglycemia was defined as a glucose monitoring level of less than 54 mg/dL for more than 15 min. Results: Nocturnal (duration 6 h, from midnight to 6 a.m.) hypoglycemia was observed in 13 patients (23.6%). All of the cases were unrecognized. Daytime (duration 18 h, from 6 a.m. to midnight) hypoglycemia was also observed in 14 patients (25.5%). Stratified analysis and logistic regression analysis disclosed that anti-insulin antibodies were significantly associated with nocturnal hypoglycemia in contrast to daytime hypoglycemia, which was not associated with anti-insulin antibodies but associated with lower HbA1c. That is, the frequency of nocturnal hypoglycemia was significantly higher in the negative group and lower in the positive group of the anti-insulin antibodies. Conclusions: These results suggest that circulating anti-insulin antibodies protect against nocturnal hypoglycemia. Full article

Dumping Syndrome (DS) is a significant complication following bariatric surgery, particularly Roux-en-Y gastric bypass (RYGB). This condition is characterised by gastrointestinal and vasomotor symptoms resulting from altered anatomy and hormonal dysregulation, notably accelerated gastric emptying and an exaggerated release of gut peptides. Based on the timing of symptom onset after food ingestion, DS is classified as early (EDS) or late (LDS). The critical roles of peptides such as GLP-1, GIP, insulin, and YY peptide are highlighted, along with the involvement of neuroendocrine pathways in symptom manifestation. Diagnosis relies on a combination of clinical evaluation and dynamic testing, with the oral glucose tolerance test (OGTT) often considered a key reference standard for diagnosis. Initial management involves dietary modifications, emphasising the glycaemic index of foods and meal distribution. In cases where nutritional interventions are insufficient, pharmacotherapy with agents such as acarbose, somatostatin analogues (octreotide and pasireotide), GLP-1 receptor agonists (liraglutide), calcium channel blockers (verapamil), and emerging therapies, including herbal medicine, may be considered. For refractory cases, surgical options like bypass reversal or partial pancreatectomy are reserved, although their efficacy can be variable. Despite advancements in understanding and treating DS, further large-scale, randomised controlled trials are essential to validate novel strategies and optimise long-term management. This review provides an updated and comprehensive overview of the aetiology, pathophysiological mechanisms, diagnostic approaches, and current management strategies for DS. Full article

Background/Objectives: Omentin, also known as intelectin-1, is a secreted adipokine with anti-inflammatory, insulin-sensitizing, and immune-modulatory functions, primarily expressed in visceral adipose tissue. While omentin has been associated with favorable metabolic outcomes, its role in cancer pathogenesis appears context-dependent and remains poorly understood. This review investigates the biological functions, expression patterns, and clinical relevance of omentin across gastrointestinal malignancies. Methods: A comprehensive review of the literature was conducted using PubMed, Scopus, and Web of Science up to August 2025 to evaluate the role of omentin in gastrointestinal cancers. Both preclinical and clinical studies evaluating omentin, its analogues and omentin-enhancing agents in gastric, colorectal, hepatic, pancreatic, and esophageal cancers were included. Results: Omentin exhibits anti-proliferative, anti-inflammatory, and anti-angiogenic effects within the tumor microenvironment in several GI malignancies. However, evidence also indicates a dual role. High intratumoral omentin expression correlates with improved prognosis in colorectal, gastric, and hepatic cancers; in contrast, elevated circulating levels–particularly in colorectal and pancreatic cancers–have been paradoxically associated with increased cancer risk and poor outcomes. Mechanistically, omentin modulates PI3K/Akt, NF-κB, AMPK, and oxidative stress pathways, and interacts with TMEM207. However, most available studies are small-scale and heterogeneous, with methodological inconsistencies and limited multi-omics integration, leaving major knowledge gaps. Conclusions: This review highlights omentin’s distinct systemic and local roles across GI cancers, underscoring its translational implications. Omentin emerges as a promising but context-dependent biomarker and therapeutic target, with future research needed to address heterogeneity, standardize assays, and validate its clinical utility in large-scale prospective studies. Full article

