Endoplasmic reticulum stress in pancreatic ß-cell dysfunctionality and diabetes mellitus: a promising target for generation of functional hPSC-derived ß-cells in vitro.

Diabetes mellitus (DM), is a chronic disorder characterized by impaired glucose homeostasis that results from the loss or dysfunction of pancreatic ß-cells leading to type 1 diabetes (T1DM) and type 2 diabetes (T2DM), respectively. Pancreatic ß-cells rely to a great degree on their endoplasmic reticulum (ER) to overcome the increased secretary need for insulin biosynthesis and secretion in response to nutrient demand to maintain glucose homeostasis in the body. As a result, ß-cells are potentially under ER stress following nutrient levels rise in the circulation for a proper pro-insulin folding mediated by the unfolded protein response (UPR), underscoring the importance of this process to maintain ER homeostasis for normal ß-cell function. However, excessive or prolonged increased influx of nascent proinsulin into the ER lumen can exceed the ER capacity leading to pancreatic ß-cells ER stress and subsequently to ß-cell dysfunction. In mammalian cells, such as ß-cells, the ER stress response is primarily regulated by three canonical ER-resident transmembrane proteins: ATF6, IRE1, and PERK/PEK. Each of these proteins generates a transcription factor (ATF4, XBP1s, and ATF6, respectively), which in turn activates the transcription of ER stress-inducible genes. An increasing number of evidence suggests that unresolved or dysregulated ER stress signaling pathways play a pivotal role in ß-cell failure leading to insulin secretion defect and diabetes. In this article we first highlight and summarize recent insights on the role of ER stress and its associated signaling mechanisms on ß-cell function and diabetes and second how the ER stress pathways could be targeted in vitro during direct differentiation protocols for generation of hPSC-derived pancreatic ß-cells to faithfully phenocopy all features of bona fide human ß-cells for diabetes therapy or drug screening.

Vitamin B6 and diabetes and its role in counteracting advanced glycation end products.

Naturally occurring forms of vitamin B6 include six interconvertible water-soluble compounds: pyridoxine (PN), pyridoxal (PL), pyridoxamine (PM), and their respective monophosphorylated derivatives (PNP, PLP, and PMP). PLP is the catalytically active form which works as a cofactor in approximately 200 reactions that regulate the metabolism of glucose, lipids, amino acids, DNA, and neurotransmitters. Most of vitamers can counteract the formation of reactive oxygen species and the advanced glycation end-products (AGEs) which are toxic compounds that accumulate in diabetic patients due to prolonged hyperglycemia. Vitamin B6 levels have been inversely associate with diabetes, while vitamin B6 supplementation reduces diabetes onset and its vascular complications. The mechanisms at the basis of the relation between vitamin B6 and diabetes onset are still not completely clarified. In contrast more evidence indicates that vitamin B6 can protect from diabetes complications through its role as scavenger of AGEs. It has been demonstrated that in diabetes AGEs can destroy the functionality of macromolecules such as protein, lipids, and DNA, thus producing tissue damage that result in vascular diseases. AGEs can be in part also responsible for the increased cancer risk associated with diabetes. In this chapter the relationship between vitamin B6, diabetes and AGEs will be discussed by showing the acquired knowledge and questions that are still open.

Recent Developments in the Role of Protein Tyrosine Phosphatase 1B (PTP1B) as a Regulator of Immune Cell Signalling in Health and Disease.

Protein tyrosine phosphatase 1B (PTP1B) is a non-receptor tyrosine phosphatase best known for its role in regulating insulin and leptin signalling. Recently, knowledge on the role of PTP1B as a major regulator of multiple signalling pathways involved in cell growth, proliferation, viability and metabolism has expanded, and PTP1B is recognised as a therapeutic target in several human disorders, including diabetes, obesity, cardiovascular diseases and hematopoietic malignancies. The function of PTP1B in the immune system was largely overlooked until it was discovered that PTP1B negatively regulates the Janus kinase-a signal transducer and activator of the transcription (JAK/STAT) signalling pathway, which plays a significant role in modulating immune responses. PTP1B is now known to determine the magnitude of many signalling pathways that drive immune cell activation and function. As such, PTP1B inhibitors are being developed and tested in the context of inflammation and autoimmune diseases. Here, we provide an up-to-date summary of the molecular role of PTP1B in regulating immune cell function and how targeting its expression and/or activity has the potential to change the outcomes of immune-mediated and inflammatory disorders.

