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Aim: Neural activity in the olfactory bulb (OB) can represent odor information during different brain and behavioral states. For example, the odor responses of mitral/tufted (M/T) cells in the OB change during learning of odor‐discrimination tasks and, at the network level, beta power increases and the high gamma (HG) power decreases during odor presentation in such tasks. However, the neural mechanisms underlying these observations remain poorly understood. Here, we investigate whether serotonergic modulation from the dorsal raphe nucleus (DRN) to the OB is involved in shaping activity during the learning process in a go/no‐go task in mice. Methods: Fiber photometry was used to record the population activity of DRN serotonergic neurons during a go/no‐go task. In vivo electrophysiology was used to record neural activity (single units and local field potentials) in the OB during the go/no‐go task. Real‐time place preference (RTPP) and intracranial light administration in a specific subarea (iClass) tests were used to assess the ability of mice to encoding reward information. Results: Odor‐evoked population activity in serotonergic neurons in the DRN was shaped during the learning process in a go/no‐go task. In the OB, neural activity from oscillations to single cells showed complex, learning‐associated changes and ability to encode information during an odor discrimination task. However, these properties were not observed after ablation of DRN serotonergic neurons. Conclusion: The activity of neural networks and single cells in the OB, and their ability to encode information about odor value, are shaped by serotonergic projections from the DRN. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effects of the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine at therapeutically relevant concentrations on beta‐cell mass and function. Methods: Viability was quantified in mouse insulinoma (MIN6) beta cells and mouse islets after 48‐h exposure to sertraline (1–10 μM) or paroxetine (0.01–1 μM) using the Trypan blue exclusion test. The effects of therapeutic concentrations of these SSRIs on insulin secretion were determined by static incubation and perifusion experiments, while islet apoptosis was investigated by Caspase‐Glo 3/7 assay, TUNEL staining and quantitative PCR analysis. Finally, proliferation of MIN6 and mouse islet beta cells was assessed by bromodeoxyuridine (BrdU) enzyme‐linked immunosorbent assay and immunofluorescence. Results: Sertraline (0.1–1 μM) and paroxetine (0.01–0.1 μM) were well tolerated by MIN6 beta cells and islets, whereas 10 μM sertraline and 1 μM paroxetine were cytotoxic. Exposure to 1 μM sertraline and 0.1 μM paroxetine significantly potentiated glucose‐stimulated insulin secretion from mouse and human islets. Moreover, they showed protective effects against cytokine‐ and palmitate‐induced apoptosis of islets, they downregulated cytokine‐induced Stat1 and Traf1 mRNA expression, and they significantly increased proliferation of mouse beta cells. Conclusions: Our data demonstrate that sertraline and paroxetine act directly on beta cells to enhance glucose‐stimulated insulin secretion and stimulate beta‐cell mass expansion by increasing proliferation and decreasing apoptosis. These drugs are therefore likely to be appropriate for treating depression in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Amyloidosis forms a large family of pathologies associated with amyloid deposit generated by the formation of amyloid fibrils or plaques. The amyloidogenic proteins and peptides involved in these processes are targeted against almost all organs. In brain they are associated with neurodegenerative disease, and the Translocator Protein (TSPO), overexpressed in these inflammatory conditions, is one of the target for the diagnostic. Moreover, TSPO ligands have been described as promising therapeutic drugs for neurodegenerative diseases. Type 2 diabetes, another amyloidosis, is due to a beta cell mass decrease that has been linked to hIAPP (human islet amyloid polypeptide) fibril formation, leading to the reduction of insulin production. In the present study, in a first approach, we link overexpression of TSPO and inflammation in potentially prediabetic patients. In a second approach, we observed that TSPO deficient rats have higher level of insulin secretion in basal conditions and more IAPP fibrils formation compared with wild type animals. In a third approach, we show that diabetogenic conditions also increase TSPO overexpression and IAPP fibril formation in rat beta pancreatic cell line (INS-1E). These data open the way for further studies in the field of type 2 diabetes treatment or prevention. [Display omitted] • TSPO is overexpressed in overweight patients. • TSPO knockout in rat increases basal insulin secretion and fibril formation. • TSPO knockout in rat down regulates insulin secretion in diabetogenic conditions. • TSPO is overexpressed in cells upon diabetogenic conditions. [ABSTRACT FROM AUTHOR]

Background: Type-2 diabetes mellitus is a metabolic disorder characterised by hyperglycemia and insulin resistance. This study aims to explore the role and mechanism of DIRAS family GTPase 3 (DIRAS3) in mediating pancreatic β-cell death and insulin secretion. Materials and Methods: A bioinformatic analysis of the GSE118230 and GSE150281 datasets was performed to screen differentially expressed genes. The pancreatic β-cell lines, INS-1 and MIN6, were treated with palmitic acid (PA) to mimic the cell models of type-2 diabetes mellitus. CCK-8 assay, 5-ethynyl-2'-deoxyuridine staining, flow cytometry, enzyme-linked immunoassay, immunofluorescence, qRT-PCR, and western immunoblotting were conducted to illustrate the role of DIRAS3 in the cell models. Results: Unlike in normal controls, DIRAS3 was highly expressed in PA-treated pancreatic β-cells in a dose- and time-dependent manner. Moreover, the silencing of DIRAS3 in the INS-1 cells attenuated PA-induced cell loss by improving cell proliferation and inhibiting apoptosis and prevented the PA-induced impairment of insulin secretion. Consistently, the overexpression of DIRAS3 in the MIN6 cells accelerated PA-induced cell loss and impaired insulin secretion. A Gene Set Enrichment Analysis predicted that phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) was a downstream signalling pathway of DIRAS3, as the inhibitory effects of DIRAS3 on the activation of the PI3K/AKT signalling pathway were confirmed in the INS-1 and MIN6 cells. Moreover, the PI3K inhibitor, LY294002, effectively reversed the protective effects of DIRAS3 silencing on the INS-1 cells. Conclusion: DIRAS3 was highly expressed in the cell models of type-2 diabetes mellitus, contributing to PA-induced cell death and impaired insulin secretion in pancreatic β-cells through the inhibition of the PI3K/AKT signalling pathway. [ABSTRACT FROM AUTHOR]

Diabetes results from insufficient insulin production by pancreatic islet β-cells or a loss of β-cells themselves. Restoration of regulated insulin production is a predominant goal of translational diabetes research. Here, we provide a brief overview of recent advances in the fields of β-cell proliferation, regeneration, and replacement. The discovery of therapeutic targets and associated small molecules has been enabled by improved understanding of β-cell development and cell cycle regulation, as well as advanced high-throughput screening methodologies. Important findings in β-cell transdifferentiation, neogenesis, and stem cell differentiation have nucleated multiple promising therapeutic strategies. In particular, clinical trials are underway using in vitro–generated β-like cells from human pluripotent stem cells. Significant challenges remain for each of these strategies, but continued support for efforts in these research areas will be critical for the generation of distinct diabetes therapies. [ABSTRACT FROM AUTHOR]

Shortcomings in cell-based therapies for patients with diabetes have been revealed to be, in part, a result of an improper extracellular matrix (ECM) environment. In vivo, pancreatic islets are emersed in a diverse ECM that provides physical support and is crucial for healthy function. β1-Integrin receptors have been determined to be responsible for modulation of beneficial interactions with ECM proteins influencing beta-cell development, proliferation, maturation, and function. β1-Integrin signaling has been demonstrated to augment insulin secretion by impacting the actin cytoskeleton via activation of focal adhesion kinase and downstream signaling pathways. In other secretory cells, evidence of a bidirectional relationship between integrins and exocytotic machinery has been demonstrated, and, thus, this relationship could be present in pancreatic beta cells. In this review, we will discuss the role of ECM–β1-integrin interplay with exocytotic proteins in controlling pancreatic beta-cell insulin secretion through their dynamic and unique signaling pathway. [ABSTRACT FROM AUTHOR]

