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Islet beta cells (β-cells) produce insulin in response to high blood glucose levels, which is essential for preserving glucose homeostasis. Voltage-gated ion channels in β-cells, including Na+, K+, and Ca2+ channels, aid in the release of insulin. The epithelial sodium channel alpha subunit (α-ENaC), a voltage-independent sodium ion channel, is also expressed in human pancreatic endocrine cells. However, there is no reported study on the function of ENaC in the β-cells. In the current study, we found that α-ENaC was expressed in human pancreatic glandule and pancreatic islet β-cells. In the pancreas of db/db mice and high-fat diet-induced mice, and in mouse islet β-cells (MIN6 cells) treated with palmitate, α-ENaC expression was increased. When α-ENaC was overexpressed in MIN6 cells, insulin content and glucose-induced insulin secretion were significantly reduced. On the other hand, palmitate injured islet β-cells and suppressed insulin synthesis and secretion, but increased α-ENaC expression in MIN6 cells. However, α-ENaC knockout (Scnn1a−/−) in MIN6 cells attenuated β-cell disorder induced by palmitate. Furthermore, α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 in β-cells. α-ENaC also modulated β-cell function in correlation with the inositol-requiring enzyme 1 alpha/X-box binding protein 1 (IRE1α/XBP1) and protein kinase RNA-like endoplasmic reticulum kinase/C/EBP homologous protein (PERK/CHOP) endoplasmic reticulum stress pathways. These results suggest that α-ENaC may play a novel role in insulin synthesis and secretion in the β-cells, and the upregulation of α-ENaC promotes islet β-cell dysfunction. In conclusion, α-ENaC may be a key regulator involved in islet β-cell damage and a potential therapeutic target for type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Introduction: Hyperglycaemia can occur because of decreased insulin secretion due to pancreatic dysfunction or insulin resistance. The different amino acid content of black soldier fly (Hermetia illucens) larvae can protect pancreatic beta cells from oxidative stress in patients with diabetes. Protein hydrolysate is a product of protein breakdown catalysed by enzymes into smaller peptides. Insulinotropic amino acids have several pathways that induce insulin synthesis. Methods: Sample preparation of larval protein hydrolysate through dissolution, homogenisation, sonication, enzyme digestion, centrifugation, and lyophilisation. Identify amino acids using LC-MS/MS by dissolving the hydrolysate and ionising the molecules to be separated by the mass analyser. The results were interpreted using the MassLynx software. The α-glucosidase inhibitory assay was conducted for hydrolysate with trypsin incubated for 7 hours. An oral glucose tolerance test was conducted to evaluate hypoglycaemic ability. The selected protein hydrolysate and sham controls were fed orally to male Sprague–Dawley rats using oral gavage. Results: The selected larval protein hydrolysate was a trypsin catalyst incubated for 7 hours. The LC-MS/MS results showed that the chosen protein hydrolysate was based on the types of insulinotropic amino acids, including lysine, methionine, histidine, proline, and ornithine. Hydrolysate insignificantly inhibits glucose absorption in the intestine through the α-glucosidase enzyme. The selected dose was 300 mg/kg BW. Conclusion: The selected hydrolysate was hydrolysed by trypsin enzyme for 7 hours, with an optimum dose of 300 mg/kg BW, to produce the desired hypoglycaemic effect. [ABSTRACT FROM AUTHOR]

Stem cell‐derived pancreatic progenitors (SC‐PPs), as an unlimited source of SC‐derived β (SC‐β) cells, offers a robust tool for diabetes treatment in stem cell‐based transplantation, disease modeling, and drug screening. Whereas, PDX1+/NKX6.1+ PPs enhances the subsequent endocrine lineage specification and gives rise to glucose‐responsive SC‐β cells in vivo and in vitro. To identify the regulators that promote induction efficiency and cellular function maturation, single‐cell RNA‐sequencing is performed to decipher the transcriptional landscape during PPs differentiation. The comprehensive evaluation of functionality demonstrated that manipulating LINC MIR503HG using CRISPR in PP cell fate decision can improve insulin synthesis and secretion in mature SC‐β cells, without effects on liver lineage specification. Importantly, transplantation of MIR503HG−/− SC‐β cells in recipients significantly restored blood glucose homeostasis, accompanied by serum C‐peptide release and an increase in body weight. Mechanistically, by releasing CtBP1 occupying the CDH1 and HES1 promoters, the decrease in MIR503HG expression levels provided an excellent extracellular niche and appropriate Notch signaling activation for PPs following differentiation. Furthermore, this exhibited higher crucial transcription factors and mature epithelial markers in CDH1High expressed clusters. Altogether, these findings highlighted MIR503HG as an essential and exclusive PP cell fate specification regulator with promising therapeutic potential for patients with diabetes. [ABSTRACT FROM AUTHOR]

Proteins are essential for cell function, and their biological performance depends on three-dimensional (3D) structures. Insulin is made up of 51 amino acids and is a critical hormone involved in glycaemia regulation. In basic education, concepts involving proteins (synthesis, structure, interactions, and function) are abstract and difficult for students to understand. The use of protein 3D models that assist in visualising biomolecular structures can be an important didactic tool to understand the complexity of protein structure. Here, we propose a practical activity for the construction of a 3D model of insulin, as a tool for teaching protein synthesis and structure to students in the 9th-grade of basic education. The activity involved three classes of one hour each. 62 students role-played the insulin mRNA translation and represented the primary structure through balloons tied to a string. They also built an 3D insulin model using Styrofoam balls and wire. The activities proved to be effective, as there was a better understanding by students regarding proteins and their characteristics. Therefore, practical classes for teaching proteins can be used in basic education to improve learning of abstract and sub-microscopic concepts. [ABSTRACT FROM AUTHOR]

Insulin gene mutations affect the structure of insulin and are considered a leading cause of neonatal diabetes and permanent neonatal diabetes mellitus PNDM. These mutations can affect the production and secretion of insulin, resulting in inadequate insulin levels and subsequent hyperglycemia. Early discovery or prediction of PNDM can aid in better management and treatment. The current study identified potential deleterious non-synonymous single nucleotide polymorphisms nsSNPs in the INS gene. The analysis of the nsSNPs in the INS gene was conducted using bioinformatics tools by implementing computational algorithms including SIFT, PolyPhen2, SNAP2, SNPs & GO, PhD-SNP, MutPred2, I-Mutant, MuPro, and HOPE tools to investigate the prediction of the potential association between nsSNPs in the INS gene and PNDM. Three mutations, C96Y, P52R, and C96R, were shown to potentially reduce the stability and function of the INS protein. These mutants were subjected to MDSs for structural analysis. Results suggested that these three potential pathogenic mutations may affect the stability and functionality of the insulin protein encoded by the INS gene. Therefore, these changes may influence the development of PNDM. Further researches are required to fully understand the various effects of mutations in the INS gene on insulin synthesis and function. These data can aid in genetic testing for PNDM to evaluate its risk and create treatment and prevention strategies in personalized medicine. [ABSTRACT FROM AUTHOR]

The genetic etiology of gestational diabetes mellitus (GDM) was suggested to overlap with type-2 diabetes(T2D). Transcription factor 7-like 2 (TCF7L2) and Proprotein Convertase Subtilisin/Kexin type 2 (PCSK2) are T2D susceptibility genes of the insulin synthesis/processing pathway. We analyzed associations of TCF7L2 and PCSK2 variants with GDM risk and evaluated their potential impact on impaired insulin processing in an eastern Indian population. The study included 114 GDM (case) and 228 non-GDM pregnant women (control). rs7903146, rs4132670, rs12255372 of TCF7L2, and rs2269023 of PCSK2 were genotyped by PCR-RFLP, and genotype distributions were compared between case and control. Fasting serum proinsulin and C-peptide levels were measured by ELISA and the Proinsulin/C-peptide ratio was considered an indicator of proinsulin conversion. Significantly higher frequency of risk allele (T) of rs12255372 (p = 0.02, OR = 2.0, 95%CI = 1.11–3.64) and rs4132670 (p = 0.002, OR = 2.26, 95%CI = 1.32–3.87) of TCF7L2 was found in GDM cases than non-GDM controls; TT genotype was associated with significantly increased disease risk. In rs7903146 (TCF7L2) and rs2269023 (PCSK2), although the frequency of risk allele (T) was not significantly higher in cases than controls, an association of TT for both variants remained significant with higher GDM risk in the recessive model. Increased serum pro-insulin and proinsulin:c-peptide ratio was found in GDM than non-GDM women and the phenomenon showed significant association with careers of risk alleles for TCF7L2 variants. In conclusion, TCF7L2 and PCSK2 variants are related to GDM risk in the studied population and hence may serve as potential biomarkers for assessing the disease risk. TCF7L2 variants contribute to impaired insulin processing. [ABSTRACT FROM AUTHOR]

