Islet Cell Research Articles

Identification of a pancreatic stellate cell gene signature and lncRNA interactions associated with type 2 diabetes progression

BackgroundType 2 diabetes (T2D) has become a significant global health threat, yet its precise causes and mechanisms remain unclear. This study aims to identify gene expression patterns specific to T2D pancreatic islet cells and to explore the potential role of pancreatic stellate cells (PSCs) in T2D progression through regulatory networks involving lncRNA-mRNA interactions.MethodsIn this study, we screened for upregulated genes in T2D pancreatic islet samples using bulk sequencing (bulkseq) datasets and mapped these gene expression profiles onto three T2D single-cell RNA sequencing (scRNAseq) datasets. The identified T2D-specific gene features were further validated in an additional T2D scRNAseq dataset, a T1D scRNAseq dataset, and a T2D bulkseq dataset. To investigate regulatory networks, we analyzed the potential lncRNA-mRNA interactions within T2D peripheral blood mononuclear cell (PBMC) bulkseq data.ResultsOur analysis identified a specific gene panel—COL1A2, VCAN, and SULF1—that was consistently upregulated in T2D pancreatic islet samples. Expression of this gene panel was strongly associated with the activation of pancreatic stellate cells (PSCs), suggesting a unique T2D-specific signature characterized by COL1A2hi/VCANhi/SULF1hi PSCs. This signature was exclusive to T2D and was not observed in Type 1 diabetes (T1D) samples, indicating a distinct role for activated PSCs in T2D progression. Furthermore, we identified six long non-coding RNAs (lncRNAs) that potentially interact with the COL1A2hi/VCANhi/SULF1hi PSCs. These lncRNAs were mapped to a lncRNA-mRNA network, suggesting they may modulate immune responses and potentially reshape the immune microenvironment in T2D.DiscussionOur findings highlight the potential immune-regulatory role of PSCs in T2D and suggest that PSC-related lncRNA-mRNA networks could serve as novel therapeutic targets for T2D treatment. This research provides insights into PSCs as a modulator in T2D progression, paving the way for innovative treatment strategies.

Retraction notice to "Cannabinoids as anti-ROS in aged pancreatic islet cells" [Life Sci. 256 (2020) 117969

Retraction notice to "Cannabinoids as anti-ROS in aged pancreatic islet cells" [Life Sci. 256 (2020) 117969

Bi-Hormonal Endocrine Cell Presence Within the Islets of Langerhans of the Human Pancreas Throughout Life.

Bi-hormonal islet endocrine cells have been proposed to represent an intermediate state of cellular transdifferentiation, enabling an increase in beta-cell mass in response to severe metabolic stress. Beta-cell plasticity and regenerative capacity are thought to decrease with age. We investigated the ontogeny of bi-hormonal islet endocrine cell populations throughout the human lifespan. Immunofluorescence microscopy was performed for insulin, glucagon, and somatostatin presence on paraffin-embedded sections of pancreata from 20 donors without diabetes aged between 11 days and 79 years of age. The mean proportional presence of glucagon-, insulin-, and somatostatin-immunoreactive cells within islets was 27.5%, 62.1%, and 12.1%, respectively. There was no change in the relative presence of alpha- or beta-cells with advancing age, but delta-cell presence showed a decline with age (R2 = 0.59, p < 0.001). The most abundant bi-hormonal cell phenotype observed co-stained for glucagon and insulin, representing 3.1 ± 0.3% of all islet cells. Glucagon/somatostatin and insulin/somatostatin bi-hormonal cells were also observed representing 2-3% abundance relative to islet cell number. Glucagon/insulin bi-hormonal cells increased with age (R2 = 0.30, p < 0.05) whilst insulin/somatostatin (R2 = 0.50, p < 0.01) and glucagon/somatostatin (R2 = 0.35, p < 0.05) cells decreased with age of donor. Findings show that bi-hormonal cells are present within human pancreatic islets throughout life, perhaps reflecting an ongoing potential for endocrine cell plasticity.

Gestational diabetes mellitus-derived miR-7-19488 targets PIK3R2 mRNA to stimulate the abnormal development and maturation of offspring-islets.