After birth, healthy neonates undergo a period of altered glucose metabolism, known as "transitional hypoglycemia." During the first 0 to 4 hours of life, the mean plasma glucose concentration decreases to 57 mg/dL, then by 72 to 96 hours of life increases to 82 mg/dL, well within the normal adult range. Recent data suggest that transitional hypoglycemia is due to persistence of the fetal beta cell's lower threshold for insulin release, resulting in a transient hyperinsulinemic state. While hypoglycemia is an expected part of the transition to postnatal life, it makes the identification of infants with persistent hypoglycemia disorders challenging. Given the risk of neurologic injury from hypoglycemia, identifying these infants is critical. Hyperinsulinism is the most common cause of persistent hypoglycemia in neonates and infants and carries a high risk of neurocognitive dysfunction given the severity of the hypoglycemia and the inability to generate ketones, a critical alternative cerebral fuel. Screening neonates at risk for persistent hypoglycemia disorders and completing evaluations prior to hospital discharge is essential to prevent delayed diagnoses and neurologic damage. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is a precursor to the development of many diseases (atherosclerosis, diabetes, etc.). It is marked by disruptions in glucose and lipid metabolism, along with hypertension. Numerous types of risk factors contribute to the development of the MetS, inflammation and insulin resistance are present throughout the metabolic abnormalities. Chrysanthemum indicum L. is a traditional Chinese plant used for both tea and medicine, known for its high content of total flavonoids, which are important secondary metabolites. Our research led to the extraction of a Buddleoside-Rich Chrysanthemum indicum L. extract (BUDE) which has demonstrated anti-inflammatory properties. Nonetheless, the specific role and mechanism of BUDE in preventing MetS remain unclear. Methods: The study initially evaluated the role of BUDE in preventing MetS. Subsequently, it investigated the anti-inflammatory properties of BUDE in the liver and pancreas in response to unhealthy diets. It then examined the level of insulin resistance and pancreatic β-cell function induced by inflammation. Additionally, an lipopolysaccharide (LPS)-induced macrophage inflammation model was used to further investigate the ameliorative effects of BUDE in inflammation. Results: BUDE has hypotensive, hypoglycemic and hypolipidemic effects. It can also resolve the imbalance between macrophage subpopulations, impede the triggering of the NF-κB signaling pathway, reduce the secretion of inflammatory mediators, ameliorate insulin resistance, and safeguard organs such as the liver and pancreas from inflammatory damage. These effects collectively contribute to preventing the development of MetS. Discussion: BUDE has the ability to modulate macrophage-mediated inflammation, leading to improved insulin resistance. Additionally, it delivers antihypertensive, hypoglycemic, and hypolipidemic effects, offering a potential for preventing MetS. [ABSTRACT FROM AUTHOR]

Background: The functional changes in alpha cells in patients with type 1 diabetes (T1D) with different residual beta cell functions remain poorly elucidated. The study aimed to investigate the relationship between glucagon secretion and C-peptide levels and to explore the relationship between glucagon response and glucose increment in respond to a secretagogue in a steamed bread meal tolerance test (BMTT) in T1D. Methods: The study enrolled 43 adult patients with T1D and 24 healthy control subjects. Patients with T1D who underwent BMTT were divided into two groups based on peak C-peptide levels: C peptide low (CPL; C-peptide < 200 pmol/L; n=14) and high (CPH; C peptide ≥ 200 pmol/L; n=29). Plasma glucose, C-peptide, glucagon levels at 0, 30, 60, 120, and 180 min were measured. The glucagon response to the BMTT was defined by areas under the curve (AUC) as early (AUC0-30), late (AUC30-180), or total (AUC0-180) glucagon. Results: Compared to healthy individuals, fasting plasma glucagon was lower and postprandial plasma glucagon level was increased in patients with T1D. Glucagon levels after BMTT between the CPL and CPH group showed significant group by time interaction. Peak glucagon and glucagon at 60-180 min, total and late glucagon response were higher in CPL than CPH group, while fasting glucagon and early glucagon response adjusted for glucose were comparable between CPL and CPH group. The higher late glucagon response and late glucagon response adjusted for glucose were associated with lower peak C-peptide in T1D. The higher late glucagon response and lower peak C-peptide were associated with the higher value of △glucose at 180 min. Conclusion: Stimulated C-peptide levels affect the paradoxical increase in postprandial glucagon secretion in patients with T1D, especially late glucagon response. The exaggerated postprandial glucagon secretion further stimulates the elevation of postprandial glucose in patients with T1D. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS. The regulation of energy homeostasis by centrally-produced GLP-1 is not yet fully understood. Here, authors show that GLP-1 neuronal circuitry in the olfactory bulb reduces food intake and enhances insulin secretion in obese mice. The increase in insulin secretion is mediated by a GABA-dependent relay in the paraventricular hypothalamus and decreased sympathetic nerve activity. [ABSTRACT FROM AUTHOR]

A recent study published in Transplant International explores the use of stem cell-derived islet transplantation as a potential treatment for type 2 diabetes. The study details the successful transplantation of islet tissue derived from induced pluripotent stem cells into a patient with type 2 diabetes, which resulted in improved islet function. However, the study also acknowledges the need for more information on quality control and the limitations of diagnosing the patient's diabetes. The authors suggest that further research is necessary to fully understand the safety and effectiveness of this treatment. The document provides a summary of the study, including information on its focus, findings, and the authors' contributions and funding. [Extracted from the article]

Objective: Beta cell destruction in type 1 diabetes (T1D) results from the combined effect of inflammation and recurrent autoimmunity. In recent years, the role played by beta cells in the development of T1D has evolved from passive victims of the immune system to active contributors in their own destruction. We and others have demonstrated that perturbations in the islet microenvironment promote endoplasmic reticulum (ER) stress in beta cells, leading to enhanced immunogenicity. Among the underlying mechanisms, secretion of extracellular vesicles (EVs) by beta cells has been suggested to mediate the crosstalk with the immune cell compartment. Methods: To study the role of cellular stress in the early events of T1D development, we generated a novel cellular model for constitutive ER stress by modulating the expression of HSPA5, which encodes BiP/GRP78, in EndoC-βH1 cells. To investigate the role of EVs in the interaction between beta cells and the immune system, we characterized the EV miRNA cargo and evaluated their effect on innate immune cells. Results: Analysis of the transcriptome showed that HSPA5 knockdown resulted in the upregulation of signaling pathways involved in the unfolded protein response (UPR) and changes the miRNA content of EVs, including reduced levels of miRNAs involved in IL-1β signaling. Treatment of primary human monocytes with EVs from stressed beta cells resulted in increased surface expression of CD11b, HLA-DR, CD40 and CD86 and upregulation of IL-1β and IL-6. Conclusion: These findings indicate that the content of EVs derived from stressed beta cells can be a mediator of islet inflammation. [ABSTRACT FROM AUTHOR]

