Β-cell Function Research Articles

Identifying and optimizing critical process parameters for large-scale manufacturing of iPSC derived insulin-producing β-cells

BackgroundType 1 diabetes, an autoimmune disorder leading to the destruction of pancreatic β-cells, requires lifelong insulin therapy. Islet transplantation offers a promising solution but faces challenges such as limited availability and the need for immunosuppression. Induced pluripotent stem cells (iPSCs) provide a potential alternative source of functional β-cells and have the capability for large-scale production. However, current differentiation protocols, predominantly conducted in hybrid or 2D settings, lack scalability and optimal conditions for suspension culture.MethodsWe examined a range of bioreactor scaleup process parameters and quality target product profiles that might affect the differentiation process. This investigation was conducted using an optimized High Dimensional Design of Experiments (HD-DoE) protocol designed for scalability and implemented in 0.5L (PBS-0.5 Mini) vertical wheel bioreactors.ResultsA three stage suspension manufacturing process is developed, transitioning from adherent to suspension culture, with TB2 media supporting iPSC growth during scaling. Stage-wise optimization approaches and extended differentiation times are used to enhance marker expression and maturation of iPSC-derived islet-like clusters. Continuous bioreactor runs were used to study nutrient and growth limitations and impact on differentiation. The continuous bioreactors were compared to a Control media change bioreactor showing metabolic shifts and a more β-cell-like differentiation profile. Cryopreserved aggregates harvested from the runs were recovered and showed maintenance of viability and insulin secretion capacity post-recovery, indicating their potential for storage and future transplantation therapies.ConclusionThis study demonstrated that stage time increase and limited media replenishing with lactate accumulation can increase the differentiation capacity of insulin producing cells cultured in a large-scale suspension environment.

Associations of physiologic subtypes based on HOMA2 indices of β-cell function and insulin sensitivity with the risk of kidney function decline, cardiovascular disease, and all-cause mortality from the 4C study

BackgroundPrevious studies have been limited by their inability to differentiate between the effects of insulin sensitivity and β-cell function on the risk of kidney function decline, cardiovascular disease (CVD), and all-cause mortality. To address this knowledge gap, we aimed to investigate whether the physiological subtypes based on homeostasis model assessment-2 (HOMA2) indices of β-cell function (HOMA2-B) and insulin sensitivity (HOMA2-S) could be used to identify individuals with subsequently high or low of clinical outcome risk.MethodsThis retrospective cohort study included 7,317 participants with a follow-up of up to 5 years. Based on HOMA2 indices, participants were categorized into four physiologic subtypes: the normal phenotype (high insulin sensitivity and high β-cell function), the insulinopenic phenotype (high insulin sensitivity and low β-cell function), the hyperinsulinaemic phenotype (low insulin sensitivity and high β-cell function), and the classical phenotype (low insulin sensitivity and low β-cell function). The outcomes included kidney function decline, CVD events (fatal and nonfatal), and all-cause mortality. Cox regression models were used to calculate hazard ratios (HRs) for outcomes, and spline models were used to examine the dose-dependent associations of HOMA2-B and HOMA2-S with outcomes.ResultsA total of 1,488 (20.3%) were classified as normal, 2,179 (29.8%) as insulinopenic, 2,173 (29.7%) as hyperinsulinemic, and 1,477 (20.2%) as classical subtypes. Compared with other physiological subtypes, the classical subtype presented the highest risk of kidney function decline (classical vs. normal HR 11.50, 95% CI 4.31–30.67). The hyperinsulinemic subtype had the highest risk of CVD and all-cause mortality (hyperinsulinemic vs. normal: fatal CVD, HR 6.56, 95% CI 3.09–13.92; all-cause mortality, HR 4.56, 95% CI 2.97–7.00). Spline analyses indicated the dose-dependent associations of HOMA2-B and HOMA2-S with outcomes.ConclusionsThe classical subtype had the strongest correlation with the risk of kidney function decline, and the hyperinsulinemic subtype had the highest risk of CVD and all-cause mortality, which should be considered for interventions with precision medicine.Graphical abstract

ECM Proteins Nidogen-1 and Decorin Restore Functionality of Human Islets of Langerhans upon Hypoxic Conditions.