Gestational diabetes mellitus (GDM) provides offspring with a hyper-metabolic intrauterine microenvironment. In this study, we aimed to identify key differential microRNAs in GDM-derived exosomes and explore the potential mechanisms of abnormal embryonic development of islets in offspring. Exosomes were extracted from umbilical vein blood of GDM and non-GDM (NGDM) parturients for microRNA sequencing. Offspring islets were collected on E18.5 and P0 to detect the expression and location of key proteins by immunofluorescence. Target binding of miR-7-19488 and PIK3R2 mRNA was verified using a dual-luciferase reporter assay. The miR-7-19488-mimic, PI3K/mTOR inhibitors were used to treat primarily islet cells to explore the relationship among miR-7-19488, PI3K, and Akt-FoxO1/mTORC1 signaling. The miR-7-19488 agomir was synthesized for further in vivo validation. GDM-derived exosomes caused the overdevelopment of offspring-islets at E18.5 with an increased production of insulin and glucagon co-staining cells, increased number of α cells synthesizing GLP-1, and stimulation of mTORC1 singling, which were more serious at birth. The up-regulated miR-7-19488 in GDM-exosomes targeted PIK3R2 mRNA, leading to translation stagnation of p85β and activation of PI3K-Akt singling in fetal islets. Importantly, the activated PI3K-Akt-FoxO1 singling promoted development and differentiation of α and β cells and enhanced the GLP-1/GLP-1R axis, which cooperates with miR-7-19488 to activate PI3K-Akt-FoxO1/mTORC1 singling, leading to the early initiation of the functional maturation of overdeveloped β cells. miR-7-19488 loaded in GDM-derived exosomes induce the abnormal overdevelopment and functional maturation of fetal islets, which is one of the contributors of high incidence of diabetes in adulthood.

Host-microbiota interplay in arsenic metabolism: Implications on host glucose homeostasis.

Arsenic (As), a naturally occurring element with unique properties, has been recognized as the largest mass poisoning in the world by the World Health Organization (WHO). Approximately 200 million people worldwide are exposed to toxic levels of arsenic due to natural and anthropogenic activities. This widespread exposure necessitates a deeper understanding of microbe-arsenic interactions and their potential influence on host exposure and health risks. It is a major causative factor for metabolic diseases, including diabetes. Arsenic exposure has been linked to dysfunction in various cell types and tissues, notably affecting pancreatic islet cells. Numerous mechanisms have been identified to be responsible for arsenic exposure under both in vitro and in vivo conditions. These mechanisms contribute to the regulation of processes underlying diabetes etiology, such as glucose-stimulated insulin secretion from pancreatic beta cells. Unlike other toxic elements, arsenic undergoes metabolism by living organisms, including microbes, plants, and animals. Other toxic elements like Lead (Pb) and mercury (Hg) are generally not metabolized in the same way as Arsenic in microbes, plants and animals. In this review, we strive to initiate a dialogue by reviewing known aspects of microbe-arsenic interactions and placing it in the context of the potential for influencing host exposure and health risks. This review provides an up-to-date insight into arsenic metabolism by the human body and its associated microbiota, as well as the deciphered molecular pathways linking the different species of arsenic in the etiology of diabetes. Additionally, the future perspectives of mitigation and detoxification of arsenic in translational medicine and limitations in current scenarios are discussed. The comprehensive review presented here underscores the importance of exploring the complex interplay between arsenic metabolism, host-microbiota interactions, and their implications on glucose homeostasis and metabolic diseases. It emphasizes the need for continued research to develop effective strategies for mitigating arsenic-related health risks and fostering better translational medicine approaches.