Introduction: Using a non-human primate (NHP) model of maternal Westernstyle diet (mWSD) feeding during pregnancy and lactation, we previously reported altered offspring beta:alpha cell ratio in vivo and insulin hypersecretion ex vivo. Mitochondria are known to maintain beta-cell function by producing ATP for insulin secretion. In response to nutrient stress, the mitochondrial network within beta cells undergoes morphological changes to maintain respiration and metabolic adaptability. Given that mitochondrial dynamics have also been associated with cellular fate transitions, we assessed whether mWSD exposure was associated with changes in markers of beta-cell maturity and/or mitochondrial morphology that might explain the offspring islet phenotype. Methods: We evaluated the expression of beta-cell identity/maturity markers (NKX6.1, MAFB, UCN3) via florescence microscopy in islets of Japanese macaque pre-adolescent (1 year old) and peri-adolescent (3-year-old) offspring born to dams fed either a control diet or WSD during pregnancy and lactation and weaned onto WSD. Mitochondrial morphology in NHP offspring beta cells was analyzed in 2D by transmission electron microscopy and in 3D using super resolution microscopy to deconvolve the beta-cell mitochondrial network. Results: There was no difference in the percent of beta cells expressing key maturity markers in NHP offspring from WSD-fed dams at 1 or 3 years of age; however, beta cells of WSD-exposed 3 year old offspring showed increased levels of NKX6.1 per beta cell at 3 years of age. Regardless of maternal diet, the beta-cell mitochondrial network was found to be primarily short and fragmented at both ages in NHP; overall mitochondrial volume increased with age. In utero and lactational exposure to maternal WSD consumption may increase mitochondrial fragmentation. Discussion: Despite mWSD consumption having clear developmental effects on offspring beta:alpha cell ratio and insulin secretory response to glucose, this does not appear to be mediated by changes to beta-cell maturity or the beta-cell mitochondrial network. In general, the more fragmented mitochondrial network in NHP beta cells suggests greater ability for metabolic flexibility. [ABSTRACT FROM AUTHOR]

Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes. Opioid use impacts metabolic homeostasis, although the mechanisms remain elusive. Here, the authors explore the OPRD1 gene (encoding the delta opioid receptor, DOP) to understand its impact on type 2 diabetes and highlight DOP as a key player between opioids and metabolic homeostasis. [ABSTRACT FROM AUTHOR]

Maturity-onset diabetes of the young (MODY) is the most frequent monogenetic diabetes form. It is caused by mutations in genes important for the development and function of pancreatic beta-cells, resulting in impaired insulin secretion capacity. Up to now, 14 different types have been described. The inheritance pattern is autosomal dominant, leading to a strong family history with more than three affected generations. Young age at diagnosis and lack of pancreatic autoantibodies are further characteristics of MODY. The presence of diabetic ketoacidosis (DKA) was long regarded as an exclusion criterion for MODY. However, in recent years, several case reports on MODY patients presenting with DKA have been published. The present study aimed to give an overview of the current knowledge of DKA in MODY patients, with a collection of published case studies as a prerequisite for this review. [ABSTRACT FROM AUTHOR]

Summary: Type 1 diabetes (T1D) is a chronic autoimmune disease targeting insulin‐producing pancreatic beta cells. T1D is a multifactorial disease incorporating genetic and environmental factors. In recent years, the advances in high‐throughput sequencing have allowed researchers to elucidate the changes in the gut microbiota taxonomy and functional capacity that accompany T1D development. An increasing number of studies have shown a role of the gut microbiota in mediating immune responses in health and disease, including autoimmunity. Fecal microbiota transplantations (FMT) have been largely used in murine models to prove a causal role of the gut microbiome in disease progression and have been shown to be a safe and effective treatment in inflammatory human diseases. In this review, we summarize and discuss recent research regarding the gut microbiota–host interactions in T1D, the current advancement in therapies for T1D, and the usefulness of FMT studies to explore microbiota–host immunity encounters in murine models and to shape the course of human type 1 diabetes. [ABSTRACT FROM AUTHOR]

Aim: To investigate metabolic risk factors (RFs) that accumulated over 20 years related to left ventricular mass index (LVMI), relative wall thickness (RWT) and LV remodelling patterns in participants with versus without early‐onset type 2 diabetes (T2D) or prediabetes (pre‐D). Methods: A total of 287 early‐onset T2D/pre‐D individuals versus 565 sociodemographic‐matched euglycaemic individuals were selected from the Coronary Artery Risk Development in Young Adults (CARDIA) study, years 0‐25. We used the area under the growth curve (AUC) derived from quadratic random‐effects models of four or more repeated measures of RFs (fasting glucose [FG], insulin, triglycerides [TG], low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol (HDL‐c), total cholesterol (total‐c), blood pressure and body mass index) to estimate the cumulative burden, and their associations with LV outcomes. Results: One standard deviation greater AUC of log (TG) (per 0.48) and HDL‐c (per 13.5 mg/dL) were associated with RWT (β 0.21 and −0.2) in the early‐onset T2D/pre‐D group, but not in the euglycaemia group (β 0.01 and 0.05, P interactions.02 and.03). In both the early‐onset T2D/pre‐D and euglycaemia groups, greater AUCs of log (FG) (per 0.17) and log (insulin) (per 0.43) were associated with higher RWT (β ranges 0.12‐0.24). Greater AUCs of systolic blood pressure (per 10 mmHg) and diastolic blood pressure (per 7.3 mmHg) were associated with higher RWT and LVMI, irrespective of glycaemic status (β ranges 0.17‐0.28). Cumulative TG (odds ratio 3.4, 95% confidence interval: 1.8‐6.3), HDL‐c (0.23, 0.09‐0.59), total‐c (1.9, 1.1‐3.1) and FG (2.2, 1.25‐3.9) were statistically associated with concentric hypertrophy in the T2D/pre‐D group only. Conclusions: Sustained hyperglycaemia and hyperinsulinaemia are associated with RWT, and those individuals with early T2D/pre‐D are potentially at greater risk because of their higher levels of glucose and insulin. Dyslipidaemia was associated with LV structural abnormalities in those individuals with early‐onset T2D/pre‐D. [ABSTRACT FROM AUTHOR]

Depression is a mood disorder that may increase risk for the development of insulin resistance (IR) and type 2 diabetes (T2D), and vice versa. However, the mechanistic pathway linking depression and T2D is not fully elucidated. The aim of this narrative review, therefore, was to discuss the possible link between depression and T2D. The coexistence of T2D and depression is twice as great compared to the occurrence of either condition independently. Hyperglycaemia and dyslipidaemia promote the incidence of depression by enhancing inflammation and reducing brain serotonin (5‐hydroxytryptamine [5HT]). Dysregulation of insulin signalling in T2D impairs brain 5HT signalling, leading to the development of depression. Furthermore, depression is associated with the development of hyperglycaemia and poor glycaemic control. Psychological stress and depression promote the development of T2D. In conclusion, T2D could be a potential risk factor for the development of depression through the induction of inflammatory reactions and oxidative stress that affect brain neurotransmission. In addition, chronic stress in depression may induce the development of T2D through dysregulation of the hypothalamic–pituitary–adrenal axis and increase circulating cortisol levels, which triggers IR and T2D. [ABSTRACT FROM AUTHOR]

The present study evaluated three green extraction methods, accelerated solvent extraction (ASE), ultrasound-assisted extraction (UAE), and laser irradiation extraction (LE), for the polyphenolic compounds and vitamin C extraction of Cornus mas L. and Crataegus monogyna fruit extracts. The polyphenols and vitamin C of extracts were quantified using HPLC-DAD, and the total phenolic content, flavonoid content, antioxidant activity (DPPH and reducing power), and antidiabetic activity were also studied. The antidiabetic activity was examined by the inhibition of α-amylase and α-glucosidase, and in vitro on a beta TC cell line (β-TC-6). The results showed significant differentiation in the extraction yield between the methods used, with the ASE and LE presenting the highest values. The C. mas fruit extract obtained by ASE exhibited the best antioxidant activity, reaching an IC50 value of 31.82 ± 0.10 µg/mL in the DPPH assay and 33.95 ± 0.20 µg/mL in the reducing power assay. The C. mas fruit extracts obtained by ASE and LE also have the highest inhibitory activity on enzymes associated with metabolic disorders: α-amylase (IC50 = 0.44 ± 0.02 µg/mL for the extract obtained by ASE, and 0.11 ± 0.01 µg/mL for the extract obtained by LE at combined wavelengths of 1270 + 1550 nm) and α-glucosidase (IC50 of 77.1 ± 3.1 µg/mL for the extract obtained by ASE, and 98.2 ± 4.7 µg/mL for the extract obtained by LE at combined wavelengths of 1270 + 1550 nm). The evaluation of in vitro antidiabetic activity demonstrated that the treatment with C. mas and C. monogyna fruit extracts obtained using ASE stimulated the insulin secretion of β-TC-6 cells, both under normal conditions and hyperglycemic conditions, as well. All results suggest that C. mas and C. monogyna fruit extracts are good sources of bioactive molecules with antioxidant and antidiabetic activity. [ABSTRACT FROM AUTHOR]

