Regulation Of Glucose Homeostasis Research Articles

Expression of PPAR-γ TF by newly synthesized thiazolidine-2,4-diones to manage glycemic control: Insights from in silico, in vitro and experimental pharmacology in wistar rats.

In pursuit of novel antidiabetic agents to combat type II diabetes mellitus, our study focused on identifying pharmacophoric features responsible for PPAR-γ expression, a key regulator of glucose homeostasis and lipid metabolism. This goal was achieved through pharmacophore model generation and screening of rationally designed library of thiazolidine-2,4-dione hybrids (7a-7f). The top hits were synthesized, characterized, and evaluated for their in vitro and in vivo antidiabetic activities. Among these, compounds 7b and 7c emerged as promising candidates, exhibiting significant in vitro inhibitory activity against human pancreatic α-amylase (HPA) and human liver α-glucosidase (HLAG) enzymes, along with enhanced glucose uptake in L6 myotube cell lines. Specifically, compound 7b showed 29.04±1.13µM HPA inhibition, 34.21±1.16µg/mL HLAG inhibition, and 77.12±1.02% glucose uptake, while compound 7c displayed 28.35±1.01µM HPA inhibition, 26.21±1.17µM HLAG inhibition, and 78.54±0.54% glucose uptake. Mechanistic studies revealed a dose-dependent increase in PPAR-γ transcription factor expression, supported by molecular docking that showed favorable interactions with key residues TYR473, SER289, and HIE323. Molecular dynamics simulations confirmed the stability of these interactions, and MM/GBSA binding free energy calculations indicated potential for further optimization. In vivo studies in STZ-induced diabetic Wistar rats demonstrated significant improvements in glucose homeostasis, insulin sensitivity, and lipid metabolism, with a notable decrease in triglycerides and VLDL levels. Compound 7c also showed an improved pharmacokinetic profile with a half-life of 4.01h and an elimination rate constant of 0.325, compared to compound 7b. Both compounds enhanced glycogen content and antioxidant biomarkers, with a high safety profile (LD50 of 500mg/kg). Overall, compound 7c stands out as a promising lead for further development, with compound 7b also showing strong potential, providing valuable insights for future antidiabetic drug development efforts.

The Molecular Mechanism of Farnesoid X Receptor Alleviating Glucose Intolerance in Turbot (Scophthalmus maximus)

To explore the molecular targets for regulating glucose metabolism in carnivorous fish, the turbot (Scophthalmus maximus) was selected as the research object to study. Farnesoid X receptor (FXR; NR1H4), as a ligand-activated transcription factor, plays an important role in glucose metabolism in mammals. However, the mechanisms controlling glucose metabolism mediated by FXR in fish are not understood. It was first found that the protein levels of FXR and its target gene, small heterodimer partner (SHP), were significantly decreased in the high-glucose group (50 mM, HG) compared with those in the normal glucose group (15 mM, CON) in primary hepatocytes of turbot. By further exploring the function of FXR in turbot, the full length of FXR in turbot was cloned, and its nuclear localization function was characterized by subcellular localization. The results revealed that the FXR had the highest expression in the liver, and its capability to activate SHP expression through heterodimer formation with retinoid X receptor (RXR) was proved, which proved RXR could bind to 15 binding sites of FXR by forming hydrogen bonds. Activation of FXR in both the CON and HG groups significantly increased the expression of glucokinase (gk) and pyruvate kinase (pk), while it decreased the expression of cytosolic phosphoenolpyruvate carboxykinase (cpepck), mitochondrial phosphoenolpyruvate carboxykinase (mpepck), glucose-6-phosphatase 1 (g6pase1) and glucose-6-phosphatase 2 (g6pase2), and caused no significant different in glycogen synthetase (gs). ELISA experiments further demonstrated that under the condition of high glucose with activated FXR, it could significantly decrease the activity of PEPCK and G6PASE in hepatocytes. In a dual-luciferase reporter assay, the FXR could significantly inhibit the activity of G6PASE2 and cPEPCK promoters by binding to the binding site ‘ATGACCT’. Knockdown of SHP after activation of FXR reduced the inhibitory effect on gluconeogenesis. In summary, FXR can bind to the mpepck and g6pase2 promoters to inhibit their expression, thereby directly inhibiting the gluconeogenesis pathway. FXR can also indirectly inhibit the gluconeogenesis pathway by activating shp. These findings suggest the possibility of FXR as a molecular target to regulate glucose homeostasis in turbot.