The Relationship of Serum Diabetes Antibodies With the Development of Early Diabetic Retinopathy Findings in Children With Type 1 Diabetes Mellitus

Purpose To explore how serum diabetes autoantibodies are related to the development of early diabetic retinopathy in children with type 1 diabetes mellitus. Methods In this prospective and observational study, 62 patients with type 1 diabetes mellitus who had not yet developed clinical diabetic retinopathy were followed up for at least 5 years. Healthy volunteers aged 10 to 20 years were also included. Insulin, pancreatic islet cells, and glutamic acid decarboxylase (GAD) autoantibodies were measured with an RIA kit at the time of type 1 diabetes mellitus diagnosis. Optical coherence tomography angiography (OCTA) was used to evaluate the foveal avascular zone (FAZ) and parafoveal vascular density (PVD) for the development of early diabetic retinopathy among the groups. Patients' OCTA findings were compared with those of healthy volunteers. The obtained data were analyzed via IBM SPSS Statistics for Windows, version 27.0. Spearman's rank correlation test and regression analysis were performed to determine independent predictors of OCTA and type 1 diabetes mellitus parameters. Results Eighteen boys and 44 girls with type 1 diabetes mellitus with a median age of 15.6 years (range: 10.08 to 20.88 years) were evaluated. Healthy control participants with a median age of 15.3 years (range: 14.2 to 18.2 years) were also included. The mean FAZ was greater in the type 1 diabetes mellitus group than in the healthy control group ( P = .013 and .119, respectively). The mean PVD was significantly lower in the type 1 diabetes mellitus group than in the healthy control group. There was no significant correlation between serum diabetes autoantibodies (GAD and insulin autoantibodies) and FAZ or PVD (FAZ and GAD; r = 0.138, P = .286, FAZ and anti-insulin; r = 0.100, P = .441, PVD and GAD; r = −0.151, P = .24, PVD and anti-insulin; r = −0.087, P = .499). Conclusions Type 1 diabetes mellitus in children without clinically detectable diabetic retinopathy is associated with impaired retinal microcirculation and irregularities at the FAZ margin. Impaired retinal microcirculation and irregularities were associated with glycated hemoglobin levels in the study group. Thus, studies with larger patient series are needed. [ J Pediatr Ophthalmol Strabismus . 20XX;X(X):XXX–XXX.]

The IL-2 SYNTHORIN molecule promotes functionally adapted Tregs in a preclinical model of type 1 diabetes.

Deficits in IL-2 signaling can precipitate autoimmunity by altering the function and survival of FoxP3+ regulatory T cells (Tregs) while high concentrations of IL-2 fuel inflammatory responses. Recently, we showed that the non-beta IL-2 SYNTHORIN molecule SAR444336 (SAR'336) can bypass the induction of autoimmune and inflammatory responses by increasing its reliance on IL-2 receptor α chain subunit (CD25) to provide a bona fide IL-2 signal selectively to Tregs, making it an attractive approach for the control of autoimmunity. In this report, we further demonstrate that SAR'336 can support non-beta IL-2 signaling in murine Tregs and limit NK and CD8+ T cells' proliferation and function. Using a murine model of spontaneous type 1 diabetes, we showed that the administration of SAR'336 slows the development of disease in mice by decreasing the degree of insulitis through the expansion of antigen-specific Tregs over Th1 cells in pancreatic islets. Specifically, SAR'336 promoted the differentiation of IL-33-responsive (ST2+), IL-10-producing GATA3+ Tregs over other Treg subsets in the pancreas, demonstrating the ability of this molecule to further orchestrate Treg adaptation. These results offer insight into the capacity of SAR'336 to generate highly specialized, tissue-localized Tregs that promote restoration of homeostasis during ongoing autoimmune disease.

NKX2.2 and KLF4 cooperate to regulate α-cell identity.

Transcription factors (TFs) are indispensable for maintaining cell identity through regulating cell-specific gene expression. Distinct cell identities derived from a common progenitor are frequently perpetuated by shared TFs, yet the mechanisms that enable these TFs to regulate cell-specific targets are poorly characterized. We report that the TF NKX2.2 is critical for the identity of pancreatic islet α cells by directly activating α-cell genes and repressing alternate islet cell fate genes. When compared with the known role of NKX2.2 in islet β cells, we demonstrate that NKX2.2 regulates α-cell genes, facilitated in part by α-cell-specific DNA binding at gene promoters. Furthermore, we have identified the reprogramming factor KLF4 as having enriched expression in α cells, where it co-occupies NKX2.2-bound α-cell promoters, is necessary for NKX2.2 promoter occupancy in α cells, and coregulates many NKX2.2 α-cell transcriptional targets. Overexpression of Klf4 in β cells is sufficient to manipulate chromatin accessibility, increase binding of NKX2.2 at α-cell-specific promoter sites, and alter expression of NKX2.2-regulated cell-specific targets. This study identifies KLF4 as a novel α-cell factor that cooperates with NKX2.2 to regulate α-cell identity.