Preserving the function and survival of pancreatic beta-cells, in order to achieve long-term glycemic control and prevent complications, is an essential feature for an innovative drug to have clinical value in the treatment of diabetes. Innovative research is developing therapeutic strategies to prevent pathogenic mechanisms and protect beta-cells from the deleterious effects of inflammation and/or chronic hyperglycemia over time. A better understanding of receptors and signaling pathways, and of how they interact with each other in beta-cells, remains crucial and is a prerequisite for any strategy to develop therapeutic tools aimed at modulating beta-cell function and/or mass. Here, we present a comprehensive review of our knowledge on membrane and intracellular receptors and signaling pathways as targets of interest to protect beta-cells from dysfunction and apoptotic death, which opens or could open the way to the development of innovative therapies for diabetes. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is an immensely debilitating chronic disease that progressively undermines the well‐being of various bodily organs and, indeed, most patients succumb to the disease due to post‐T2DM complications. Although there is evidence supporting the activation of the phosphoinositide 3‐kinase (PI3K)/Akt signaling pathway by insulin, which is essential in regulating glucose metabolism and insulin resistance, the significance of this pathway in T2DM has only been explored in a few studies. The current review aims to unravel the mechanisms by which different classes of PI3Ks control the metabolism of glucose; and also to discuss the original data obtained from international research laboratories on this topic. We also summarized the role of the PI3K/Akt signaling axis in target tissues spanning from the skeletal muscle to the adipose tissue and liver. Furthermore, inquiries regarding the impact of disrupting this axis on insulin function and the development of insulin resistance have been addressed. We also provide a general overview of the association of impaired PI3K/Akt signaling pathways in the pathogenesis of the most prevalent diabetes‐related complications. The last section provides a special focus on the therapeutic potential of this axis by outlining the latest advances in active compounds that alleviate diabetes via modulation of the PI3K/Akt pathway. Finally, we comment on the future research aspects in which the field of T2DM therapies using PI3K modulators might be developed. [ABSTRACT FROM AUTHOR]

Currently, there are more than 10 million patients with diabetes mellitus in Japan. Therefore, the need to explore the pathogenesis of diabetes and the complications leading to its cure is becoming increasingly urgent. Pathological examination of pancreatic tissues from patients with type 2 diabetes reveals a decrease in the volume of beta cells because of a combination of various stresses. In human type 2 diabetes, islet amyloid deposition is a unique pathological change characterized by proinflammatory macrophage (M1) infiltration into the islets. The pathological changes in the pancreas with islet amyloid were different according to clinical factors, which suggests that type 2 diabetes can be further subclassified based on islet pathology. On the other hand, diabetic peripheral neuropathy is the most frequent diabetic complication. In early diabetic peripheral neuropathy, M1 infiltration in the sciatic nerve evokes oxidative stress or attenuates retrograde axonal transport, as clearly demonstrated by in vitro live imaging. Furthermore, islet parasympathetic nerve density and beta cell volume were inversely correlated in type 2 diabetic Goto‐Kakizaki rats, suggesting that diabetic peripheral neuropathy itself may contribute to the decrease in beta cell volume. These findings suggest that the pathogenesis of diabetes mellitus and diabetic peripheral neuropathy may be interrelated. [ABSTRACT FROM AUTHOR]

[Display omitted] Type 1 diabetes mellitus (T1DM) is a chronic disease affecting millions worldwide. Insulin therapy is currently the golden standard for treating T1DM; however, it does not restore the normal glycaemic balance entirely, which increases the risk of secondary complications. Beta-cell therapy may be a possible way of curing T1DM and has already shown promising results in the clinic. However, low retention rates, poor cell survival, and limited therapeutic potential are ongoing challenges, thus increasing the need for better cell encapsulation devices. This study aimed to develop a mechanically reinforced vascular endothelial growth factor (VEGF)-delivering encapsulation device suitable for beta cell encapsulation and transplantation. Poly(l-lactide- co -ε-caprolactone) (PLCL)/gelatin methacryloyl (GelMA)/alginate coaxial nanofibres were produced using electrospinning and embedded in an alginate hydrogel. The encapsulation device was physically and biologically characterised and was found to be suitable for INS-1E beta cell encapsulation, vascularization, and transplantation in terms of its biocompatibility, porosity, swelling ratio and mechanical properties. Lastly, VEGF was incorporated into the hydrogel and the release kinetics and functional studies revealed a sustained release of bioactive VEGF for at least 14 days, making the modified alginate system a promising candidate for improving the beta cell survival after transplantation. [ABSTRACT FROM AUTHOR]

The association between chronic HCV infection and type 2 diabetes mellitus (T2DM) has been established; however, there is limited research on β-cell function particularly in the pre-diabetic population. Here, we evaluated indices of β-cell function and insulin sensitivity across the spectrum from normal glucose tolerance to T2DM in individuals with and without chronic hepatitis C (CHC), and the effects of antiviral treatments on these variables. A total of 153 non-cirrhotic, non-fibrotic CHC patients with a BMI <25 were enrolled in the study. Among them, 119 were successfully treated with either direct acting antiviral (DAA) drugs or pegylated interferon/ribavirin (IFN/RBV) anti-HCV therapy. Fasting state- and oral glucose tolerance test (OGTT)-derived indexes were used to evaluate β-cell function and insulin sensitivity. Among all subjects, 19 (13%) had T2DM and 21% exhibited pre-diabetes including 8% isolated impaired fasting glucose (IFG) and 13% combined IFG and impaired glucose tolerance (IGT). Early and total insulin secretion adjusted for the degree of insulin resistance were decreased in pre-diabetic CHC patients compared to HCV-uninfected individuals. Viral eradication through DAA or IFN/RBV therapy demonstrated positive impacts on insulin sensitivity and β-cell function in CHC patients who achieved sustained virologic response (SVR), regardless of fasting or OGTT state. These findings emphasize the role of HCV in the development of β-cell dysfunction, while also suggesting that viral eradication can improve insulin secretion, reverse insulin resistance, and ameliorate glycemic control. These results have important implications for managing pre-diabetic CHC patients and could prevent diabetes-related clinical manifestations and complications. [ABSTRACT FROM AUTHOR]

Context Low-dose sulfonylureas (SUs) have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation. Objective To evaluate potential synergy between low-dose SU plus a dipeptidyl peptidase 4 (DPP4) inhibitor. Methods Unblinded randomized crossover study at the Clinical Research Centre, University of Dundee. Thirty participants with T2DM (HbA1c < 64 mmol/mol) were treated with diet or metformin. Participants completed 4, 14-day blocks in a random order: control, gliclazide 20 mg (SU), sitagliptin 100 mg (DPP4 inhibitor [DPP4i]), or combination (SUDPP4i). A mixed meal test was conducted after each intervention. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose <3 mmol/L on continuous glucose monitoring, subanalyses by genotype (KNCJ11 E23K), gender, and body mass index. Results SU combination with DPP4i showed additive effect on glucose lowering: mean glucose area under the curve (mean 95% CI) (mmol/L) was control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (P <.001). Glucose sensitivity mirrored the additive effect (pmol min−1 m−2 mM−1): control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-114.3) (P =.04). The additive effect was seen in men but not women. Glucose time in range <3 mmol/L on continuous glucose monitoring (%) was unaffected: control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (P =.65). Conclusion Low-dose sulfonylurea plus DPP4i has a potent glucose-lowering effect through augmentation of beta-cell function. A double-blind randomized controlled trial would formalize efficacy and safety of this combination, which may avoid negative aspects of SU. [ABSTRACT FROM AUTHOR]