Impaired Incretin Homeostasis in Nondiabetic Moderate-to-Severe CKD.

Key Points Total incretin levels and incretin response during oral glucose tolerance testing were significantly higher among patients with moderate-to-severe nondiabetic patients with CKD compared with healthy people.Unlike in healthy individuals, increased incretin response was not correlated with insulin response and coincided with persistently greater glucagon levels to oral glucose tolerance testing in CKD.Disruption in the incretin system and glucagon dynamics may contribute to metabolic complications in moderate-to-severe CKD. Background Incretins are regulators of insulin secretion and glucose homeostasis metabolized by dipeptidyl peptidase-4 (DPP-4). CKD may modify incretin release, metabolism, or response. Methods We performed 2-hour oral glucose tolerance testing in 59 people with nondiabetic CKD (eGFR <60 ml/min per 1.73 m2) and 39 matched controls. We measured total area under the curve and incremental area under the curve (iAUC) of plasma total glucagon-like peptide-1 (GLP-1) and total glucose-dependent insulinotropic polypeptide (GIP). Fasting DPP-4 levels and activity were measured. Linear regression was used to adjust for demographic, body composition, and lifestyle factors. Results Mean (SD) eGFR was 38±13 and 89±17 ml/min per 1.73 m2 in patients with CKD and controls, respectively. GLP-1 total area under the curve and GIP iAUC were higher in patients with CKD than controls with a mean of 1531±1452 versus 1364±1484 pM×min and 62,370±33,453 versus 42,365±25,061 pg×min/ml, respectively. After adjustment, CKD was associated with 15,271 pM×min/ml greater GIP iAUC (95% confidence intervals [CIs], 387 to 30,154) compared with controls. Adjustment for covariates attenuated associations of CKD with higher GLP-1 iAUC (adjusted difference, 122; 95% CI, −619 to 864). Plasma glucagon levels were higher at 30 minutes (mean difference, 1.6; 95% CI, 0.3 to 2.8 mg/dl) and 120 minutes (mean difference, 0.84; 95% CI, 0.2 to 1.5 mg/dl) in patients with CKD compared with controls. There were no differences in insulin levels or plasma DPP-4 activity or levels between groups. Conclusions Overall, incretin response to oral glucose is preserved or augmented in moderate-to-severe CKD, without apparent differences in circulating DPP-4 concentration or activity. However, neither insulin secretion nor glucagon suppression is enhanced.

Molecular mechanisms of the obesity associated with Bardet-Biedl syndrome: An update.

Obesity is a prominent feature of Bardet-Biedl syndrome (BBS), which represents a major and growing public health problem. More than half of BBS patients carry mutations in one of eight genes that encode subunits of a protein complex known as the BBSome, which has emerged as a key regulator of energy and glucose homeostasis. However, the mechanisms underlying obesity in BBS are complex. Numerous studies have identified a high prevalence of insulin resistance and metabolic syndrome among individuals with BBS. However, the exact mechanisms are not fully understood. This review summarized evidence from experiments using mouse and cell models, focusing on the energy imbalance that leads to obesity in patients with BBS. The studies discussed in this review contribute to understanding the functional role of the BBSome in the obesity associated with BBS, laying the foundation for developing new preventive or therapeutic strategies for obese patients.