Exosomes: compositions, biogenesis, and mechanisms in diabetic wound healing.

Diabetic wounds are characterized by incomplete healing and delayed healing, resulting in a considerable global health care burden. Exosomes are lipid bilayer structures secreted by nearly all cells and express characteristic conserved proteins and parent cell-associated proteins. Exosomes harbor a diverse range of biologically active macromolecules and small molecules that can act as messengers between different cells, triggering functional changes in recipient cells and thus endowing the ability to cure various diseases, including diabetic wounds. Exosomes accelerate diabetic wound healing by regulating cellular function, inhibiting oxidative stress damage, suppressing the inflammatory response, promoting vascular regeneration, accelerating epithelial regeneration, facilitating collagen remodeling, and reducing scarring. Exosomes from different tissues or cells potentially possess functions of varying levels and can promote wound healing. For example, mesenchymal stem cell-derived exosomes (MSC-exos) have favorable potential in the field of healing due to their superior stability, permeability, biocompatibility, and immunomodulatory properties. Exosomes, which are derived from skin cellular components, can modulate inflammation and promote the regeneration of key skin cells, which in turn promotes skin healing. Therefore, this review mainly emphasizes the roles and mechanisms of exosomes from different sources, represented by MSCs and skin sources, in improving diabetic wound healing. A deeper understanding of therapeutic exosomes will yield promising candidates and perspectives for diabetic wound healing management.

New Perspectives and Prospects of microRNA Delivery in Diabetic Wound Healing.

The remarkable potential of microRNAs (miRNAs) as a class of biotherapeutic agents in the treatment of diverse pathological conditions has garnered significant interest in recent years. To heal both acute and chronic wounds, miRNAs work by post-transcriptionally controlling various proteins and the pathways that are linked to them. Diabetes mellitus predisposes to several macro- and microvascular defects of end organs such as atherosclerosis, peripheral artery disease, retinopathy, nephropathy, neuropathy, and impaired wound healing. Here, miRNAs emerge as a beacon of hope, with the capacity to heal diabetic wounds by precisely modulating the expression of genes involved in the healing process. Despite the therapeutic promise, the journey to realizing the full potential of miRNAs is fraught with challenges. Their intrinsic instability and the inefficient delivery into target cells pose significant barriers to their clinical application. Consequently, a major focus of current research is the discovery of novel miRNAs and the development of innovative delivery systems that can effectively transport these nucleic acids into the cells where they are needed most. This review delves into the intricate roles that miRNAs play at various stages of diabetic wound healing, providing a comprehensive overview of the latest research findings. The review also addresses the obstacles and opportunities that come with translating miRNA-based strategies into clinical practice, offering a critical assessment of the field's advancements and the hurdles that remain to be overcome. SIGNIFICANCE STATEMENT: The potential of microRNA delivery using new biological or nonbiological carriers may create a revolutionary treatment method for chronic wounds of diabetes.

X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction.

Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

Advanced Mass Spectrometry-Based Biomarker Identification for Metabolomics of Diabetes Mellitus and Its Complications.

Over the years, there has been notable progress in understanding the pathogenesis and treatment modalities of diabetes and its complications, including the application of metabolomics in the study of diabetes, capturing attention from researchers worldwide. Advanced mass spectrometry, including gas chromatography-tandem mass spectrometry (GC-MS/MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and ultra-performance liquid chromatography coupled to electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS), etc., has significantly broadened the spectrum of detectable metabolites, even at lower concentrations. Advanced mass spectrometry has emerged as a powerful tool in diabetes research, particularly in the context of metabolomics. By leveraging the precision and sensitivity of advanced mass spectrometry techniques, researchers have unlocked a wealth of information within the metabolome. This technology has enabled the identification and quantification of potential biomarkers associated with diabetes and its complications, providing new ideas and methods for clinical diagnostics and metabolic studies. Moreover, it offers a less invasive, or even non-invasive, means of tracking disease progression, evaluating treatment efficacy, and understanding the underlying metabolic alterations in diabetes. This paper summarizes advanced mass spectrometry for the application of metabolomics in diabetes mellitus, gestational diabetes mellitus, diabetic peripheral neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic encephalopathy, diabetic cardiomyopathy, and diabetic foot ulcers and organizes some of the potential biomarkers of the different complications with the aim of providing ideas and methods for subsequent in-depth metabolic research and searching for new ways of treating the disease.

