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Background: The impact of diabetes on the risk of Alzheimer's disease remains uncertain. This study aimed to explore this issue from multiple perspectives by using the Mendelian randomization (MR) approach. Methods: Instrumental variables for predicting six diabetic traits (including insulin and blood glucose), eight metabolic risk factors for diabetes (including total cholesterol and blood pressure), and seven diabetic genes were extracted from their summary data. These data were derived from multiple European cohorts and included 31,684 to 810,865 subjects respectively. The two-sample MR, multivariate MR, and summary-data-based Mendelian randomization (SMR) methods were employed to determine the associations of these traits or genes with the risk of Alzheimer's disease. Results: The two-sample MR showed that elevated fasting insulin and total cholesterol levels were associated with an increased risk of dementia in Alzheimer's disease (P = 0.022, P = 0.041). Elevated systolic and diastolic blood pressure levels were associated with a decreased risk of dementia in Alzheimer's disease (P = 0.036, P = 0.025). The multivariate MR reported that adjusting for telomere length (a well-established biomarker of aging) did not change these findings (P < 0.05). Additionally, the two-sample MR showed that type 1 and type 2 diabetes did not affect the risk of Alzheimer's disease. The SMR also indicated that the diabetic genes did not affect the risk of this disease. Conclusion: Multiple MR approaches concluded that fasting insulin, total cholesterol, and blood pressure, rather than diabetes, were potential metabolic variables that had an impact on the risk of Alzheimer's disease. However, aging might not be involved in these correlations. [ABSTRACT FROM AUTHOR]

Background: Diabetes care incorporates multiple integrated elements like self-care practices, patient education and awareness, societal support, equitable access to healthcare facilities and trained healthcare professionals, commitment from the diabetes associations and government policies. There is a dearth of research exploring the barriers experienced by both People with Type 1 diabetes (PwT1D) and People with Type 2 diabetes (PwT2D) in accessing the holistic elements of diabetes care. This study thus aimed at exploring the perceived barriers among PwT1D and PwT2D in accessing diabetes care services in urban and rural areas of Nepal. Method: This study was a qualitative research using phenomenological approach where an in-depth interview with 23 participants on insulin was conducted. This included 15 PwT1D and 8 PwT2D, residing in the capital and rural areas and attending the hospitals and clinic in the urban and semi-urban regions in Nepal. A semi-structured questionnaire was used for the interview. The interviews were transcribed verbatim and deductive thematic analysis was done. Results: Majority were female participants and most had received a formal education and were visiting the hospitals located in capital city. Mean age for PwT1D was (27.86 ± 1.85) years whereas the median age for PwT2D was [47.5 (IQR, 16.5)] years. Seven themes were generated from the study representing key barriers from patient's perspective. These were: Theme (1) Double stigma: Diabetes diagnosis and insulin use, Theme (2) Non-adherence to insulin and Self-Monitoring of Blood Glucose (SMBG), Theme (3) Logistic challenges in rural areas: Scarcity of healthcare professionals and other healthcare facilities, Theme (4) Dissatisfaction with healthcare services, Theme (5) Patients seeking alternative treatment strategies over allopathic treatment, Theme (6) Limitations of health insurance scheme and Theme (7) Limited role of national diabetes organizations. Conclusion: There is a need in raising awareness among general public especially on T1DM to address the issue of diabetes stigma. An effort in implementation of policies supporting diabetes care and refinement of National Health Insurance Scheme is equally essential. Similarly, strengthening of Health Care System by ensuring availability of insulin, laboratory facilities and trained healthcare professionals in rural areas should be focused to address the inequity in access to healthcare in rural and urban sectors. [ABSTRACT FROM AUTHOR]

Fetal glucagon concentrations are elevated in the presence of a compromised intrauterine environment, as in cases of placental insufficiency and perinatal acidaemia. Our objective was to investigate the impact of late gestation fetal hyperglucagonaemia on in vivo insulin secretion and pancreatic islet structure. Chronically catheterized late gestation fetal sheep received an intravenous infusion of glucagon at low (5 ng/kg/min; GCG‐5) or high (50 ng/kg/min; GCG‐50) concentrations or a vehicle control (CON) for 8–10 days. Glucose‐stimulated fetal insulin secretion (GSIS) was measured following 3 h (acute response) and 8–10 days (chronic response) of experimental infusions. Insulin, glucose and amino acid concentrations were measured longitudinally. The pancreas was collected at the study end for histology and gene expression analysis. Acute exposure (3 h) to GCG‐50 induced a 3‐fold increase in basal insulin concentrations with greater GSIS. Meanwhile, chronic exposure to both GCG‐5 and GCG‐50 decreased basal insulin concentrations 2‐fold by day 8–10. Chronic GCG‐50 also blunted GSIS at the study end. Fetal amino acid concentrations were decreased within 24 h of GCG‐5 and GCG‐50, while there were no differences in fetal glucose. Histologically, GCG‐5 and GCG‐50 had lower β‐ and α‐cell proliferation, as well as lower α‐cell mass and pancreas weight, while GCG‐50 had lower islet area. This study demonstrates that chronic glucagon elevation in late gestation fetuses impairs β‐cell proliferation and insulin secretion, which has the potential to contribute to later‐life diabetes risk. We speculate that the action of glucagon in lower circulating fetal amino acid concentrations may have a suppressive effect on insulin secretion. Key points: We have previously demonstrated in a chronically catheterized fetal sheep model that experimentally elevated glucagon in the fetus impairs placental function, reduces fetal protein accretion and lowers fetal weight.In the present study, we further characterized the effects of elevated fetal glucagon on fetal physiology with a focus on pancreatic development and β‐cell function.We show that experimentally elevated fetal glucagon results in lower β‐ and α‐cell proliferation, as well as decreased insulin secretion after 8−10 days of glucagon infusion.These results have important implications for β‐cell reserve and later‐life predisposition to diabetes. [ABSTRACT FROM AUTHOR]

Diabetes Mellitus (DM) is the most hazardous public health challenge requiring engineering study to prevent disease complications. In this paper, a Sorensen-based diabetic model is presented in which the insulin-glucose process of a Type 1 patient is maintained by considering other factors such as physical characteristics and changes in mental aspects of the diabetic patient. The purpose of the research is to include a non-linear model of a patient with diabetes who is affected by stress, meals, exercise, and Insulin Sensitivity (IS), and a suitable RECCo controller is designed as a notable recent innovation that implements the concept of ANYA fuzzy rule-based system, which is an online adaptive type of controller that is used in this research work with an uncertainty case of the condition, where the blood glucose must be regulated. To ensure the performance of the proposed controller, a simple insulin pump is designed in a practical case, and a hardware experiment is conducted. The result of the hardware is analyzed and shows the success of the implementation of the controller in blood glucose regulation, thereby preventing complications such as hypoglycemia and hyperglycemia. The comparison analysis of RECCo was performed with other types of controllers, such as MPC and MRAC. The accuracy of the model was validated using the N-BEATS algorithm with a data-set collected from the simulated model, which is around 98%. [ABSTRACT FROM AUTHOR]

In the recent years, transdermal drug delivery system (TDDS) has gained a lot of success for drug delivery. Transdermal patches have been utilized for delivering the drugs via TDDS. These patches deliver drugs in dissolve lipid form, that enables them to have desired efficiency. Recent advancement in transdermal patches has resulted in formation of novel transdermal patches such as smart patches, degradable, dimensional (3D)-printed patches and release patches, etc. These patches have been utilized in vaccines, gene therapy, insulin delivery, hormonal deficiencies, cardiovascular diseases, etc. This review summarizes the recent advancements in transdermal patches as well as its latest applications. [ABSTRACT FROM AUTHOR]

Introduction: Chronic kidney disease (CKD) is a pervasive disease of the current century that usually affects the adult population, especially people with diabetes and hypertension. According to the recent studies, inflammation, oxidative stress, apoptosis, and mitochondrial dysfunction are determining risk factors in the pathogenesis of CKD. Melatonin as a strong antioxidant is produced in various tissues including the kidneys. The present clinical trial aims to examine the efficacy of melatonin supplementation on metabolic parameters, oxidative stress, and inflammatory biomarkers in diabetic patients with CKD. Methods: This is a double-blind, randomized, placebo-controlled clinical study that will be investigated the impacts of melatonin supplementation in diabetic patients with CKD. Laboratory findings will be applied to diagnose diabetic CKD. Forty-eight eligible diabetic subjects with CKD will be selected and randomly assigned to receive 5 mg melatonin tablets or identical placebo twice daily for 10 weeks. Participants will be asked to remain on their usual diet and physical activity. The primary outcome of this study is changes in oxidative stress and inflammatory biomarkers. The secondary outcomes include changes in lipid profile, renal function indicators, fasting blood sugar and serum insulin, systolic and diastolic blood pressure (SBP and DBP), serum phosphorous concentration, sleep quality, body weight, body mass index (BMI), and waist circumference (WC). Statistical analysis will be conducted using the SPSS software (version 25). Discussion: We hypothesize that melatonin administration may be useful for treating diabetic CKD by modulating oxidative stress, inflammation, regulating lipid metabolism, and increasing insulin sensitivity through different mechanisms. The current trial will exhibit the effects of melatonin, whether negative or positive, on diabetic CKD status. Ethical aspects: The current trial received approval from Medical Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran (IR.TUMS.SHARIATI.REC.1402.072). Trial registration: This study had been registered in Iranian Registry of Clinical Trials. Registration number: IRCT20170202032367N9 on 11 August 2023. https://www.irct.ir/trial/70709. [ABSTRACT FROM AUTHOR]