Background/Objectives: Oral insulin continues to constitute a challenge due to its low uptake by the gut wall and degradation by gastrointestinal proteolytic enzymes. Such concerns might be surmounted by means of nanoparticle delivery. Methods: In this study, glargine insulin has been loaded into solid lipid nanoparticles prepared via coacervation from Shea and Mango soaps, due to hydrophobic ion pairing. Subsequently, ex vivo tied-up-gut experiments were performed with fluorescently labeled peptide. Additionally, re-dispersible oral solid dosage forms (powders and tablets) were obtained from nanoparticle suspensions via freeze-drying and spray-drying. Results: Solid lipid nanoparticles are capable of enhancing peptide permeation into different gut sections. Furthermore, spray-drying permits the preparation, which can be scaled up, of a re-dispersible powder from the nanoparticle suspension. Conclusions: This engineered process is suitable for the formulation of solid oral dosage forms, such as granulates and tablets, and presents promising potential for oral insulin delivery, paving the way for the assessment of its pharmacological efficacy in further in vivo studies. Full article

The use of insulin as a treatment for diabetes mellitus has been marred by several challenges. These setbacks incurred in an attempt to better manage diabetes, together with past innovative strategies, have encouraged science and the clinical community to continue to endeavour for an ideal insulin analogue that demonstrates heightened pharmacokinetic profiles and thermal stability. This review therefore seeks to provide an update on emerging insulin analogues. This review aims to update the science and clinical community of the recent developments on novel insulin analogues design and engineering. Through this exercise, we believe this review consolidates cutting-edge innovations on insulin development and diabetes management. The accelerated innovation of design and engineering in the biotechnology and peptide field has seen more insulin analogues reported in the last decade. Although the analogues are often limited to preclinical studies, Degludec, Icodec, and Efsitora have been the exceptions. The emerging insulin analogues include those with extended pharmacokinetic profile, increased thermostability, are glucose-responsive, and are hepato-preferential insulin analogues. Due to the fast pace of innovation in the design of insulin analogues, more insulin analogues are likely to emerge in the clinical space in the near future. Such innovations should be applauded and encouraged as they aim to strive for better management of diabetes mellitus. Full article

Glucagon-like peptide-1 receptor agonists, originally developed for the treatment of metabolic disorders, have recently emerged as promising candidates for the management of substance use disorders. This review synthesizes preclinical, clinical, and translational evidence on the effects of glucagon-like peptide-1 receptor agonists across addiction models involving alcohol, nicotine, psychostimulants, and opioids. In animal studies, glucagon-like peptide-1 receptor agonists consistently reduce drug intake, attenuate dopamine release in reward circuits, and decrease relapse-like behavior. Clinical and observational studies provide preliminary support for these findings, particularly among individuals with comorbid obesity or insulin resistance. However, several translational barriers remain, including limited blood–brain barrier penetration, species differences in pharmacokinetics, and variability in treatment response due to genetic and metabolic factors. Ethical considerations and methodological heterogeneity further complicate clinical translation. Future directions include the development of central nervous system penetrant analogues, personalized medicine approaches incorporating pharmacogenomics, and rigorously designed trials in diverse populations. Glucagon-like peptide-1 receptor agonists may offer a novel therapeutic strategy that addresses both metabolic and neuropsychiatric dimensions of addiction, warranting further investigation to define their role in the evolving landscape of substance use disorder treatment. Full article

Background: Though evidence is limited, animal products like pork sausages and cheese may affect satiety differently due to their distinct protein, fat, and calcium content. This study therefore compared their acute effects on breakfast using appetite-related markers. Methods: A total of 11 women and 13 men, with a mean age of 23.0 ± 2.6 years and mean BMI of 24.5 ± 2.6 kg/m², participated in this crossover design study. Concentrations of active ghrelin, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), insulin, glucose, leptin, and blood lipids were measured. Subjective feelings of appetite using visual analogue scales were analyzed (0–4 h) as a response to two test breakfasts meals with a similar energy and macronutrient content. Appetite feelings and energy intake from an ad libitum buffet lunch were subsequently measured. Data were analyzed using two different ANOVA methods. Results: The pork sausage breakfast was characterized by an earlier triglyceride (TG) peak than the cheese. A slower TG clearance was seen with the cheese breakfast. Ghrelin suppression was longer in the pork sausage breakfast. Active GLP-1 concentration was higher following the cheese breakfast and active GIP declined slower. The two ANOVA methods disagreed regarding the insulin effect. Subjective feelings of hunger before buffet and ad libitum energy intake were higher in males (791 ± 64 kcal) compared with females (344 ± 32 kcal), but did not differ between breakfast types. Conclusions: Acute consumption of pork and cheese of the same energy, fat, and protein content provided detectable differences in appetite-related hormones and lipid responses. Appetite and lipid metabolism were affected by the major differentiators of the test meals, namely calcium, fatty acids and amino acids compositions. Full article

