Search Results (427)

Background/Objectives: Nanoemulsions and microemulsions are promising drug delivery systems capable of enhancing the solubility, stability, and bioavailability of active pharmaceutical ingredients, particularly for central nervous system (CNS) disorders. This study presents a bibliometric analysis of scientific publications on intranasal nanoemulsions from 2004 to 2024, based on data from the Scopus database. Methods: A total of 379 articles were analyzed using Bibliometrix and VOSviewer to identify publication trends, leading countries and institutions, prominent journals, and keyword networks. Results: Publications grew significantly over the last decade, with India, the United States, and China leading in volume. Keyword analysis revealed strong thematic clusters related to “brain targeting,” “drug delivery,” and “intranasal administration,” highlighting this route’s potential for bypassing the blood–brain barrier. The most studied compounds included curcumin, quercetin, carbamazepine, diazepam, and insulin, each with therapeutic applications in neurodegenerative and psychiatric disorders. Conclusions: The findings highlight growing interest in intranasal nano- and microemulsions as a non-invasive and efficient CNS delivery strategy. Future research can bridge translational gaps, enhancing efficacy and safety while meeting regulatory expectations for patient-centered drug development. This study provides a comprehensive overview of current trends and serves as a guide for advancing innovative intranasal delivery platforms. Full article

Background/Objectives: Diabetes mellitus (DM) is an increasingly prevalent endocrine disorder affecting humans and companion animals. Type 1 DM (T1DM) and type 2 DM (T2DM) are well characterized in humans, and canine DM most often resembles T1DM, marked by insulin dependence and β-cell destruction. Conversely, feline DM shares key features with human T2DM, including insulin resistance, obesity-related inflammation, and islet amyloidosis. This review provides a comprehensive comparative analysis of antidiabetic therapies in humans, dogs, and cats, focusing on three core areas: disease pathophysiology, pharmacological and delivery strategies, and translational implications. In human medicine, a wide array of insulin analogs, oral hypoglycemic agents, and incretin-based therapies, including glucagon-like peptide-1 receptor agonists (liraglutide) and sodium-glucose cotransporter-2 inhibitors (empagliflozin), are available. Veterinary treatments remain limited to species-adapted insulin formulations and off-label use of human drugs. Interspecies differences in gastrointestinal physiology, drug metabolism, and behavioral compliance influence therapeutic efficacy and pharmacokinetics. Recent innovations, such as microneedle patches for insulin delivery and continuous glucose monitoring systems, show promise in humans and animals. Companion animals with naturally occurring diabetes serve as valuable models for preclinical testing of novel delivery platforms and long-acting formulations under real-world settings. While these technologies show potential, challenges remain in regulatory approval and behavioral adaptation in animals. Conclusions: Future research should prioritize pharmacokinetic bridging studies, veterinary-specific formulation trials, and device validation in animal models. By highlighting shared and species-specific characteristics of DM pathogenesis and treatment, this review advocates a One Health approach toward optimized antidiabetic therapies that benefit human and veterinary medicine. Full article

Maturity-onset diabetes of the young type 10 (MODY10) is a monogenic diabetes subtype caused by heterozygous mutations in the insulin gene (INS), leading to defective proinsulin processing, endoplasmic reticulum (ER) stress, and β-cell dysfunction. Current management relies on sulfonylureas or insulin therapy, but these fail to address the underlying genetic defect. Recent research has elucidated the molecular mechanisms of MODY10, including ER stress induced by proinsulin misfolding, activation of the unfolded protein response (UPR), and β-cell apoptosis. Emerging therapies such as Adeno-Associated Virus (AAV)-mediated gene delivery to induce the glucose-responsive hepatic insulin expression, plasmid-based single-chain insulin analogs, and cell-based therapies show promise in preclinical studies. However, critical challenges remain, including immune responses to AAV vectors, incomplete correction of dominant-negative mutant effects, and the need for long-term safety data. This review summarizes current knowledge on MODY10 genetics, pathophysiology, and therapeutic innovations, while identifying key gaps for future research to enable precision medicine approaches. Full article