Background: Since 1982, recombinant insulin has been used as a substitute for pancreatic insulin from animals. However, increasing demand in medical and food industries warrants the development of more efficient production methods. In this study, we aimed to develop a novel and efficient method for insulin production using a yeast secretion system. Methods: Here, insulin C-peptide was replaced with a hydrophilic fusion partner (HL18) containing an affinity tag for the hypersecretion and easy purification of proinsulin. The HL18 fusion partner was then removed by in vitro processing with the Kex2 endoprotease (Kex2p), and authentic insulin was recovered via affinity chromatography. To improve the insulin functions, molecular chaperones of the host strain were reinforced via the constitutive expression of HAC1. Results: The developed method was successfully applied for the expression of cow, pig, and chicken insulins in yeast. Moreover, biological activity of recombinant insulins was confirmed by growth stimulation of cell line. Conclusions: Therefore, replacement of the C-peptide of insulin with the HL18 fusion partner and use of Kex2p for in vitro processing of proinsulin guarantees the economic production of animal insulins in yeast. [ABSTRACT FROM AUTHOR]

Diabetes, a metabolic disorder characterized by hyperglycemia, underscores the importance of normal pancreatic β‐cell development and function in maintaining glucose homeostasis. Poly(A)‐specific ribonuclease (PARN) serves as the principal regulator of messenger RNA (mRNA) stability, yet its specific role in pancreatic β cells remains unclear. This study utilizes mice with targeted PARN deficiency in β cells to elucidate this role. Notably, Parn conditional knockout mice present unaltered β‐cell development and insulin sensitivity but reduced glucose‐stimulated insulin secretion (GSIS). The observed outcomes are corroborated in NIT‐1 cells. Furthermore, transcriptomic analyses reveal aberrant mRNA expression of genes crucial for insulin secretion in PARN‐deficient β cells. Insights from linear amplification of complementary DNA ends and sequencing and coimmunoprecipitation experiments reveal an interaction between PARN and polypyrimidine tract‐binding protein 1 (PTBP1), regulating the RNA stability of solute carrier family 30, member 8 (Slc30a8) and carbohydrate sulfotransferase 3 (Chst3). Interference with either PARN or PTBP1 disrupts this stability. These data indicate that PARN deficiency hampers GSIS and insulin maturation by destabilizing Slc30a8 and Chst3 RNAs. These findings provide compelling evidence indicating that PARN is a potential therapeutic target for enhancing insulin maturation and secretion. [ABSTRACT FROM AUTHOR]

Introduction: Familial hypercholesterolemia, the highly prevalent form of dyslipidemia, is a well-known risk factor for premature heart disease and stroke worldwide. Statins, which inhibit 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, are the first-choice treatment for dyslipidemias, and have been effective in reducing the risk of stroke and myocardial infarction. However, emerging evidence indicates that statins may increase the incidence of new-onset type 2 diabetes by reducing β-cell mass and function. Notably, past in vitro reports studying the effects of statins on β-cells were performed without including free fatty acids in the model. This factor should have been addressed since these agents are used to treat individuals with hyperlipidemia. Methods: Here, we used a mouse insulinoma MIN6 β-cell culture model to assess the efficacy, cytotoxicity, and insulin-suppressive effects of simvastatin and pravastatin in the presence of palmitic, linoleic, and oleic acids cocktail to mimic mixed lipids challenge in a biologically relevant setting. Results and discussion: Our findings indicate that simvastatin was more effective in lowering intracellular cholesterol but was more cytotoxic as compared to pravastatin. Similarly, simvastatin exhibited a higher suppression of total insulin content and insulin secretion. Both drugs suppressed insulin secretion in phases 1 and 2, dose-dependently. No significant effect was observed on mitochondrial respiration. More importantly, elution experiments showed that insulin content diminution by simvastatin treatment was reversible, while exogenous mevalonate did not improve total insulin content. This suggests that simvastatin's influence on insulin content is independent of its specific inhibitory action on HMG-CoA reductase. In conclusion, our study identified that simvastatin was more effective in lowering intracellular cholesterol, albeit it was more toxic and suppressive of β-cells function. Notably, this suppression was found to be reversible. [ABSTRACT FROM AUTHOR]

Depression impairs self-management in diabetic patients, exacerbates insulin resistance, and elevates glycated hemoglobin (HbA1c) levels, thereby increasing diabetes risk. This study analyzed data from 30,386 participants in the National Health and Nutrition Examination Survey (NHANES), assessing depression severity using the 9-item Patient Health Questionnaire (PHQ-9) and evaluating diabetes status through clinical markers such as HbA1c, random blood glucose, and fasting blood glucose. Participants were stratified by depression severity and diabetes status to examine the relationship between depression and diabetes risk. We applied descriptive statistics, logistic regression models, subgroup analyses, and restricted cubic spline (RCS) modeling to explore this association. The results revealed that greater depression severity was significantly associated with increased diabetes incidence, elevated HbA1c, fasting glucose, and insulin levels. Multivariate regression analysis confirmed a consistent positive correlation between depression severity and diabetes risk. Subgroup analyses further identified significant relationships between depression and various demographic and behavioral factors, including gender, race, BMI, smoking status, and prediabetic conditions. Additionally, the RCS model demonstrated a clear increase in diabetes risk with rising PHQ-9 scores. In conclusion, our study demonstrates that the severity of depression is positively correlated with the risk of diabetes, and this association may be closely linked to various glycemic and lipid metabolic parameters. [ABSTRACT FROM AUTHOR]

Stress hyperglycaemia is common in critical illness. We have previously observed that increasing severity of respiratory failure in patients with severe COVID-19 is associated with increased insulin demand. Given previously reported direct effects of hypoxia on insulin action, we reasoned that rapid improvements in oxygenation following prone positioning may improve insulin sensitivity and increase risk of hypoglycaemia. A retrospective multi-centre service evaluation comparing blood glucose and insulin administration in patients with COVID-19 pneumonitis receiving prone mechanical ventilation, comparing the 16 h pre-prone and 16 h post-prone time periods. 155 patients were included in this analysis. Oxygenation improved significantly following prone positioning (change in SpO2/FIO2 per hour prone: 3.01 ± 0.14, P < 0.0001). Glycaemic control was similar during the supine and prone study periods, and there were no hypoglycaemic events in the prone study period. Prone positioning was associated with an unexpected modest but significant increase in insulin requirements (mean difference in total insulin dose (IU): 8.32 ± 2.14, P < 0.001) that was robust to several sensitivity analyses, and could not be explained by changes in carbohydrate intake. We did not observe an increased rate of hypoglycaemia during prone ventilation and the adequacy of glycaemic control was comparable during the supine and prone study periods. Unexpectedly, prone ventilation was associated with an increase in insulin requirements despite significant improvement in hypoxaemia. Our findings support the safety of prone ventilation with respect to glycaemic control and identify a novel relationship between ventilation position and insulin requirements in critical illness. [ABSTRACT FROM AUTHOR]

Background: Vegan and vegetarian dietary patterns are known to beneficially modulate risk factors for cardiovascular disease; however, the current literature does not differentiate between various plant-based diets. This study aimed to examine the association between various plant-based diets and plasma lipids and glycaemic indices compared to a regular meat-eating diet. Methods: A cross-sectional study of Australian adults (n = 230) aged 30-75yrs habitually consuming the following were recruited: vegan, lacto-vegetarian, pesco-vegetarian, semi-vegetarian, or regular meat-eater. Multivariable regression analysis was used to adjust for covariates. Results: Compared to regular meat-eaters, vegans had significantly lower total cholesterol (-0.77mmol/L,95% CI -1.15, -0.39, P < 0.001), low-density lipoprotein cholesterol (LDL-C, -0.71mmol/L, 95% CI -1.05, -0.38, P < 0.001), non-high-density lipoprotein cholesterol (non-HDL-C, -0.75mmol/L, 95% CI -1.11, -0.39, P < 0.001), total cholesterol/HDL-C-ratio (-0.49mmol/L, 95% CI -0.87, -0.11, P = 0.012), fasting blood glucose (FBG, -0.29mmol/L, 95% CI -0.53, -0.06, P = 0.014), haemoglobin A1C (-1.85mmol/mol, 95% CI -3.00, -0.71, P = 0.002) and insulin (-1.76mU/L, 95% CI -3.26, -0.26, P = 0.021) concentrations. Semi-vegetarians had significantly lower LDL-C (-0.41mmol/L, 95% CI -0.74, -0.08, P = 0.041) and non-HDL-C (-0.40mmol/L, 95% CI -0.76, -0.05, P = 0.026) and lacto-ovo vegetarians had significantly lower FBG (-0.34mmol/L, 95% CI -0.56, -0.11, P = 0.003) compared to regular meat-eaters. There were no differences in HDL-C and triglycerides between plant-based and regular-meat diets. Conclusions: Plasma lipaemic and glycaemic measures as a collective were more favourable among vegans, whereas among lacto-ovo vegetarians and semi-vegetarians, only some measures were favourable. Trial registration: ACTRN12621000743864. Date 6/11/2021. [ABSTRACT FROM AUTHOR]