Efficient drug delivery remains a critical challenge for treating neurodegenerative diseases, such as Alzheimer's disease (AD). Using innovative nanomaterials, delivering current medications like acetylcholinesterase inhibitors to the brain through the intranasal route is a promising strategy for managing AD. Here, we developed a unique combinational drug delivery system based on N,N,N-trimethyl chitosan nanoparticles (NPs). These NPs encapsulate rivastigmine, the most potent acetylcholinesterase inhibitor, along with insulin, a complementary therapeutic agent. The spherical NPs exhibited a zeta potential of 17.6 mV, a size of 187.00 nm, and a polydispersity index (PDI) of 0.29. Our findings demonstrate significantly improved drug transport efficiency through sheep nasal mucosa using the NPs compared to drug solutions. The NPs exhibited transport efficiencies of 73.3% for rivastigmine and 96.9% for insulin, surpassing the efficiencies of the drug solutions, which showed transport efficiencies of 52% for rivastigmine and 21% for insulin ex vivo. These results highlight the potential of a new drug delivery system as a promising approach for enhancing nasal transport efficiency. These combinational mucoadhesive NPs offer a novel strategy for the simultaneous cerebral delivery of rivastigmine and insulin, which could prove helpful in developing effective treatments of AD and other neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

Background: Diabetes is a metabolic disorder characterized by an imbalance in insulin synthesis or utilization, resulting in elevated blood glucose levels. Type 2 diabetes (T2D) is characterized by high blood glucose levels, which are primarily caused by insulin resistance, resulting in a variety of complications and a significant impact on vital organs. The primary function of protein tyrosine phosphatase 1B (PTP1B) is to regulate the signaling pathways of insulin and leptin, both of which are involved in cellular metabolism and glucose homeostasis. PTP1B catalyzes the de-phosphorylation of active insulin receptors and insulin receptor substrates, resulting in insulin signaling downregulation. Methods: In this study, natural compounds from the ZINC database were screened against the PTP1B protein using the PyRx 0.8 tool. The physicochemical and drug-likeness characteristics of the top five screened compounds were investigated using the SwissADME web tool. Results: The compounds ZINC899884, ZINC56981, ZINC252509722, ZINC1843029, and ZINC21789 interacted and bound with PTP1B protein strongly, and their binding energies were higher than those of the control compounds. Furthermore, these compounds have good druglike properties. Conclusion: This study suggests that these compounds can be used as PTP1B inhibitors for diabetes management. However, additional experimental studies are needed to optimize them as PTP1B inhibitors. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without a previous diagnosis of diabetes. While the etiology of GDM remains elusive, the close association of GDM with increased maternal adiposity and advanced gestational age implicates insulin resistance as a culpable factor for the pathogenesis of GDM. Pregnancy is accompanied by the physiological induction of insulin resistance in the mother secondary to maternal weight gain. This effect serves to spare blood glucose for the fetus. To overcome insulin resistance, maternal β-cells are conditioned to release more insulin into the blood. Such an adaptive response, termed β-cell compensation, is essential for maintaining normal maternal metabolism. β-cell compensation culminates in the expansion of β-cell mass and augmentation of β-cell function, accounting for increased insulin synthesis and secretion. As a result, a vast majority of mothers are protected from developing GDM during pregnancy. In at-risk pregnant women, β-cells fail to compensate for maternal insulin resistance, contributing to insulin insufficiency and GDM. However, gestational β-cell compensation ensues in early pregnancy, prior to the establishment of insulin resistance in late pregnancy. How β-cells compensate for pregnancy and what causes β-cell failure in GDM are subjects of investigation. In this mini-review, we will provide clinical and preclinical evidence that β-cell compensation is pivotal for overriding maternal insulin resistance to protect against GDM. We will highlight key molecules whose functions are critical for integrating gestational hormones to β-cell compensation for pregnancy. We will provide mechanistic insights into β-cell decompensation in the etiology of GDM. [ABSTRACT FROM AUTHOR]

Aim: To elucidate how proinsulin synthesis and insulin was affected by metformin under conditions of nutrient overstimulation. Materials and Methods: Isolated human pancreatic islets from seven donors were cultured at 5.5 mmol/L glucose and 0.5 mmol/L palmitate for 12, 24 or 72 h. Metformin (25 μmol/L) was introduced after initial 12 h with palmitate. Proinsulin and insulin were measured. Expression of prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE), was determined by western blot. Adolescents with obesity, treated with metformin and with normal glucose tolerance (n = 5), prediabetes (n = 14), or type 2 diabetes (T2DM; n = 7) were included. Fasting proinsulin, insulin, glucose, 2‐h glucose and glycated haemoglobin were measured. Proinsulin/insulin ratio (PI/I) was calculated. Results: In human islets, palmitate treatment for 12 and 24 h increased proinsulin and insulin proportionally. After 72 h, proinsulin but not insulin continued to increase which was coupled with reduced expression of PC1/3 and CPE. Metformin normalized expression of PC1/3 and CPE, and proinsulin and insulin secretion. In adolescents with obesity, before treatment, fasting proinsulin and insulin concentrations were higher in subjects with T2DM than with normal glucose tolerance. PI/I was reduced after metformin treatment in subjects with T2DM as well as in subjects with prediabetes, coupled with reduced 2‐h glucose and glycated haemoglobin. Conclusions: Metformin normalized proinsulin and insulin secretion after prolonged nutrient‐overstimulation, coupled with normalization of the converting enzymes, in isolated islets. In adolescents with obesity, metformin treatment was associated with improved PI/I, which was coupled with improved glycaemic control. [ABSTRACT FROM AUTHOR]

Kaempferol is a flavonoid present in many eatable plants. Researchers discovered a link between consuming foods high in kaempferol and lowering the threat for acquiring many diseases, including cardiovascular disease, diabetes, obesity and cancer. Kaempferol can inhibit AHR transcription, modulate ERK signalling pathway and NF-κB pathways, block MAPK and AP1 signalling pathways and perform more anticancer roles. Kaempferol also has the ability to act against diabetes via suppressed phosphorylation of (IKK) IkB kinase, (IRS-1) insulin receptor substrate-1 and (IKK) IkB kinase through the hepatic IKK/NF-B signalling pathways and significantly enhanced insulin secretion and synthesis. Kaempferol protects cardiomyocytes from anoxia/reoxygenation (A/R)-induced damage by lowering LDH release, improving cell survival, reducing A/R-induced ROS formation, and release of cytochrome c. This knowledge may aid in understanding health advantages of medicinal plants that contain kaempferol and may lead to the development of the flavonoid as a potential agents for disease aversion and therapy. [ABSTRACT FROM AUTHOR]

Insulin-positive (+) cells (IPCs), detected in multiple organs, are of great interest as a probable alternative to ameliorate pancreatic beta-cells dysfunction and insulin deficiency in diabetes. Liver is a potential source of IPCs due to it common embryological origin with pancreas. We previously demonstrated the presence of IPCs in the liver of healthy and diabetic rats, but detailed description and analysis of the factors, which potentially can induced ectopic hepatic expression of insulin in type 1 (T1D) and type 2 diabetes (T2D), were not performed. In present study we evaluate mass of hepatic IPCs in the rat models of T1D and T2D and discuss factors, which may stimulate it generation: glycaemia, organ injury, involving of hepatic stem/progenitor cell compartment, expression of transcription factors and inflammation. Quantity of IPCs in the liver was up by 1.7-fold in rats with T1D and 10-fold in T2D compared to non-diabetic (ND) rats. We concluded that ectopic hepatic expression of insulin gene is activated by combined action of a number of factors, with inflammation playing a decision role. [ABSTRACT FROM AUTHOR]