Transplantation of donor islets of Langerhans is a potential therapeutic approach for patients with diabetes mellitus; however, its success is limited by islet death and dysfunction during the initial hypoxic conditions at the transplantation site. This highlights the need to support the donor islets in the days post-transplantation until the site is vascularized. It was previously demonstrated that the extracellular matrix (ECM) proteins nidogen-1 (NID1) and decorin (DCN) improve the functionality and survival of the β-cell line, EndoC-βH3, and the viability of human islets post-isolation. To advance the use of these ECM proteins toward a clinical application and elucidate the mechanisms of action in primary islets, the study assesses the effects of ECM proteins NID1 and DCN on isolated human donor islets cultured in normoxic and hypoxic conditions. NID1- and DCN-treatment restore β-cell functionality of human donor islets in a hypoxic environment through upregulation of genes involved in glycolytic pathways and reducing DNA fragmentation in hypoxic conditions comparable to normoxic control islets. The results demonstrate that the utilization of NID1 or DCN with islets of Langerhans may have the potential to overcome the hypoxia-induced cell death observed post-transplantation and improve transplant outcomes.

EPA and DHA inhibit LDL-induced upregulation of human adipose tissue NLRP3 inflammasome/IL-1β pathway and its association with diabetes risk factors

Elevated numbers of atherogenic lipoproteins (apoB) predict the incidence of type 2 diabetes (T2D). We reported that this may be mediated via the activation of the NLRP3 inflammasome, as low-density lipoproteins (LDL) induce interleukin-1 beta (IL-1β) secretion from human white adipose tissue (WAT) and macrophages. However, mitigating nutritional approaches remained unknown. We tested whether omega-3 eicosapentaenoic and docosahexaenoic acids (EPA and DHA) treat LDL-induced upregulation of WAT IL-1β-secretion and its relation to T2D risk factors. Twelve-week intervention with EPA and DHA (2.7 g/day, Webber Naturals) abolished baseline group-differences in WAT IL-1β-secretion between subjects with high-apoB (N = 17) and low-apoB (N = 16) separated around median plasma apoB. Post-intervention LDL failed to trigger IL-1β-secretion and inhibited it in lipopolysaccharide-stimulated WAT. Omega-3 supplementation also improved β-cell function and postprandial fat metabolism in association with higher blood EPA and mostly DHA. It also blunted the association of WAT NLRP3 and IL1B expression and IL-1β-secretion with multiple cardiometabolic risk factors including adiposity. Ex vivo, EPA and DHA inhibited WAT IL-1β-secretion in a dose-dependent manner. In conclusion, EPA and DHA treat LDL-induced upregulation of WAT NLRP3 inflammasome/IL-1β pathway and related T2D risk factors. This may aid in the prevention of T2D and related morbidities in subjects with high-apoB.Clinical Trail Registration ClinicalTrials.gov (NCT04496154): Omega-3 to Reduce Diabetes Risk in Subjects with High Number of Particles That Carry “Bad Cholesterol” in the Blood – Full Text View - ClinicalTrials.gov.

Enhanced BMP Signaling Alters Human β-Cell Identity and Function.