(Proline3)PP, or (P³)PP, is an enzymatically stable, neuropeptide Y4 receptor (NPY4R)-selective, pancreatic polypeptide (PP) analogue with established weight-lowering and pancreatic islet morphology benefits in obesity-diabetes. In the current study, we now investigate the impact of twice-daily (P³)PP administration (25 nmol/kg) for 11 days on islet cell lineage, using streptozotocin (STZ) diabetic Ins1^Cre/+;Rosa26-eYFP and Glu^CreERT2;Rosa26-eYFP transgenic mice with enhanced yellow fluorescent protein (eYFP) labelling of beta-cell and alpha-cells, respectively. (P³)PP had no obvious impact on body weight or blood glucose levels in STZ-diabetic mice at the dose tested, but did return food intake towards control levels in Ins1^Cre/+;Rosa26-eYFP mice. Notably, pancreatic insulin content was augmented by (P³)PP treatment in both Ins1^Cre/+;Rosa26-eYFP and Glu^CreERT2;Rosa26-eYFP mice, alongside enhanced beta-cell area and reduced alpha-cell area. Beneficial (P³)PP-induced changes on islet morphology were consistently associated with decreased beta-cell apoptosis, while (P³)PP also augmented beta-cell proliferation in Ins1^Cre/+;Rosa26-eYFP mice. Alpha-cell turnover rates were returned towards healthy control levels by (P³)PP intervention in both mouse models. In terms of islet cell lineage, increased transition of alpha- to beta-cells as well as decreased beta- to alpha-cell differentiation were shown to contribute towards the enhancement of beta-cell area in (P³)PP-treated mice. Together these data reveal, for the first time, sustained NPY4R activation positively modulates beta-cell turnover, as well as islet cell plasticity, to help preserve pancreatic islet architecture following STZ-induced metabolic stress. Full article

Background: Branched-chain amino acids (BCAAs, isoleucine, leucine, and valine) are commonly applied to promote muscle protein synthesis. However, the effects of BCAAs on exercise-induced substrate metabolism, performance and post-exercise fatigue during endurance exercise remain unclear. Methods: In a double-blind cross-over design, eleven active males completed 1 h of constant load exercise (CLE) at 60% VO₂max power followed by a time to exhaustion (TTE) test at 80% VO₂max power after supplementation with BCAAs or placebo on consecutive three days. During exercise, indirect calorimetry was used to measure the carbohydrate (CHO) and fat oxidation rate, as well as the cycling efficiency. In addition, rating of perceived exertion (RPE) and visual analogue scale (VAS) scores were obtained at interval times during the whole period. Fingertips and venous blood (n = 8) were collected for the measurement of metabolic responses at different time points during exercise. Results: Compared to the placebo group, the fat oxidation rate was significantly higher after 20 and 30 min of CLE (p < 0.05). The CHO oxidation rates showed a significant increase in the BCAA group during TTE (p < 0.05). Meanwhile, the cycling efficiency during TTE was significantly improved (p < 0.05). Interestingly, VAS significantly decreased post-exercise in the BCAA group (p < 0.05). Additionally, the levels of blood insulin between the two groups were significantly higher in the post-exercise period compared to the pre-exercise periods (p < 0.001), while insulin levels were significantly lower in the post-exercise period with supplemental BCAAs compared to the placebo (p < 0.001). BCAAs also enhanced the levels of blood ammonia in the post-exercise period compared to the fasting and pre-exercise periods (BCAA: p < 0.01; Placebo: p < 0.001). However, in the post-exercise period, blood ammonia levels were significantly lower in the BCAA group than in the placebo group (p < 0.05). Conclusions: This study shows the critical role of BCAAs during exercise in active males and finds that BCAA supplementation enhanced fat oxidation during the CLE, increased carbohydrate oxidation and exercise efficiency during the TTE, and reduced immediate post-exercise fatigue. Full article

Metabolic diseases like obesity and diabetes are on the rise, and therapies with biomacromolecules (such as proteins, peptides, antibodies, and oligonucleotides) play a crucial role in their treatment. However, these drugs are traditionally injected. For patients with chronic diseases (e.g., metabolic diseases), long-term injections are accompanied by inconvenience and low compliance. Oral administration is preferred, but the delivery of biomacromolecules is challenging due to gastrointestinal barriers. In this article, we introduce the available biomacromolecule drugs for the treatment of metabolic diseases. The gastrointestinal barriers to oral drug delivery and strategies to overcome these barriers are also explored. We then discuss strategies for alleviating metabolic defects, including glucose metabolism, lipid metabolism, and energy metabolism, with oral biomacromolecules such as insulin, glucagon-like peptide-1 receptor agonists, proprotein convertase subtilisin/kexin type 9 inhibitors, fibroblast growth factor 21 analogues, and peptide YY analogues. Full article