Current Challenges in Pancreas and Islet Transplantation: A Scoping Review.

Type 1 diabetes mellitus is an autoimmune condition characterized by the destruction of pancreatic β-cells, necessitating insulin therapy to prevent life-threatening complications such as diabetic ketoacidosis. Despite advancements in glucose monitoring and pharmacological treatments, managing this disease remains challenging, often leading to long-term complications and psychological burdens, including diabetes distress. Advanced treatment options, such as whole-pancreas transplantation and islet transplantation, aim to restore insulin production and improve glucose control in selected patients with diabetes. The risk of transplant rejection necessitates immunosuppressive therapy, which increases susceptibility to infections and other adverse effects. Additionally, surgical complications, including infection and bleeding, are significant concerns, particularly for whole-pancreas transplantation. Recently, stem cell-derived therapies for type 1 diabetes have emerged as a promising alternative, offering potential solutions to overcome the limitations of formerly established transplantation methods. The purpose of this scoping review was to: (1) summarize the current evidence on achieved insulin independence following various transplantation methods of insulin-producing cells in patients with type 1 diabetes; (2) compare insulin independence rates among whole-pancreas transplantation, islet cell transplantation, and stem cell transplantation; and (3) identify limitations, challenges and potential future directions associated with these techniques. We systematically searched three databases (PubMed, Scopus, and Web of Science) from inception to November 2024, focusing on English-language, peer-reviewed clinical studies. The search terms used were 'transplantation' AND 'type 1 diabetes' AND 'insulin independence'. Studies were included if they reported on achieved insulin independence, involved more than 10 patients with type 1 diabetes, and had a mean follow-up period of at least one year. Reviewers screened citations and extracted data on transplant type, study population size, follow-up duration, and insulin independence rates. We identified 1380 papers, and after removing duplicates, 705 papers remained for title and abstract screening. A total of 139 English-language papers were retrieved for full-text review, of which 48 studies were included in this review. The findings of this scoping review indicate a growing body of literature on transplantation therapy for type 1 diabetes. However, significant limitations and challenges, like insufficient rates of achieved insulin independence, risks related to immunosuppression, malignant diseases, and ethical issues remain with each of the established techniques, highlighting the need for innovative approaches such as stem cell-derived islet transplantation to promote β-cell regeneration and protection.

Loss of β-cell KATP reduces Ca2+ sensitivity of insulin secretion and Trpm5 expression.

Loss-of-function (LOF) mutations in KATP channels cause hyperexcitability and insulin hypersecretion, resulting in congenital hyperinsulinism (CHI). Paradoxically, despite the initial insulin hypersecretion, many CHI cases, as well as KATP knockout (KO) animals, eventually 'crossover' to undersecretion and even diabetes. Here we confirm that Sur1 KO islets exhibit higher intracellular [Ca2+] ([Ca2+]i) at all [glucose], but show decreased glucose-stimulated insulin secretion. However, when [Ca2+]i is artificially elevated by increasing extracellular [Ca2+], insulin secretion from Sur1 KO islets increases to the same levels as WT islets. This indicates that a right-shift in [Ca2+]i-dependence of insulin secretion, rather than loss of insulin content or intrinsic secretability, is the primary cause for the crossover. Chronic pharmacological inhibition of KATP channel activity by slow release of glibenclamide in pellet-implanted mice causes a very similar 'crossover' to glucose intolerance and impaired insulin secretion to that seen in Sur1 KO animals. Whole islet and single cell transcriptomic analysis reveal markedly reduced Trpm5 in both conditions. Glibenclamide pellet-implanted Trpm5 KO mice also exhibited significant glucose intolerance. However, this was not as severe as in WT animals, which suggests that decreased expression of Trpm5 may play a small role in the disruption of insulin secretion with KATP loss.