The present article is an opinion piece mainly based on selected articles in the field of sarcopenia, with possible relevance for pregnancy. Sarcopenia has gained increasing interest in recent years, since it has emerged that sarcopenia may determine significant health consequences, with related substantial health care expenditure. In particular, some studies suggested that sarcopenia may cause increased risk for several diseases, such as type 2 diabetes, obesity, and major cardiovascular events. On the other hand, some studies have reported that the association between sarcopenia and these diseases may be bidirectional. In particular, this holds for type 2 diabetes, because sarcopenia and type 2 diabetes share many etiological and pathogenetic factors, such as insulin resistance, oxidative stress, low-grade chronic inflammation, and adiposity. It is also worth noting that some studies have shown a non-negligible sarcopenia prevalence even in people below 40 years of age, and therefore of reproductive age. Taken together, the above considerations support the hypothesis that sarcopenia may be present in women with gestational diabetes (GDM), which shares common traits with type 2 diabetes. Notably, we hypothesize that sarcopenia may exacerbate GDM-related complications and may influence maternal–fetal outcomes, such as preterm birth or cesarean delivery. Additionally, since pregnancy often presents with insulin resistance independently of any comorbidity, it is plausible that sarcopenia may be present during pregnancy even in cases of normal glycemia. However, there is a lack of data about sarcopenia prevalence in pregnancy and its potential impact on outcomes. Therefore, future studies addressing these aspects are advisable. Full article

Background: The rate at which amino acids (AAs) are absorbed from casein glycomacropeptide (CGMP) when given as a protein substitute in phenylketonuria (PKU) is unknown. This three-way randomised, controlled, crossover study aimed to compare the AA absorption profile of phenylalanine (Phe)-free L-amino acids (L-AAs), low-Phe CGMP (CGMP) and casein in healthy adult subjects. Methods: Area under the curve (AUC) was measured over 240 minutes after ingesting one dose of each protein source on three separate occasions, under the same test conditions. A total of 0.4 g/kg protein equivalent of each test product (L-AA, CGMP and casein) was given. Fasted blood samples were collected from healthy volunteers at 30, 60, 90, 120, 150, 180 and 240 minutes post-test. Insulin, blood urea nitrogen, glucose and total (TAAs), essential (EAAs), large neutral (LNAAs) and branch chain (BCAAs) amino acids were measured at each time point. Results: A total of 20 subjects (11 females), median age 43 y (range 23–49), with a median BMI 24.2 (20–30.5) were recruited. AUC was compared across groups. Statistically significant differences were noted for: AUC for TAAs and BCAAs between CGMP and L-AAs vs. casein [TAAs p = 0.008 and p = 0.03; BCAAs p = <0.001 and p = 0.002]. There were no AUC differences between L-AAs and CGMP. AUC was largest for L-AAs, then CGMP and finally casein. For LNAAs, EAAs, insulin, glucose and urea, there were no statistically significant differences. There was a consistent delivery of AAs for casein demonstrated by a sustained curve, but the absorption curves for L-AAs and CGMP were transient, rising rapidly and falling, with the exception of tyrosine with CGMP which showed a gradual increase over 240 minutes in contrast to L-AAs and casein. Conclusions: Amino acids from CGMP and L-AAs were absorbed more rapidly than casein, inferring CGMP did not mimic casein, a slow-release protein source. The tyrosine concentration curve for CGMP suggests a beneficial effect on the Phe: tyrosine ratio. Kinetic labelled studies will help bring greater understanding on the utilisation of AAs particularly important for protein synthesis. Full article

Implantable electronic devices are driving innovation in modern medical technology and have significantly improved patients’ quality of life. This review comprehensively analyzes the latest technological trends in implantable electronic devices used in major organs, including the heart, brain, and skin. Additionally, it explores the potential for application in the gastrointestinal system, particularly in the field of biliary stents, in which development has been limited. In the cardiac field, wireless pacemakers, subcutaneous implantable cardioverter-defibrillators, and cardiac resynchronization therapy devices have been commercialized, significantly improving survival rates and quality of life of patients with cardiovascular diseases. In the field of brain–neural interfaces, biocompatible flexible electrodes and closed-loop deep brain stimulation have improved treatments of neurological disorders, such as Parkinson’s disease and epilepsy. Skin-implantable devices have revolutionized glucose management in patients with diabetes by integrating continuous glucose monitoring and automated insulin delivery systems. Future development of implantable electronic devices incorporating pressure or pH sensors into biliary stents in the gastrointestinal system may significantly improve the prognosis of patients with bile duct cancer. This review systematically organizes the technological advances and clinical outcomes in each field and provides a comprehensive understanding of implantable electronic devices by suggesting future research directions. Full article