The Ppy gene encodes pancreatic polypeptide (PP) secreted by PP‐ or γ‐cells, which are a subtype of endocrine cells localised mainly in the islet periphery. For a detailed characterisation of PP cells, we aimed to establish PP cell lines. To this end, we generated a mouse model harbouring the SV40 large T antigen (TAg) in the Rosa26 locus, which is expressed upon Ppy‐promoter‐mediated Cre–loxP recombination. Whereas Insulin1‐CreERT‐mediated TAg expression in beta cells resulted in insulinoma, surprisingly, Ppy‐Cre‐mediated TAg expression resulted in the malignant transformation of Ppy‐lineage cells. These mice showed distorted islet structural integrity at 5 days of age compared with normal islets. CK19+ duct‐like lesions contiguous with the islets were observed at 2 weeks of age, and mice developed aggressive pancreatic ductal adenocarcinoma (PDAC) at 4 weeks of age, suggesting that PDAC can originate from the islet/endocrine pancreas. This was unexpected as PDAC is believed to originate from the exocrine pancreas. RNA‐sequencing analysis of Ppy‐lineage islet cells from 7‐day‐old TAg+ mice showed a downregulation and an upregulation of endocrine and exocrine genes, respectively, in addition to the upregulation of genes and pathways associated with PDAC. These results suggest that the expression of an oncogene in Ppy‐lineage cells induces a switch from endocrine cell fate to PDAC. Our findings demonstrate that Ppy‐lineage cells may be an origin of PDAC and may provide novel insights into the pathogenesis of pancreatic cancer, as well as possible therapeutic strategies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Diabetes, a complex multisystem metabolic disorder characterized by hyperglycemia, leads to complications that reduce quality of life and increase mortality. Diabetes pathophysiology includes dysfunction of beta cells, adipose tissue, skeletal muscle, and liver. Type 1 diabetes (T1D) results from immune-mediated beta cell destruction. The more prevalent type 2 diabetes (T2D) is a heterogeneous disorder characterized by varying degrees of beta cell dysfunction in concert with insulin resistance. The strong association between obesity and T2D involves pathways regulated by the central nervous system governing food intake and energy expenditure, integrating inputs from peripheral organs and the environment. The risk of developing diabetes or its complications represents interactions between genetic susceptibility and environmental factors, including the availability of nutritious food and other social determinants of health. This perspective reviews recent advances in understanding the pathophysiology and treatment of diabetes and its complications, which could alter the course of this prevalent disorder. A comprehensive review of recent insights into the pathophysiology of type 1 and type 2 diabetes and their complications, highlighting recent advances in disease classification and the development of therapies that hold the promise to alter the course of this prevalent disorder. [ABSTRACT FROM AUTHOR]

In this study, the antidiabetic activities of Lepionurus sylvestris Blume extract (LSB) in rats was investigated. The in vitro antidiabetic properties of LSB was evaluated using α-amylase, α-glucosidase and DPP-IV inhibitory assays, while the antioxidant assay was analysed using DPPH, ABTS and FRAP assays. Type 2 diabetes was with high-fructose/streptozotocin, and the diabetic animals were treated with LSB for 5 weeks. At the end of the experiment, the effects of LSB were evaluated via insulin level, lipid profile and hepatorenal function biomarkers. The level of oxido-inflammatory parameters, histopathology and insulin immunohistochemical staining in the pancreas was evaluated. Diabetic rats manifested significant increases in the blood glucose level, food/water intake, lipid profiles, hepatorenal function biomarkers, as well as a marked decreases in the body weight and serum insulin levels. Histopathological and insulin immunohistochemical examination also revealed decreased pancreatic beta cells and insulin positive cells, respectively. These alterations were associated with significant increases in malondialdehyde, TNF-α and IL-1β, in addition to significant declines in GSH, SOD and CAT activities. LSB significantly reduced blood glucose level, glucose intolerance, serum lipids, restored altered hepatorenal and pancreatic functions in the treated diabetic rats. Further, LSB showed antioxidant and anti-inflammatory activities by reducing malondialdehyde, TNF-α, IL-1β, and increasing antioxidant enzymes activities in the pancreatic tissues. A total of 77 secondary metabolites were tentatively identified in the UPLC-Q-TOF-MS analysis of LSB. Overall, these findings provides insight into the potentials of LSB as an antidiabetic agent which may be associated to the plethora bioactive compounds in the plant. [ABSTRACT FROM AUTHOR]

Long-term exposure to hyperglycemic conditions leads to β-cell dysfunction, particularly mitochondrial dysfunction, and inflammatory and oxidative stress responses, which are considered the primary causes of β-cell death and the hallmarks of diabetes. Plant-active ingredients may play a key role in glycemic control. Epigallocatechin gallate (EGCG) is a characteristic catechin derived from tea that possesses anti-diabetic properties. Nonetheless, its underlying mechanisms remain elusive. Herein, the protective role of EGCG on high glucose (33 mM)-induced pancreatic beta cell dysfunction and its possible molecular mechanisms were investigated. Briefly, MIN6 cells were treated with glucose and EGCG (10 µM, 20 µM, and 40 µM) for 48 h. Our results revealed that EGCG dose-dependently restored mitochondrial membrane potential and concomitantly alleviated cell apoptosis. Mechanistically, the expression level of apoptotic protein BAX and Dynamic related protein 1 (DRP1) was significantly downregulated following EGCG treatment, whereas that of the anti-apoptotic protein BCL-2 was significantly upregulated. Taken together, EGCG alleviated high glucose-induced pancreatic beta cell dysfunction by targeting the DRP1-related mitochondrial apoptosis pathway and thus can serve as a nutritional intervention for the preservation of beta cell dysfunction in patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

NSG mice are among the most immunodeficient mouse model being used in various scientific branches. In diabetelogical research diabetic NSG mice are an important asset as a xenotransplantation model for human pancreatic islets or pluripotent stem cell-derived islets. The treatment with the beta cell toxin streptozotocin is the standard procedure for triggering a chemically induced diabetes. Surprisingly, little data has been published about the reproducibility, stress and animal suffering in these NSG mice during diabetes induction. The 3R rules, however, are a constant reminder that existing methods can be further refined to minimize suffering. In this pilot study the dose–response relationship of STZ in male NSG mice was investigated and additionally animal suffering was charted by applying the novel 'Relative Severity Assessment' algorithm. By this we successfully explored an STZ dose that reliably induced diabetes while reduced stress and pain to the animals to a minimum using evidence-based and objective parameters rather than criteria that might be influenced by human bias. [ABSTRACT FROM AUTHOR]

Regeneration, the ability to replace injured tissues and organs, is a phenomenon commonly associated with lower vertebrates but is also observed in mammals, in specific tissues. In this study, we investigated the regenerative potential of pancreatic islets following moderate beta-cell loss in mice. Using a rapid model of moderate ablation, we observed a compensatory response characterized by transient inflammation and proliferation signatures, ultimately leading to the recovery of beta-cell identity and function. Interestingly, this proliferative response occurred independently of inflammation, as demonstrated in ablated immunodeficient mice. Furthermore, exposure to high-fat diet stimulated beta-cell proliferation but negatively impacted beta-cell function. In contrast, an equivalent slower ablation model revealed a delayed but similar proliferative response, suggesting proliferation as a common regenerative response. However, high-fat diet failed to promote proliferation in this model, indicating a differential response to metabolic stressors. Overall, our findings shed light on the complex interplay between beta-cell loss, inflammation, and stress in modulating pancreatic islet regeneration. Understanding these mechanisms could pave the way for novel therapeutic strategies based on beta-cell proliferation. Rapid and moderate 50% DT-induced beta-cell ablation prompts a compensatory response in the pancreatic islet, despite the absence of an obvious metabolic pressure to regenerate. [ABSTRACT FROM AUTHOR]