Background: For ages, botanical medicine has been used in the treatment of diabetes mellitus (DM). Notoginsenoside R1 (NGR1), a Panax notoginseng (Burkill) F.H.Chen metabolite, has been documented to possess antidiabetic action in vivo. However, its precise molecular mechanism of action is not clear. Objectives: We evaluated NGR1's effects on blood glucose in vivo and then evaluated in vitro whether NGR1 has effects on insulin secretion and the probable molecular pathways involved in NGR1-induced insulin secretion. Methods: Diabetes was induced in mice by streptozotocin. Glucose tolerance test was performed before and after NGR1 was administered intraperitoneally to diabetic animals for 4 weeks. Static and perifusion experiments were performed using isolated female BALB/c mouse islets. Preproinsulin (Ins) mRNA expression was measured using q-PCR. Protein expression of PI3K/Akt pathway was assessed using the fully automated Wes™ capillary-based protein electrophoresis. Results: Treatment of diabetic mice with NGR1 improved their glucose intolerance. In vitro , NGR1 increased insulin secretion in a concentration-dependent manner. NGR1 initiated the secretion of insulin at 2 mM glucose and augmented glucose-stimulated insulin secretion which was sustained throughout NGR1 perifusion. NGR1-induced insulin secretion was not altered by a voltage gated calcium channel blocker or protein kinase A inhibitor. NGR1 did not significantly modulate Ins mRNA expression. However, NGR1 significantly increased the levels of phospho-Akt and phopho-p-85. Conclusion: In conclusion, this study has shown that NGR1 ameliorates hyperglycemia in diabetic mice. NGR1 has a direct insulin secretagogue activity on mouse islets, stimulates insulin secretion at both basal and postprandial glucose concentrations, and activates PI3K/Akt pathway to induce insulin secretion. These results suggest that NGR1 may provide an alternative therapy to manage DM. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus is a metabolic disease categorized by hyperglycemia, resistance to insulin, and ß-cell dysfunction. Around the globe, approximately 422 million people have diabetes, out of which 1.5 million die annually. In spite of innovative advancements in the treatment of diabetes, no biological drug has been known to successfully cure and avert its progression. Thereupon, natural drugs derived from plants are emerging as a novel therapeutic strategy to combat diseases like diabetes. Objective: The current study aims to investigate the antidiabetic potential of natural compounds of Oryza sativa L. indica (black rice) in disease treatment. Methods: Antioxidant activity and alpha amylase assays were performed to evaluate the therapeutic potential of the extract of Oryza sativa L. indica. Gas chromatography–mass spectrometry (GC–MS) was used for identification of constituents from the ethanol extract. ADMET profiling (absorption, distribution, metabolism, excretion, and toxicity), network pharmacology, and molecular dynamics simulation were employed in order to uncover the active ingredients and their therapeutic targets in O. sativa L. indica against type 2 diabetes mellitus. Results: GC–MS of the plant extract provided a list of 184 compounds. Lipinski filter and toxicity parameters screened out 18 compounds. The topological parameters of the protein–protein interaction (PPI) were used to shortlist the nine key proteins (STAT3, HSP90AA1, AKT1, SRC, ESR1, MAPK1, NFKB1, EP300, and CREBBP) in the type 2 diabetes mellitus pathways. Later, molecular docking analysis and simulations showed that C14 (1H-purine-8-propanoic acid,.alpha.-amino-2, 3, 6, 7-tetrahydro-1,3,7-trimethyl-2,6-dioxo-) and C18 (cyclohexane-carboxamide, N-furfuryl) bind with AKT1 and ESR1 with a binding energy of 8.1, 6.9, 7.3, and 7.2 kcal/mol, respectively. RMSD (root-mean-square deviation) and RMSF (root-mean-square fluctuation) values for AKT1 and ESR1 have shown very little fluctuation, indicating that proteins were stabilized after ligand docking. Conclusion: This study suggests therapeutic drug candidates against AKT1 and ESR1 to treat type 2 diabetes mellitus. However, further wet-lab analysis is required to discover the best remedy for type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori (H. pylori) is a known gastro-intestinal pathogen but implicated in extra-gastric diseases. The relationship between H. pylori infection and type 2 diabetes (T2DM) remains insufficiently elucidated, particularly in terms of molecular mediators such as microRNAs (miRNAs) and messenger RNAs (mRNAs). Objective: We aimed to characterize expression pattern of insulin signalling mRNAs and targeted miRNAs in T2DM patients exposed to H. pylori infection. Methods: We conducted a cross-sectional study among patients diagnosed with type 2 diabetes mellitus and were aged 18 to 60 years. Overnight fasting blood samples were collected and processed for plasma and serum. The plasma samples were used for glucose estimation and the serum used for H. pylori IgG screening. Total RNA was extracted from the serum with commercial kit, and mRNAs and miRNAs quantified by RT-qPCR with specific primers and under predetermined amplification conditions. Clinical data were obtained from medical records of patients. Results: Among 351 patients enrolled, 267 (76.1%) were females, 224 (63.8%) were married, and 79 (22.5%) had tertiary education. Expression level of insulin receptor mRNA was significantly lower in H. pylori positive T2DM patients compared to H. pylori negative (P <.05). There was no evidence of a difference in insulin receptor substrate 1 mRNA level (P >.05). Although not statistically significant, the expression levels of miRNA-222 and miRNA-155 in the patients exposed to H. pylori were higher than that of the unexposed group (P >.05). Conclusions: We found a significantly reduced serum insulin receptor messenger RNA level and higher levels of miRNA-222 and miRNA-155 in H. pylori exposed T2DM patients. The findings suggest a possible role of the infection in insulin signalling alteration in the patients. [ABSTRACT FROM AUTHOR]

Background: Zinc (Zn), a fundamental trace element in human biology, exhibits pivotal roles in sustaining vital physiological processes and regulating metabolic homeostasis. Insufficient zinc intake has been linked to deleterious consequences on growth, reproductive functions, metabolic activities, and immune responses in both humans and animals. Oral zinc supplementation is usually performed to meet zinc requirement. Previous studies have shown that long-term supplementation of zinc in mice impaired AKT signaling and induced adipocyte hypertrophy in visceral adipose tissue. Methods: The presented study was conducted to investigate the role and mechanism of short-term zinc supplementation on lipids metabolism. Zinc sulfate was supplemented in the drinking water of C57/BL6J male mice at 30 ppm or 90 ppm for one week. Water consumption, food intake, and body weight were analyzed, adipose tissue and serum profile of metabolites were investigated, and the key genes related to lipid metabolism were analyzed. Results: Short-term zinc supplementation decreased visceral adipose tissue weight and adipocyte size compared to the control group, but no difference was observed in food intake, water consumption, and body weight between the two groups. Further studies revealed that short-term zinc supplementation significantly increased the serum insulin level while decreasing the serum NEFA content. In addition, zinc supplementation increased the expression of Atgl and Hsl in the visceral adipose tissue compared with the control mice. Furthermore, the phosphorylation level of HSL and protein level of PPARg in the epididymal adipose tissue increased by zinc supplementation compared with the control mice. In comparison, the protein level of FASN was down-regulated by short-term zinc supplementation in the epididymal adipose tissue, although the expression of lipogenic genes was not changed. The expression of F4/80 and Tnfa were increased in zinc-supplemented adipose tissue as compared with the control group. Conclusions: Our findings suggest that short-term zinc supplementation might reduce fat deposition by enhancing lipolysis in mice. Future studies could focus on the effect of intermittent zinc supplementation on fat reduction in both animal models and humans. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is currently regarded as a global public health crisis for which lifelong treatment with conventional drugs presents limitations in terms of side effects, accessibility, and cost. Type 2 diabetes (T2DM), usually associated with obesity, is characterized by elevated blood glucose levels, hyperlipidemia, chronic inflammation, impaired β-cell function, and insulin resistance. If left untreated or when poorly controlled, DM increases the risk of vascular complications such as hypertension, nephropathy, neuropathy, and retinopathy, which can be severely debilitating or life-threatening. Plant-based foods represent a promising natural approach for the management of T2DM due to the vast array of phytochemicals they contain. Numerous epidemiological studies have highlighted the importance of a diet rich in plant-based foods (vegetables, fruits, spices, and condiments) in the prevention and management of DM. Unlike conventional medications, such natural products are widely accessible, affordable, and generally free from adverse effects. Integrating plant-derived foods into the daily diet not only helps control the hyperglycemia observed in DM but also supports weight management in obese individuals and has broad health benefits. In this review, we provide an overview of the pathogenesis and current therapeutic management of DM, with a particular focus on the promising potential of plant-based foods. [ABSTRACT FROM AUTHOR]