An optimized fractionation method reveals insulin-induced membrane surface localization of GLUT1 to increase glycolysis in LβT2 cells

Insulin is an important regulator of whole-body glucose homeostasis. In insulin sensitive tissues such as muscle and adipose, insulin induces the translocation of glucose transporter 4 (GLUT4) to the cell membrane, thereby increasing glucose uptake. However, insulin also signals in tissues that are not generally associated with glucose homeostasis. In the human reproductive endocrine axis, hyperinsulinemia suppresses the secretion of gonadotropins from gonadotrope cells of the anterior pituitary, thereby linking insulin dysregulation to suboptimal reproductive health. In the mouse, gonadotropes express the insulin receptor which has the canonical signaling response of IRS, AKT, and mTOR activation. However, the functional outcomes of insulin action on gonadotropes are unclear. Here, we demonstrate through use of an optimized cell fractionation protocol that insulin stimulation of the LβT2 gonadotropic cell line results in the unexpected translocation of GLUT1 to the plasma membrane. Using our high purity fractionation protocol, we further demonstrate that though Akt signaling in response to insulin is intact, insulin-induced translocation of GLUT1 occurs independently of Akt activation in LβT2 cells.

LCoRL Regulates Growth and Metabolism.

Genome-wide association studies (GWAS) in humans and livestock have identified genes associated with metabolic traits. However, the causality of many of these genes on metabolic homeostasis is largely unclear due to a lack of detailed functional analyses. Here we report ligand-dependent corepressor-like (LCoRL) as a metabolic regulator for body weight and glucose homeostasis. Although GWAS data show that LCoRL is strongly associated with body size, glucose homeostasis, and other metabolic traits in humans and livestock, functional investigations had not been performed. We generated Lcorl knockout mice (Lcorl-/-) and characterized the metabolic traits. We found that Lcorl-/- pups are born smaller than the wild-type (WT) littermates before reaching normal weight by 7 to 9 weeks of age. While aging, Lcorl-/- mice remain lean compared to WT mice, which is associated with a decrease in daily food intake. Glucose tolerance and insulin sensitivity are improved in Lcorl-/- mice. Mechanistically, this stunted growth is linked to a reduction of circulating levels of IGF-1. The expression of the genes downstream of GH signaling and the genes involved in glucose and lipid metabolism are altered in the liver of Lcorl-/- mice. Furthermore, Lcorl-/- mice are protected against a high-fat diet challenge and show reduced exercise capacity in an exercise stress test. Collectively, our results are congruent with many of the metabolic parameters linked to the Lcorl locus as reported in GWAS in humans and livestock.

Pancreatic β-cells package double C2-like domain beta protein into extracellular vesicles via tandem C2 domains.

Double C2-like domain beta (DOC2B) is a vesicle priming protein critical for glucose-stimulated insulin secretion in β-cells. Individuals with type 1 diabetes (T1D) have lower levels of DOC2B in their residual functional β-cell mass and platelets, a phenotype also observed in a mouse model of T1D. Thus, DOC2B levels could provide important information on β-cell dys(function). Our objective was to evaluate the DOC2B secretome of β-cells. In addition to soluble extracellular protein, we assessed DOC2B localized within membrane-delimited nanoparticles - extracellular vesicles (EVs). Moreover, in rat clonal β-cells, we probed domains required for DOC2B sorting into EVs. Using Single Extracellular VEsicle Nanoscopy, we quantified EVs derived from clonal β-cells (human EndoC-βH1, rat INS-1 832/13, and mouse MIN6); two other cell types known to regulate glucose homeostasis and functionally utilize DOC2B (skeletal muscle rat myotube L6-GLUT4myc and human neuronal-like SH-SY5Y cells); and human islets sourced from individuals with no diabetes (ND). EVs derived from ND human plasma, ND human islets, and cell lines were isolated with either size exclusion chromatography or differential centrifugation. Isolated EVs were comprehensively characterized using dotblots, transmission electron microscopy, nanoparticle tracking analysis, and immunoblotting. DOC2B was present within EVs derived from ND human plasma, ND human islets, and INS-1 832/13 β-cells. Compared to neuronal-like SH-SY5Y cells and L6-GLUT4myc myotubes, clonal β-cells (EndoC-βH1, INS-1 832/13, and MIN6) produced significantly more EVs. DOC2B levels in EVs (over whole cell lysates) were higher in INS-1 832/13 β-cells compared to L6-GLUT4myc myotubes; SH-SY5Y neuronal-like cells did not release appreciable DOC2B. Mechanistically, we show that DOC2B was localized to the EV lumen; the tandem C2 domains were sufficient to confer sorting to INS-1 832/13 β-cell EVs. Clonal β-cells and ND human islets produce abundant EVs. In cell culture, appreciable DOC2B can be packaged into EVs, and a small fraction is excreted as a soluble protein. While DOC2B-laden EVs and soluble protein are present in ND plasma, further studies will be necessary to determine if DOC2B originating from β-cells significantly contributes to the plasma secretome.