Simultaneous values of glucose rate of change (RoC) and glucose can be presented in a dynamic glucose region plot, and risk spaces can be specified for (RoC, glucose) values expected to remain in the target range (glucose 3.9–10.0 mmol/L) or leave or return to the target range within the next 30 min. We downloaded continuous glucose monitoring (CGM) data for 60 days from persons with type 1 diabetes using two different systems for automated insulin delivery (AID), A (n = 65) or B (n = 85). The relative distribution of (RoC, glucose) values in risk spaces was compared. The fraction of all (RoC, glucose) values anticipated to remain in the target range in the next 30 min was higher with system A (62.5%) than with system B (56.8%) (difference 5.7, 95% CI (2.2–9.2%), p = 0.002). The fraction of (RoC, glucose) values in the target range with a risk of progressing to the above range (glucose > 10.0 mmol/L) was slightly lower in system A than in B (difference −1.1 (95% CI: −1.8–−0.5%, p < 0.001). Dynamic glucose region plots and the concept of risk spaces are novel strategies to obtain insight into glucose homeostasis and to demonstrate clinically relevant differences comparing two AID systems. Full article

Adipose tissue inflammation contributes to obesity-induced insulin resistance. However, increasing evidence shows that high BMI (obesity) is not an accurate predictor of poor metabolic health in individuals. The molecular mechanisms regulating the metabolically activated M1 macrophage phenotype in the adipose tissues leading to insulin resistance remain largely unknown. Although the Janus Kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling in myeloid cells are known to promote the M2 phenotype in tumors, we demonstrate here that the Jak2/Stat3 pathway amplifies M1-mediated adipose tissue inflammation and insulin resistance under metabolic challenges. Ablating Jak2 in the myeloid compartment reduces insulin resistance in obese mice, which is associated with a decrease in infiltration of adipose tissue macrophages (ATMs). We show that the adoptive transfer of Jak2-deficient myeloid cells improves insulin sensitivity in obese mice. Furthermore, the protection of obese mice with myeloid-specific Stat3 deficiency against insulin resistance is also associated with reduced tissue infiltration by macrophages. Jak2/Stat3 in the macrophage is required for the production of pro-inflammatory cytokines that promote M1 macrophage polarization in the adipose tissues of obese mice. Moreover, free fatty acids (FFAs) activate Stat3 in macrophages, leading to the induction of M1 cytokines. Silencing the myeloid cell Stat3 with an in vivo siRNA targeted delivery approach reduces metabolically activated pro-inflammatory ATMs, thereby alleviating obesity-induced insulin resistance. These results demonstrate Jak2/Stat3 in myeloid cells is required for obesity-induced insulin resistance and inflammation. Moreover, targeting Stat3 in myeloid cells may be a novel approach to ameliorate obesity-induced insulin resistance. Full article

In healthy humans, insulin at physiological concentrations exerts acute vasodilatory actions on both resistance and terminal arterioles, leading, respectively, to increased total blood flow and the microvascular network volume being perfused. The process of increasing capillary network volume is frequently referred to as “capillary recruitment”. Together these two vascular actions of insulin enhance the delivery of oxygen, nutrients, and insulin itself to tissues. Both processes are diminished by insulin resistance. Here we examined interactions between insulin’s acute (within 2 h) actions on blood pressure (both central and peripheral) and on capillary recruitment in healthy controls and in four distinct groups of people with heightened cardio-metabolic disease (CMD) risk: individuals with obesity, metabolic syndrome, and type 1 or type 2 diabetes. Insulin increased microvascular blood volume (MBV) more effectively in controls than in each of the four CMD risk groups (p < 0.001). Conversely, insulin lowered both central and peripheral systolic pressure (p < 0.05 or less) in each of the CMD risk groups but not in the controls. The insulin-induced blood pressure decrements were greater in the metabolic syndrome, type 2 diabetes, and obesity groups (p < 0.05 or less) than in the controls. The greater blood pressure declines likely reflect decreased sympathetic baroreceptor reflex tone. These effects on blood pressure combined with the diminished dilation of terminal arterioles due to microvascular insulin resistance in the CMD risk subjects led to decreased distal microvascular perfusion as evidenced by changes in MBV. These findings highlight the complex interplay between insulin’s actions on resistance and terminal arterioles in individuals with a high CMD risk, underscoring the importance of addressing microvascular dysfunction in these conditions. Full article