Skeletal muscle is one of the predominant sites involved in glucose disposal, accounting for ∼80% of postprandial glucose uptake, and plays a critical role in maintaining glycemic homeostasis. Dysregulation of energy metabolism in skeletal muscle is involved in developing insulin resistance and type 2 diabetes (T2D). Transcriptomic responses of skeletal muscle to exercise found that the expression of Klf3 was increased in T2D Goto-Kakizaki (GK) rats and decreased after exercise with improved hyperglycemia and insulin resistance, implying that Klf3 might be associated with insulin sensitivity and glucose metabolism. We also found that knockdown of Klf3 promoted basal and insulin-stimulated glucose uptake in L6 myotubes, whereas overexpression of Klf3 resulted in the opposite. Through pairwise comparisons of L6 myotubes transcriptome, we identified 2,256 and 1,988 differentially expressed genes in Klf3 knockdown and overexpression groups, respectively. In insulin signaling, the expression of Slc2a4, Akt2, Insr, and Sorbs1 was significantly increased by Klf3 knockdown and decreased with Klf3 overexpression; Ptprf and Fasn were markedly downregulated in Klf3 reduced group and upregulated in Klf3 overexpressed group. Moreover, downregulation of Klf3 promoted the expression of glucose transporter 4 (GLUT4) and protein kinase B (AKT) proteins, as well as the translocation of GLUT4 to the cell membrane in the basal situation, and enhanced insulin sensitivity, characterized by increased insulin-stimulated GLUT4 translocation and AKT, TBC1 domain family member 1 (TBC1D1) and TBC1 domain family member 4 (TBC1D4) phosphorylation, whereas overexpression of Klf3 showed contrary results. These results suggest that Klf3 affects glucose uptake and insulin sensitivity via insulin signal transduction and intracellular metabolism, offering a novel potential treatment strategy for T2D. NEW & NOTEWORTHY: The knockdown of Klf3 increased glucose uptake and improved insulin sensitivity in L6 myotubes, whereas its overexpression had the opposite effect. To explore the underlying mechanisms, we evaluated the transcriptional profiles of L6 myotubes after Klf3 knockdown and overexpression and revealed that metabolism and insulin-related pathways were significantly impacted. Klf3 also influenced the expression or modification of glucose transporter 4 (GLUT4), protein kinase B (AKT), TBC1 domain family member 1 (TBC1D1), and TBC1 domain family member 4 (TBC1D4) in the insulin signaling pathway, affecting insulin sensitivity and glucose uptake. [ABSTRACT FROM AUTHOR]

Background: Aspartame is a low-calorie artificial non-sugar sweetener and is commonly used as a sugar substitute in foods and beverages. Pancreas has a vital role in carbohydrate metabolism. The aim of the study was to study the effect of aspartame on the structure of pancreas. Methods: Eighteen albino Wistar rats (200-250gm) were divided into three groups; control group, aspartame-treated group, was treated with aspartame (250 mg/kg/day) for six months and withdrawal group: was treated with aspartame (250 mg/kg/day) for six months then left without treatment for another month. Serum amylase and lipase were measured, and histological study of the pancreas was conducted. Results: histopathological changes were detected in both pancreatic acini and islets of Langerhans, increased collagen deposition around the acini and blood vessels. Additionally, aspartame supplementation resulted in elevated levels of serum amylase and lipase. Upon withdrawal of aspartame, an obvious improvement was noticed in the withdrawal group in comparison with the aspartame-treated group. Conclusions: Aspartame produces degenerative changes in the pancreas of the rats and causes uprising of serum pancreatic enzymes. Withdrawal of aspartame results in partial restoration of the histological structure of the pancreas. From these results, it is recommended to spot a light on the dangerous impacts of the usage of aspartame in clinical studies. [ABSTRACT FROM AUTHOR]

Amyloidosis is characterized by the deposition of fibrillar aggregates, with a specific peptide or protein as the primary component, in affected tissues or organs. Excessive proliferation and deposition of amyloid fibrils can cause organismal dysfunction and lethal pathological outcomes associated with amyloidosis. In this study, a nanochaperone (nChap-NA) was developed to inhibit protein misfolding and fibrillation by simulating the function of natural molecular chaperones. The nanochaperone was prepared by self-assembly of two block copolymers PEG-b-PCL and PCL-b-P(NIPAM-co-AANTA), which had a phase-separated surface consisting of hydrophobic PNIPAM microdomains with coordinative NTA(Zn) moieties and hydrophilic PEG chains. The hydrophobic interaction of the PNIPAM microdomain and the coordination of NTA(Zn) synergistically work together to effectively trap the amyloid monomer and block its fibrillation site. Insulin and human islet amyloid polypeptide (hIAPP) were used as model proteins to investigate the nanochaperone's inhibition of amyloid misfolding and fibrillation. It was proved that the nanochaperone could stabilize the natural conformation of the trapped insulin and hIAPP, and effectively inhibit their fibrillation. In vivo study demonstrated that the nanochaperone could effectively preserve the bioactivity of insulin and reduce the cytotoxicity caused by hIAPP aggregation. This study may provide a promising strategy for the prophylactic treatment of amyloidosis. [ABSTRACT FROM AUTHOR]

Diabetes is a major risk factor for Alzheimer's disease (AD). Amino acid compound 2 (AAC2) improves glycemic and cognitive functions in diabetic mouse models through mechanisms distinct from insulin. Our goal was to compare the effects of AAC2, insulin, and their nanofiber-forming combination on early asymptomatic AD pathogenesis in APP/PS1 mice. Insulin, but not AAC2 or the combination treatment (administered intraperitoneally every 48 h for 120 days), increased seizure-related mortality, altered the brain fat-to-lean mass ratio, and improved specific cognitive functions in APP/PS1 mice. NanoString and pathway analysis of cerebral gene expression revealed dysregulated synaptic mechanisms, with upregulation of Bdnf and downregulation of Slc1a6 in insulin-treated mice, correlating with insulin-induced seizures. In contrast, AAC2 promoted the expression of Syn2 and Syp synaptic genes, preserved brain composition, and improved survival. The combination of AAC2 and insulin counteracted free insulin's effects. None of the treatments influenced canonical amyloidogenic pathways. This study highlights AAC2's potential in regulating synaptic gene expression in AD and insulin-induced contexts related to seizure activity. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a common metabolic disease that poses a severe threat to human health. Despite a range of therapeutic approaches, there remains a lack of effective and safe therapies with the existing drugs. Therefore, there is an urgent need to develop novel, effective, and safe therapeutic strategies for DM. Free fatty acid receptor 4 (FFAR4), also known as GPR120, is a member of the G protein-coupled receptor family, which has received considerable attention as an attractive new therapeutic target for treating DM. In the present study, based on the structure of TUG-891, which has excellent activity and selectivity, a series of novel FFAR4 agonists was designed by replacing the phenylpropanoic acid β position carbon atom with an oxygen atom, while replacing the linking oxymethylene with an amide-linking group. The target compounds were evaluated for FFAR4 agonistic activity, and the preferred compounds were evaluated for selectivity, oral glucose tolerance in normal ICR mice, antidiabetic activity in diet-induced obese (DIO) mice, pharmacokinetic properties in ICR mice and molecular modeling studies. The results showed that compound 10f possessed excellent FFAR4 agonistic activity and selectivity, significantly improved glucose tolerance in normal ICR mice, lowered blood glucose and promoted insulin secretion in a dose-dependent manner in DIO mice, and showed favorable pharmacokinetic properties. These results indicate that compound 10f may be a promising compound that deserves further structure–activity relationship and pharmacological studies for the development of antidiabetic drugs. [ABSTRACT FROM AUTHOR]

Rice is one of the major cereal crops in several Asian countries. It contains a variety of nutrients and provides valuable health benefits. The antidiabetic activity of rice combined with cereals has not been studied. Therefore, the present study was carried out to determine and compare the effects of extracts from Black rice (BRE), Pathum rice (PTRE), Black rice combined with cereals (BRCE), and Pathum rice combined with cereals (PTRCE) on body weight, blood glucose levels, serum insulin levels and blood chemistry of Streptozotocin (STZ)-induced diabetic rats. The results revealed that BRCE exhibited the highest activity in reducing fasting blood glucose (FBG) levels and increasing serum insulin levels, and also recovered the lipid profiles, renal function and hepatic function resulting from STZ in the diabetic rats, followed by BRE, PTRCE and PTRE, respectively. Also, BRCE exhibited an activity with similar potential to Glibenclamide. The findings indicate that the rice extracts possess antidiabetic activity which exerts the activity by increasing serum insulin resulting in reduction of blood glucose. Rice combined with cereals provides better antidiabetic activity and could be a source of valuable antidiabetic materials. [ABSTRACT FROM AUTHOR]

Biocompatibility is essential for drug delivery systems to ensure safety. Poly(lactic acid) (PLA) and its copolymers with glycolic acid and caprolactone, are known as safe biodegradable implants and carriers of drugs in clinical use. These polymers have been clinically used for the delivery of peptides, such as: LHRH, somatostatin and growth hormone. While the safety of PLA has been confirmed, the biocompatibility of PLA- based stereocomplexes with peptides has not been investigated. Stereocomplex is a complex formed by two molecules with opposite enantiomeric configuration. D-PLA consists of a chiral monomer thus can adopts a three dimensional structure which is a mirror image of a helix structure, therefore, complexes with insulin into a stereocomplex. In previous reports we demonstrated the formation of such stereocomplex. This study presents the safety evolution of a stereocomplex composed of the water soluble diblock copolymer of D-polylactic acid-co-polyetheylene glycol (DPLA-PEG) and Insulin, following subcutaneous administration of 17 mg sterecomoplex/mouse to Akita−/+ins2 mice. The mice were monitored for blood glucose levels and weight along the experiment, while growth necropsy and histopathology examination were done post sacrificing. Results demonstrated normal body weight gain with no pathological finding of an internal organ and no inflammatory signs at the injection site except of minimal macrophages, after 16 weeks following polymer administration. Hence, Stereocomplex of D-PLA-PEG/insulin is considered biocompatible with no adversity. [ABSTRACT FROM AUTHOR]