Metabolic, genetic and immunological features of relatives of type 1 diabetes patients with elevated insulin resistance.

Insulin resistance plays a pivotal role in the preclinical stages of type 1 diabetes (T1D). This study aims at exploring the genetic, metabolic, and immunological features associated with insulin resistance among individuals at risk of developing T1D. We retrospectively selected relatives of individuals with T1D from participants in the TrialNet Pathway to Prevention study. They were categorized into two groups: high-H (n = 27) and low-H (n = 30), based on the upper and lower quartiles of insulin resistance assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Genetic predisposition was determined using the T1D Genetic Risk Score 1 (GRS1). Additionally, glucose control was evaluated through an oral glucose tolerance test and levels of metabolic hormones and inflammatory cytokines were measured in the serum. Flow cytometry analysis was employed to assess frequency and phenotype of islet-specific CD8 T cells. While GRS1 were similar between the low-H and high-H groups, high-H individuals displayed a distinct metabolic profile, characterized by compensatory hyperinsulinemia, even while maintaining normoglycemia. Circulating cytokine levels were similar between the two groups. However, immune profiling revealed a central memory and activated profile of GAD65-specific CD8 T cells, along with an increased frequency of insulin-specific CD8 T cells in high-H individuals. The enrichment in insulin-specific CD8 T cells was independent of body mass. These findings highlight the intricate interplay between insulin resistance, genetic factors, and immune activation in the context of T1D susceptibility, indicating potential connections between insulin resistance and immune responses specific to islet cells.

Beneficial Actions of 4-Methylumbelliferone in Type 1 Diabetes by Promoting β Cell Renewal and Inhibiting Dedifferentiation.

Background/Objectives: This study aims to investigate the effects of 4-methylumbelliferone (4-MU) on islet morphology, cell phenotype and function, and to explore possible mechanisms of β cell regeneration. Methods: The Type 1 diabetes (T1D) model was induced by continuous dose injection of streptozotocin (STZ), and mice were treated with 4-MU for 3 weeks. Plasma insulin level, islet cell phenotype and immune infiltration were determined by IPGTT, ELISA, HE and immunofluorescence. The Ins2Cre/+/Rosa26-eGFP transgenic mice model was used to detect β identity change. Primary rodent islets were incubated with 4-MU or vehicle in the presence or absence of STZ, AO/PI staining, and a scanning electron microscope (SEM), PCR and ELISA were used to evaluated islet viability, islet morphology, the specific markers of islet β cells and insulin secretion. Results: Treatment with 4-MU significantly decreased blood glucose and increased plasma insulin levels in STZ-induced diabetes. The plasma insulin level in the STZ group was 7.211 ± 2.602 ng/mL, which was significantly lower than the control group level (26.94 ± 4.300 ng/mL, p < 0.001). In contrast, the plasma insulin level in the STZ + 4-MU group was 22.29 ± 7.791 ng/mL, which was significantly higher than the STZ group (p < 0.05). The 4-MU treatment increased islet and β cells numbers and decreased α cell numbers in STZ-induced diabetes. Conclusions: Islet inflammation as indicated by insulin and CD3 was caused by infiltrates, and the β cell proliferation as indicated by insulin and Ki67 was boosted by 4-MU. β cell dedifferentiation was inhibited by 4-MU as assessed by insulin and glucagon double-positive cells and confirmed by Ins2Cre/+/Rosa26-eGFP mice. In cultured primary rodent islets, 4-MU restored islet viability, protected islet morphology, inhibited β-cell dedifferentiation, and promoted insulin secretion. The benefits of 4-MU in T1D have been proved to be associated with β cells self-replication, dedifferentiation inhibition and immune progression suppression, which help to maintain β cell mass.