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have transformed type 2 diabetes mellitus (T2DM) management by promoting glucosuria, lowering glycated hemoglobin (HbA1c), blood pressure, and weight; however, their use is limited by genitourinary infections and ketoacidosis. Phytocannabinoids—bioactive compounds from Cannabis sativa—exhibit multi-target pharmacology, including interactions with cannabinoid receptors, Peroxisome Proliferator-Activated Receptors (PPARs), Transient Receptor Potential (TRP) channels, and potentially SGLT2. Objective: To evaluate the potential of phytocannabinoids as novel modulators of renal glucose reabsorption via SGLT2 and to compare their efficacy, safety, and pharmacological profiles with synthetic SGLT2 inhibitors. Methods: We performed a narrative review encompassing the following: (1) the molecular and physiological roles of SGLT2; (2) chemical classification, natural sources, and pharmacokinetics/pharmacodynamics of major phytocannabinoids (Δ⁹-Tetrahydrocannabinol or Δ⁹-THC, Cannabidiol or CBD, Cannabigerol or CBG, Cannabichromene or CBC, Tetrahydrocannabivarin or THCV, and β-caryophyllene); (3) in silico docking and drug-likeness assessments; (4) in vitro assays of receptor binding, TRP channel modulation, and glucose transport; (5) in vivo rodent models evaluating glycemic control, weight change, and organ protection; (6) pilot clinical studies of THCV and case reports of CBD/BCP; (7) comparative analysis with established synthetic inhibitors. Results: In silico studies identify high-affinity binding of several phytocannabinoids within the SGLT2 substrate pocket. In vitro, CBG and THCV modulate SGLT2-related pathways indirectly via TRP channels and CB receptors; direct IC₅₀ values for SGLT2 remain to be determined. In vivo, THCV and CBD demonstrate glucose-lowering, insulin-sensitizing, weight-reducing, anti-inflammatory, and organ-protective effects. Pilot clinical data (n = 62) show that THCV decreases fasting glucose, enhances β-cell function, and lacks psychoactive side effects. Compared to synthetic inhibitors, phytocannabinoids offer pleiotropic benefits but face challenges of low oral bioavailability, polypharmacology, inter-individual variability, and limited large-scale trials. Discussion: While preclinical and early clinical data highlight phytocannabinoids’ potential in SGLT2 modulation and broader metabolic improvement, their translation is impeded by significant challenges. These include low oral bioavailability, inconsistent pharmacokinetic profiles, and the absence of standardized formulations, necessitating advanced delivery system development. Furthermore, the inherent polypharmacology of these compounds, while beneficial, demands comprehensive safety assessments for potential off-target effects and drug interactions. The scarcity of large-scale, well-controlled clinical trials and the need for clear regulatory frameworks remain critical hurdles. Addressing these aspects is paramount to fully realize the therapeutic utility of phytocannabinoids as a comprehensive approach to T2DM management. Conclusion: Phytocannabinoids represent promising multi-target agents for T2DM through potential SGLT2 modulation and complementary metabolic effects. Future work should focus on pharmacokinetic optimization, precise quantification of SGLT2 inhibition, and robust clinical trials to establish efficacy and safety profiles relative to synthetic inhibitors. Full article