Glycyrrhetinic acid (GA) is found in the roots and rhizomes of the legume licorice genus. The sweetness of GA is 250 times of sucrose. GA has a variety of biological activities. To develop new functional additive with hypoglycemic properties, the GA was modified with amino acids. The carboxyl group in C-30 of GA was modified with glycine, aspartic acid and arginine, respectively, to successfully prepare three amino acid amide derivatives of GA. The total yields of N-glycyrrhetinylglycine, N-glycyrrhetinyl aspartic acid and N-glycyrrhetinylarginine were 43.60%, 39.33% and 35.10%, respectively. The modification of C-30 of GA was modified with amino acid can significantly reduce the log P value and promote the hydrophilicity of GA. The N-glycyrrhetinylarginine had effective inhibition on α-glucosidase and is superior to GA. The inhibition on α-glucosidase by GA and N-Glycyrrhetinyl amino acid were reversible and mixed type. The GA and N-glycyrrhetinylarginine can effectively increase glucose consumption and glycogen synthesis to regulate insulin resistance. The GA and N-glycyrrhetinylarginine can regulate the insulin resistance in HepG2-IR cells via PI3K/Akt signaling pathway. [Display omitted] • Glycyrrhetinic acid was successfully modified by glycine, aspartic acid and arginine. • The modifications by amino acid promoted the hydrophilicity of glycyrrhetinic acid. • The modification by arginine enhanced the inhibition on α-glucosidase. • The N-glycyrrhetinylarginine regulated insulin resistance in HepG2-IR cells. • The regulation of N-glycyrrhetinylarginine in HepG2-IR cells via PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

Background and Purpose: High levels of Ca2+ in the endoplasmic reticulum (ER), established by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), are required for protein folding and cell signalling. Excessive ER Ca2+ release or decreased SERCA activity induces unfolded protein accumulation and ER stress in pancreatic β‐cells, leading to defective insulin secretion and diabetes. Here we have investigated the consequences of enhancing ER Ca2+ uptake on β‐cell survival and function. Experimental Approach: The effects of SERCA activator, CDN1163, on Ca2+ homeostasis, protein expression, mitochondrial activities, insulin secretion, and lipotoxicity have been studied in mouse pancreatic β‐cells and MIN6 cells. Key Results: CDN1163, increased insulin synthesis and exocytosis from islets. CDN1163 also increased the sensitivity of the cytosolic Ca2+ oscillation response to glucose and potentiated it in dispersed and sorted β‐cells. CDN1163 augmented the ER and mitochondrial Ca2+ content, the mitochondrial membrane potential, respiration, and ATP synthesis. CDN1163 up‐regulated expression of inositol 1,4,5‐trisphosphate receptors and antioxidant enzymes, and mitochondrial biogenesis, including peroxisome proliferator‐activated receptor γ coactivator 1α (PGC1α). Overexpression of SERCA2a or 2b replicated the effects of CDN1163, while knockdown of SERCA2 abolished the stimulatory actions of CDN1163. In palmitate‐treated β‐cells, CDN1163 prevented ER Ca2+ depletion, mitochondrial dysfunction, cytosolic and mitochondrial oxidative stress, defective insulin secretion, and apoptotic cell death. Conclusions and Implications: Activation of SERCA enhanced mitochondrial bioenergetics and antioxidant capability, suppressing the cytotoxic effects of palmitate. Our results suggest that targeting SERCA could be a novel therapeutic strategy to protect β‐cells from lipotoxicity and the development of Type 2 diabetes. [ABSTRACT FROM AUTHOR]

• A minimal model is proposed to study the insulin synthesis and secretion processes. • Identifies possible factors responsible for reduced insulin secretion. • Identifies potential factors responsible for elevated basal insulin secretion. • Compares the restoration capabilities between insulin synthesis and secretion. • Explores restoration strategies for compensating the beta-cells mass. Insulin, secreted from pancreatic β -cells, plays a vital role in maintaining glucose homeostasis in our body. In various pathophysiological conditions like diabetes, cancer, etc., this glucose-insulin relationship is altered. However, the underlying mechanisms behind the β -cell malfunctioning under these pathophysiological conditions remain a research topic. The current study aimed to explore the key factors responsible for impaired insulin secretion from β -cells. We studied insulin synthesis and secretion processes through a minimal mathematical model incorporating insulin mRNA, proinsulin pool, and insulin granules. Defects in the insulin granule trafficking and exocytosis processes hamper first- and second-phase insulin secretion and might be one of the main reasons for β -cell dysfunction in type 2 diabetes. The long-term effect of abnormal insulin synthesis could hamper insulin secretion and make the scenario more critical, causing complete insulin loss inside the β -cells. Besides, uncontrolled insulin synthesis could increase basal insulin secretion and drive toward fasting hypoglycemia. The present study also hypothesizes that regulation of insulin synthesis through targeting transcription and translation is a potential therapeutic strategy for controlling impaired insulin secretion. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a disease with endocrine and metabolic disorders. The main symptoms are hyperandrogenemia (HA), insulin resistance (IR), and ovulation disorder. However, the pathogenesis and pathophysiological process of these major symptoms in PCOS are still not well defined. In recent studies, the chronic low‐grade inflammatory state has become one of the factors affecting PCOS. Some alterable immune factors in PCOS, such as interleukin‐15 and interleukin‐1, have been identified to be related to androgen synthesis and insulin resistance in PCOS. In addition, a disturbed immune microenvironment in the ovary leads to impaired follicular growth and ovulation. Previous studies have roughly reviewed the relationship between immunity and PCOS. However, the link between the different clinical manifestations of PCOS and immunity has not been well explored and analyzed. The clinical presentation of each patient is diverse, and symptomatic treatment is mainly used. Therefore, this article reviews several representative immunological factors that affect these three symptoms to explore the underlying mechanism, which will be beneficial for developing new treatment strategies. [ABSTRACT FROM AUTHOR]

Objective: In the last two decades, genetic studies have strongly supported the effective role of genetic factors on the synthesis of insulin from the pancreas. The purpose of this research is to determine the effect of aerobic and resistance exercises on the expression of NeruoD1 and PDX1 in pancreatic tissue, as well as serum insulin and glucose levels in type 2 diabetic rats. Materials and Methods: 21 male wistar rats (220±10 g) were included. Then diabetic rats were randomly assigned into 3 groups: 1) control (no-training), 2) resistance training and 3) aerobic training. Exercise training lasted 10 weeks and 5 times weekly for training groups. After intervention, NeruoD1 and PDX1 expression in pancreas, insulin and glucose were compared between groups. Data compared by one way ANOVA and Tukey's post hoc test between groups (P < 0.05). Results: Compared to control rats, resistance and aerobic training led to significant increase in serum insulin (P= 0.001, P= 0.013 respectively), PDX1 expression (P= 0.001, P= 0.001 respectively) and decrease glucose (P: 0.001, P: 0.001 respectively). Significant difference was not observed between control and aerobic groups with regard to NeruoD1 expression (P= 0.077). In addition, NeruoD1 expression in resistance group was significantly higher than aerobic and control groups (P= 0.018, P= 0.001, respectively). Conclusion: Despite the improvement of insulin and glucose in response to both aerobic and resistance training, it seems that resistance training affects genes affecting insulin synthesis and transcription more than aerobic training. [ABSTRACT FROM AUTHOR]

We have demonstrated that oligodeoxynucleotide IMT504 promotes significant improvement in the diabetic condition in diverse animal models. Based on these results, here we evaluated whether these effects observed in vivo could be due to direct effects on β‐cells. We demonstrate by immunofluorescence that IMT504 enters the cell and locates in cytoplasm where it induces GSK‐3β phosphorylation that inactivates this kinase. As GSK‐3β tags Pdx1 for proteasomal degradation, by inactivating GSK‐3β, IMT504 induces an increase in Pdx1 protein levels, demonstrated by Western blotting. Concomitantly, an increase in Ins2 and Pdx1 gene transcription was observed, with no significant increase in insulin content or secretion. Enhanced Pdx1 is promising since it is a key transcription factor for insulin synthesis and is also described as an essential factor for the maintenance β‐cell phenotype and function. Dose‐dependent inhibition of H2O2‐induced apoptosis determined by ELISA as well as decreased expression of Bax was also observed. These results were confirmed in another β‐cell line, beta‐TC‐6 cells, in which a cytokine mix induced apoptosis that was reversed by IMT504. In addition, an inhibitor of IMT504 entrance into cells abrogated the effect IMT504. Based on these results we conclude that the β‐cell recovery observed in vivo may include direct effects of IMT504 on β‐cells, by maintaining their identity/phenotype and protecting them from oxidative stress and cytokine‐induced apoptosis. Thus, this work positions IMT504 as a promising option in the framework of the search of new therapies for type I diabetes treatment. [ABSTRACT FROM AUTHOR]