The Molecular Mechanisms of Cuproptosis and Small-Molecule Drug Design in Diabetes Mellitus.

In the field of human health research, the homeostasis of copper (Cu) is receiving increased attention due to its connection to pathological conditions, including diabetes mellitus (DM). Recent studies have demonstrated that proteins associated with Cu homeostasis, such as ATOX1, FDX1, ATP7A, ATPB, SLC31A1, p53, and UPS, also contribute to DM. Cuproptosis, characterized by Cu homeostasis dysregulation and Cu overload, has been found to cause the oligomerization of lipoylated proteins in mitochondria, loss of iron-sulfur protein, depletion of glutathione, production of reactive oxygen species, and cell death. Further research into how cuproptosis affects DM is essential to uncover its mechanism of action and identify effective interventions. In this article, we review the molecular mechanism of Cu homeostasis and the role of cuproptosis in the pathogenesis of DM. The study of small-molecule drugs that affect these proteins offers the possibility of moving from symptomatic treatment to treating the underlying causes of DM.

Role of arachidonic acid in ischemic heart disease under different comorbidities: risk or protection?

In a translational study involving animal models and human subjects, Lv et al. demonstrate that arachidonic acid (AA) exhibits cardioprotective effects in diabetic myocardial ischemia, suggesting a departure from its known role in promoting ferroptosis-a form of cell death characterized by iron-dependent lipid peroxidation. However, the study does not address how underlying diabetic conditions might influence the metabolic pathways of AA, which are critical for fully understanding its impact on heart disease. Diabetes can significantly alter lipid metabolism, which in turn might affect the enzymatic processes involved in AA's metabolism, leading to different outcomes in the disease process. Further examination of the role of diabetes in modulating AA's effects could enhance the understanding of its protective mechanism in ischemic conditions. This could also lead to more targeted and effective therapeutic strategies for managing myocardial ischemia in diabetic patients, such as optimizing AA levels to prevent heart damage while avoiding exacerbating factors like ferroptosis.

Targeting Protein Kinases to Protect Beta-Cell Function and Survival in Diabetes.

The prevalence of diabetes is increasing worldwide. Massive death of pancreatic beta-cells causes type 1 diabetes. Progressive loss of beta-cell function and mass characterizes type 2 diabetes. To date, none of the available antidiabetic drugs promotes the maintenance of a functional mass of endogenous beta-cells, revealing an unmet medical need. Dysfunction and apoptotic death of beta-cells occur, in particular, through the activation of intracellular protein kinases. In recent years, protein kinases have become highly studied targets of the pharmaceutical industry for drug development. A number of drugs that inhibit protein kinases have been approved for the treatment of cancers. The question of whether safe drugs that inhibit protein kinase activity can be developed and used to protect the function and survival of beta-cells in diabetes is still unresolved. This review presents arguments suggesting that several protein kinases in beta-cells may represent targets of interest for the development of drugs to treat diabetes.

Potential Metabolic Pathways Involved in Osteoporosis and Evaluation of Fracture Risk in Individuals with Diabetes.

Diabetes has a significant global prevalence. Chronic hyperglycemia affects multiple organs and tissues, including bones. A large number of diabetic patients develop osteoporosis; however, the precise relationship between diabetes and osteoporosis remains incompletely elucidated. The activation of the AGE-RAGE signaling pathway hinders the differentiation of osteoblasts and weakens the process of bone formation due to the presence of advanced glycation end products. High glucose environment can induce ferroptosis of osteoblasts and then develop osteoporosis. Hyperglycemia also suppresses the secretion of sex hormones, and the reduction of testosterone is difficult to effectively maintain bone mineral density. As diabetes therapy, thiazolidinediones control blood glucose by activating PPAR-γ. Activated PPAR-γ can promote osteoclast differentiation and regulate osteoblast function, triggering osteoporosis. The effects of metformin and insulin on bone are currently controversial. Currently, there are no appropriate tools available for assessing the risk of fractures in diabetic patients, despite the fact that the occurrence of osteoporotic fractures is considerably greater in diabetic individuals compared to those without diabetes. Further improving the inclusion criteria of FRAX risk factors and clarifying the early occurrence of osteoporosis sites unique to diabetic patients may be an effective way to diagnose and treat diabetic osteoporosis and reduce the risk of fracture occurrence.

Multi-omics analysis of diabetic pig lungs reveals molecular derangements underlying pulmonary complications of diabetes mellitus.