Inflammation contributes to the pathophysiology of diabetes. Identifying signaling pathways involved in pancreatic β-cell failure and identity loss can give insight into novel potential treatment strategies to prevent the loss of functional β-cell mass in diabetes. It is reported earlier that the immunosuppressive drug tacrolimus has a detrimental effect on human β-cell identity and function by activating bone morphogenetic protein (BMP) signaling. Here it is hypothesized that enhanced BMP signaling plays a role in inflammation-induced β-cell failure. Single-cell transcriptomics analyses of primary human islets reveal that IL-1β+IFNγ and IFNα treatment activated BMP signaling in β-cells. These findings are validated by qPCR. Furthermore, enhanced BMP signaling with recombinant BMP2 or 4 triggers a reduced expression of key β-cell maturity genes, associated with increased ER stress, and impaired β-cell function. Altogether, these results indicate that inflammation-activated BMP signaling is detrimental to pancreatic β-cells and that BMP-signaling can be a target to preserve β-cell identity and function in a pro-inflammatory environment.

Insulin level, glycemia, insulin resistance and β-cell function in relation to the lifestyle of Arctic indigenous people. Are there conditions for diabetes and which type?

Modern studies suggest that lifestyle changes of the indigenous Arctic residents lead to the loss of the "adaptive polar type of metabolism", which is characterized by the intensification of protein metabolism, optimization of lipid metabolism, and minimization of carbohydrate metabolism at low insulin concentrations. How to survive the era of change? To assess insulinemia, glycemia, β-cell secretory activity, and insulin sensitivity in Arctic indigenous people in relation to their lifestyle. A cross-sectional study of a population of indigenous Arctic residents (Nenets, Komi) aged from 22 to 60 years was conducted. Insulin levels were studied in blood serum using ELISA, and glucose levels using the spectrophotometric method. Insulin resistance (HOMA-IR) and β-cell function (HOMA1-%β) indices were calculated. 397 people were examined; 89 (22%) of them were nomadic people (NP) and 44 (49%) were male. Another 308 (78%) were sedentary people (SP), and 69 (22%) were male. The insulin level was significantly lower in NP (6.0 [3.5-11.8] µU/ml) compared to SP (8.3 [4.6-13.1] µU/ml), p=0.006. There was no difference in glycemia (4.6 [4.2-5.0] in NP and 4.6 [4.1-5.2] in SP) between lifestyles.The HOMA-IR was significantly lower in NP (1.3 [0.7-2.4]) than in SP (1.8 [0.95-2.8]), p=0.013. IR-HOMA >2 units was 1.8 times more frequent in the SP than in NP, with adjusted for sex, age, and BMI OR=0.56; 95% CI: 0.33-0.96, p=0.034. The median HOMA1-%β was 128 [67-241] % in NP and 144 [93-236]% in SP with no significant differences between groups. The proportion of individuals with HOMA1-%β <48.9 was 17% in NP versus 5% in SP, p<0.001. The adjusted odds of having HOMA1-%β <48.9 in NP are 3.5 times higher than in SP; 95% CI: 1.56-7.92, p=0.002. Fifty-six cases of glycemia ≥5.6 mmol/l were identified: 13.5% in NP and 14.3% in SP. The ratio IR-HOMA >2/ HOMA1-%β <48.9/BMI was 1.8 units/45%/25.2 kg/m2 in NP and 3.0 units/88%/29.6 kg/m2 in SP. Maintaining a nomadic lifestyle helps keep lower insulin concentrations; at the same time, glycemic levels in the groups were similar. In the NP group, there was a high proportion of individuals with low β-cell secretory activity, predominantly men; in the SP group, more individuals were insulin-resistant. Analysis of cases of glycemia ≥5.6 mmol/l confirmed, that hyperglycemia in a nomadic lifestyle was associated with β-cell hypofunction and the absence of obesity; on the contrary, in a sedentary lifestyle, it was associated with increased insulin resistance and obesity.

Characterization and functional evaluation of goat PDX1 regulatory modules through comparative analysis of conserved interspecies homologs.