Pancreatic Eosinophilic Infiltrates of Infants of Diabetic Mothers Revisited

Background: Infants of diabetic mothers (IDM) frequently show eosinophilic infiltrates around the pancreatic islets. We review 2 IDM, describe the pancreatic histology and review the literature. Case reports: Two term IDM died at 1 h and 43 days respectively. Both had eosinophilic infiltrates with frequent Charcot Leyden crystals surrounding the primary islets, had occasional eosinophils in these primary islets, but the infiltrate spared the acini and the intralobular islet tissue. There was no necrosis, fibrosis, or vasculitis. From the literature, this has been described as early as 28 weeks gestation, and occasionally was associated with peri-islet fibrosis. Conclusion: This infiltrate occurs antenatally, surrounds the primary islets, spares intralobular islet cells, persists past the neonatal period, and is not uniformly associated with islet or peri-islet injury. As eosinophils contribute to a variety of pancreatic inflammatory conditions, investigation may lead to further insights into the effect of maternal diabetes on the infant.

Biotechnology Revolution Shaping the Future of Diabetes Management.

Diabetes mellitus (DM) has a millennia-long history, with early references dating back to ancient Egypt and India. However, it was not until the 20th century that the connection between diabetes and insulin was fully understood. The sequencing of insulin in the 1950s initiated the convergence of biotechnology and diabetes management, leading to the development of recombinant human insulin in 1982. This marked the start of peptide-based therapies in DM. Recombinant peptides for DM treatment: Numerous recombinant peptides have been developed since, starting with modified insulin molecules, with the aim of bettering DM management through fine-tuning the glycemic response to insulin. Peptide-based therapies in DM have expanded substantially beyond insulin to include agonists of Glucagon-like peptide-1 receptor and Glucose-dependent insulinotropic polypeptide receptor, glucagon receptor antagonists, and even peptides exerting multiple receptor agonist effects, for better metabolic control. Insulin pumps, continuous glucose monitoring, and automated insulin delivery systems: The development of modern delivery systems combined with real-time glucose monitoring has significantly advanced diabetes care. Insulin pumps evolved from early large devices to modern sensor-augmented pumps with automated shutoff features and hybrid closed-loop systems, requiring minimal user input. The second-generation systems have demonstrated superior outcomes, proving highly effective in diabetes management. Islet cell transplantation, organoids, and biological pancreas augmentation represent innovative approaches to diabetes management. Islet cell transplantation aims to restore insulin production by transplanting donor beta cells, though challenges persist regarding graft survival and the need for immunosuppression. Organoids are a promising platform for generating insulin-producing cells, although far from clinical use. Biological pancreas augmentation relies on therapies that promote beta-cell (re)generation, reduce stress, and induce immune tolerance. Further biotechnology-driven perspectives in DM will include metabolic control via biotechnology-enabled tools such as custom-designed insulin hybrid molecules, machine-learning algorithms to control peptide release, and engineering cells for optimal peptide production and secretion.

Application of diffusion chambers for cell macroencapsulation: from concept to clinical trials (literature review)

Macroencapsulation of cells allows to isolate the donor biomaterial from the influence of the recipient’s organism. The degree of isolation can vary from mechanical isolation of donor cells within the implantation site to complete immune isolation of the transplanted biological material. The diffusion chamber was the first device used for macroencapsulation. The initial stage of research of this technique was aimed at expanding the range of cell and tissue implantation in allogenic and xenogenic models and clarifying the mechanisms underlying the graft rejection reaction. Later the design of the diffusion chamber underwent a number of changes that determined the modern application of the macroencapsulation method. The derivative of the diffusion chamber – the engineering chamber in complex with the arterio-venous shunt is used as a tissue modeling tool for creation of soft tissue flaps of different composition with the axial type of blood supply. An alternative design of the flow chamber allows the formation of soft tissue flaps on intact vessels. The engineering chamber is also used for growing various types of tissues and organ fragments (cardiac transverse striated muscle tissue, lymphoid tissue, fragments of liver, thymus, pancreas). A separate direction in studying the range of practical applications of the diffusion chamber is the development and testing of methods of transplantation of pancreatic islet cells into animals when creating allo- and xenogeneic experimental models for the treatment of diabetes mellitus. Some devices are already undergoing clinical trials and are available as a product for experimental studies.