Obesity and lipid metabolism dysregulation are often associated with insulin resistance, and can lead to type 2 diabetes. However, mechanisms linking insulin resistance, high levels of plasma free fatty acids (FFA), and β cell failure remain unclear. The aim of this work was to search for proteins whose synthesis was modified by a short exposure to FFA. This could help in the future to identify molecular mechanisms underlying islet dysfunction in the presence of FFA. Therefore, we assessed by mass spectrometry de novo protein synthesis of freshly isolated rat islets after palmitate short exposure. Quantitative proteome and secretome analyses were performed by combining metabolic incorporation of azidohomoalanine (AHA) and pulse labeling with stable isotope labeling by amino acids in cell culture (SILAC). We showed that pancreatic islets, in response to 4-h exposure to palmitate, increased the synthesis of ribosomal proteins and proteins of the cytoskeleton, and increased their secretion of proteins involved in insulin synthesis and insulin secretion, as well as insulin itself. First, these results show that de novo protein quantification analysis by LC-MS/MS is a useful method to investigate cellular modifications induced by FFA on pancreatic islets. Also, these results show that short exposure to palmitate increases the expression of ribosomal proteins and proteins involved in insulin secretion, and it remains to be determined if these effects are responsible or linked to the harmful effect of palmitate on β cells. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a chronic disease characterized by decreased insulin synthesis or increased blood glucose due to insulin resistance. In this study, we aimed to investigate the protective role of Origanum majorana L. on the biochemical parameters of rats induced by streptozotocin (STZ). Male Sprague-Dawley (SD) rats weighing 300-400 g were used. Rats were divided into 3 groups control, diabetes mellitus, and diabetes mellitus + Origanum majorana L. Citrate buffer was used i.p. in the control group. To induce experimental diabetes in rats, streptozotocin (60 mg/kg) was injected intraperitoneally (i.p.). After 48 hours, rats with blood glucose values higher than 200 mg/dL were considered diabetic. Diabetic rats were divided into two groups. While the first group was not treated, the second group received 200 mg/kg of Origanum majorana L. extract for 6 weeks. In this study, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and creatinine values were measured in serum. Malondialdehyde (MDA) and glutathione (GSH) levels were measured in kidney and liver tissues. It was found that AST, ALT, and creatinine values increased in diabetes and decreased significantly in the treatment group. MDA levels were increased and GSH values were decreased in diabetes. Origanum majorana L. treatment decreased lipid peroxidation and resulted in a significant increase in GSH levels. In conclusion, our findings show that Origanum majorana L. treatment has a protective effect against nephropathy in diabetes by preventing oxidative damage. [ABSTRACT FROM AUTHOR]

Hyperglycemia, a common metabolic abnormality associated with diabetes mellitus, is primarily brought on by insufficient insulin synthesis at the cellular level or/and errors in insulin action. Such an endocrine condition causes major health issues and is spreading rapidly around the globe. The widespread control of diabetes with oral drug administration without producing any side effects is still regarded as a difficult undertaking, and the rising cost of traditional treatment in developing nations is another issue of concern. Traditional preparations of herbal plant extracts in the form of medications have already drawn a lot of attention in an effort to treat these problems. Locals use the crude extract of Swertia chirayita and Zizyphus mauritiana, two prominent Nepalese medicinal plants, for a variety of ailments, including type 2 diabetes. The current study's objectives were hydroalcoholic extract extraction of plant material, phytochemical analysis of Swertia chirayita and Zizyphus mauritiana, and formulation, development, and assessment of phytosomes. This study confirms the glucose tolerance activity with help of phytosomes containing the extracts of Swertia chirayita and Zizyphus mauritiana. The increase in blood glucose level can be controlled with help of phytosomes containing these extracts, along with it phytosomes showed a sustained release activity that best fitted with Korsmeyer peppas model. [ABSTRACT FROM AUTHOR]

Objective. One functional neuroendocrine tumor that causes hypoglycemia due to inappropriately high insulin production is an insulinoma. In rats, two genes coding for insulin, insulin 1 (Ins1) and insulin 2 (Ins2) are found on chromosome 1. Ins1 was produced from an Ins2 transcript, and it was inserted into the genome via an RNA-mediated duplication-transposition event, according to some structural feature analyses. Methods. In this study, the author has looked at how overexpression of the PTEN gene in the insulinoma cell line Rin-5F affects the expression of the insulin genes, Ins 1 and Ins 2. Results. In the insulinoma cell line, overexpression of the PTEN gene boosts Ins2 gene mRNA expression but not Ins1 gene mRNA expression. It has been reported that PTEN upregulates insulin signaling by increasing insulin receptor substrate (IRS)-2 mRNA levels. Also, PTEN has been reported to be secreted in exosomes and thereafter, into extracellular space. Conclusions. The present study suggested that overexpression of PTEN might induce the increasing Ins 2 gene expression, one of the phosphorylated genes against the IRS-2 through the insulin/IGF-1 receptor. Our knowledge of the molecular pathways of PTEN relating the synthesis of insulin has been increased by the present study. [ABSTRACT FROM AUTHOR]

Loss of the β cell population is a crucial feature of type 2 diabetes. Restoring the β cell mass by stimulating β cell proliferation and preventing its apoptosis was proposed as a therapeutic approach to treating diabetes. Therefore, researchers have been increasingly interested in identifying exogenous factors that can stimulate β cell proliferation in situ and in vitro. Adipokine chemerin, which is secreted from adipose tissue and the liver, has been identified as a chemokine that plays a critical role in the regulation of metabolism. In this study, we demonstrate that chemerin as a circulating adipokine promotes β cell proliferation in vivo and in vitro. Chemerin serum levels and the expression of the main receptors within islets are highly regulated under a variety of challenging conditions, including obesity and type 2 diabetes. As compared to their littermates, mice overexpressing chemerin had a larger islet area and increased β cell mass with both a normal and high-fat diet. Moreover, in chemerin-overexpressed mice, we observed improved mitochondrial homeostasis and increased insulin synthesis. In summary, our findings confirm the potential role of chemerin as an inducer of β cell proliferation, and they provide novel insights into the helpful strategy to expand β cell population. [ABSTRACT FROM AUTHOR]

Pancreatic beta cell function is an important component of glucose homeostasis. Here, we investigated the function of PIMT (PRIP-interacting protein with methyl transferase domain), a transcriptional co-activator binding protein, in the pancreatic beta cells. We observed that the protein levels of PIMT, along with key beta cell markers such as PDX1 (pancreatic and duodenal homeobox 1) and MafA (MAF bZIP transcription factor A), were reduced in the beta cells exposed to hyperglycemic and hyperlipidemic conditions. Consistently, PIMT levels were reduced in the pancreatic islets isolated from high fat diet (HFD)-fed mice. The RNA sequencing analysis of PIMT knockdown beta cells identified that the expression of key genes involved in insulin secretory pathway, Ins1 (insulin 1), Ins2 (insulin 2), Kcnj11 (potassium inwardly-rectifying channel, subfamily J, member 11), Kcnn1 (potassium calcium-activated channel subfamily N member 1), Rab3a (member RAS oncogene family), Gnas (GNAS complex locus), Syt13 (synaptotagmin 13), Pax6 (paired box 6), Klf11 (Kruppel-Like Factor 11), and Nr4a1 (nuclear receptor subfamily 4, group A, member 1) was attenuated due to PIMT depletion. PIMT ablation in the pancreatic beta cells and in the rat pancreatic islets led to decreased protein levels of PDX1 and MafA, resulting in the reduction in glucose-stimulated insulin secretion (GSIS). The results from the immunoprecipitation and ChIP experiments revealed the interaction of PIMT with PDX1 and MafA, and its recruitment to the insulin promoter, respectively. Importantly, PIMT ablation in beta cells resulted in the nuclear translocation of insulin. Surprisingly, forced expression of PIMT in beta cells abrogated GSIS, while Ins1 and Ins2 transcript levels were subtly enhanced. On the other hand, the expression of genes, PRIP/Asc2/Ncoa6 (nuclear receptor coactivator 6), Pax6, Kcnj11, Syt13, Stxbp1 (syntaxin binding protein 1), and Snap25 (synaptosome associated protein 25) associated with insulin secretion, was significantly reduced, providing an explanation for the decreased GSIS upon PIMT overexpression. Our findings highlight the importance of PIMT in the regulation of insulin synthesis and secretion in beta cells. [ABSTRACT FROM AUTHOR]