PDX1 is a crucial transcription factor in pancreas development and mature β-cell function. However, the regulation of PDX1 expression in larger animals mirroring human pancreas morphogenesis and endocrine maturation remains poorly understood. Therefore, we conducted a comparative analysis to characterize regulatory regions of goat PDX1 gene and assessed their transcriptional activity by transient transfection of several transgenic EGFP constructs in β- and non-β cell lines. We recognized several highly conserved regions encompassing the promoter and cis-regulatory elements (Area I-IV) at 5' flanking sequence of the genes. Within the promoter, we identified that a key E-box and nearby CAAT element synergistically drive transcription, constituting the basal promoter of goat PDX1 gene. Furthermore, each recognized regulatory area separately enhances this basal promoter activity in β-cells compared to non-β cells; however, cooperatively, they exhibit a bifunctional regulatory effect on transcription. Additionally, the intact ~ 3kb upstream region (Area I-III) functions as the most efficient reporter transgene in vitro and shows islet-specific expression in native rat pancreas. Together, our findings suggest that the regulation of goat PDX1 gene is governed by conserved regions similar to other mammals, while both structurally and functionally, these regions exhibit a closer resemblance to those found in humans.

Incretin-Based Therapies: A Promising Approach for Modulating Oxidative Stress and Insulin Resistance in Sarcopenia.

Recent studies have linked sarcopenia development to the hallmarks of diabetes, oxidative stress, and insulin resistance. The anti-oxidant and insulin sensitivityenhancing effects of incretin-based therapies may provide a promising option for the treatment of sarcopenia. This review aimed to unveil the role of oxidative stress and insulin resistance in the pathogenesis of sarcopenia and explore the potential benefits of incretin-based therapies in individuals with sarcopenia. PubMed, the Cochrane Library, and Google Scholar databases were searched by applying keywords relevant to the main topic, to identify articles that met our selection criteria. Incretin-based therapies manifested anti-oxidant effects by increasing the anti-oxidant defense system and decreasing free radical generation or by indirectly minimizing glucotoxicity, which was mainly achieved by improving insulin signaling and glucose homeostasis. Likewise, these drugs exhibit insulin-sensitizing activities by increasing insulin secretion, transduction, and β-cell function or by reducing inflammation and lipotoxicity. Incretin-based therapies, as modulators of oxidation and insulin resistance, may target the main pathophysiological factors of sarcopenia, thus providing a promising strategy for the treatment of this disease.

Lipid Dynamics in Pancreatic β-Cells: Linking Physiology to Diabetes Onset.

Significance: Glucose-induced lipid metabolism is essential for preserving functional β-cells, and its disruption is linked to type 2 diabetes (T2D) development. Lipids are an integral part of the cells playing an indispensable role as structural components, energy storage molecules, and signals. Recent Advances: Glucose presence significantly impacts lipid metabolism in β-cells, where fatty acids are primarily synthesized de novo and/or are transported from the bloodstream. This process is regulated by the glycerolipid/free fatty acid cycle, which includes lipogenic and lipolytic reactions producing metabolic coupling factors crucial for insulin secretion. Disrupted lipid metabolism involving oxidative stress and inflammation is a hallmark of T2D. Critical Issues: Lipid metabolism in β-cells is complex involving multiple simultaneous processes. Exact compartmentalization and quantification of lipid metabolism and its intermediates, especially in response to glucose or chronic hyperglycemia, are essential. Current research often uses non-physiological conditions, which may not accurately reflect invivo situations. Future Directions: Identifying and quantifying individual steps and their signaling, including redox, within the complex fatty acid and lipid metabolic pathways as well as the metabolites formed during acute versus chronic glucose stimulation, will uncover the detailed mechanisms of glucose-stimulated insulin secretion. This knowledge is crucial for understanding T2D pathogenesis and identifying pharmacological targets to prevent this disease. Antioxid. Redox Signal. 00, 000-000.