β-Cell Secretory Capacity Predicts Metabolic Outcomes over 6 Years following Human Islet Transplantation.

Transplanted islet functional β-cell mass is measured by the β-cell secretory capacity derived from the acute insulin response to glucose-potentiated arginine (AIRpot), however, data are limited beyond one-year post-transplant for individuals with type 1 diabetes. We evaluated changes in β-cell secretory capacity in a single-center longitudinal analysis and examined relationships with measures of islet cell hormone metabolism and clinical measures of graft function (mixed-meal tolerance test [MMTT] C-peptide, BETA-2 score, and continuous glucose monitoring [CGM]). Eleven individuals received purified human pancreatic islets over one or two intra-portal infusions to achieve insulin-independence and were followed over a median (IQR) 6 (5-7) years. β-cell secretory capacity remained stable over 3-years before declining. Fasting glucagon and proinsulin secretory ratios under glucose-potentiation were inversely correlated with AIRpot. A functional β-cell mass of 40% normal predicted insulin-independence and was strongly predicted by MMTT C-peptide-to-glucose and BETA-2 score. A functional β-cell mass of >20% predicted excellent glycemic outcomes including ≤1% time <60 mg/dL, ≤2% time >180 mg/dL and ≥90% time-inrange 70-180 mg/dL. β-cell replacement approaches should target a functional β-cell mass >40% to provide sufficient islet reserve for sustained insulin-independence. MMTT C-peptide-to-glucose and BETA-2 score can inform changes in functional β-cell mass in the clinical setting.

Cycling alpha cells in regenerative drug-treated human pancreatic islets may serve as key beta cell progenitors.

Diabetes results from an inadequate number of insulin-producing human beta cells. There is currently no clinically available effective means to restore beta cell mass in millions of people with diabetes. Although the DYRK1A inhibitors, either alone or in combination with GLP-1 receptor agonists (GLP-1) or transforming growth factor β (TGF-β) superfamily inhibitors (LY), induce beta cell replication and increase beta cell mass, the precise mechanisms of action remain elusive. Here we perform single-cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone or with GLP-1 or LY. We identify cycling alpha cells as the most responsive cells to DYRK1A inhibition. Lineage trajectory analyses suggest that cycling alpha cells may serve as precursor cells that transdifferentiate into beta cells. Collectively, in addition to enhancing expression of beta cell phenotypic genes in beta cells, our findings suggest that regenerative drugs may be targeting cycling alpha cells in human islets.

Semaglutide alleviates the pancreatic β cell function via the METTL14 signaling and modulating gut microbiota in type 2 diabetes mellitus mice.

Semaglutide, a novel long-acting GLP-1RA, stimulates insulin and suppresses islet-secreted glucagon to reduce glucose levels. It has been unveiled that m6A mRNA modification plays a pivotal role in regulating β cell function. However, it remains unclear whether semaglutide can elicit protective effects through manipulating m6A modification and the underlying mechanism. We aimed to elucidate the role played by semaglutide in m6A modification, and to explore its specific regulatory targets. Furthermore, we also delve into its effects on gut microbiota. Five-week-old male C57BL/6 mice were assigned to two dietary groups and fed a control or high-fat diet for 4weeks. Then T2DM was induced in high-fat diet-fed mice via streptozotocin (STZ), the main groups were resampled to include treatment with semaglutide (SEM, 40μg/kg) for another 4weeks, totaling three groups: Control, Model (T2DM), T2DM+SEM. Additionally, we elucidated specific regulatory targets and signaling pathways in palmitic acid (PA)-stimulated beta-TC-6 cells. Immunofluorescence, Western blot, and RT-qPCR were used in the study. Semaglutide mitigated pancreatic damage, enhanced islet cell proliferation, and restored islet size and alpha- and beta-cell masses. It also improved the expression of METTL14, pancreatic duodenal homeobox 1 (PDX-1), and protecting mitochondria, and modulated the PDX1 expression in an m6A-dependent manner. Concurrently, semaglutide significantly decreases the abundance of Firmicutes, Actinobacteriota, and Lactobacillus, while increasing the Bacteroides and norank_f_Muribaculaceae content, and the production of short-chain fatty acids (SCFA). Semaglutide positively influences by regulating m6A modifications to alleviate pancreatic beta cell dysfunction and modulate the gut microbiome.