O-GlcNAcylation modulates mTORC1 and autophagy in β-cells, driving diabetes progression.

Type 2 diabetes (T2D) arises when pancreatic β-cells fail to produce sufficient insulin to control blood glucose appropriately. Aberrant nutrient sensing by O-GlcNAcylation and mTORC1 is linked to T2D and the failure of insulin-producing β-cells. However, the nature of their crosstalk in β-cells remains unexplored. Recently, O-GlcNAcylation, a post-translation modification controlled by enzymes OGT/OGA, emerged as a pivotal regulator for β-cell health; deficiency in either enzyme causes β-cell failure. The present study investigates the previously unidentified connection between nutrient sensor OGT and mTORC1 crosstalk to regulate β-cell mass and function in vivo. We show reduced OGT and mTORC1 activity in islets of preclinical β-cell dysfunction model and obese human islets. Using loss or gain of function of OGT, we identified that O-GlcNAcylation positively regulates mTORC1 signaling in β-cells. O-GlcNAcylation negatively modulates autophagy, as the removal of OGT increases autophagy, while the deletion of OGA decreases it. Increasing mTORC1 signaling, via deletion of TSC2, alleviates the diabetic phenotypes by increasing β-cell mass but not β-cell function in OGT deficient mice. Downstream phospho-protein signaling analysis reveal diverging impact on MKK4 and calmodulin signaling between islets with OGT, TSC2, or combined deletion. These data provide new evidence of OGT's significance as an upstream regulator of mTORC1 and autophagy, crucial for the regulation of β-cell function and glucose homeostasis.

Role of red pigment concentrating hormone in regulating eyestalk neuroendocrine systems in the mud crab Scylla paramamosain

The eyestalk ganglion is a predominant neuroendocrine organ in crustaceans that synthesize crustacean hyperglycemic hormone (CHH) family participating in physiological activities such as ovarian development, glucose homeostasis, and molting. Red pigment concentrating hormone (RPCH) contributes to a diversity of physiological influences, including ovarian development; however, its role in modulating CHH-family neuropeptides in the eyestalk ganglion remains unclear. In this study, we characterized the putative RPCH receptor (RPCHR) in the mud crab Scylla paramamosain and revealed that it was expressed in a variety of tissues, including the eyestalk ganglion. In vivo administration of mature RPCH peptide significantly restrained vitellogenesis inhibiting hormone (VIH) expression and significantly enhanced RPCHR, crustacean hyperglycemic hormone (CHH) and molt inhibiting hormone (MIH) gene expression, while in contrast, in vivo injection of RPCH-dsRNA for knockdown dramatically enhanced VIH expression and decreased RPCHR, CHH and MIH expression in the eyestalk ganglion. The present study comprehensively reports that RPCH may be responsible for the regulation of ovarian maturation, glucose homeostasis, and molting in S. paramamosain through the modulation of CHH family neuropeptides in the eyestalk ganglion.