Objective: Caffeine, an adenosine receptor antagonist, is a potent central nervous system stimulant that also impairs insulin signaling. Recent studies have suggested that coffee consumption lowers serum urate (SU) and protects against gout by unknown mechanisms. We hypothesized that caffeine lowers SU by affecting activity of urate transporters. Methods: We examined the effect of caffeine and adenosine on basal and insulin stimulation of net 14C‐urate uptake in the human renal proximal tubule cell line PTC‐05 and on individual urate transporters expressed in Xenopus laevis oocytes. Results: We found that caffeine and adenosine efficiently inhibited both basal and insulin stimulation of net 14C‐urate uptake mediated by endogenous urate transporters in PTC‐05 cells. In oocytes expressing individual urate transporters, caffeine (>0.2 mM) more efficiently inhibited the basal urate transport activity of GLUT9 isoforms, OAT4, OAT1, OAT3, NPT1, ABCG2, and ABCC4 than did adenosine without significantly affecting URAT1 and OAT10. However, unlike adenosine, caffeine at lower concentrations (<0.2 mM) very effectively inhibited insulin activation of urate transport activity of GLUT9, OAT10, OAT1, OAT3, NPT1, ABCG2, and ABCC4 by blocking activation of Akt and extracellular signal–regulated kinase. Conclusion: We postulate that inhibition of urate transport activity of the re‐absorptive transporters GLUT9, OAT10, and OAT4 by caffeine is a key mechanism in its urate‐lowering effects. Additionally, the ability of caffeine to block insulin‐activated urate transport by GLUT9a and OAT10 suggests greater relative inhibition of these transporters in hyperinsulinemia. [ABSTRACT FROM AUTHOR]

Aim: Diminished hepatic insulin clearance (HIC) is observed in obese adults and is presumed to be mediated by fatty liver. However, few reports have examined HIC in Chinese children with metabolic (dysfunction)‐associated fatty liver disease (MAFLD). This study aimed to investigate the correlation between HIC, insulin sensitivity and β‐cell function in obese Chinese children with MAFLD. Methods: In total, 204 obese children (74 MAFLD) aged 4–17 years were enrolled into this study. HIC, insulin sensitivity and β‐cell function were calculated using the oral glucose tolerance test (1.75 g/kg body weight). Correlation analyses between the HIC and clinical variables were performed using Pearson's product–moment correlation coefficients. HIC and glucose homeostasis were assessed in a high‐fat diet mouse model, and liver samples were collected for molecular analysis. Results: Obese children with MAFLD exhibited significantly lower HIC (AUCC‐peptide/insulin ratio, p = 0.0019), higher insulin resistance (homeostatic model assessment of insulin resistance, p = 0.002), and increased compensatory β‐cell function (homeostatic model assessment‐β, p = 0.046) than obese children without liver involvement. Notably, HIC was negatively correlated with insulin sensitivity (r = −0.5035, p < 0.0001) and β‐cell function (r = −0.4576, p < 0.0001). However, pancreatic β‐cell dysfunction (p = 0.046) was accompanied by future reduced HIC (p = 0.034) in children with MAFLD in prediabetes. In a high‐fat diet mouse model, MAFLD mice showed a 50% reduction in insulin‐degrading enzyme expression, consistent with the observed decrease in HIC. Conclusions: A lower HIC may offload pancreatic β‐cells at an early stage. However, obese children with MAFLD are at risk of developing diabetes, and preventive efforts should be prioritized. [ABSTRACT FROM AUTHOR]

Aim: To thoroughly investigate the impact of sustained neuropeptide Y4 receptor (NPY4R) activation in obesity‐associated diabetes. Methods: Initially, the prolonged pharmacodynamic profile of the enzymatically stable pancreatic polypeptide (PP) analogue, [P3]PP, was confirmed in normal mice up to 24 h after injection. Subsequent to this, [P3]PP was administered twice daily (25 nmol/kg) for 28 days to high‐fat‐fed mice with streptozotocin‐induced insulin deficiency, known as HFF/STZ mice. Results: Treatment with [P3]PP for 28 days reduced energy intake and was associated with notable weight loss. In addition, circulating glucose was returned to values of approximately 8 mmol/L in [P3]PP‐treated mice, with significantly increased plasma insulin and decreased glucagon concentrations. Glucose tolerance and glucose‐stimulated insulin secretion were improved in [P3]PP‐treated HFF/STZ mice, with no obvious effect on peripheral insulin sensitivity. Benefits on insulin secretion were associated with elevated pancreatic insulin content as well as islet and beta‐cell areas. Positive effects on islet architecture were linked to increased beta‐cell proliferation and decreased apoptosis. Treatment intervention also decreased islet alpha‐cell area, but pancreatic glucagon content remained unaffected. In addition, [P3]PP‐treated HFF/STZ mice presented with reduced plasma alanine transaminase and aspartate transaminase levels, with no change in circulating amylase concentrations. In terms of plasma lipid profile, triglyceride and cholesterol levels were significantly decreased by [P3]PP treatment, when compared to saline controls. Conclusion: Collectively, these data highlight for the first time the potential of enzymatically stable PP analogues for the treatment of obesity and related diabetes. [ABSTRACT FROM AUTHOR]

Aim: To assess the effects of a small‐molecule nicotinamide N‐methyltransferase (NNMT) inhibitor, 5A1MQ, on body composition, metabolic variables, fatty liver pathologies, and circulating biomarkers in diet‐induced obese (DIO) mice, and characterize its plasma pharmacokinetics (PK) and tissue distribution in vivo. Materials and Methods: DIO mice were administered vehicle or 5A1MQ once daily for 28 days. Longitudinal measures of body composition, blood glucose and plasma insulin levels, and terminal measures of liver histopathology and serum markers, were evaluated. Plasma and tissue PK were established in age‐ and strain‐matched mice after intravenous, oral, and subcutaneous dosing of 5A1MQ. Results: 5A1MQ treatment dose‐dependently limited body weight and fat mass gains, improved oral glucose tolerance and insulin sensitivity, and suppressed hyperinsulinaemia in DIO mice. Liver histology from 5A1MQ‐treated DIO mice showed attenuated hepatic steatosis and macrophage infiltration, and correspondingly reduced liver weight, size, and triglyceride levels. 5A1MQ treatment normalized circulating levels of alanine transaminase, aspartate transaminase, and ketone bodies, supporting an overall improvement in liver and metabolic functions. The pharmacodynamic effects of 5A1MQ were further corroborated by its high systemic exposure and effective distribution to metabolically active tissues, including adipose, muscle and liver, following subcutaneous dosing of mice. Conclusions: This work validates NNMT inhibition as a viable pharmacological approach to ameliorate metabolic imbalances and improve liver pathologies that develop with obesity. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness of integrated personalized diabetes management (iPDM) through telemedicine (tele‐iPDM) with regard to glycaemic control. Methods: A 6‐month single‐centre, open‐label, prospective randomized controlled trial enrolled insulin‐treated patients with type 2 diabetes, aged 18–65 years with glycated haemoglobin (HbA1c) levels of 7.5%–10.5%. The tele‐iPDM group received insulin adjustment by investigators through a cloud‐based telemonitoring platform for 6 months (blood glucose monitoring reviewed weekly from Weeks 0 to 12 and then monthly from Weeks 13 to 24). The control group performed self‐monitoring and insulin adjustment. The primary outcome was the difference in HbA1c change from baseline between the two groups at 24 weeks. Secondary outcomes included changes in HbA1c at 12 weeks, fasting plasma glucose, body weight, body mass index (BMI), the percentage of individuals achieving HbA1c <7% at 24 weeks, the percentage of individuals with an HbA1c reduction of >0.5% at 24 weeks, and incidences of hypoglycaemic events. Results: A total of 151 participants were enrolled, with a mean age of 53.36 ± 8.08 years and a mean diabetes duration of 12.38 ± 8.47 years. The baseline HbA1c was 8.47 ± 0.76%. The mean HbA1c decreased from baseline to 12 and 24 weeks in both groups. At 12 weeks, HbA1c reduction from baseline was −1.2% (95%CI −1.42 to −0.98) in the tele‐iPDM group and −0.57% (95%CI −0.79 to −0.36) in the control group. The mean difference in HbA1c between the tele‐iPDM and usual care groups at 12 weeks was −0.63% (95%CI −0.94 to −0.32; p < 0.001). At 24 weeks, HbA1c reduction from baseline was −1.14% (95%CI −1.38 to −0.89) in the tele‐iPDM group and − 0.49% (95%CI −0.73 to −0.25) in the control group. The mean difference in HbA1c between the tele‐iPDM and usual care groups was −0.65% (95%CI −0.99 to −0.30; p < 0.001). There were no significant differences in body weight, BMI, or hypoglycaemic events between the two groups. Conclusion: Telemonitoring can support the iPDM care model in individuals with insulin‐treated type 2 diabetes. It improves the efficiency of diabetes care, enhances glycaemic control at 12 weeks, and sustains glycaemic control at 24 weeks. [ABSTRACT FROM AUTHOR]

Aim: The real‐world benefits of continuous glucose monitoring (CGM) in the broad type 2 diabetes (T2D) population are not well studied. Our study evaluated the impact of CGM use on health care resource utilization over 12 months in adults with T2D. Materials and Methods: This retrospective cohort analysis used Optum's de‐identified Market Clarity data of >79 million people to evaluate CGM use in people with T2D who were treated with non‐insulin (NIT), basal insulin (BIT) and prandial insulin therapy (PIT). The primary outcomes were changes in all‐cause hospitalizations, acute diabetes‐related hospitalizations and acute diabetes‐related emergency room visits during the 6‐ and 12‐month post‐index period following transition from blood glucose monitoring to CGM. A pre‐specified subgroup analysis assessed glucose control and medication changes among people with T2D over 1 year. Results: The analysis included 74 679 adults with T2D (NIT; n = 25 269), (BIT; n = 16 264) and (PIT; n = 33 146). Significant reductions in all‐cause hospitalizations, acute diabetes‐related hospitalizations and acute diabetes‐related emergency room visits were observed in the 6‐month post‐index period that were sustained during the 6–12 month post‐index period (NIT, −10.1%, −31.0%, −30.7%; BIT, −13.9%, −47.6%, −28.2%; and PIT, −22.6%, −52.7%, −36.6%, respectively). A subgroup analysis of 6030 people showed mean glycated haemoglobin reductions at approximately 3 months, which were also sustained throughout the post‐index period: NIT, −1.1 (0.05)%; BIT, −1.1 (0.06)%; and PIT, −0.9 (0.04)%, p < 0.0001. Conclusions: CGM use in real‐life across different therapeutic regimens in adults with T2D was associated with reductions in health care resource utilization with improved glucose control over 1 year. [ABSTRACT FROM AUTHOR]