Initially intended to control blood glucose levels in patients with type 2 diabetes, semaglutide, a potent glucagon-like peptide 1 analogue, has been established as an effective weight loss treatment by controlling appetite. Integrating the latest clinical trials, semaglutide in patients with or without diabetes presents significant therapeutic efficacy in ameliorating cardiometabolic risk factors and physical functioning, independent of body weight reduction. Semaglutide may modulate adipose tissue browning, which enhances human metabolism and exhibits possible benefits in skeletal muscle degeneration, accelerated by obesity and ageing. This may be attributed to anti-inflammatory, mitochondrial biogenesis, antioxidant and autophagy-regulating effects. However, most of the supporting evidence on the mechanistic actions of semaglutide is preclinical, demonstrated in rodents and not actually confirmed in humans, therefore warranting caution in the interpretation. This article aims to explore potential innovative molecular mechanisms of semaglutide action in restoring the balance of several interlinking aspects of metabolism, pointing to distinct functions in inflammation and oxidative stress in insulin-sensitive musculoskeletal and adipose tissues. Moreover, possible applications in protection from infections and anti-aging properties are discussed. Semaglutide enhancement of the core molecular mechanisms involved in the progress of obesity and diabetes, although mostly preclinical, may provide a framework for future research applications in human diseases overall. Full article

Background: Previous studies have suggested that antidiabetic drug use may be associated with amyotrophic lateral sclerosis. However, these studies are limited by many confounding and reverse causality biases. We aimed to determine whether antidiabetic drug use has causal effects on ALS. Methods: Drug-target Mendelian randomization analysis was conducted to evaluate the association between genetic variation in the targets of antidiabetic drugs and ALS risk. The antidiabetic drugs included sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin/insulin analogues, metformin, and SGLT2 inhibitors. Summary statistics for ALS were retrieved from previous genome-wide association studies comprising 27,205 ALS patients and 55,058 controls. The instrumental variables for these drugs are from previous published articles. Results: Genetic variation in SGLT2 inhibition targets was associated with lower risk of ALS (odds ratio [OR] = 0.32, 95% CI = 0.14–0.74; p = 0.008). We did not find that genetic variation in metformin targets was associated with ALS (OR = 1.61, 95% CI = 0.94–2.73; p = 0.081). Nevertheless, mitochondrial complex I, a target of metformin, was associated with a higher risk of ALS (OR = 1.83, 95% CI = 1.01–3.32; p = 0.047). The analysis showed that genetic variation in sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin or insulin analogues targets was not associated with ALS (all p > 0.05). Conclusions: The complex interaction between hypoglycemic, antioxidation, and anti-inflammatory effects may account for the different results across antidiabetic drug types. These findings provide key evidence to guide the use of antidiabetic drugs and will help to identify novel therapeutic targets in ALS. Full article

Background and Objectives: Expansion of white adipose tissue causes systemic inflammation and increased risk of metabolic diseases due to its endocrine function. Resveratrol was suggested to be able to prevent obesity-related disorders by mimicking caloric restriction; however, its structure–activity relationships and molecular targets are still unknown. We aimed to compare the effects of resveratrol and its analogues on adipocyte metabolism and lipid accumulation in vitro. Methods: Mouse embryonic fibroblasts were differentiated to adipocytes in the absence or presence of resveratrol or its derivatives (oxyresveratrol, monomethylated resveratrol, or trimethylated resveratrol). Intracellular lipid content was assessed by Oil Red O staining. Glucose uptake and its response to insulin were estimated by 2-NBDG, and mitochondrial activity was assayed via resazurin reduction. Involvement of potential molecular pathways was investigated by concurrent treatment with their inhibitors. Results: Although lipid accumulation was significantly reduced by all analogues without altering protein content, oxyresveratrol was the most potent (IC50 = 4.2 μM), while the lowest potency was observed with trimethylated resveratrol (IC50 = 27.4 μM). Increased insulin-stimulated glucose uptake was restored by each analogue with comparable efficiency. The enhanced mitochondrial activity was normalized by resveratrol and its methylated derivatives, while oxyresveratrol had a minor impact on it. Among the examined pathways, inhibition of SIRT1, PGC-1α, and JNK diminished the lipid-reducing effect of the compounds. Autophagy appeared to play a key role in the effect of all compounds but oxyresveratrol. Conclusions: Resveratrol and its analogues can mimic caloric restriction with complex mechanisms, including activation of SIRT1, PGC-1α, and JNK, making them possible drug candidates to treat obesity-related diseases. Full article