8182 New Mouse Model Mirrors Human MODY8: Opening Doors to Understanding Exocrine-Endocrine Crosstalk in the Diabetic Pancreas

Abstract Disclosure: K. El Jellas: None. V. Salerno: None. L.S. Katz: None. J. Hu: None. G. Fogarty: None. A. Mandal: None. A. DiStefano-Forti: None. D. Scott: None. M. Lowe: None. A. Molven: None. R.N. Kulkarni: None. Maturity-onset diabetes of the young, type 8 (MODY8) is a dominantly inherited form of monogenic diabetes, caused by heterozygous mutations in the carboxyl ester lipase (CEL) gene expressed in pancreatic acinar cells. MODY8 is characterized by chronic pancreatitis and exocrine dysfunction. Despite the intimate anatomical relationship between the endocrine and exocrine pancreas, little is known about the biological components mediating exocrine-endocrine communication in regulating glucose homeostasis. Here, we report a refined mouse model that bears the mutation present in MODY8 patients on one allele, and the humanized normal variable number of tandem repeat (VNTR) of CEL with 16 repeats (16R) on the other, mimicking the genetic make-up seen in MODY8 patients. Examination of glucose homeostasis revealed that inducing stress (e.g. by high-fat diet) leads to glucose intolerance in MODY8/16R mice and a blunted glucose-stimulated insulin-secretion compared to their control littermates. Histopathological analyses demonstrated features of chronic pancreatitis in some pancreatic lobes, including inflammation, acinar atrophy, acinar-to-ductal metaplasia, fibrosis and fat infiltration, mirroring the morphology of the human disease. Moreover, we applied immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO) to intact pancreata and found that beta-cell mass was significantly decreased in the MODY8/16R mice, with a large number of islets located within fatty lobes. These results are coupled with comparative proteomics and lipidomic profiling with the aim of understanding the molecular signatures of exocrine and endocrine cells during pathogenesis. In conclusion, we have generated a mouse that recapitulates several features of the exocrine and endocrine phenotype characteristic of human MODY8. This novel model provides a unique opportunity, not possible in humans, to characterize pancreatic endocrine-exocrine communication in a longitudinal manner as a response to diverse environmental stressors. Presentation: 6/2/2024

A-035 Profiling of circulating-microRNAs' signatures in Pre-diabetic versus Diabetic patients

Abstract Background MicroRNAs (miRs) are small non-coding RNAs involved in the process of gene regulation, and hence affect various diseases including metabolic pathways in diabetes. Given their key roles, they are promising candidates as potential biomarkers or better understanding of disease etiology. In this study, our aim is to identify miRs signatures of plasma circulating-miRs related to glycemic control, vitamin D deficiency and platelet activation in diabetic, pre-diabetic versus non-diabetic patients. Methods Plasma samples were collected from 24 patients (both sexes) in total (eight non-diabetic (ND) control, twelve diabetic (DM), and four pre-diabetic (PD)), classified based on their glycemic control (HbA1c levels). miRs were extracted using the miRNeasy Serum/Plasma Advanced kit of Qiagen, run and analyzed on Next Generation Sequencing (NGS). Results Differential expression analysis revealed miRs expression variations between diabetic to pre-diabetic and non-diabetic groups. Expression levels of 131 miRs varied significantly between DM to ND group (92 down- and 39 up- regulated), and 141 miRs in PD compared to ND (97 down- and 39 up- regulated). Although DM and PD had similar differential expression, three miRs (has-miR4776-5p, -6778-3p, and 5002-3p) were over-expressed in PD with very low p-value. Differential expression comparisons accounting sex were performed showing significant differences between males to females that will be presented here. Conclusions Our findings supports the important involvement of circulating miRs in the regulation of glucose homeostasis and pathogenesis of diabetes.Further investigation of candidate miRs could identify promising new biomarkers for the early diagnosis and prevention of Diabetes and related health complications.

Sema4D deficiency enhances glucose tolerance through GLUT2 retention in hepatocytes