A Perspective On A Promising Role For Caffeine In Modulating The Casr In Pancreatic Β-Cells

The extracellular calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that plays a crucial role in the parathyroid glands and kidneys in maintaining calcium (Ca2+) homeostasis. The extracellular CaSR is present in various cell types not implicated in controlling plasma Ca2+ levels. There is accumulating evidence that CaSR plays a significant role in regulating the function of β-cells in the pancreas. Divalent cations and insulin are released together during exocytosis, and their concentration in the restricted intercellular compartments of the pancreatic islet increases to activate CaSR in neighboring cells. Subsequently, the activated CaSR stimulates insulin vesicle release in the adjacent cells, and by repeating these steps, the signal is amplified in the whole islet. Recent work developed a photoaffinity-tagged glutathione derivative (DAZ-G) as a chemical tool. The study demonstrated that DAZ-G can identify and analyze CaSR ligands. The use of DAZ-G identified caffeine as a positive allosteric modulator of the CaSR, suggesting that the physiological effects of caffeine are partly attributed to its stimulation of the CaSR. Future work may utilize caffeine to activate the CaSR in pancreatic β-cells to improve their secretory function

Metformin Preserves Insulin Secretion in Pancreatic β-cells through FGF21/Akt Pathway In vitro and In vivo.

In our previous studies, it was found that metformin can elevate the expression of FGF21 in the peripheral blood of type 2 diabetic rats and improve insulin sensitivity in diabetic rats. However, whether this effect is mediated by increased FGF21 expression in pancreatic islet β-cells is still unknown. Therefore, this study focuses on the effect of metformin on insulin secretion in pancreatic β-cells. Metformin can effectivly improve insulin resistance. Metformin influencing pancreatic β- cell function is inclusive. In this study, we sought to analyze possible variations in insulin secretion and possible signaling mechanisms after metformin intervention. The study employed an in vivo model of a high-fat diet in streptozocin-induced diabetic rats and an in vitro model of rat pancreatic β-cells (INS-1 cells) that were subjected to damage caused by hyperglycemia and hyperlipidemia. After treating INS-1 cells in normal, high-glucose, and high-glucose+metformin, we measured insulin secretion by glucose-stimulated insulin secretion (GSIS). Insulin was measured using an enzyme-linked immunosorbent assay. FGF21 expression was detected by RT-PCR and Western blot, as well as that p-Akt and t-Akt expression were detected by Western blot in INS-1 cells and diabetic rat islets. Finally, to verify the regulation of the FGF21 /Akt axis in metformin administration, additional experiments were carried out in metformin-stimulated INS-1 cells. High-glucose could significantly stimulate insulin secretion while metformin preserved insulin secretion. Expression of FGF21 and p-Akt was decreased in high-glucose, however, metformin could reverse this effect in INS-1 cells and diabetic rat islets. Our results demonstrate a protective role of metformin in preserving insulin secretion through FGF21/Akt signaling in T2DM.

Comparative efficacy, toxicity, and insulin-suppressive effects of simvastatin and pravastatin in fatty acid-challenged mouse insulinoma MIN6 β-cell model.

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

Vector of glycated hemoglobin in the formation of dysglycemia in postmenopause: Emphasis on early diagnosis and therapy