Pancreatic Safety of Tirzepatide and Its Effects on Islet Cell Function: A Systematic Review and Meta‐Analysis

ABSTRACTBackgroundEndogenous glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) regulate islet cell function. GLP‐1 receptor agonists (GLP‐1RAs) have been associated with an elevated risk of acute pancreatitis. Data on the pancreatic safety of tirzepatide (a dual GLP‐1 and GIP agonist) and its effects on islet cell function in randomized controlled trials (RCTs) are scarce. Moreover, no meta‐analysis has comprehensively examined such effects of tirzepatide.MethodsElectronic databases were searched for RCTs with tirzepatide as the intervention and a placebo or active comparator as the control. The primary outcome was adjudication‐confirmed pancreatitis; secondary outcomes were the percent changes from baseline in serum pancreatic amylase, lipase, insulin, C‐peptide, glucagon, and homeostasis model assessment of insulin resistance (HOMA2‐IR).ResultsSeventeen RCTs with 18 published reports involving 14,645 subjects were analyzed. Over a follow‐up duration of 12–72 weeks, tirzepatide had identical risks of pancreatitis to placebo (tirzepatide 5 mg: RR 2.04, 95% CI [0.27–15.69], p = 0.49; 10 mg: RR 0.63, 95% CI [0.08–5.12], p = 0.67; and 15 mg: RR 1.26, 95% CI [0.36–4.98], p = 0.72). Tirzepatide was also associated with comparable risks of pancreatitis to insulin and GLP‐1RAs. However, tirzepatide (at all doses) caused greater increases in pancreatic amylase and lipase than placebo and insulin. Individuals on tirzepatide 15 mg and GLP‐1RAs had similar risks of having increased lipase levels. The percent reductions in fasting insulin were greater with tirzepatide 10 and 15 mg than with placebo. All doses of tirzepatide caused greater percent reductions in fasting insulin, C‐peptide, and glucagon than GLP‐1RAs. Compared to placebo and GLP‐1RAs, the percent reductions in HOMA2‐IR were greater with all doses of tirzepatide.ConclusionThe meta‐analysis provides evidence of the safety of tirzepatide regarding pancreatitis and establishes its positive effect on islet cell functions and insulin resistance.

Investigating the antidiabetic properties of Apium graveolens extract and its inhibition of enzymes associated with hyperglycemia.

Apium graveolens Linn., also known as celery, is a member of the Apiaceae family and has shown promising pharmacological properties, including diabetes. Indeed, the current investigation aimed to investigate the potential inhibitory effects of A. graveolens seed aqueous extract on the digestive enzymes involved in carbohydrate metabolism and its efficiency in reducing blood sugar levels in diabetic mice induced by streptozotocin. I administered oral doses of an aqueous extract from A. graveolens seeds to both normal and diabetic animals to evaluate acute toxicity and its potential antidiabetic effects. I observed the glycemia and body weight of the animals for four weeks. In vitro tests were also done to see how the seed extract affected the activities of α-amylase and α-glucosidase. Following administration of the extract, diabetic mice showed a notable reduction in blood glucose concentration. This reduction was similar to the standard metformin treatment after two and four weeks. Moreover, A. graveolens demonstrated significant inhibitory effects on α-amylase and α-glucosidase activity, with IC50 values of 840.15±0.02 and 114.81±0.05, respectively. At 500mg/kg/day, histological analysis indicated degenerative alterations in pancreatic islet cells. These results indicate that the aqueous extract derived from the seeds of A. graveolens possesses promising antihyperglycemic properties in diabetic mice, along with notable inhibition of α-amylase and α-glucosidase activity. Further investigation is needed to characterize the active compounds present in A. graveolens seeds.