BackgroundThe glucose transporter 2 (GLUT2) is constitutively expressed in pancreatic beta cells and hepatocytes of mice. It is the most important receptor in glucose-stimulated insulin release and hepatic glucose transport. The Sema4D is a signalin receptor on cell membranes. The correlation between Sema4D and GLUT2 has not been reported previously. We investigated whether knockdown of Sema4D could exert a hypoglycemic effect based on the increased GLUT2 expression in Sema4D -/- mice hepatocytes.MethodsThe glucose tolerance test and insulin tolerance test in sema4D -/- and sema4D +/+ mice were compared before and after streptozotocin (STZ) injection; the expression of GLUT2 content on the membrane surface of both groups was verified by Western blot. Then, the levels of insulin and C-peptide in the serum of the two groups of mice after STZ injection were measured by ELISA; the differentially expressed mRNAs in the liver of the two groups of mice were analyzed by transcriptomic analysis; then the differences in the expression of GLUT2, glycogen, insulin and glucagon in the two groups of mice were compared by tissue section staining. Finally, metabolomics analysis was performed to analyze the metabolites differentially expressed in the two groups of mice.Key findingsFirst, Sema4D -/- male mice exhibited significantly greater glucose tolerance than wild-type mice in a hyperglycemic environment. Secondly, Sema4D -/- mice had more retained GLUT2 in liver membranes after STZ injection according to an immunofluorescence assay. After STZ injection, Sema4D -/- male mice did not exhibit fasting hyperinsulinemia like wild-type mice. Finally, analysis of metabolomic and immunohistochemical data also revealed that Sema4D -/- mice produce hypoglycemic effects by enhancing the pentose phosphate pathway, but not glycogen synthesis.ConclusionsThus, Sema4D may play an important role in the regulation of glucose homeostasis by affecting GLUT2 synthesis.

Insulin Signaling Pathway Mediates FoxO-Pepck Axis Regulation of Glucose Homeostasis in Drosophila suzukii.

The agricultural pest Drosophila suzukii exhibits a strong preference for feeding on fresh fruits, demonstrating high adaptability to sugary environments. Meanwhile, high sugar levels stimulate insulin secretion, thereby regulating the steady state of sugar metabolism. Understanding the mechanisms related to sugar metabolism in D. suzukii is crucial due to its adaptation to these specific environmental conditions. The insulin signaling pathway is an evolutionarily conserved phosphorylation cascade with significant roles in development and metabolism. We observed that the activation of the insulin signaling pathway inhibited FoxO activity and downregulated the expression of Pepck, thereby activating glycolysis and reducing glucose levels. By contrast, inhibiting insulin signaling increased the FoxO activity and upregulated the expression of Pepck, which activated gluconeogenesis and led to increased glucose levels. Our findings demonstrated the crucial role of the insulin signaling pathway in mediating glucose metabolism through the FoxO-Pepck axis, which supports the ecological adaptation of D. suzukii to high-sugar niches, thereby providing insights into its metabolic control and suggesting potential strategies for pest management. Elucidating these molecular processes is important for understanding metabolic regulation and ecological specialization in D. suzukii.

The role of receptor activity-modifying proteins in obesity and diabetes mellitus.

Receptor activity-modifying proteins (RAMPs) modulate the expression and activity of numerous G protein-coupled receptors, primarily those within class B1. These receptors have important physiological roles, including the regulation of food intake, energy metabolism, and glucose homeostasis. Dysregulation of these pathways can lead to obesity and diabetes mellitus, which present an ever-expanding global challenge. Whilst the roles of class B1 receptors and their peptide agonists in obesity and diabetes have been investigated, the contribution of RAMPs is less well understood. This review summarises the results of RAMP knockout studies, highlighting the involvement of these proteins in the incidence of disease. It then moves to discuss how receptor, RAMP, and agonist expression change in disease states, and the benefits (or detriments) of these agonists to the pathways implicated in disease pathophysiology. Whilst much of the data centres around the calcitonin family of receptors, as their interactions with RAMPs are well established, this review then discusses receptors whose roles in obesity and diabetes are well founded, but the significance of whose interactions with RAMPs is more recently emerging. The conclusion of this study of the literature is, however, that the information surrounding RAMPs is conflicting and multifaceted, and more research is required to fully understand their contribution to obesity and diabetes.