Introduction. The close relationship of postmenopause with insulin resistance (IR) and metabolic syndrome (MetS) marks a high cardiometabolic risk of dysglycemia, determining the need for its early diagnosis and therapy. Pathogenetically substantiated criteria for the diagnosis of prediabetes and the nature of early drug therapy for type 2 diabetes mellitus (T2DM) are debated. Information on the relationship between glucose homeostasis parameters and menopausal MetS is fragmentary.Aim. To evaluate the associations of glycated hemoglobin (HbA1c) levels with indices of IR, β-cell function and MetS character- istics in a cohort of postmenopausal women with different carbohydrate metabolic states.Materials and methods. In 94 Caucasian postmenopausal women 58.0 (53.0; 63.0) years old the following were determined: HbA1c, fasting glycemia (FG), TyG and HOMA2 indices, C-peptid, BMI, waist circumference (WC), blood pressure (BP), triglycerides (TG), HDL-C levels. When classifying women by HbA1c (ADA criteria), 15 had normoglycemia, 24 prediabetes, 55 T2DM. ME (25–75%) was assessed using SPSS (version 17); intergroup differences according to the Mann – Whitney test; Spearman and partial correlation analysis were performed.Results. HbA1c age independently correlated with IR parameters: TyG (R = 0.590; p < 0.001), HOMA2-IR (R = 0.318; p < 0.05) and beta cell function: HOMA2-B (R = -0.355; p < 0.001); with lipid markers of MetS (TG, HDL-C, respectively R = 0.382; -0.448; p < 0.001), anthropometric and blood pressure levels.Conclusion. Associations of HbA1c in postmenopausal women with a spectrum of glucose homeostasis parameters and MetS mark it as a vector of formation and progression of dysglycemia due to a close connection with the functional state of β-cells and the importance of lipoglucotoxicity in the dynamics of postmenopausal IR. The obtained data pathogenetically determine the use of HbA1c in the verification of dysglycemia and the early administration of combined antihyperglycemic therapy aimed at preserving β-cell function. The potential of dipeptidyl peptidase-4 inhibitors in slowing the progression of type 2 diabetes mellitus is considered

Plant-Based Diets and Phytochemicals in the Management of Diabetes Mellitus and Prevention of Its Complications: A Review.

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

The role of GRB2 in diabetes, diabetes complications and related disorders.

Growth factor receptor-bound protein 2 (GRB2) is a key adaptor protein involved in multiple signalling pathways, and its dysregulation is associated with various diseases. Type 2 diabetes is a systemic condition characterized by insulin resistance and impaired β-cell function. The complications of diabetes significantly reduce life expectancy and quality of life, imposing a substantial burden on society. However, the role of GRB2 in diabetes and associated complications is largely unknown. Emerging evidence suggests that GRB2 plays a crucial role in insulin resistance, inflammation, immune activation and the regulation of cellular processes such as cell proliferation, growth, metabolism, angiogenesis, apoptosis and differentiation. Dysregulation of GRB2-mediated pathways contributes to the progression of diabetic neuropathy, cognitive dysfunction, nephropathy, retinopathy and related disorders. This review provides a comprehensive overview of the current understanding of the role of GRB2 in diabetes, diabetes complications and related disorders, alongside recent advances in the development of GRB2-targeted therapies. Elucidating the complex role of GRB2 in these disorders provides valuable insights into potential therapeutic strategies targeting GRB2-mediated pathways.

Dapagliflozin mitigates cellular stress and inflammation through PI3K/AKT pathway modulation in cardiomyocytes, aortic endothelial cells, and stem cell-derived β cells

Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is well-recognized for its therapeutic benefits in type 2 diabetes (T2D) and cardiovascular diseases. In this comprehensive in vitro study, we investigated DAPA’s effects on cardiomyocytes, aortic endothelial cells (AECs), and stem cell-derived beta cells (SC-β), focusing on its impact on hypertrophy, inflammation, and cellular stress. Our results demonstrate that DAPA effectively attenuates isoproterenol (ISO)-induced hypertrophy in cardiomyocytes, reducing cell size and improving cellular structure. Mechanistically, DAPA mitigates reactive oxygen species (ROS) production and inflammation by activating the AKT pathway, which influences downstream markers of fibrosis, hypertrophy, and inflammation. Additionally, DAPA’s modulation of SGLT2, the Na+/H + exchanger 1 (NHE1), and glucose transporter (GLUT 1) type 1 highlights its critical role in maintaining cellular ion balance and glucose metabolism, providing insights into its cardioprotective mechanisms. In aortic endothelial cells (AECs), DAPA exhibited notable anti-inflammatory properties by restoring AKT and phosphoinositide 3-kinase (PI3K) expression, enhancing mitogen-activated protein kinase (MAPK) activation, and downregulating inflammatory cytokines at both the gene and protein levels. Furthermore, DAPA alleviated tumor necrosis factor (TNFα)-induced inflammation and stress responses while enhancing endothelial nitric oxide synthase (eNOS) expression, suggesting its potential to preserve vascular function and improve endothelial health. Investigating SC-β cells, we found that DAPA enhances insulin functionality without altering cell identity, indicating potential benefits for diabetes management. DAPA also upregulated MAFA, PI3K, and NRF2 expression, positively influencing β-cell function and stress response. Additionally, it attenuated NLRP3 activation in inflammation and reduced NHE1 and glucose-regulated protein GRP78 expression, offering novel insights into its anti-inflammatory and stress-modulating effects. Overall, our findings elucidate the multifaceted therapeutic potential of DAPA across various cellular models, emphasizing its role in mitigating hypertrophy, inflammation, and cellular stress through the activation of the AKT pathway and other signaling cascades. These mechanisms may not only contribute to enhanced cardiac and endothelial function but also underscore DAPA’s potential to address metabolic dysregulation in T2D.Graphical abstract