Moringa oleifera, a widely recognized plant more commonly known as moringa, has obtained significant research interest in recent years due to its prospective physiological advantages, including its claimed ability to counteract carcinogenesis. The moringa plant has been found to possess bioactive components that exhibit promising anticancer activities against different human cancers, such as breast cancer, prostate cancer, pancreatic cancer, etc. The cytotoxic properties of moringa seed extracts on cancerous cells have also been provided in this paper along with other notable health benefits. The extracts derived from moringa seeds inhibit cancer proliferation and promote cancer cell apoptosis through multiple signaling pathways. They also stimulated intracellular reactive oxygen species (ROS) production and subsequently induced caspase‐3 activity. The impact of moringin and avenanthramide 2f on the stimulation of caspases 2, 4, 8, and 9 results in reduction in the proliferation of cancer cells. The results reported by research studies hold significant implications for identifying and targeting specific molecular entities that could serve as potential therapeutic targets in search of effective cancer treatments. Furthermore, the flavonoids in moringa seed can remove mitochondrial reactive oxygen species, protecting beta cells and bringing hyperglycemia under control. M. oleifera seed oil can reduce the risk of cardiovascular diseases via reduced malondialdehyde (MDA) formation and modulation of cardiac superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity. This article provides a comprehensive summary of the noteworthy discoveries derived from a rigorous investigation that explored into the impact of moringa seeds on the prevention/reduction of various cancers and other complex diseases. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Recent advancements in the technology of generating pancreatic beta cells from human pluripotent stem cells (SC-beta cells) have facilitated the exploration of cell replacement therapies for treating T1D. However, the persistent threat of autoimmunity poses a significant challenge to the survival of transplanted SC-beta cells. Genetic engineering is a promising approach to enhance immune resistance of beta cells as we previously showed by inactivating the Renalase (Rnls) gene. Here, we demonstrate that Rnls loss of function in beta cells shapes autoimmunity by mediating a regulatory natural killer (NK) cell phenotype important for the induction of tolerogenic antigen-presenting cells. Rnls-deficient beta cells mediate cell--cell contact-independent induction of hallmark anti-inflammatory cytokine Tgfb1 in NK cells. In addition, surface expression of regulatory NK immune checkpoints CD47 and Ceacam1 is markedly elevated on beta cells deficient for Rnls. Altered glucose metabolism in Rnls mutant beta cells is involved in the upregulation of CD47 surface expression. These findings are crucial to better understand how genetically engineered beta cells shape autoimmunity, giving valuable insights for future therapeutic advancements to treat and cure T1D. [ABSTRACT FROM AUTHOR]

Background Charting cellular trajectories over gene expression is key to understanding dynamic cellular processes and their underlying mechanisms. While advances in single-cell RNA-sequencing technologies and computational methods have pushed forward the recovery of such trajectories, trajectory inference remains a challenge due to the noisy, sparse, and high-dimensional nature of single-cell data. This challenge can be alleviated by increasing either the number of cells sampled along the trajectory (breadth) or the sequencing depth, i.e. the number of reads captured per cell (depth). Generally, these two factors are coupled due to an inherent breadth-depth tradeoff that arises when the sequencing budget is constrained due to financial or technical limitations. Results Here we study the optimal allocation of a fixed sequencing budget to optimize the recovery of trajectory attributes. Empirical results reveal that reconstruction accuracy of internal cell structure in expression space scales with the logarithm of either the breadth or depth of sequencing. We additionally observe a power law relationship between the optimal number of sampled cells and the corresponding sequencing budget. For linear trajectories, non-monotonicity in trajectory reconstruction across the breadth-depth tradeoff can impact downstream inference, such as expression pattern analysis along the trajectory. We demonstrate these results for five single-cell RNA-sequencing datasets encompassing differentiation of embryonic stem cells, pancreatic beta cells, hepatoblast and multipotent hematopoietic cells, as well as induced reprogramming of embryonic fibroblasts into neurons. By addressing the challenges of single-cell data, our study offers insights into maximizing the efficiency of cellular trajectory analysis through strategic allocation of sequencing resources. [ABSTRACT FROM AUTHOR]

Simple Summary: Glucotoxicity is a condition that leads to β-cell death, driving a decrease in insulin secretion and leading to hyperglycemia and, eventually, diabetes. Here, we investigate whether connexin Cx30.2 could protect against glucotoxicity-induced apoptosis in β cells. We found that RIN-m5F β cells exposed to high glucose exhibited increased Cx30.2 protein expression. Interestingly, decreased expression of Cx30.2 by specific siRNAs resulted in augmented β-cell death, suggesting that Cx30.2 has an important role in maintaining cell survival during glucotoxicity. Overall, Cx30.2 could be an attractive pharmacological target to avoid high glucose-induced β-cell apoptosis. Glucotoxicity may exert its deleterious effects on pancreatic β-cell function via a myriad of mechanisms, leading to impaired insulin secretion and, eventually, type 2 diabetes. β-cell communication requires gap junction channels to be present among these cells. Gap junctions are constituted by transmembrane proteins of the connexins (Cxs) family. Two Cx genes have been identified in β cells, Cx36 and Cx30.2. We have found evidence that the glucose concentration on its own is sufficient to regulate Cx30.2 gene expression in mouse islets. In this work, we examine the involvement of the Cx30.2 protein in the survival of β cells (RIN-m5F). Methods: RIN-m5F cells were cultured in 5 mM D-glucose (normal) or 30 mM D-glucose (high glucose) for 24 h. Cx30.2 siRNAs was used to downregulate Cx30.2 expression. Apoptosis was measured by means of TUNEL, an annexin V staining method, and the cleaved form of the caspase-3 protein was determined using Western blot. Results: High glucose did not induce apoptosis in RIN-m5F β cells after 24 h; interestingly, high glucose increased the Cx30.2 total protein levels. Moreover, this work found that the downregulation of Cx30.2 expression in high glucose promoted apoptosis in RIN-m5F cells. Conclusion: The data suggest that the upregulation of Cx30.2 protects β cells from hyperglycemia-induced apoptosis. Furthermore, Cx30.2 may be a promising avenue of therapeutic investigation for the treatment of glucose metabolic disorders. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a metabolic chronic disease in which insulin resistance and insufficient insulin production lead to elevated blood glucose levels. The prevalence of T2D is growing worldwide, mainly due to obesity and the adoption of Western diets. Replacing animal foods with healthy plant foods is associated with a lower risk of T2D in prospective studies. In randomized controlled trials, the consumption of healthy plant foods in place of animal foods led to cardiometabolic improvements in patients with T2D or who were at high risk of the disease. Dietary patterns that limit or exclude animal foods and focus on healthy plant foods (eg, fruits, vegetables, whole grains, nuts, legumes), known as healthy, plant-based diets, are consistently associated with a lower risk of T2D in cohort studies. The aim of this review is to examine the differential effects of plant foods and animal foods on T2D risk and to describe the existing literature about the role of healthy, plant-based diets, particularly healthy vegan diets, in T2D prevention and management. The evidence from cohort studies and randomized controlled trials will be reported, in addition to the potential biological mechanisms that seem to be involved. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to present a fractional nonlinear mathematical model with beta-cell kinetics and glucose–insulin feedback in order to describe changes in plasma glucose levels and insulin levels over time that may be associated with changes in beta-cell kinetics. We discuss the solution to the problem with respect to its existence, uniqueness, non-negativity, and boundedness. Using three different fractional derivative operators, the proposed model is examined. To approximate fractional-order systems, we use an efficient numerical Euler method in Caputo, Caputo–Fabrizio, and Atangana–Baleanu sense. Several asymptomatic behaviors are observed in the proposed models based on these three operators. These behaviors do not appear in integer-order derivative models. These behaviors are essential for understanding fractional-order systems dynamics. Our results provide insight into fractional-order systems dynamics. These operators analyze local and global stability and Hyers–Ulam stability. Furthermore, the numerical solutions for the proposed model are simulated using the three methods. [ABSTRACT FROM AUTHOR]