Abstract PR-05: Endocrine beta-cell stress promotes pancreatic ductal adenocarcinoma through endocrine-exocrine cell crosstalk

Abstract For a long time, the pancreas was thought to have separate cellular compartments that functioned distinctly from one another. The endocrine pancreas (islets of Langerhans) regulates glucose homeostasis, while the exocrine pancreas (acini and ducts) produces and secretes digestive enzymes. However, it has recently become clear that the endocrine and exocrine compartments communicate with one another, and dysfunction in one leads to dysfunction in the other, resulting in diabetes or pancreatitis. However, whether and how the endocrine pancreas drives the development of pancreatic ductal adenocarcinoma (PDAC), an exocrine tumor, remains unresolved. Strikingly, we found that genetic ablation of insulin-producing islet beta (β) cells (Akita) in a faithful Kras/Trp53-driven PDAC model (KPC: Kras LSL-G12D /+; Trp 53172 /+; Pdx1-Cre) suppressed PDAC progression. Conversely, obesity-induced β cell hormone dysregulation promoted Kras-driven PDAC development. Single-cell RNA sequencing (scRNA-seq) analysis of wild-type and obese mice (high-fat diet-fed and leptin-deficient (Lep ob/ob )) revealed increased expression of the peptide hormone cholecystokinin (CCK) in a subset of β cells concordant with increasing obesity, and transgenic β cell overexpression of CCK was sufficient to promote exocrine tumorigenesis in KC mice. Combined in silico (pseudotime (TrajectoryNET) and archetypal (AANet) analysis) and experimental (CreER) lineage tracing demonstrated that CCK-expressing β cells originated from a pre-existing immature β cell population (virgin β cells). Grainger causality analysis of transcriptional networks uncovered a stress-induced JNK-cJun pathway that promotes CCK expression β cells, which we confirmed using JNK inhibitors in β cell models. Together, our findings identify cellular and molecular mechanisms of β cell adaptation to obesity that contribute to obesity-driven pancreatic cancer. Furthermore, we define a critical role for endocrine-exocrine signaling in PDAC progression and stress-induced β cell pathways which could be leveraged to target the endocrine pancreas to subvert exocrine tumorigenesis. Citation Format: Cathy Garcia, Aarthi Venkat, Daniel McQuaid, Sherry Agabiti, Alex Tong, Rebecca Cardone, Richard Kibbey, Smita Krishnaswamy, Mandar Muzumdar. Endocrine beta-cell stress promotes pancreatic ductal adenocarcinoma through endocrine-exocrine cell crosstalk [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-05.

SRSF2 is essential for maintaining pancreatic beta-cell identity and regulating glucose homeostasis in mice

Diabetes is characterized by decreased beta-cell mass and islet dysfunction. The splicing factor SRSF2 plays a crucial role in cell survival, yet its impact on pancreatic beta cell survival and glucose homeostasis remains unclear. We observed that the deletion of Srsf2 specifically in beta cells led to time-dependent deterioration in glucose tolerance, impaired insulin secretion, decreased islet mass, an increased number of alpha cells, and the onset of diabetes by the age of 10 months in mice. Single-cell RNA sequencing (scRNA-seq) analyses revealed that, despite an increase in populations of unfolded protein response (UPR)-activated and undifferentiated beta cells within the SRSF2_KO group, there was a notable decrease in the expression of UPR-related and endoplasmic reticulum (ER)-related genes, accompanied by a loss of beta-cell identity. This suggests that beta cells have transitioned from an adaptive phase to a maladaptive phase in islets of 10-month-old SRSF2_KO mice. Further results demonstrated that deletion of SRSF2 caused decreased proliferation in beta cells within 3-month-old islets and Min6 cells. These findings underscore the essential role of SRSF2 in controlling beta-cell proliferation and preserving beta-cell function in mice.

Cow's Milk Bioactive Molecules in the Regulation of Glucose Homeostasis in Human and Animal Studies.