Long-term effects of arsenic on glucose-insulin homeostasis: A gene-environment interaction study

Abstract Background Arsenic exposure and genetic factors are associated with an increased risk of type 2 diabetes, yet study of environment-gene interaction on glucose-insulin homeostasis remains scarce. We aimed to investigate the associations and interactions of urinary total arsenic (UTAs) and genetic susceptibility with glucose-insulin homeostasis through a longitudinal epidemiological study. Methods A total of 6136 observations (3063 participants) from the baseline, 3-year follow-up, and 6-year follow-up of the Wuhan-Zhuhai cohort were included in this study. In each study period, we repeatedly measured UTAs, fasting plasma glucose (FPG), fasting plasma insulin (FPI), and homeostasis model-assessed insulin resistance (HOMA-IR) and β-cell function (HOMA-β). Polygenic risk scores (PRSs) specific for all traits were constructed by corresponding genome-wide association summary statistics. Linear mixed models were used to assess associations and interactions of UTAs and PRSs with four indicators of glucose-insulin homeostasis. Results After adjustment for all covariates, the βs (95% CIs) for the annual growth rates of FPG, FPI, and HOMA-IR were 0.020 (0.008, 0.032), 0.007 (0.002, 0.013), and 0.011 (0.004, 0.017), respectively, associated with each ln-unit increase in UTAs. Compared to subjects with the first-quartile PRS and low UTAs, participants with the fourth-quartile PRS and high UTAs had a 0.029 (0.012, 0.047) or 0.032 (0.012, 0.051) ln-unit increase in the annual growth rate of FPI or HOMA-IR, respectively. UTAs and PRS had significant interactions on the longitudinal progressive increases of FPI and HOMA-IR (P interaction < 0.05). Conclusions Arsenic exposure and genetic variants are significantly synergistic risk factors for dysregulation and progressive deterioration of glucose-insulin homeostasis. Our findings emphasize the importance of reducing arsenic exposure to maintain normal glucose-insulin metabolism, especially for those at higher genetic risk. Key messages • Arsenic exposure was associated with annual increased rates of FPG, FPI, and HOMA-IR. • Arsenic exposure and trait-specific PRSs are synergistic risk factors for glucose-insulin homeostasis impairment.

Identification of new phenotypes in type 2 diabetes with acute myocardial infarction: toward a precision medicine?