Objective: Complications from diabetic foot wounds, including bacterial infection, ulceration and gangrene, are major causes of hospitalisation and are responsible for 85% of amputations in patients with diabetes. Given that orally administered investigational therapeutic Cytoreg (Cytorex de Venezuela SA, Venezuela), a defined aqueous mixture of hydrofluoric, hydrochloric, sulfuric, phosphoric, citric and oxalic acids, has been shown to increase levels of arterial blood oxygen in a Wistar rat model, oral and oral+topical Cytoreg were tested on patients with diabetic foot ulcers (DFUs) under a humanitarian, compassionate-use protocol. Method: All patients received oral Cytoreg (5.0 ml concentrate in fruit juice) for 30 days; half also received weekly wound washing with Cytoreg concentrate in isotonic saline (1:50 volume/volume) (oral+topical group). In addition to standard clinical observations, wounds were monitored against the Saint Elian checklist system for the diabetic foot. Results: A total of 10 patients took part in the study. Complete wound closure was observed in 4/5 patients in the oral+topical group; in the remaining patient, necrotic and fibrin tissues on the wound edges were eliminated. Half (2/4) of the patients receiving oral-only Cytoreg experienced complete wound closure; one patient in this group was removed prematurely because of an unrelated illness and was not replaced. During the study, no significant differences were observed between groups in either the oxygen saturation of the affected tissues or in insulin and glycaemia levels (p<0.05). Significant increases in arterial haemoglobin and arterial oxygen partial pressure (p<0.05) were observed, and significant decreases were measured in the levels of glycosylated haemoglobin, aspartate aminotransferase, glutamic-pyruvic transaminase, creatine and urea (p<0.05). Conclusion: The results of this study justify an expanded clinical study for the treatment of DFUs with Cytoreg. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the admission indicators and characteristics of individuals diagnosed with type 1 diabetes (T1D) to ascertain potential impact on the choice of glucose control therapy after discharge. Methods: A total of 398 eligible T1D patients were selected. We conducted multivariable logistic regression analysis to determine the independent influence of predictors on the selection of glucose control therapy after discharge. To explore the influencing factors of different subgroups, we additionally performed subgroup analyses based on gender and age. Results: Our study revealed that body mass index (BMI) was noteworthy influence factor for prescription of insulin and non-insulin antidiabetic drug (NIAD prescription) in T1D patients of general population [OR = 1.109 (1.033-1.195), p = 0.006], male [OR = 1.166 (1.040−1.318), p = 0.011] and individuals below the age of 30 years [OR = 1.146 (1.020−1.301), p = 0.028]. Diastolic blood pressure (DBP) was a protective factor for NIAD prescription in the general population [OR = 0.971 (0.949-0.992), p = 0.008] and women [OR = 0.955 (0.923−0.988), p = 0.008]. The other risk factor of NIAD prescription in men was dyslipidemia [OR = 4.824 (1.442−22.246), p = 0.020]. Pulse pressure [OR = 1.036 (1.007–1.068), p = 0.016] constituted an additional risk factor of NIAD prescription among individuals below the age of 30 years. The risk factors of NIAD prescription for people aged 30 to 50 years were length of stay [OR = 1.097 (1.014–1.196), p = 0.026] and initial blood glucose [OR = 1.078 (1.007–1.168), p = 0.047]. In the case of individuals aged above 50 years, physicians exhibited a higher tendency to prescribe supplementary non-insulin medications to men [OR = 9.385 (1.501–87.789), p = 0.029]. Conclusions: We identified notable factors that influence discharge prescriptions in patients with T1D. In order to enhance the treatment outcome for the patient, clinicians ought to have a special focus on these indicators or factors. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy is one of the most serious and common complications of diabetes with a wide spectrum, affecting 30–50% of diabetic patients. However, the current treatments of this disorder, mainly based on controlling blood glucose level, show an inadequate clinical outcome. Better approaches are needed. In this fashion, it is noted that promoting nerve regeneration and preventing nerve degeneration should be focused on equally and appropriately. In this mini review, how more effective approaches are in targeting PI3K/AKT and MEK/ERK pathways in the treatment of peripheral diabetic neuropathy is discussed. Future treatment of peripheral diabetic neuropathy should consider these approaches. [ABSTRACT FROM AUTHOR]

Introduction: Insulin is an essential treatment within diabetes management; however, it takes on a role of enhancement within image and performance enhancing drug (IPED) communities due to its anabolic effects. This study sought to provide insight into how IPED users perceive and manage the risks linked to insulin. Methods: We conducted semi‐structured interviews with 10 individuals from Australia and United Kingdom who used insulin as part of their IPED protocols. The analysis followed an iterative categorisation approach and applied the lens of situated rationality theory. Results: The decision to incorporate insulin was influenced by peers' experiences and preferences. Participants highlighted the risks and responsibilities associated with insulin use, emphasising the need for precise lifestyle habits. They recognised the potential dangers and called for comprehensive harm reduction strategies within IPED communities to respond to such concerns. Some participants expressed reluctance to discuss insulin openly, underlining the importance of education and awareness to mitigate health risks associated with underground and uninformed use. Discussion and Conclusions: While people who use IPEDs demonstrate awareness of the risks associated with insulin, their practices of routinisation moderate these risks within the context of IPED use. Silence as a risk‐reduction strategy highlights vulnerabilities among certain prospective users, while the hierarchical structure of IPED use establishes expertise and status within the community. Reconsidering insulin risks entails reframing harm reduction messages to better match the social dynamics of IPED communities. Closer ties between IPED communities can enhance support accessibility, particularly through peers, who, with their firsthand knowledge, can offer tailored guidance. [ABSTRACT FROM AUTHOR]

Purpose: The insulin-like growth factor (IGF) system includes IGF-I, IGF-II insulin and their membrane receptors. IGF system also includes a family of proteins namely insulin-like growth factor-binding proteins (IGFBPs) composed for six major members (IGFBP-1 to IGFBP6), which capture, transport and prolonging half-life of IGFs. However, it has been described that IGFBPs can also have other functions. Methods: IGFBP5 expression was inhibited by shRNAs, migration was analyzed by scratch-wound assays, invasion assays were performed by the Boyden chamber method, spheroids formation assays were performed on ultra-low attachment surfaces, expression and phosphorylation of proteins were analyzed by Western blot. Results: IGFBP5 is a repressor of IGF-IR expression, but it is not a repressor of IR in MCF-7 breast cancer cells. In addition, IGFBP5 is a suppressor of migration and MMP-9 secretion induced by IGF-I and insulin, but it does not regulate invasion in MCF-7 cells. IGFBP5 also is a repressor of MCF-7 spheroids formation. However treatment with 340 nM rescues the inhibitory effect of IGFBP in the MCF-7 spheroids formation. Conclusion: IGFBP5 regulates IGF-IR expression, migration and MMP-9 secretion induced by IGF-I and/or insulin, and the spheroids formation in MCF-7 breast cancer cells. [ABSTRACT FROM AUTHOR]

Aims: The present analysis estimated the cost‐effectiveness of treatment with the Tandem t: slim X2 insulin pump with Control IQ technology (CIQ) in children with type 1 diabetes in Sweden. Methods: A four‐state Markov model and probabilistic sensitivity analyses (PSA) were used to assess the cost‐effectiveness of CIQ use compared with treatment with multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII) in conjunction with CGM. Data sources included clinical input data from a recent retrospective, observational study, cost data from local diabetes supply companies and government agencies, and published literature. Outcomes measures were quality adjusted life years (QALYs) at 10, 20 and 30‐year time horizons based on cost per QALY and incremental cost‐effectiveness ratio (ICER). Results: A total of 84 type 1 diabetes children were included (CIQ, n = 37; MDI, n = 19; CSII, n = 28). For all time horizons, the use of CIQ was a dominant strategy (e.g. more effective and less costly) compared with MDI or CSII use: 10‐year ICER, SEK ‐88,010.37 and SEK ‐91,723.92; 20‐year ICER, SEK −72,095.33 and SEK −87,707.79; and 30‐year ICER, SEK −65,573.01 and SEK ‐85,495.68, respectively. PSA confirmed that CIQ use was less costly compared with MDI and CSII. Conclusions: Initiation of CIQ use in children with type 1 diabetes is cost‐saving, besides previously shown improved glycaemic control, and increased quality of life. Further investigations are needed to more fully elucidate the cost‐effectiveness of these technologies in different countries with existing differences in payment models. [ABSTRACT FROM AUTHOR]