Introduction and aim: Type 3 Familial Partial Lipodystrophy (FPLD3) is a rare metabolic disease related to pathogenic PPARG gene variants. FPLD3 is characterized by a loss of fatty tissue in the upper and lower limbs, hips, and face. FPLD3 pathophysiology is usually associated with metabolic comorbidities such as type 2 diabetes, insulin resistance, hypertriglyceridemia, and liver dysfunction. Here, we clinically and molecularly characterized FPLD3 patients harboring novel PPARG pathogenic variants. Materials and methods: Lipodystrophy-suspected patients were recruited by clinicians from an Endocrinology Reference Center. Clinical evaluation was performed, biological samples were collected for biochemical analysis, and DNA sequencing was performed to define the pathogenic variants associated with the lipodystrophic phenotype found in our clinically diagnosed FPLD subjects. Bioinformatics predictions were conducted to characterize the novel mutated PPARγ proteins. Results: We clinically described FPLD patients harboring two novel heterozygous PPARG variants in Brazil. Case 1 had the c.533T > C variant, which promotes the substitution of leucine to proline in position 178 (p.Leu178Pro), and cases 2 and 3 had the c.641 C > T variant, which results in the substitution of proline to leucine in the position 214 (p.Pro214Leu) at the PPARγ2 protein. These variants result in substantial conformational changes in the PPARγ2 protein. Conclusion: Two novel PPARG pathogenic variants related to FPLD3 were identified in a Brazilian FPLD cohort. These data will provide new epidemiologic data concerning FPLD3 and help understand the genotype-phenotype relationships related to the PPARG gene. [ABSTRACT FROM AUTHOR]

Diabetes mellitus, a major global health concern, is emerging as the primary human disease in the twenty-first century, with beta cell damage and dysfunction playing a critical role, particularly in type 2 diabetes. Inflammation and oxidative stress are critical in beta cell damage associated with type 2 diabetes. Current anti-diabetic drugs frequently fail to achieve intended efficacy and are associated with side effects, necessitating novel treatments that target the underlying pathophysiology. Chalcones have gained popularity due to their varied biological activity. In this study, we use an alloxan-induced beta cell damage zebrafish model to evaluate the potential anti-inflammatory and beta cell protective properties of DKO3 ((E)-1-(5-methylfuran-2-yl)-3-(3-nitrophenyl) prop-2-en-1-one), a synthetic chalcone. DKO3 exhibits dose-dependent anti-inflammatory and α-glucosidase activity in vitro. DKO3 reduced oxidative stress, restored antioxidant enzyme levels, decreased lipid peroxidation and cellular damage, inhibited cellular apoptosis, and regulated proinflammatory cytokine levels. It prevented alloxan-induced beta cell damage, increased PPAR-γ expression, and influenced insulin-sensitive genes such as SIRT1, GLUT2, GSK3, and INSA. These findings underscore DKO3's potential therapeutic utility in managing diabetes and related inflammatory conditions. [Display omitted] • Chalcones derivative, DKO3 exhibited antioxidant and α-glucosidase inhibition. • In in-vivo zebrafish, DKO3 function against alloxan-induced oxidative stress. • DKO3 protected β-cell damage and reduced lipid peroxidation, LDH and NO. • DKO3 exhibited high affinity for PPAR-γ, thus up regulates its expression. • DKO3 enhanced glucose uptake and regulates insulin-sensitive genes. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Remote ischaemic preconditioning (rIPC) for cardioprotection is severely impaired in diabetes, and therapeutic options to restore it are lacking. The vascular endothelium plays a key role in rIPC. Given that the activity of endothelial nitric oxide synthase (eNOS) is inhibited by proline‐rich tyrosine kinase 2 (Pyk2), we hypothesized that pharmacological Pyk2 inhibition could restore eNOS activity and thus restore remote cardioprotection in diabetes.New Zealand obese (NZO) mice that demonstrated key features of diabetes were studied. The consequence of Pyk2 inhibition on endothelial function, rIPC and infarct size after myocardial infarction were evaluated. The impact of plasma from mice and humans with or without diabetes was assessed in isolated buffer perfused murine hearts and aortic rings.Plasma from nondiabetic mice and humans, both subjected to rIPC, caused remote tissue protection. Similar to diabetic humans, NZO mice demonstrated endothelial dysfunction. NZO mice had reduced circulating nitrite levels, elevated arterial blood pressure and a larger infarct size after ischaemia and reperfusion than BL6 mice. Pyk2 increased the phosphorylation of eNOS at its inhibitory site (Tyr656), limiting its activity in diabetes. The cardioprotective effects of rIPC were abolished in diabetic NZO mice. Pharmacological Pyk2 inhibition restored endothelial function and rescued cardioprotective effects of rIPC.Endothelial function and remote tissue protection are impaired in diabetes. Pyk2 is a novel target for treating endothelial dysfunction and restoring cardioprotection through rIPC in diabetes. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to compare the effects of High-Intensity Interval Training (HIIT) and Moderate-Intensity Continuous Training (MICT) on glycemic control, beta-cell function, and aerobic fitness in women with Type 2 Diabetes Mellitus (T2DM). Methods: Thirty-six women with T2DM were assigned equally to HIIT, MICT, and control (CON) groups. Participants in the exercise cohorts underwent a 12-week training regimen (three sessions per week), while the CON group maintained an inactive lifestyle. Glycaemia variables, beta-cell function, maximal oxygen uptake (VO2max), lipid profiles, and body composition were assessed at baseline and post-intervention. Results: Both HIIT and MICT interventions led to significant improvements in glucose, insulin, HbA1c, and insulin resistance index. Moreover, visceral adiposity index (VAI), lipid accumulation product (LAP), total cholesterol (TC), and low-density lipoprotein (LDL) levels significantly decreased in the HIIT and MICT groups after 12 weeks. Triglyceride (TG) levels decreased only after MICT, while high-density lipoprotein (HDL) levels increased after both interventions. Maximal oxygen uptake (VO2max), body mass, body mass index (BMI), and waist circumference (WC) significantly improved in all exercise groups. Notably, the HIIT group showed greater reductions in body mass compared to MICT. Nevertheless, beta-cell function remained unaltered after these two exercise regimens. Conclusion: Both HIIT and MICT interventions effectively managed T2DM in women, regardless of exercise intensity. The HIIT regimen can be considered for time-efficient lifestyle interventions in people with T2DM. [ABSTRACT FROM AUTHOR]

Cellular senescence is a programmed stress response in which cells secrete immunogenic factors that promote senescent cell removal by the immune system or immune surveillance. Different types of senescence occur in pancreatic islet β-cells and senescent β-cells accumulate during aging and diabetes but whether these cells are subject to immune surveillance is unknown. We hypothesize that the subpopulation of stressed senescent β-cells is under immune surveillance to limit their accumulation during aging. Available evidence supports the existence of mechanisms for islet-resident immune surveillance of stressed senescent β-cells involving macrophages and the likelihood of impairment of these mechanisms in diabetes. Elucidation of the mechanisms of islet immune surveillance holds promise for improved therapeutic targeting of senescent β-cells in diabetes. Cellular senescence is a programmed state of cell cycle arrest that involves a complex immunogenic secretome, eliciting immune surveillance and senescent cell clearance. Recent work has shown that a subpopulation of pancreatic β-cells becomes senescent in the context of diabetes; however, it is not known whether these cells are normally subject to immune surveillance. In this opinion article, we advance the hypothesis that immune surveillance of β-cells undergoing a senescence stress response normally limits their accumulation during aging and that the breakdown of these mechanisms is a driver of senescent β-cell accumulation in diabetes. Elucidation and therapeutic activation of immune surveillance mechanisms in the pancreas holds promise for the improvement of approaches to target stressed senescent β-cells in the treatment of diabetes. [ABSTRACT FROM AUTHOR]