Glucose-responsive insulin delivery systems that effectively regulate insulin retention and release in response to real-time fluctuation of glucose levels are highly desirable for diabetes care with minimized risk of hypoglycemia. Herein, we report a class of glucose-sensitive copolymer microgels, prepared from a simple one-pot precipitation copolymerization of 4-vinylphenylboronic acid (VPBA), 2-(dimethylamino) ethyl acrylate (DMAEA), and oligo(ethylene glycol) methyl ether methacrylate (M_w = 300, MEO₅MA), for gated glucose-responsive insulin release within the physiologically desirable glucose level range. The composition of the p(VPBA-DMAEA-MEO₅MA) copolymer microgels were analyzed using NMR and FTIR spectra. The cis-diols of glucose can reversibly bind with the −B(OH)₂ groups of the VPBA component in the microgels, resulting in the formation of negatively charged boronate esters that induce the volume phase transition of the microgels. The DMAEA component is incorporated to reduce the pK_a of VPBA, thus improving the glucose sensitivity of the microgels at physiological pH. The neutral hydrophilic MEO₅MA component is used to tune the onset of the glucose responsiveness of the microgels to the physiologically desirable levels. The more the MEO₅MA component copolymerized in the microgels, the greater the glucose concentration required to initiate the swelling of the microgels to trigger the release of insulin. When the onset of the glucose response was tuned to 4−5 mM, the copolymer microgels retained insulin effectively in the hypo-/normo-glycemic range but also released insulin efficiently in response to the elevation of glucose levels in the hyperglycemic range, which is essential for diabetes management. The copolymer microgels display no cytotoxicity in vitro. Full article

Calcium channel blockers (CCBs), originally developed for cardiovascular indications, have gained attention for their therapeutic potential in neuropsychiatric, endocrine, and pain-related disorders. In neuropsychiatry, nimodipine and isradipine, both L-type CCBs, show mood-stabilizing and neuroprotective effects, with possible benefits in depression, bipolar disorder, and schizophrenia. In endocrinology, verapamil, a non-dihydropyridine L-type blocker, has been associated with the preservation of pancreatic β-cell function and reduced insulin dependence in diabetes. CCBs may also aid in managing primary aldosteronism and pheochromocytoma, particularly in patients with calcium signaling mutations. In pain medicine, α2δ ligands and selective blockers of N-type and T-type channels demonstrate efficacy in neuropathic and inflammatory pain. However, their broader use is limited by challenges in central nervous system (CNS) penetration, off-target effects, and heterogeneous trial outcomes. Future research should focus on pharmacogenetic stratification, novel delivery platforms, and combination strategies to optimize repurposing of CCBs across disciplines. Full article

Childhood obesity is a substantial health problem worldwide. The origin of obesity (increased adiposity) can be partly traced back to intrauterine life. However, the determinants of fetal fat deposition remain unclear. This study investigated the association between cord blood adipocytokines related to lipid metabolism (leptin, adiponectin, and insulin-like growth factor-1 [IGF-1]) and fetal adiposity during gestation. A prospective study was conducted in a cohort of 94 singleton pregnancies. Fetal ultrasonography was performed at 24, 30, and 36 weeks of gestation. Estimated fetal adiposity (EFA) was calculated by integrating measurements of cross-sectional arm and thigh fat area percentages and anterior abdominal wall thickness. Plasma cytokine levels and C-peptide immunoreactivity (as a proxy for fetal insulin resistance) were evaluated in cord blood samples obtained at delivery. The associations of cord blood leptin, adiponectin and IGF-1 levels with EFA at 24, 30, and 36 weeks were determined by multiple linear regression, adjusted for potential covariates. The multivariate analyses indicated that leptin was significantly correlated with EFA at 30 and 36 weeks. Leptin was also positively correlated with C-peptide immunoreactivity in the umbilical cord. Cord adiponectin levels were not associated with EFA across gestation. Cord IGF-1 levels were significantly correlated with EFA and estimated fetal body weight (EFW) at 36 weeks. In conclusion, cord leptin was associated with EFA at 30 and 36 weeks, and IGF-1 was associated with EFA at 36 and EFW at 36 weeks. In Conclusion, cord leptin was associated with EFA at 30 and 36 weeks, and IGF-1 was associated with EFA and EFW at 36 weeks. Considering the effects of leptin and IGF-1 on fetal insulin resistance and lipid metabolism, increased levels of leptin and IGF-1 are potential plasma biomarkers of increased fetal adiposity, which may predispose to infant obesity and metabolic dysfunction in later life. Full article