Background and objectives: Genetic studies have indicated the effective role of transcription factors in insulin synthesis and secretion, especially in the case of diabetes. This study aimed to assess the effects of high-intensity interval training on transcription factor 7-like 2/ glucagon-like peptide 1 (TCF7L2 / GLP-1) axis in pancreatic tissue of obese rats with type 2 diabetes mellitus (T2DM). Methods: For this purpose, obesity was induced in 21 male Wistar rats (weighting 220±10 g) by exposure to a high-fat diet for six weeks. Then, the rats were randomly assigned to a non-diabetic, a control T2DM, and an exercise diabetic group. Next, T2DM was induced by intraperitoneal injection of streptozotocin (25 mg/kg). The rats in the exercise group participated in a HIIT program, five times a week, for six weeks. After the intervention, TCF7L2 and GLP1 expression in the pancreas tissue was determined by real-time PCR. Serum insulin, glucose, and beta cell function were compared between the study groups. Data were analyzed using one-way ANOVA and Tukey post hoc test at a significance level of 0.05. Results: Induction of T2DM increased glucose level and TCF7L2 expression but decreased insulin, beta cell function, and GLP-1R expression. In addition, HIIT significantly decreased TCF7L2 expression as well as glucose level, serum insulin, and beta cell function; however, it did not significantly change GLP1R expression compared with the control diabetes rats. Conclusion: Based on the findings, the improvement of serum insulin and glucose level following HIIT may be attributed to the decrease in TCF7L2 gene expression in the pancreatic tissue of diabetic rats. [ABSTRACT FROM AUTHOR]

We investigated whether silibinin, a flavonoid, might be useful for treating diabetes mellitus by treating five groups of rat RINm5F β-insulinemia cells as follows: control streptozotocin (STZ) group administered citrate buffer and dimethyl sulfoxide; STZ group administered 20 mM STZ; silibinin group administered 50 µM silibinin; pre-silibinin group administered 50 µM silibinin 5 h before administering 20 mM STZ; simultaneous group administered 50 µM silibinin at the same time as 20 mM STZ. For all groups, MTT assay and flow cytometry were used to evaluate cell viability and necrosis, respectively. Glucose-stimulated insulin secretion (GSIS) and insulin cell content were determined using enzyme-linked immunosorbent assay. Also, expression of genes, pancreatic and duodenal homeobox 1 (pdx1), neuronal differentiation 1 (neurod1), v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog A (mafa), glucose transporter 2 (glut2)) was determined using the real-time polymerase chain reaction. We found that silibinin improved the viability of RINm5F cells and increased GSIS and cellular insulin under glucotoxic conditions. Silibinin increased the expression of neurod1, mafa and glut2, but reduced pdx1 expression. Our findings suggest that silibinin might increase glucose sensitivity and insulin synthesis under glucotoxic conditions, which could be useful for diabetes treatment. [ABSTRACT FROM AUTHOR]

Pancreatic β cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in β cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in β cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects β cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect β cells' fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to β cell failure. [ABSTRACT FROM AUTHOR]

Pancreatic β-cells, by secreting insulin, play a key role in the control of glucose homeostasis, and their dysfunction is the basis of diabetes development. The metabolic milieu created by high blood glucose and lipids is known to play a role in this process. In the last decades, cholesterol has attracted significant attention, not only because it critically controls β-cell function but also because it is the target of lipid-lowering therapies proposed for preventing the cardiovascular complications in diabetes. Despite the remarkable progress, understanding the molecular mechanisms responsible for cholesterol-mediated β-cell function remains an open and attractive area of investigation. Studies indicate that β-cells not only regulate the total cholesterol level but also its redistribution within organelles, a process mediated by vesicular and non-vesicular transport. The aim of this review is to summarize the most current view of how cholesterol homeostasis is maintained in pancreatic β-cells and to provide new insights on the mechanisms by which cholesterol is dynamically distributed among organelles to preserve their functionality. While cholesterol may affect virtually any activity of the β-cell, the intent of this review is to focus on early steps of insulin synthesis and secretion, an area still largely unexplored. [ABSTRACT FROM AUTHOR]

Chemical synthesis of insulin superfamily proteins (ISPs) has recently been widely studied to develop next‐generation drugs. Separate synthesis of multiple peptide fragments and tedious chain‐to‐chain folding are usually encountered in these studies, limiting accessibility to ISP derivatives. Here we report the finding that insulin superfamily proteins (e.g. H2 relaxin, insulin itself, and H3 relaxin) incorporating a pre‐made diaminodiacid bridge at A‐B chain terminal disulfide can be easily and rapidly synthesized by a single‐shot automated solid‐phase synthesis and expedient one‐step folding. Our new H2 relaxin analogues exhibit almost identical structures and activities when compared to their natural counterparts. This new synthetic strategy will expediate production of new ISP analogues for pharmaceutical studies. [ABSTRACT FROM AUTHOR]

Chemical synthesis of insulin superfamily proteins (ISPs) has recently been widely studied to develop next‐generation drugs. Separate synthesis of multiple peptide fragments and tedious chain‐to‐chain folding are usually encountered in these studies, limiting accessibility to ISP derivatives. Here we report the finding that insulin superfamily proteins (e.g. H2 relaxin, insulin itself, and H3 relaxin) incorporating a pre‐made diaminodiacid bridge at A‐B chain terminal disulfide can be easily and rapidly synthesized by a single‐shot automated solid‐phase synthesis and expedient one‐step folding. Our new H2 relaxin analogues exhibit almost identical structures and activities when compared to their natural counterparts. This new synthetic strategy will expediate production of new ISP analogues for pharmaceutical studies. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a chronic disease characterized by decreased insulin synthesis and/or increased blood glucose due to insulin resistance. In this study, streptozotocin (STZ)-induced diabetic rats were evaluated and it was aimed to investigate the protective effects of Origanum onites L. (OO) against possible changes in these parameters. Male Sprague-Dawley rats weighing 300-400g were divided into three groups control (C), diabetes mellitus (DM) and diabetes mellitus + OO (OO group). DM was induced by administration of STZ 60 mg/kg dose intraperitoneally (i.p.) after 48 hours, rats with blood glucose values higher than 200 mg/dL were considered DM. Origanum extract was administered i.p. to the OO group at 50 mg/kg per day for 6 weeks. Serum AST, ALT, creatinine, and inflammatory cytokine levels were measured. MDA and GSH levels were measured in liver tissues. AST, ALT, creatinine, and MDA levels were found to be increased in the DM group, while a significant decrease in these levels was observed in the treated group. While GSH values fell in the DM group, a significant increase occurred in the OO group (n=6, p<0.0001; two-way ANOVA). When the plasma levels of cytokines were examined, an increase was observed in the DM group and a significant decrease was observed in the OO group. When we evaluate our findings, we think that OO has a protective effect against complications that may occur in DM by preventing oxidant damage and inflammation. Further studies are needed on the protective effects of OO in DM. [ABSTRACT FROM AUTHOR]

Type 2 Diabetes Mellitus (T2DM) is influenced by the action of both hereditary and environmental factors. These factors are comprehended in the disease interaction with β cells and insulin sensitivity to the receptors.The main cause of T2DM development is ageing, obesity, and oxidative stress. The dysfunction of the β cells of the pancreas leads to insulin insensitivity in the liver, muscle and fat metabolism. These occur due to the result of oxidative stress. Lipid peroxidation is a key initiating factor in the development of oxidative stress, which results in T2DM and its related micro-and macro-vascular problems. These are initially compensated for the generation of excess insulin synthesis, thus ensuring normal glucose tolerance. When these compensatory processes are disrupted, the majority of persons develop T2DM. Although the gene is the primary cause of T2DM, the environment also plays an important role in the disease's progression. Particularly, a sedentary lifestyle characterised by excessive food consumption and physical inactivity is a known risk factor for obesity and type 2 diabetes. This review has briefly discussed the significance of numerous causal factors, and genomic and biochemical pathways which are responsible for increasing the production of oxidative stress, a crucial component for the etiology and development of T2DM. The conclusion drawn was that the analysis of oxidative stress markers may be one of the potential methods for the diagnosis and prognosis of T2DM. Furthermore, this review will be helpful to establish the broaden conceptual framework for future studies on oxidative stress with relation to etiology of type 2 diabetes and therapeutic development. [ABSTRACT FROM AUTHOR]