Abstract Background Type 2 diabetes mellitus (T2DM) is a highly heterogeneous entity, with multiple subgroups differing by clinic presentation, disease progression and risk of complications such as myocardial infarction (MI). A new T2DM phenotyping classification has been recently proposed to help to improve treatment tailoring and target early treatments, and we aimed to identify the prevalence and characteristics of the new phenotypes. Methods All consecutive adults with a history T2DM hospitalized in a french Coronary Intensive Care Unit for an acute MI between February 1st, 2021 and January 31st, 2023 were included. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance). We stratified patients into five subgroups : 1/ SAID=severe autoimmune diabetes; 2/ SIDD=severe insulin-deficient diabetes; 3/ SIRD=severe insulin-resistant diabetes; 4/ MOD=mild obesity-related diabetes; and 5/ MARD=mild age-related diabetes. Results Among the 266 patients included, characteristics according to diabetes phenotypes are summarized in the Table. Conclusions Our prospective study showed that in real-world T2DM patients with acute MI, unclassical phenotypes, i.e. hyperinsulinaemic and insulinopaenic were common. Given the large discrepancies in characteristics, our findings suggest the relevance of the new substratification. However, its clinical utlity and translation in tailored treatment strategies and prognosis remains to be determined.Table.

Cystic fibrosis-related diabetes is associated with reduced islet protein expression of GLP-1 receptor and perturbation of cell-specific transcriptional programs

Insulin secretion is impaired in individuals with cystic fibrosis (CF), contributing to high rates of CF-related diabetes (CFRD) and substantially increasing disease burden. To develop improved therapies for CFRD, better knowledge of pancreatic pathology in CF is needed. Glucagon like peptide-1 (GLP-1) from islet α cells potentiates insulin secretion by binding GLP-1 receptors (GLP-1Rs) on β cells. We determined whether expression of GLP-1 and/or its signaling components are reduced in CFRD, thereby contributing to impaired insulin secretion. Immunohistochemistry of pancreas from humans with CFRD versus no-CF/no-diabetes revealed no difference in GLP-1 immunoreactivity per islet area, whereas GLP-1R immunoreactivity per islet area or per insulin-positive islet area was reduced in CFRD. Using spatial transcriptomics, we observed several differentially expressed α- and/or β-cell genes between CFRD and control pancreas. In CFRD, we found upregulation of α-cell PCSK1 which encodes the enzyme (PC1/3) that generates GLP-1, and downregulation of α-cell PCSK1N which inhibits PC1/3. Gene set enrichment analysis also revealed α and β cell-specific pathway dysregulation in CFRD. Together, our data suggest intra-islet GLP-1 is not limiting in CFRD, but its action may be restricted due to reduced GLP-1R protein levels. Thus, restoring β-cell GLP-1R protein expression may improve β-cell function in CFRD.

One-year outcomes of a digital twin intervention for type 2 diabetes: a retrospective real-world study

This retrospective observational study, building on prior research that demonstrated the efficacy of the Digital Twin (DT) Precision Treatment Program over shorter follow-up periods​​, aimed to examine glycemic control and reduced anti-diabetic medication use after one-year in a DT commercial program. T2D patients enrolled had adequate hepatic and renal function and no recent cardiovascular events. DT intervention powered by artificial intelligence utilizes precision nutrition, activity, sleep, and deep breathing exercises. Outcome measures included HbA1c change, medication reduction, anthropometrics, insulin markers, and continuous glucose monitoring (CGM) metrics. Of 1985 enrollees, 132 (6.6%) were lost to follow-up, leaving 1853 participants who completed one-year. At one-year, participants exhibited significant reductions in HbA1c [mean change: -1.8% (SD 1.7%), p < 0.001], with 1650 (89.0%) achieving HbA1c below 7%. At baseline, participants were on mean 1.9 (SD 1.4) anti-diabetic medications, which decreased to 0.5 (SD 0.7) at one-year [change: -1.5 (SD 1.3), p < 0.001]. Significant reductions in weight [mean change: -4.8 kg (SD 6.0 kg), p < 0.001], insulin resistance [HOMA2-IR: -0.1 (SD 1.2), p < 0.001], and improvements in β-cell function [HOMA2-B: +21.6 (SD 47.7), p < 0.001] were observed, along with better CGM metrics. These findings suggest that DT intervention could play a vital role in the future of T2D care.