Obesity disrupts glucose metabolism, leading to insulin resistance (IR) and cardiometabolic diseases. Consumption of cow's milk and other dairy products may influence glucose metabolism. Within the complex matrix of cow's milk, various carbohydrates, lipids, and peptides act as bioactive molecules to alter human metabolism. Here, we summarize data from human studies and rodent experiments illustrating how these bioactive molecules regulate insulin and glucose homeostasis, supplemented with in vitro studies of the mechanisms behind their effects. Bioactive carbohydrates, including lactose, galactose, and oligosaccharides, generally reduce hyperglycemia, possibly by preventing gut microbiota dysbiosis. Milk-derived lipids of the milk fat globular membrane improve activation of insulin signaling pathways in animal trials but seem to have little impact on glycemia in human studies. However, other lipids produced by ruminants, including polar lipids, odd-chain, trans-, and branched-chain fatty acids, produce neutral or contradictory effects on glucose metabolism. Bioactive peptides derived from whey and casein may exert their effects both directly through their insulinotropic effects or renin-angiotensin-aldosterone system inhibition and indirectly by the regulation of incretin hormones. Overall, the results bolster many observational studies in humans and suggest that cow's milk intake reduces the risk of, and can perhaps be used in treating, metabolic disorders. However, the mechanisms of action for most bioactive compounds in milk are still largely undiscovered.

The Intake of Dietary Lipids Improves Glucose Tolerance via Modulating Gut Microbiota.

The composition of gut microbiota is determined not only by genetic factors but also by environmental factors, such as diet, exercise, and disease conditions. Among these factors, diet is crucial in changing the gut microbial composition. Dietary lipids composed of different fatty acids not only alter host metabolism but also have a significant impact on the composition of gut microbiota. However, the molecular mechanisms underlying the relationship between these host effects and their impact on gut microbiota remain unclear. Here, we demonstrated that intake of different dietary lipids improved glucose tolerance by modulating gut microbiota. The results of our analysis show that the taxa of bacteria that increase in number as a result of dietary lipid intake play an important role in glucose metabolism. Thus, we have identified a new mechanism underlying the function of dietary lipids in regulating glucose homeostasis. Our findings contribute to possible new methods to prevent and treat metabolic disorders by modifying the composition of gut microbiota.

Regulation of Energy and Glucose Homeostasis by the Nucleus of the Solitary Tract and the Area Postrema.

The central nervous system regulates feeding, weight and glucose homeostasis in rodents and humans, but the site-specific mechanisms remain unclear. The dorsal vagal complex in the brainstem that contains the nucleus of the solitary tract (NTS) and area postrema (AP) emerges as a regulatory center that impacts energy and glucose balance by monitoring hormonal and nutrient changes. However, the specific mechanistic metabolic roles of the NTS and AP remain elusive. This mini-review highlights methods to study their distinct roles and recent findings on their metabolic differences and similarities of growth differentiation factor 15 (GDF15) action and glucose sensing in the NTS and AP. In summary, future research aims to characterize hormonal and glucose sensing mechanisms in the AP and/or NTS carries potential to unveil novel targets that lower weight and glucose levels in obesity and diabetes.

Redox Status as a Key Driver of Healthy Pancreatic Beta-Cells.

Redox status plays a multifaceted role in the intricate physiology and pathology of pancreatic beta-cells, the pivotal regulators of glucose homeostasis through insulin secretion. They are highly responsive to changes in metabolic cues where reactive oxygen species are part of it, all arising from nutritional intake. These molecules not only serve as crucial signaling intermediates for insulin secretion but also participate in the nuanced heterogeneity observed within the beta-cell population. A central aspect of beta-cell redox biology revolves around the localized production of hydrogen peroxide and the activity of NADPH oxidases which are tightly regulated and serve diverse physiological functions. Pancreatic beta-cells possess a remarkable array of antioxidant defense mechanisms although considered relatively modest compared to other cell types, are efficient in preserving redox balance within the cellular milieu. This intrinsic antioxidant machinery operates in concert with redox-sensitive signaling pathways, forming an elaborate redox relay system essential for beta-cell function and adaptation to changing metabolic demands. Perturbations in redox homeostasis can lead to oxidative stress exacerbating insulin secretion defect being a hallmark of type 2 diabetes. Understanding the interplay between redox signaling, oxidative stress, and beta-cell dysfunction is paramount for developing effective therapeutic strategies aimed at preserving beta-cell health and function in individuals with type 2 diabetes. Thus, unraveling the intricate complexities of beta-cell redox biology presents exciting avenues for advancing our understanding and treatment of metabolic disorders.