Dysregulation of insulin signaling in the Alzheimer's disease (AD) brain has been extensively reported. Serine racemase (SR) modulates insulin secretion in pancreatic islets. This study aimed to examine whether SR regulates insulin synthesis and secretion in neurons, thereby modulating insulin signaling in the AD brain. Srr‐knockout (Srr−/−) mice generated with the CRISPR/Cas9 technique were used. Using immunofluorescence and fluorescence in situ hybridization, levels of insulin protein and insulin(ins2) mRNA were significantly increased in the hippocampal but not in hypothalamic sections of Srr−/− mice compared with WT mice. Real‐time quantitative PCR revealed that ins2 mRNA from primary hippocampal neuronal cultures of Srr−/− mice was significantly increased compared with that from cultured neurons of WT mice. Notably, the secretion of proinsulin C‐peptide was increased in Srr−/− neurons relative to WT neurons. By examining membrane fractional proteins with immunoblotting, Srr−/− neurons retained ATP‐dependent potassium channels on plasmalemma and correspondingly contained higher levels of p‐AMPK. After treatment with Aβ42, the phosphorylation levels of insulin receptor substrate at serine 616 636 (p‐IRS1ser616,636) were significantly lower, whereas p‐AKT308 and p‐AKT473 were higher in Srr−/− neurons than in WT neurons, respectively. The phosphorylated form of c‐Jun N‐terminal kinase decreased in the cultured Srr−/− neurons relative to the WT neurons upon Aβ42 treatment. In contrast, phosphorylated protein kinase R remained at the same levels. Further, reactive oxygen species were reduced in cultured Srr−/− neurons under Aβ42 treatment relative to the WT neurons. Collectively, our study indicated that Srr deletion promoted insulin synthesis and secretion of proinsulin C‐peptide, thereby reversing insulin resistance by Aβ42. This study suggests that targeting the neuronal SR may be utilized to enhance insulin signaling which is inhibited at the early stage of the AD brain. [ABSTRACT FROM AUTHOR]

Pancreatic β cell expansion and functional maturation during the birth-to-weaning period is driven by epigenetic programs primarily triggered by growth factors, hormones, and nutrients provided by human milk. As shown recently, exosomes derived from various origins interact with β cells. This review elucidates the potential role of milk-derived exosomes (MEX) and their microRNAs (miRs) on pancreatic β cell programming during the postnatal period of lactation as well as during continuous cow milk exposure of adult humans to bovine MEX. Mechanistic evidence suggests that MEX miRs stimulate mTORC1/c-MYC-dependent postnatal β cell proliferation and glycolysis, but attenuate β cell differentiation, mitochondrial function, and insulin synthesis and secretion. MEX miR content is negatively affected by maternal obesity, gestational diabetes, psychological stress, caesarean delivery, and is completely absent in infant formula. Weaning-related disappearance of MEX miRs may be the critical event switching β cells from proliferation to TGF-β/AMPK-mediated cell differentiation, whereas continued exposure of adult humans to bovine MEX miRs via intake of pasteurized cow milk may reverse β cell differentiation, promoting β cell de-differentiation. Whereas MEX miR signaling supports postnatal β cell proliferation (diabetes prevention), persistent bovine MEX exposure after the lactation period may de-differentiate β cells back to the postnatal phenotype (diabetes induction). [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) has a complex etiology which is not yet fully elucidated. The identification of gene perturbations and hub genes of T2D may deepen our understanding of its genetic basis. We aimed to identify highly perturbed genes and hub genes associated with T2D via an extensive bioinformatics analytic workflow consisting of five steps: systematic review of Gene Expression Omnibus and associated literature; identification and classification of differentially expressed genes (DEGs); identification of highly perturbed genes via meta-analysis; identification of hub genes via network analysis; and downstream analysis of highly perturbed genes and hub genes. Three meta-analytic strategies, random effects model, vote-counting approach, and p value combining approach, were applied. Hub genes were defined as those nodes having above-average betweenness, closeness, and degree in the network. Downstream analyses included gene ontologies, Kyoto Encyclopedia of Genes and Genomes pathways, metabolomics, COVID-19-related gene sets, and Genotype-Tissue Expression profiles. Analysis of 27 eligible microarrays identified 6284 DEGs (4592 downregulated and 1692 upregulated) in four tissue types. Tissue-specific gene expression was significantly greater than tissue non-specific (shared) gene expression. Analyses revealed 79 highly perturbed genes and 28 hub genes. Downstream analyses identified enrichments of shared genes with certain other diabetes phenotypes; insulin synthesis and action-related pathways and metabolomics; mechanistic associations with apoptosis and immunity-related pathways; COVID-19-related gene sets; and cell types demonstrating over- and under-expression of marker genes of T2D. Our approach provided valuable insights on T2D pathogenesis and pathophysiological manifestations. Broader utility of this pipeline beyond T2D is envisaged. [ABSTRACT FROM AUTHOR]

Aim: To examine the effect of lncRNA Kcnq1ot1 on pancreatic β cells in the development of diabetes. Methods: The expression levels of Kcnq1ot1 were detected in the islets of diabetes mouse models and the serum of patients with type 2 diabetes by qRT-PCR. CCK8, Ki67 staining, immunohistochemical analyses, glucose-stimulated insulin secretion and intraperitoneal glucose tolerance test were performed to detect the effect of Kcnq1ot1 on β-cell proliferation and insulin secretion in vitro and in vivo. The relationship between Kcnq1ot1 and miR-15b-5p was predicted by bioinformatics prediction, which was confirmed by luciferase reporter assay. Results: Kcnq1ot1 was more abundant in the pancreas. The expression of Kcnq1ot1 was decreased in the islets of db/db mice and diet-induced obese mice and in the serum of patients with type 2 diabetes. Silencing Kcnq1ot1 inhibited the β-cell proliferation concomitant with a reduction in the levels of Ccnd1 and Ccnd2. Insulin synthesis and secretion were impaired, along with the decreased expression of Ins1, Ins2, and insulin-related transcription factors. Moreover, Kcnq1ot1 knockdown in vivo reduced glucose tolerance and decreased insulin secretion, consistent with the reduction in the relative islet area and Ki67-positive β-cells detected by immunochemistry and immunofluorescence staining, respectively. Mechanistically, Kcnq1ot1 directly targeted miR-15b-5p which regulated β-cell proliferation and insulin secretion through Ccnd1 and Ccnd2. Notably, the suppression of miR-15b-5p attenuated the inhibition of Min6 proliferation and insulin production induced by Kcnq1ot1 knockdown. Conclusion: Kcnq1ot1 regulated β-cell proliferation and insulin secretion via the miR-15b-5p/Ccnd1 and Ccnd2 axis, which is worthy of further investigation considering its potential in diabetes treatment. [ABSTRACT FROM AUTHOR]

Diabetes Mellitus, being a polygenic disorder, have a set of risk genes involved in the onset of the insulin resistance, obesity and impaired insulin synthesis. Recent genome wide association studies (GWAS) shows the intimacy of CDK5 regulatory subunit Associated protein 1-Like 1 (Cdkal1) with the pathophysiology of the diabetes mellitus and its complications, although the exact molecular relation is still unknown. In this short review, we have summarized all the diverse biological roles of Cdkal1 in relation to the onset of diabetes mellitus. Variations in the Cdkal1 transcript are responsible for the accumulation of misfolded insulin and thus generating oxidative and ER stress in the pancreatic β-cells, leading to their destruction. Recent studies have shown that Cdkal1 has an intrinsic thiomethyl transferase activity, which is essential for proper posttranslational processing of pre-proinsulin to produce mature insulin. Moreover, Cdkal1 has also been claimed as an endogenous inhibitor of cdk5, which prevents the cdk5-induced interruption in insulin synthesis through PDX1 translocation from nucleus to cytosol. Recent clinical studies have identified the risk single nucleotide polymorphisms (SNPs) of Cdkal1 as one of the root causes for the onset of diabetic complications. To the best of our knowledge, it is the first comprehensive review which elaborates most of the potential Cdkal1-dependent molecular mechanisms studied yet. In this review, we present a compiled and concise summary about all the diverse roles of Cdkal1 in the context of type 2 diabetes mellitus and its associated complications. This review will be helpful to target Cdkal1 as a potential option for the management of type 2 diabetes mellitus in future. [ABSTRACT FROM AUTHOR]