Aims: While randomized controlled trials data on the long‐term effect of glucose‐lowering drugs (GLDs) on liver‐related outcomes are lacking, population‐based studies have evaluated the associations of GLDs with liver‐related outcomes in individuals with type 2 diabetes (T2D). we aimed to conduct a systematic review of population‐based studies evaluating the effects of GLDs on liver‐related outcomes in people with T2D. Methods: PubMed, Web of Science, and Embase databases were systematically searched for population‐based studies testing the associations of GLDs with liver‐related outcomes in individuals with T2D and no liver disease other than non‐alcoholic fatty liver disease (NAFLD) from inception to 23 February 2024. GLDs included SGLT2is, TZDs, insulin, GLP‐1 RAs and dipeptidyl peptidase‐4 inhibitors (DPP4Is). Results: Ten cohort studies, comprising 1,274,641 participants, met the inclusion criteria. The median follow‐up period ranged from 8.9 to 76 months. Of all the GLDs under investigation, SGLT2is were associated with the strongest reduction in NAFLD incidence, cirrhosis, and composite liver‐related events compared to other medications. TZDs were associated with a reduced risk of developing NAFLD and cirrhosis but were not significantly associated with a lower incidence of hepatocellular carcinoma. GLP‐1 RAs demonstrated a significant association with reduced liver‐related mortality. Conclusions: Observational data from population‐based studies suggest that GLDs such as SGLT2is are associated with beneficial long‐term liver‐related outcomes in T2D patients with NAFLD. Additional studies, including randomized controlled trials with long‐term follow‐up, are needed to confirm these findings. Registration Number: PROSPERO CRD442024536872. [ABSTRACT FROM AUTHOR]

Insulin resistance arising from Non-Alcoholic Fatty Liver Disease (NAFLD) stands as a prevalent global ailment, a manifestation within societies stemming from individuals' suboptimal dietary habits and lifestyles. This form of insulin resistance emerges as a pivotal factor in the development of type 2 diabetes mellitus (T2DM). Emerging evidence underscores the significant role of hepatokines, as hepatic-secreted hormone-like entities, in the genesis of insulin resistance and eventual onset of type 2 diabetes. Hepatokines exert influence over extrahepatic metabolism regulation. Their principal functions encompass impacting adipocytes, pancreatic cells, muscles, and the brain, thereby playing a crucial role in shaping body metabolism through signaling to target tissues. This review explores the most important hepatokines, each with distinct influences. Our review shows that Fetuin-A promotes lipid-induced insulin resistance by acting as an endogenous ligand for Toll-like receptor 4 (TLR-4). FGF21 reduces inflammation in diabetes by blocking the nuclear translocation of nuclear factor-κB (NF-κB) in adipocytes and adipose tissue, while also improving glucose metabolism. ANGPTL6 enhances AMPK and insulin signaling in muscle, and suppresses gluconeogenesis. Follistatin can influence insulin resistance and inflammation by interacting with members of the TGF-β family. Adropin show a positive correlation with phosphoenolpyruvate carboxykinase 1 (PCK1), a key regulator of gluconeogenesis. This article delves into hepatokines' impact on NAFLD, inflammation, and T2DM, with a specific focus on insulin resistance. The aim is to comprehend the influence of these recently identified hormones on disease development and their underlying physiological and pathological mechanisms. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF)-related diabetes (CFRD), characterized by partial to complete impaired insulin secretion, is the most common extra-pulmonary complication of CF. Actually, insulin is the only approved therapy for its management. Advanced hybrid closed loop (AHCL) systems are the gold standard therapy for type 1 diabetes and have been proposed for other insulin-dependent forms of diabetes, including CFRD. With AHCL systems, people with CFRD can better manage several typical disease-related issues, such as minimal insulin requirements, its variability due to exacerbations or concomitant steroid therapies, nutritional behaviors, the co-existence of CF complications as intestinal malabsorption or liver disease. SmartGuard, the AHCL system for Medtronic Minimed 780G, requires a minimum of 8 units per day to operate. In this paper, we expose a case of two young women with CFRD with total daily insulin requirements < 8 UI, using off-label SmartGuard system over a 3 years of follow-up period, suggesting an evaluation of its use also in people with minimal insulin needs, considering its beneficial impact in glucose control and quality of life. [ABSTRACT FROM AUTHOR]

Overconsumption of food, especially dietary fat, leads to metabolic disorders such as obesity and type 2 diabetes. Long‐chain fatty acids, such as palmitoleate are recognized as the risk factors for these disorders owing to their high‐energy content and lipotoxicity. In contrast, medium‐chain fatty acids (MCFAs) metabolic benefits; however, their underlying molecular mechanisms remain unclear. GPR84 is an MCFA receptor, particularly for C10:0. Although evidence from in vitro experiments and oral administration of C10:0 in mice suggests that GPR84 is related to the metabolic benefits of MCFAs via glucose metabolism, its precise roles in vivo remain unclear. Therefore, the present study investigated whether GPR84 affects glucose metabolism and metabolic function using Gpr84‐deficient mice. Although Gpr84‐deficient mice were lean and had increased endogenous MCFAs under high‐fat diet feeding conditions, they exhibited hyperglycemia and hyperlipidemia along with lower plasma insulin and glucagon‐like peptide‐1 (GLP‐1) levels compared with wild‐type mice. Medium‐chain triglyceride (C10:0) intake suppressed obesity, and improved plasma glucose and lipid levels, and increased plasma GLP‐1 levels in wild‐type mice; however, these effects were partially attenuated in Gpr84‐deficient mice. Our results indicate that long‐term MCFA‐mediated GPR84 activation improves the dysfunction of glucose and lipid homeostasis. Our findings may be instrumental for future studies on drug development with GPR84 as a potential target, thereby offering new avenues for the treatment of metabolic disorders like obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Diabetes currently affects approximately 500 million people worldwide and is one of the most common causes of mortality in the United States. To diagnose and monitor diabetes, finger-prick blood glucose testing has long been used as the clinical gold standard. For diabetes treatment, insulin is typically delivered subcutaneously through cannula-based syringes, pens, or pumps in almost all type 1 diabetic (T1D) patients and some type 2 diabetic (T2D) patients. These painful, invasive approaches can cause non-adherence to glucose testing and insulin therapy. To address these problems, researchers have developed miniaturized blood glucose testing devices as well as microfluidic platforms for non-invasive glucose testing through other body fluids. In addition, glycated hemoglobin (HbA1c), insulin levels, and cellular biomechanics-related metrics have also been considered for microfluidic-based diabetes diagnosis. For the treatment of diabetes, insulin has been delivered transdermally through microdevices, mostly through microneedle array-based, minimally invasive injections. Researchers have also developed microfluidic platforms for oral, intraperitoneal, and inhalation-based delivery of insulin. For T2D patients, metformin, glucagon-like peptide 1 (GLP-1), and GLP-1 receptor agonists have also been delivered using microfluidic technologies. Thus far, clinical studies have been widely performed on microfluidic-based diabetes monitoring, especially glucose sensing, yet technologies for the delivery of insulin and other drugs to diabetic patients with microfluidics are still mostly in the preclinical stage. This article provides a concise review of the role of microfluidic devices in the diagnosis and monitoring of diabetes, as well as the delivery of pharmaceuticals to treat diabetes using microfluidic technologies in the recent literature. [ABSTRACT FROM AUTHOR]

Microneedle patch (MNP) has become a hot research topic in the field of transdermal drug delivery due to its ability to overcome the stratum corneum barrier. Among the various types of microneedles, dissolving microneedles represent one of the most promising transdermal delivery methods. However, the most used method for preparing dissolving microneedles, namely microfabrication, suffers from issues such as long drying time, susceptibility to humidity, and large batch-to-batch variability, which limit the development of dissolving microneedles. In this study, we report for the first time a method for preparing dissolving microneedles using freeze-drying technology. We screened substrates suitable for freeze-dried microneedle patch (FD-MNP) and used coating technology to enhance the mechanical strength of FD-MNP, allowing them to meet the requirements for skin penetration. We successfully prepared FD-MNP using hyaluronic acid as the substrate and insulin as the model drug. Scanning electron microscopy revealed that the microneedles had a porous structure. After coating, the mechanical strength of the microneedles was 0.61 N/Needle, and skin penetration rate was 97%, with a penetration depth of 215 μm. The tips of the FD-MNP dissolved completely within approximately 60 s after skin penetration, which is much faster than conventional MNP (180 s). In vitro transdermal experiments showed that the FD-MNP shortened the lag time for transdermal delivery of rhodamine 123 and insulin compared to conventional MNP, indicating a faster transdermal delivery rate. Pharmacological experiments showed that the FD-MNP lowered mouse blood glucose levels more effectively than conventional MNP, with a relative pharmacological availability of 96.59 ± 2.84%, higher than that of conventional MNP (84.34 ± 3.87%), P = 0.0095. After storage under 40℃ for two months, the insulin content within the FD-MNP remained high at 95.27 ± 4.46%, which was much higher than that of conventional MNP (58.73 ± 3.71%), P < 0.0001. In conclusion, freeze-drying technology is a highly valuable method for preparing dissolving microneedles with potential applications in transdermal drug delivery. [ABSTRACT FROM AUTHOR]