Copyright of Firat Universitesi Sağlik Bilimleri Tip Dergisi is the property of Firat Universitesiu, Saglik Bilimleri Enstitusu and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Type 2 Diabetes Mellitus (T2DM) is characterized by hyperglycemia resulting from resistance to insulin and decreased insulin secretion by the beta cells of the pancreas. Intracellular magnesium is required as co-factor for many enzymes involved in lipid metabolism. Magnesium deficiency has been found to have a role in the disruption of lipid metabolism in patients of type 2 diabetes mellitus. Materials and Methods: This hospital based observational cross-sectional study was done between July 2021 and June,2022. 160 cases of Type 2 DM attending the Department of Medicine, Assam Medical College & Hospital, Dibrugarh were enrolled for the study, as per inclusion and exclusion criteria. Results: Mean age was 52.59±7.13 years. Mean HbA1c was 10.02 ±1.83 %. Mean serum magnesium level was 1.54±0.42 mg/dl. Mean serum triglyceride was 267.27±89.13 mg/dl, mean total cholesterol was 271.65±65.18 mg/dl, mean LDLc was 143.31±15.07 mg/dl and mean HDLc was 39.86±10.55 mg/dl. There was a statistically significant negative correlation between serum magnesium and LDLc (r= -0.906), serum magnesium and Triglycerides, (r= -0.995) and serum magnesium and Cholesterol levels (r=-0.991) and a statistically significant positive correlation between serum magnesium and HDLc r=+0.596). Conclusion: Low serum magnesium levels in diabetics correlate with dyslipidemia in Type 2 DM patients. Further studies are required to clinically investigate the role of magnesium in helping prevent dyslipidemia and complications among Type 2 DM patients. [ABSTRACT FROM AUTHOR]

Context Regular exercise is a key prevention strategy for obesity and type 2 diabetes (T2D). Exerkines secreted in response to exercise or recovery may contribute to improved systemic metabolism. Conversely, an impaired exerkine response to exercise and recovery may contribute to cardiometabolic diseases. Objective We investigated if the exercise-induced regulation of the exerkine, growth differentiation factor 15 (GDF15) and its putative upstream regulators of the unfolded protein response (UPR)/integrated stress response (ISR) is impaired in skeletal muscle in patients with T2D compared with weight-matched glucose-tolerant men. Methods Thirteen male patients with T2D and 14 age- and weight-matched overweight/obese glucose-tolerant men exercised at 70% of VO2max for 1 hour. Blood and skeletal muscle biopsies were sampled before, immediately after, and 3 hours into recovery. Serum and muscle transcript levels of GDF15 and key markers of UPR/ISR were determined. Additionally, protein/phosphorylation levels of key regulators in UPR/ISR were investigated. Results Acute exercise increased muscle gene expression and serum GDF15 levels in both groups. In recovery, muscle expression of GDF15 decreased toward baseline, whereas serum GDF15 remained elevated. In both groups, acute exercise increased the expression of UPR/ISR markers, including ATF4 , CHOP , EIF2K3 (encoding PERK), and PPP1R15A (encoding GADD34), of which only CHOP remained elevated 3 hours into recovery. Downstream molecules of the UPR/ISR including XBP1-U , XBP1-S , and EDEM1 were increased with exercise and 3 hours into recovery in both groups. The phosphorylation levels of eIF2α-Ser51, a common marker of unfolded protein response (UPR) and ISR, increased immediately after exercise in controls, but decreased 3 hours into recovery in both groups. Conclusion In conclusion, exercise-induced regulation of GDF15 and key markers of UPR/ISR are not compromised in patients with T2D compared with weight-matched controls. [ABSTRACT FROM AUTHOR]

Copyright of Revista Latinoamericana de Hipertension is the property of Revista Latinoamericana de Hipertension and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Sedentary behavior (SB) has been linked to risk factors of cardiometabolic disease, with inconsistent findings reported in the literature. We aimed to assess the associations of SB with multiple biomarkers of inflammation and insulin resistance in adults. Domain-specific SB, sitting time and moderate-to-vigorous physical activity (MVPA) were measured in 78 adults (mean ± SD 52.0 ± 10.8 y). Body fat percentage (BF%) was assessed using multi-frequency bioelectrical impedance. A blood draw assessed glucose, insulin, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, and adiponectin. Adiponectin-leptin ratio (ALR), homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) were calculated. Multivariable linear regression analyses, controlling for age, sex, MVPA, and BF%, were used to assess associations. After adjustment for age, sex and MVPA, total SB (7.5 ± 2.5 h/day) was positively associated with leptin, insulin, HOMA-IR, HOMA-β (Standardized Beta (β) range 0.21–0.32) and negatively associated with ALR (β = -0.24, p < 0.05 for all). Similarly, total sitting time (7.2 ± 2.9 h/day) was associated with TNF-α (β = 0.22) and ALR (β = -0.26). These associations were attenuated to non-significance after adjustment for BF%. Leisure screen time was detrimentally associated with IL-6 (β = 0.24), leptin (β = 0.21), insulin (β = 0.37), HOMA-IR (β = 0.37), and HOMA-β (β = 0.34), independent of age, sex and MVPA (p < 0.05 for all). Only the associations with insulin (β = 0.26), HOMA-IR (β = 0.26), and HOMA-β (β = 0.23) remained significant after further controlling BF% (p < 0.05). Self-reported SB is associated with biomarkers of inflammation and insulin resistance, independent of MVPA, and in some cases BF%. [ABSTRACT FROM AUTHOR]

Iron overload (IO) is known to contribute to metabolic dysfunctions such as type 2 diabetes and insulin resistance. Using L6 skeletal muscle cells overexpressing the CDGSH iron–sulfur domain‐containing protein 1 (CISD1, also known as mitoNEET) (mitoN) protein, we examined the potential role of MitoN in preventing IO‐induced insulin resistance. In L6 control cells, IO resulted in insulin resistance which could be prevented by MitoN as demonstrated by western blot of p‐Akt and Akt biosensor cells. Mechanistically, IO increased; mitochondrial iron accumulation, mitochondrial reactive oxygen species (ROS), Fis1‐dependent mitochondrial fission, mitophagy, FUN14 domain‐containing protein 1 (FUNDC1) expression, and decreased Parkin. MitoN overexpression was able to reduce increases in mitochondrial iron accumulation, mitochondrial ROS, mitochondrial fission, mitophagy and FUNDC1 upregulation due to IO. MitoN did not have any effect on the IO‐induced downregulation of Parkin. MitoN alone also upregulated peroxisome proliferator‐activated receptor gamma coactivator 1 alpha (PGC1α) protein levels, a master regulator of mitochondrial biogenesis. The use of mitochondrial antioxidant, Skq1, or fission inhibitor, Mdivi‐1, prevented IO‐induced insulin resistance implying both mitochondrial ROS and fission play a causal role in the development of insulin resistance. Taken together, MitoN is able to confer protection against IO‐induced insulin resistance in L6 skeletal muscle cells through regulation of mitochondrial iron content, mitochondrial ROS, and mitochondrial fission. [ABSTRACT FROM AUTHOR]