Selenoprotein P (SELENOP) is a major selenium (Se)-containing protein (selenoprotein) in human plasma that is mainly synthesized in the liver. SELENOP transports Se to the cells, while SELENOP synthesized in peripheral tissues is incorporated in a paracrine/autocrine manner to maintain the levels of cellular selenoproteins, called the SELENOP cycle. Pancreatic β cells, responsible for the synthesis and secretion of insulin, are known to express SELENOP. Here, using MIN6 cells as a mouse model for pancreatic β cells and Selenop small interfering (si)RNA, we found that Selenop gene knockdown (KD) resulted in decreased cell viability, cellular pro/insulin levels, insulin secretion, and levels of several cellular selenoproteins, including glutathione peroxidase 4 (Gpx4) and selenoprotein K (Selenok). These dysfunctions induced by Selenop siRNA were recovered by the addition of Se. Ferroptosis-like cell death, regulated by Gpx4, was involved in the decrease of cell viability by Selenop KD, while stress-induced nascent granule degradation (SINGD), regulated by Selenok, was responsible for the decrease in proinsulin. SINGD was also observed in the pancreatic β cells of Selenop knockout mice. These findings indicate a significant role of SELENOP expression for the function of pancreatic β cells by maintaining the levels of cellular selenoproteins such as GPX4 and SELENOK. [Display omitted] ● Significant role of SELENOP expression for the function of pancreatic beta cells by maintaining the levels of cellular selenoproteins ● Ferroptosis-like cell death, regulated by Gpx4, was involved in the decrease of cell viability by Selenop KD ● Stress-induced nascent granule degradation, regulated by Selenok, was responsible for the decrease in proinsulin by Selenop KD [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is associated with defective pancreatic β-cell adaptation in pregnancy, but the underlying mechanism remains obscure. Our previous studies demonstrated that GDM women display increased plasma adrenomedullin (ADM) levels, and non-obese GDM mice show decreased serum concentrations of insulin and the number of β-cells in pancreas islets. The aims of this study is to examine if ADM and its receptors are expressed in female mouse pancreas, and if so, whether insulin secretion is regulated by ADM in mouse β-cell line, NIT-1 cells and isolated mouse pancreatic islets. Present study shows that ADM and its receptor components CRLR, RAMPs are present in mouse pancreatic islets and co-localized with insulin. The expressions of ADM, CRLR and RAMP2 in islets from pregnant mice are reduced compared to that of non-pregnant mice. NIT-1-β cells express ADM and its receptor mRNA, and glucose dose-dependently stimulates expressions. Furthermore, ADM inhibits NIT-1-β cell growth, and this inhibition is reversed by ADM antagonist, ADM22-52. The glucose-induced insulin secretion was suppressed by ADM in NIT-1-β cells and isolated pancreatic islets from pregnant mice. These inhibitory effects are accompanied by upregulation of endoplasmic reticulum (ER) stress biomarker genes in NIT-1-β cells. This study unveils that reduced ADM and its receptors may play a role in β-cell adaptation during pregnancy, while increased plasma ADM in GDM may contribute to the β-cells dysfunction, and blockade of ADM may reverse β-cell insulin production. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common type of dementia. The evolution and aggregation of amyloid beta (β) oligomers is linked to insulin resistance in AD, which is also the major characteristic of type 2 diabetes (T2D). Being physically inactive can contribute to the development of AD and/or T2D. Aerobic exercise training (AET), a type of physical exercise, can be useful in preventing or treating the negative outcomes of AD and T2D. AD, T2D and AET can regulate the expression of microRNAs (miRNAs). Here, we review some of the changes in miRNAs expression regulated by AET, AD and T2D. MiRNAs play an important role in the gene regulation of key signaling pathways in both pathologies, AD and T2D. MiRNA dysregulation is evident in AD and has been associated with several neuropathological alterations, such as the development of a reactive gliosis. Expression of miRNAs are associated with many pathophysiological mechanisms involved in T2D like insulin synthesis, insulin resistance, glucose intolerance, hyperglycemia, intracellular signaling, and lipid profile. AET regulates miRNAs levels. We identified 5 miRNAs (miR-21, miR-29a/b, miR-103, miR-107, and miR-195) that regulate gene expression and are modulated by AET on AD and T2D. The identified miRNAs are potential targets to treat the symptoms of AD and T2D. Thus, AET is a non-pharmacological tool that can be used to prevent and fight the negative outcomes in AD and T2D. [ABSTRACT FROM AUTHOR]

In this study, a novel star -hyperbranched polyurethane (SR-HPU) with a star-shaped glucose-based PHBV (GS-PHBV) core was synthesized for sustained-release of insulin. The successful synthesis of GS-PHBV , SR-HPU , and preparation of INS-PUF were confirmed by 1HNMR and ATR-IR analysis. Thermogravimetric analysis (TGA), X-Ray diffraction analysis (XRD), and water contact angle (WCA) analysis demonstrated that due to the block copolymerization of GS-PHBV with HDI and PEG, the crystalline patterns of the final films were disrupted, which led to an increase in their hydrophilicity. These results aligned with other findings from in vitro biodegradability and cytocompatibility studies of films as well. As a result, gravimetric measurements of the films in phosphate buffer solution (PBS) (pH 7.4 at 37°) revealed that SR-HPU lost more weight (∼28%) than GS-PHBV (∼4%) after 35 days of degradation, which was also in good agreement with the water contact angles of them (82.9° vs 58.4°). Also, the surface topographical changes of the porous structure before and after degradation were compared by field emission scanning electron microscopy (FESEM)micrographs. XRD and Energy dispersive X-ray (EDX) mapping results revealed that insulin is uniformly present within the highly porous SR-HPU matrix. In vitro cytotoxicity studies of films on (L929) indicated excellent biocompatibility with high cell viability and rapid cell proliferation. Moreover, the findings from the in vitro release studies of INS-PUF showed that a prolonged insulin release pattern had been achieved for 8 weeks and followed the Higuchi model. [Display omitted] • A glucose-initiated polyester polyol was synthesized by direct esterification. • The star polyol was used for the synthesis of a star -hyperbranched bio polyurethane. • A novel delivery system for insulin was prepared by the dispersion technique. • The resulting implantable film shows good biocompatibility and biodegradability. • It is a promising agent for biomedical applications and particularly in drug delivery. [ABSTRACT FROM AUTHOR]

Organochlorine compounds (OC) include synthetic insecticides previously used throughout the world before being banned for their adverse effects and environmental persistence; DDT (dichlorodiphenyltrichloroethane) was one of the most widely used. Epidemiological evidence suggests that higher levels of some OC, including metabolites of DDT, such as dichlorodiphenyldichloroethylene (DDE), are associated with type 2 diabetes mellitus (T2D). DDE exposure may affect pancreatic cellular functions associated with glucose control and possibly cause beta cell dysfunction. The in vitro effect of DDE exposure on pancreatic beta cell insulin secretion was investigated using Beta-Tumor Cell-6 (B-TC-6) murine pancreatic beta cells. DDE exposure significantly increased insulin secretion suggesting a role for DDE in altering insulin synthesis and secretion. Reactive oxygen species (ROS) levels were not significantly increased indicating that oxidative stress is not responsible for the DDE-induced insulin secretion. Pancreatic and duodenal homeobox factor-1 (PDX-1) levels were not significantly increased suggesting that DDE exposure does not alter insulin transcription, but prohormone convertase (PC) levels were increased suggesting a role for DDE in altering insulin translation. Based on these in vitro results, DDE may play a role in beta cell dysfunction by affecting mechanisms that regulate insulin secretion but it is not likely to be the major mechanism behind the DDE/T2D epidemiological association. [ABSTRACT FROM AUTHOR]