Growing evidence shows that the lung is an organ prone to injury by diabetes mellitus. However, the molecular mechanisms of these pulmonary complications have not yet been characterized comprehensively. To systematically study the effects of insulin deficiency and hyperglycaemia on the lung, we combined proteomics and lipidomics with quantitative histomorphological analyses to compare lung tissue samples from a clinically relevant pig model for mutant INS gene-induced diabetes of youth (MIDY) with samples from wild-type littermate controls. Among others, the level of pulmonary surfactant-associated protein A (SFTPA1), a biomarker of lung injury, was moderately elevated. Furthermore, key proteins related to humoral immune response and extracellular matrix organization were significantly altered in abundance. Importantly, a lipoxygenase pathway was dysregulated as indicated by 2.5-fold reduction of polyunsaturated fatty acid lipoxygenase ALOX15 levels, associated with corresponding changes in the levels of lipids influenced by this enzyme. Our multi-omics study points to an involvement of reduced ALOX15 levels and an associated lack of eicosanoid switching as mechanisms contributing to a proinflammatory milieu in the lungs of subjects with diabetes mellitus.

AGEs induce MMP-9 promoter demethylation through the GADD45α-mediated BER pathway to promote breast cancer metastasis in patients with diabetes.

Scientific evidence has linked diabetes to a higher incidence and increased aggressiveness of breast cancer; however, mechanistic studies of the numerous regulators involved in this process are insufficiently thorough. Advanced glycation end products (AGEs) play an important role in the chronic complications of diabetes, but the mechanisms of AGEs in breast cancer are largely unexplored. In this study, we first demonstrate that high AGE levels in breast cancer tissues are associated with the diabetic state and poor patient outcomes. Furthermore, AGEs interact with the receptor for AGEs (RAGE) to promote breast cancer cell migration and invasion. Mechanistically, based on RNA sequencing (RNA-seq) analysis, we reveal that growth arrest and DNA damage gene 45α (GADD45α) is a vital protein upregulated by AGEs through a P53-dependent pathway. Next, GADD45α recruits thymine DNA glycosylase for base excision repair to form the demethylation complex at the promoter region of MMP-9 and enhance MMP-9 transactivation through DNA demethylation. Overall, our results indicate a critical regulatory role of AGEs in patients with breast cancer and diabetes and reveal a novel mechanism of epigenetic modification in promoting breast cancer metastasis.

Nrf2 Signaling Pathway as a Key to Treatment for Diabetic Dyslipidemia and Atherosclerosis.

Diabetes mellitus (DM) is a chronic endocrine disorder that affects more than 20 million people in the United States. DM-related complications affect multiple organ systems and are a significant cause of morbidity and mortality among people with DM. Of the numerous acute and chronic complications, atherosclerosis due to diabetic dyslipidemia is a condition that can lead to many life-threatening diseases, such as stroke, coronary artery disease, and myocardial infarction. The nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway is an emerging antioxidative pathway and a promising target for the treatment of DM and its complications. This review aims to explore the Nrf2 pathway's role in combating diabetic dyslipidemia. We will explore risk factors for diabetic dyslipidemia at a cellular level and aim to elucidate how the Nrf2 pathway becomes a potential therapeutic target for DM-related atherosclerosis.

Metabolomics Signature in Prediabetes and Diabetes: Insights From Tandem Mass Spectrometry Analysis.

OBJECTIVE: This study investigates the metabolic differences between normal, prediabetic and diabetic patients with good and poor glycaemic control (GGC and PGC). DESIGN: In this study, 1102 individuals were included, and 50 metabolites were analysed using tandem mass spectrometry. The diabetes diagnosis and treatment standards of the American Diabetes Association (ADA) were used to classify patients. METHODS: The nearest neighbour method was used to match controls and cases in each group on the basis of age, sex and BMI. Factor analysis was used to reduce the number of variables and find influential underlying factors. Finally, Pearson's correlation coefficient was used to check the correlation between both glucose and HbAc1 as independent factors with binary classes. RESULTS: Amino acids such as glycine, serine and proline, and acylcarnitines (AcylCs) such as C16 and C18 showed significant differences between the prediabetes and normal groups. Additionally, several metabolites, including C0, C5, C8 and C16, showed significant differences between the diabetes and normal groups. Moreover, the study found that several metabolites significantly differed between the GGC and PGC diabetes groups, such as C2, C6, C10, C16 and C18. The correlation analysis revealed that glucose and HbA1c levels significantly correlated with several metabolites, including glycine, serine and C16, in both the prediabetes and diabetes groups. Additionally, the correlation analysis showed that HbA1c significantly correlated with several metabolites, such as C2, C5 and C18, in the controlled and uncontrolled diabetes groups. CONCLUSIONS: These findings could help identify new biomarkers or underlying markers for the early detection and management of diabetes.