LEAP2, a liver-derived antagonist for the ghrelin receptor, GHSR1a, counteracts the effects of ghrelin on appetite and energy balance. Less is known about its impact on blood glucose-regulating hormones from pancreatic islets. Here, we investigate whether acyl-ghrelin (AG) and LEAP2 regulate islet hormone release in a cell-type- and sex-specific manner. Hormone content from secretion experiments with isolated islets from male and female mice was measured by radioimmunoassay and mRNA expression by qPCR. LEAP2 enhanced insulin secretion in islets from males (P < 0.01) but not females (P > 0.2), whilst AG-stimulated somatostatin release was significantly reversed by LEAP2 in males (P < 0.001) but not females (P > 0.2). Glucagon release was not significantly affected by AG and LEAP2. Ghsr1a, Ghrelin, Leap2, Mrap2, Mboat4, and Sstr3 islet mRNA expression did not differ between sexes, whereas the SSTR3 antagonist MK4256 enhanced glucose-induced insulin secretion in islets from males only. In control male islets maintained without 17-beta oestradiol (E2), AG exerted an insulinostatic effect (P < 0.05), with a trend towards reversal by LEAP2 (P = 0.06). Both were abolished by 72 h E2 pre-treatment (10 nmol/L, P > 0.2). AG-stimulated somatostatin release was inhibited by LEAP2 from control (P < 0.001) but not E2-treated islets (P > 0.2). LEAP2 and AG did not modulate insulin secretion from MIN6 beta cells and Mrap2 was downregulated (P < 0.05) and Ghsr1a upregulated (P < 0.0001) in islets from Sst-/- mice. Our findings show that AG and LEAP2 regulate insulin and somatostatin release in an opposing and sex-dependent manner, which in males can be modulated by E2. We suggest that regulation of SST release is a key starting point for understanding the role of GHSR1a in islet function and glucose metabolism. [ABSTRACT FROM AUTHOR]

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Background and purpose: Maintaining mitochondrial quality is attracting attention as a new strategy to treat diabetes and diabetic complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin‐related protein (Drp) 1 and filamin, mediates chronic heart failure and cilnidipine, initially developed as an L/N‐type Ca2+ channel blocker, improves heart failure by inhibiting Drp1‐filamin protein complex. We investigated whether cilnidipine improves hyperglycaemia of various diabetic mice models. Experimental Approach: Retrospective analysis focusing on haemoglobin A1c (HbA1c) was performed in hypertensive and hyperglycaemic patients taking cilnidipine and amlodipine. After developing diabetic mice by streptozotocin (STZ) treatment, an osmotic pump including drug was implanted intraperitoneally, followed by weekly measurements of blood glucose levels. Mitochondrial morphology was analysed by electron microscopy. A Ca2+ channel‐insensitive cilnidipine derivative (1,4‐dihydropyridine [DHP]) was synthesized and its pharmacological effect was evaluated using obese (ob/ob) mice fed with high‐fat diet (HFD). Key Results: In patients, cilnidipine was superior to amlodipine in HbA1c lowering effect. Cilnidipine treatment improved systemic hyperglycaemia and mitochondrial morphological abnormalities in STZ‐exposed mice, without lowering blood pressure. Cilnidipine failed to improve hyperglycaemia of ob/ob mice, with suppressing insulin secretion. 1,4‐DHP improved hyperglycaemia and mitochondria abnormality in ob/ob mice fed HFD. 1,4‐DHP and cilnidipine improved basal oxygen consumption rate of HepG2 cells cultured under 25 mM glucose. Conclusion and implications: Inhibition of Drp1‐filamin protein complex formation becomes a new strategy for type 2 diabetes treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose: Metal‐based therapeutic agents are limited by the required concentration of metal‐based agents. Hereby, we determined if combination with 17β‐oestradiol (E2) could reduce such levels and the therapy still be effective in type 2 diabetes mellitus (T2DM). Experimental Approach: The metal‐based agent (vanadyl acetylacetonate [VAC])– 17β‐oestradiol (E2) combination is administered using the membrane‐permeable graphene quantum dots (GQD), the vehicle, to form the active GQD–E2–VAC complexes, which was characterized by fluorescence spectra, infrared spectra and X‐ray photoelectron spectroscopy. In db/db type 2 diabetic mice, the anti‐diabetic effects of GQD–E2–VAC complexes were evaluated using blood glucose levels, oral glucose tolerance test (OGTT), serum insulin levels, homeostasis model assessment (homeostasis model assessment of insulin resistance [HOMA‐IR] and homeostasis model assessment of β‐cell function [HOMA‐β]), histochemical assays and western blot. Key Results: In diabetic mice, GQD–E2–VAC complex had comprehensive anti‐diabetic effects, including control of hyperglycaemia, improved insulin sensitivity, correction of hyperinsulinaemia and prevention of β‐cell loss. Co‐regulation of thioredoxin interacting protein (TXNIP) activation by the combination of metal complex and 17β‐oestradiol contributed to the enhanced anti‐diabetic effects. Furthermore, a potent mitochondrial protective antioxidant, coniferaldehyde, significantly potentiates the protective effects of GQD–E2–VAC complexes. Conclusion and Implications: A metal complex–E2 combinatorial approach achieved simultaneously the protection of β cells and insulin enhancement at an unprecedented low dose, similar to the daily intake of dietary metals in vitamin supplements. This study demonstrates the positive effects of combination and multi‐modal therapies towards type 2 diabetes treatment. [ABSTRACT FROM AUTHOR]

Purpose: ANGPTL8, commonly referred to as betatrophin, has demonstrated promise as a dependable marker for the onset of complications associated with diabetes mellitus, such as dyslipidemia. The objective of this study is to evaluate the lipid profile and ANGPTL8 levels in people diagnosed with Type 1 Diabetes Mellitus (T1DM). Methods: A retrospective case-control study was performed on a group of 100 adolescent females, aged 13–17 years. This group consisted of individuals diagnosed with T1DM from the Diabetes and Endocrine Department at Medina's King Fahad Hospital in Saudi Arabia. Additionally, 100 healthy adolescent females of the same age range were included as controls. The hospital conducted laboratory studies to evaluate glucose, HbA1c, insulin, and lipid profiles. The ANGPTL8 levels were quantified using Enzyme-Linked Immunosorbent Assay (ELISA). Results: Patients with T1DM had ANGPTL8 levels that were twice as high as those observed in individuals without any health conditions. The two groups had contrasting levels of fasting blood glucose (FBG), glycated hemoglobin (HbA1c), C-peptides, triacylglycerol (TG), and cholesterol, along with elevated Atherogenic Index of Plasma readings. Diabetes mellitus patients had considerably elevated values compared to the control group. There was a significant correlation between ANGPTL8 concentrations and lipid abnormalities, with P-values less than 0.05. 56% of the 100 patients exhibited dyslipidemia. The research found a correlation between dyslipidemia and elevated levels of ANGPTL8 in diabetic patients. The concentration of ANGPTL8 had a positive correlation with glucose, HbA1c, TG, and C-peptides while displaying a negative correlation with high-density lipoprotein cholesterol (HDL-C). Conclusion: ANGPTL8 levels were found to be elevated in Saudi young women who were diagnosed with TIDM. ANGPTL8 may potentially contribute to dyslipidemia in individuals with T1DM, hence increasing the susceptibility to cardiovascular disease (CVD). Therefore, ANGPTL8 has the potential to impact lipid metabolism, namely Triglycerides, as a biological route. The results highlight the need to analyze lipid profiles and do ANGPTL8 testing in young females diagnosed with T1DM at an early stage to prevent complications. [ABSTRACT FROM AUTHOR]

Despite the fact that environmental pollution has been implicated in the global rise of diabetes, the research on the impact of emerging pollutants such as novel flame retardants remains limited. In line with the shift towards the use of non-animal approaches in toxicological testing, this study aimed to investigate the effects of two novel flame retardants tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP) in rat (INS1E) and human (NES2Y) pancreatic beta-cell lines. One-week exposure to 1 μM and 10 μM TDCIPP and TPhP altered intracellular insulin and proinsulin levels, but not the levels of secreted insulin (despite the presence of a statistically insignificant trend). The exposures also altered the protein expression of several factors involved in beta-cell metabolic pathways and signaling, including ATP citrate lyase, isocitrate dehydrogenase 1, perilipins, glucose transporters, ER stress-related factors, and antioxidant enzymes. This study has brought new and valuable insights into the toxicity of TDCIPP and TPhP on beta-cell function and revealed alterations that might impact insulin secretion after more extended exposure. It also adds to the scarce studies using in vitro pancreatic beta-cells models in toxicological testing, thereby promoting the development of non-animal testing strategy for identifying pro-diabetic effects of chemical pollutants. [ABSTRACT FROM AUTHOR]

Exosomes are extracellular vesicles that play a role in intercellular communication through the transportation of their cargo including mRNAs, microRNAs, proteins, and nucleic acids. Exosomes can also regulate glucose homeostasis and insulin secretion under diabetic conditions. However, the role of exosomes in insulin secretion in islet β-cells under physiological conditions remains to be clarified. The aim of this study was to investigate whether exosomes derived from pancreatic islet β-cells could affect insulin secretion in naïve β-cells. We first confirmed that exosomes derived from the RIN-m5f β-cell line interfered with the glucose-stimulated insulin secretion (GSIS) of recipient β-cells without affecting cell viability. The exosomes significantly reduced the protein expression levels of phosphorylated Akt, phosphorylated GSK3α/β, CaMKII, and GLUT2 (insulin-related signaling molecules), and they increased the protein expression levels of phosphorylated NFκB-p65 and Cox-2 (inflammation-related signaling molecules), as determined by a Western blot analysis. A bioinformatics analysis of Next-Generation Sequencing data suggested that exosome-carried microRNAs, such as miR-1224, -122-5p, -133a-3p, -10b-5p, and -423-5p, may affect GSIS in recipient β-cells. Taken together, these findings suggest that β-cell-derived exosomes may upregulate exosomal microRNA-associated signals to dysregulate glucose-stimulated insulin secretion in naïve β-cells. [ABSTRACT FROM AUTHOR]