Understanding signaling pathways that regulate pancreatic β-cell function to produce, store, and release insulin, as well as pathways that control β-cell proliferation, is vital to find new treatments for diabetes mellitus. Transforming growth factor-beta (TGF-β) signaling is involved in a broad range of β-cell functions. The canonical TGF-β signaling pathway functions through intracellular smads, including smad2 and smad3, to regulate cell development, proliferation, differentiation, and function in many organs. Here, we demonstrate the role of TGF-β/smad2 signaling in regulating mature β-cell proliferation and function using β-cell-specific smad2 null mutant mice. β-cell-specific smad2-deficient mice exhibited improved glucose clearance as demonstrated by glucose tolerance testing, enhanced in vivo and ex vivo glucose-stimulated insulin secretion, and increased β-cell mass and proliferation. Furthermore, when these mice were fed a high-fat diet to induce hyperglycemia, they again showed improved glucose tolerance, insulin secretion, and insulin sensitivity. In addition, ex vivo analysis of smad2-deficient islets showed that they displayed increased glucose-stimulated insulin secretion and upregulation of genes involved in insulin synthesis and insulin secretion. Thus, we conclude that smad2 could represent an attractive therapeutic target for type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Impaired insulin synthesis is accompanied by hyperglycemia and the development of diabetic cardiomyopathy. Echocardiography and left-ventricular catheterization were employed for studying the contractile function of the left ventricle in 2 weeks after administration of streptozotocin (60 mg/kg). The results obtained by both methods were similar and indicated the development of systolic dysfunction with a 27% decrease in cardiac output. The invasive study showed that the maximum rate of left-ventricular pressure development, the contractility index, and systolic left-ventricular pressure were within the normal range, but the peak ejection rate was reduced by 28%. BP was normal, but the vascular stiffness index was increased by about 1.5 times and inversely correlated with the peak ejection rate (r=-0.69). The results showed that systolic dysfunction in type 1 diabetes model was due to reduced ejection from the left ventricle at normal rate of left-ventricular pressure development. [ABSTRACT FROM AUTHOR]

Introduction. Chronic inflammation and oxidative stress conditions have been reported in women with polycystic ovary syndrome (PCOS). Peroxiredoxin 4 (Prx4) is a related antioxidant in insulin synthesis. We hypothesized that insulin resistance in these women is associated with total oxidant status (TOS) and inflammatory factors. Materials and Methods. Two hundred three people including 104 PCOS patients and 99 healthy women, who were matched for age and body mass index (BMI), entered the study. Waist circumference of the participants was measured; serum glucose, lipid profile, insulin, Prx4, TOS, hs-CRP, and TNF-α were also evaluated. Results. The Prx4 level was significantly lower in PCOS than in the control group. In addition, marked increase was observed in the concentration of TOS, hs-CRP, and TNF-α in PCOS, compared to the healthy women. There was a positive correlation of TOS with hs-CRP, TNF-α, and HOMA-IR. The risk of PCOS for subjects with high hs-CRP was 60 times greater than those who had low serum hs-CRP concentration; after performing multiple logistic regression analyses with the backward method, TNF-α was considered as an effective biomarker to predict PCOS β = 49.087 (all p < 0.05). Conclusion. This study identified increased oxidative stress and inflammation in PCOS; this may be due to decrease in the antioxidants, such as Prx4. [ABSTRACT FROM AUTHOR]

Due to the importance of zinc as an antioxidant and its crucial role in insulin synthesis, its deficiency may affect adversely diabetic state. So, this study aimed to modulate these effects using Curcuma longa as natural antioxidant. Rats were divided into four groups: two groups fed a zinc sufficient diet one non-diabetic and the other diabetic, while the others two groups diabetic rats fed a zinc-deficient diet, one non-treated group and the other treated with curcuma 1% diet. After four weeks of dietary manipulation, fasting animals were scarified. Zinc deficiency decreased body weight, insulin, zinc tissues, alkaline phosphatase, reduced glutathione, glutathione peroxidase, superoxide dismutase and catalase. Conversely glucose, lipids profile, transaminases and malondialdehyde were increased. However, the above-mentioned parameters were significantly improved following curcuma supplementation. So it seems that curcuma is a potent factor for reducing the oxidative severity of zinc deficiency in experimental diabetes through its antioxidants actions. [ABSTRACT FROM AUTHOR]

The article offers information on diabetes mellitus (DM), a metabolic disorder characterized by deficit in secretion of insulin or altering the metabolism of carbohydrates, fat and protein. It classifies DM in several critical categories on the basis of its causes which include cell destruction, progressive deficit of insulin secretion and genetic defects in cell function. It also discusses the symptoms, treatment and risk factors associated with DM.

OBJECTIVE To develop a technique for isolation and culture of canine insulinoma cells and assess expression of cellular hexokinases (glucokinase and hexokinase 1) and expression and secretion of insulin from these cells in vitro. SAMPLE Pancreatic insulinomas and normal pancreatic tissue from 4 and 3 dogs, respectively. PROCEDURES Tissues were collected by surgical excision or at necropsy. Insulinoma cells from 2 dogs were cult:ured for up to 10 weeks with standard techniques; insulin synthesis in vitro was confirmed by immunohistochemical analysis of freshly prepared slides of cultured cells, and insulin secretion was assessed by measurement of insulin concentrations in culture medium with an ultrasensitive mouse insulin ELISA. Expression of cellular hexokinases in insulinomas and adjacent normal (nontumor) pancreatic tissue from the same dog (n = 3) was examined by quantitative reverse transcript:ase PCR assay. RESULTS Insulinoma cells survived for up to 10 weeks but did not proliferate in culture. Insulin was detected in isolated cells and secreted into culture medium for up to 10 weeks. Both cellular hexokinases were expressed; glucokinase appeared to be overexpressed in insulinomas, compared with normal pancreatic tissue from the same dogs. CONCLUSIONS AND CLINICAL RELEVANCE Canine insulinomas expressed hexokinases responsible for glucose responsiveness. Insulinoma cells were successfully maintained in short-term culture; cultured cells remained functional tor 10 weeks as evidenced by cellular insulin content and had detectable secretion of insulin into the culture medium for 2 5 weeks. Apparent glucokinase overexpression by insulinomas suggested a possible mechanism underlying excessive insulin release by these tumors. (Am J Vet Res 2021,82: 110-117). [ABSTRACT FROM AUTHOR]

Background. Mutations in human KLF11 may lead to the development of maturity-onset diabetes of the young 7 (MODY7). This occurs due to impaired insulin synthesis in the pancreas. To date, the clinical and functional characteristics of the novel KLF11 mutation c.1061G > T have not yet been reported. Methods. Whole-exon sequencing was used to screen the proband and family members with clinical suspicion of the KLF11 variant. Luciferase reporter assays were used to investigate whether the KLF11 variant binds to the insulin promoter. Real-time PCR, western blotting, and glucose-stimulated insulin secretion (GSIS) analysis were used to analyze the KLF11 variant that regulates insulin expression and insulin secretion activity in beta cell lines. The Freestyle Libre H (Abbott Diabetes Care Ltd) was used to dynamically monitor the proband daily blood glucose levels. Results. Mutation screening for the whole exon genes identified a heterozygous KLF11 (c.1061G > T) variant in the proband, her mother, and her maternal grandfather. Cell-based luciferase reporter assays using wild-type and mutant transgenes revealed that the KLF11 (c.1061G > T) variant had impaired insulin promoter regulation activity. Moreover, this variant was found to impair insulin expression and insulin secretion in pancreatic beta cells. The proband had better blood glucose control without staple food intake (p < 0.05). Conclusions. Herein, for the first time, we report a novel KLF11 (c.1061G > T) monogenic mutation associated with MODY7. This variant has impaired insulin promoter regulation activity and impairs insulin expression and secretion in pancreatic beta cells. Therefore, administering oral antidiabetic drugs along with dietary intervention may benefit the proband. [ABSTRACT FROM AUTHOR]

Pancreatic β-cell dysfunction plays a decisive role in the progression of type 2 diabetes. Retinol-binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes, although its effect on β-cell function remains elusive, and the underlying mechanisms are unknown. Here, we found that elevated circulating RBP4 levels were inversely correlated with pancreatic β-cell function in db/db mice across different glycemic stages. RBP4 directly suppressed glucose-stimulated insulin secretion (GSIS) in primary isolated islets and INS-1E cells in a dose- and time-dependent manner. RBP4 transgenic (RBP4-Tg) overexpressing mice showed a dynamic decrease of GSIS, which appeared as early as 8 weeks old, preceding the impairment of insulin sensitivity and glucose tolerance. Islets isolated from RBP4-Tg mice showed a significant decrease of GSIS. Mechanistically, we demonstrated that the stimulated by retinoic acid 6 (STRA6), RBP4's only known specific membrane receptor, is expressed in β-cells and mediates the inhibitory effect of RBP4 on insulin synthesis through the Janus kinase 2/STAT1/ISL-1 pathway. Moreover, decreasing circulating RBP4 level could effectively restore β-cell dysfunction and ameliorate hyperglycemia in db/db mice. These observations revealed a role of RBP4 in pancreatic β-cell dysfunction, which provides new insight into the diabetogenic effect of RBP4. [ABSTRACT FROM AUTHOR]