Background/Objectives: Pregnancies complicated by idiopathic polyhydramnios are linked to a heightened risk of numerous maternal and perinatal complications. We aim to study the implications of polyhydramnios in term pregnancies complicated with gestational diabetes mellitus (GDM). Methods: A prospective cohort study including 340 GDM cases was conducted. An ultrasound scan was conducted at term between 37 and 40 weeks and amniotic fluid volume (AFV) was assessed by measuring the amniotic fluid index (AFI) and the single deepest pocket (SDP). Maternal demographics and obstetric and perinatal outcomes were evaluated after delivery. We performed comparisons between groups with normal AFV and polyhydramnios (AFI ≥ 24 cm or SDP ≥ 8 cm), and between groups with normal and increased AFV (AFI or SDP ≥ 75th centile). A multivariate logistic regression analysis was performed to study association between AVF measurements and adverse maternal and perinatal outcomes. Results: We found that women with GDM and polyhydramnios at term had a higher risk of maternal (54.3 vs. 27.5%, p < 0.001) and perinatal adverse outcomes (65.7% vs. 46.5%, p < 0.03). The increased AFV group showed a higher risk of fetal overgrowth (LGA: 21.4% vs. 8.2%, p < 0.001 and macrosomia: 19.8% vs. 5.4%, p < 0.001, respectively) and a lesser risk of delivering an SGA fetus (6.3% vs. 13.6%, respectively). Both AFI and SDP showed a significant correlation with newborn weight (r = 0.27; p < 0.001 and r = 0.28; p < 0.001, respectively) and newborn centile (r = 0.26; p < 0.001 and r = 0.26 for both). Subsequent to conducting a multivariate logistic regression analysis adjusted for pregestational BMI, nulliparity, and insulin treatment, both AFI and SDP were significantly associated with perinatal complications, but AFI showed a stronger association with fetal overgrowth (aOR 1.11; p = 0.004 for a LGA fetus and aOR 1.12; p = 0.002 for macrosomia) and with lower risk of delivering an SGA fetus (aOR 0.89; p = 0.009) or IUGR fetus (aOR 0.86; p = 0.03). ROC analysis showed a poor diagnostic performance of both AFI and SDP for identifying macrosomia (AUC 0.68 for AFI, and 0.65 for SDP). Conclusions: Detection of polyhydramnios at term, whether using AFI or SDP, identifies a subgroup of women with gestational diabetes with higher risks of obstetric and perinatal complications. Cases with increased AFV (AFI ≥ 18 cm or SDP ≥ 6.5 cm) are also associated with an increased risk of fetal overgrowth and may require more intensive monitoring for management and optimal delivery timing, with the aim of improve perinatal outcomes. Full article

Forskolin (FSK) induces the browning of white adipose tissue (WAT) through the activation of adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) generation. When administered intravenously or orally, FSK undergoes significant metabolism and accumulation in the liver and other tissues, resulting in high side effects and low anti-obesity effects due to trivial amounts reaching WAT. This study examines the potential anti-obesity and metabolic effects of the inguinal WAT (IWAT) delivery of FSK in high-fat diet-induced C57BL/6J obese mice. Mice received one of the following treatments twice weekly for 4 weeks: 1. Control into both IWAT depots (Con^both); 2. FSK 15 mg/kg body weight (BW)/injection into both inguinal WAT (IWAT) depots (FSK15^both); 3. FSK 7.5 mg/kg BW/injection into both IWAT depots (FSK7.5^both); and 4. FSK 7.5 mg/kg BW/injection into the left IWAT depot (FSK7.5^left). Both the FSK15^both and FSK7.5^both treatments improved metabolic parameters by lowering blood glucose, enhancing glucose tolerance, and reducing serum insulin and cholesterol. The FSK15^both treatment had a greater impact on IWAT, resulting in smaller adipocytes and increased expression of Ucp1 and Tmem26 mRNA levels. All FSK treatments also reduced inflammatory and lipogenic markers in the liver, indicating improved hepatic metabolism. These findings suggest that local delivery of FSK into subcutaneous WAT is a potential strategy for combating obesity and improving metabolic health. However, further studies are needed to confirm the statistical and biological significance of these effects. Full article