Single-cell transcriptomics reveals a role for pancreatic duct cells as potential mediators of inflammation in diabetes mellitus.

Introduction: Inflammation of the pancreas contributes to the development of diabetes mellitus. Although it is well-accepted that local inflammation leads to a progressive loss of functional beta cell mass that eventually causes the onset of the disease, the development of islet inflammation remains unclear. Methods: Here, we used single-cell RNA sequencing to explore the cell type-specific molecular response of primary human pancreatic cells exposed to an inflammatory environment. Results: We identified a duct subpopulation presenting a unique proinflammatory signature among all pancreatic cell types. Discussion: Overall, the findings of this study point towards a role for duct cells in the propagation of islet inflammation, and in immune cell recruitment and activation, which are key steps in the pathophysiology of diabetes mellitus.

Rephrasing the 'David-Goliath' story in the field of diabetes.

Diabetes Mellitus has become a serious threat to public health. This non-communicable disease is spreading like wildfire to shape in the form of a global pandemic. It affects several organs during silent progression in the human body. The pathophysiological fallouts associate dysregulation of numerous cellular pathways. MicroRNAs have emerged as potent gene expression regulators by post-transcriptional mechanisms in the last two decades or so. Many microRNAs display differential expression patterns under hyperglycemia affecting coupled cellular signaling cascades. The present article attempts to unfold the involvement of microRNAs as biomarkers in diabetic conditions in current scenarios identifying their therapeutic significance.

Bone morphogenetic protein 10, a rising star in the field of diabetes and cardiovascular disease.

Early research suggested that bone morphogenetic protein 10 (BMP10) is primarily involved in cardiac development and congenital heart disease processes. BMP10 is a newly identified cardiac-specific protein. In recent years, reports have emphasized the effects of BMP10 on myocardial apoptosis, fibrosis and immune response, as well as its synergistic effects with BMP9 in vascular endothelium and role in endothelial dysfunction. We believe that concentrating on this aspect of the study will enhance our knowledge of the pathogenesis of diabetes and the cardiovascular field. However, there have been no reports of any reviews discussing the role of BMP10 in diabetes and cardiovascular disease. In addition, the exact pathogenesis of diabetic cardiomyopathy is not fully understood, including myocardial energy metabolism disorders, microvascular changes, abnormal apoptosis of cardiomyocytes, collagen structural changes and myocardial fibrosis, all of which cause cardiac function impairment directly or indirectly and interact with one another. This review summarizes the research results of BMP10 in cardiac development, endothelial function and cardiovascular disease in an effort to generate new ideas for future research into diabetic cardiomyopathy.

[Evaluation of endogenous residual insulin secretion by C-peptide measurement]. / Évaluation de la sécrétion résiduelle d'insuline par le dosage du peptide-C.

C-peptide measurement allows an estimation of the residual endogenous insulin secretion in diabetic patients. Nowadays plasmatic testing is convenient and unexpensive, but we lack standardized tests. Therefore, there are no official recommendation regarding its use. As an indication, in some circumstances, C-peptide measurement could be used to specify the type of diabetes, help guide the treatment strategy and potentially assess the risk for complications. Its use is still limited and not recommended on a routine base for all patients living with diabetes, but in the future, tests standardization and establishment of reference ranges could give more insight on the clinical relevance of C-peptide measurement.

Le dosage du peptide-C est une mesure permettant d'évaluer la sécrétion endogène résiduelle d'insuline chez les patients diabétiques. Le dosage plasmatique est facilement réalisable actuellement, pour un coût modeste, mais l'absence de standardisation des tests ne permet pas d'émettre des recommandations officielles par rapport à son utilisation. À titre indicatif, dans certaines situations, le dosage du peptide-C peut être utilisé pour préciser le type de diabète, guider les traitements médicamenteux et potentiellement évaluer les risques de complications. Son utilisation est pour le moment limitée et n'est pas recommandée en routine pour tous les patients atteints de diabète, mais à l'avenir, la formalisation du dosage et l'établissement de valeurs de référence pourraient permettre de définir son utilisation clinique.