Pancreatic Β-cell Function Research Articles

Bcl-2 and Bcl-xL in Diabetes: Contributions to Endocrine Pancreas Viability and Function

Diabetes is a chronic metabolic disorder whose prevalence increases every year, affecting more than 530 million adults worldwide. Type 1 (T1D) and type 2 diabetes (T2D), the most common forms of diabetes, are characterized by the loss of functional pancreatic β-cells, mostly due to apoptosis. B-cell leukemia/lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), two anti-apoptotic proteins belonging to the Bcl-2 family, are crucial for regulating the intrinsic pathway of apoptosis. However, over the years, they have been implicated in many other cellular processes, including intracellular Ca2+ homeostasis and the regulation of mitochondrial metabolism. Thus, understanding the biological processes in which these proteins are involved may be crucial to designing new therapeutic targets. This review summarizes the roles of Bcl-2 and Bcl-xL in apoptosis and metabolic homeostasis. It focuses on how the dysregulation of Bcl-2 and Bcl-xL affects pancreatic β-cell function and survival, and the consequences for diabetes development.

Chemerin loss-of-function attenuates glucagon-like peptide-1 secretion in exercised obese mice.

To investigate the role of chemerin reduction in mediating exercise-induced Glucagon-like peptide-1 (GLP-1) secretion and the amelioration of pancreatic β-cell function in obesity. Obesity models were established using wild-type and chemerin systemic knockout mice, followed by 8 weeks of moderate-intensity continuous aerobic exercise training. Serum chemerin levels, GLP-1 synthesis, glucose tolerance, pancreatic β-cell function, structure, and apoptosis were assessed. In vitro experiments were conducted on STC-1 cells, derived from murine intestinal endocrine cells, to evaluate GLP-1 secretion following exogenous chemerin treatment. Additionally, colonic tissue inflammation and apoptosis were analyzed using qPCR and TUNEL staining. In obese wild-type mice, moderate-intensity aerobic exercise significantly reduced serum chemerin levels, enhanced GLP-1 secretion, and improved glucose tolerance, pancreatic β-cell structure, function, and apoptosis. These effects were absent in obese chemerin knockout mice. Exogenous chemerin treatment reduced GLP-1 secretion in STC-1 cells. Furthermore, the beneficial effects of exercise on colonic inflammation and apoptosis observed in wild-type mice were abolished in chemerin knockout mice. Reduction of chemerin is crucial for the beneficial effects of aerobic exercise on GLP-1 secretion and pancreatic β-cell function in obesity. The mechanisms behind these effects may involve improvements in colonic inflammation and apoptosis. These findings offer new insights into the molecular mechanisms through which exercise improves obesity-related metabolic dysfunction.

Lasia spinosa Stem Aqueous Extract Potentiates Antidiabetic Effects Exhibiting Antioxidant Genes Upregulation and DNA-Damage Protection.

This research elucidated the hypoglycemic effect correlated with DNA-protective and antioxidative activity of Lasia spinosa stem aqueous extract (LSSAE) using streptozotocin-induced type 2 diabetic rat models. LSSAE, characterized by phytochemical screening, gas chromatography-mass spectroscopy (GC-MS), and FTIR analyses, was investigated for its DNA-protective activity by exposing PBR322 plasmid DNA to Fenton's reagents. Long Evans rats, treated by LSSAE, were found to be improved for body weight, fasting blood glucose level, and oral glucose load. A 30-day supplement of LSSAE significantly recovered serum biochemical markers, including hepatic (i.e., ALP, AST, ALT, and TB); renal (i.e., creatinine and uric acid); and lipid profiles (i.e., TC, TG, HDLc, LDLc, and VLDLc). An increased level of superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH), and a decreased level of malondialdehyde (MDA) were observed in LSSAE-treated rat liver. Antioxidant enzyme activities were evaluated by mRNA expression level of antioxidant genes (CAT, SOD2, GPX1, PON1, PFK1, GAPDH, using the 2-ΔΔCT method, normalized with housekeeping gene, ß-ACTIN) using qRT-PCR. Additionally, histological examination confirmed the restoration of morphology, and function of pancreatic β-cell, kidney, liver, and spleen. Results reveal that LSSAE exerts an antidiabetic effect through upregulation of antioxidant genes, DNA protection and modulation of biochemical and histological parameters.

The Aryl Hydrocarbon Receptor (AhR) Is a Novel Gene Involved in Proper Physiological Functions of Pancreatic β-Cells.

The Kynurenine pathway is crucial in metabolizing dietary tryptophan into bioactive compounds known as kynurenines, which have been linked to glucose homeostasis. The aryl hydrocarbon receptor (AhR) has recently emerged as the endogenous receptor for the kynurenine metabolite, kynurenic acid (KYNA). However, the specific role of AhR in pancreatic β-cells remains largely unexplored. This study aimed to investigate the expression of AhR in human pancreatic islets using publicly available RNA-sequencing (RNA-seq) databases and to explore its correlations with various metabolic parameters and key β-cell markers. Additionally, functional experiments were conducted in INS-1 cells, a rat β-cell line, to elucidate the role of Ahr in β-cell biology. RNA-seq data analysis confirmed the expression of AHR in human islets, with elevated levels observed in pancreatic islets obtained from diabetic and obese donors compared to non-diabetic or lean donors. Furthermore, AHR expression showed an inverse correlation with the expression of key β-cell functional genes, including insulin, PDX-1, MAFA, KCNJ11, and GCK. Silencing Ahr expression using siRNA in INS-1 cells decreased insulin secretion, insulin content, and glucose uptake efficiency, while cell viability, apoptosis rate, and reactive oxygen species (ROS) production remained unaffected. Moreover, Ahr silencing led to the downregulation of major β-cell regulator genes, Ins1, Ins2, Pdx-1, and Glut2, at both the mRNA and protein levels. In summary, this study provides novel insights into the role of AhR in maintaining proper β-cell function. These findings suggest that AhR could be a potential target for future therapeutic strategies in treating type 2 diabetes (T2D).

Exploring insulin resistance and pancreatic function in individuals with overweight and obesity: Insights from OGTTs and IRTs.

To investigate insulin resistance and pancreatic β-cell function in overweight or obese people under the same glucose tolerance conditions. The subjects were categorized based on the results of the oral glucose tolerance test (OGTT) and the BMI classification criteria. Basal and postprandial glucose concentrations, insulin concentrations, pancreatic β-cell function (HOMA-β), the insulin resistance index (HOMA-IR), and the insulin early secretion index (ΔI30/ΔG30) were compared between the different weight groups. Among individuals with similar glucose tolerances, those in the obese group presented higher HOMA-β, HOMA-IR, and ΔI30/ΔG30 values than did those in the normal weight and overweight groups. Additionally, in individuals with normal glucose tolerance and early diabetes, OGTT 1-h plasma glucose concentrations demonstrated a stronger correlation with early insulin secretion across different body weights. When the same glucose-tolerant population was grouped by weight, OGTTs were significantly less different than IRTs. Therefore, integrating both tests is the optimal approach. In individuals with preobesity, there is an increase in pancreatic β-cell function to maintain normal blood glucose levels. As the disease progresses, obesity substantially increases insulin resistance, which acts as a disease-promoting factor. Furthermore, OGTT 1-h plasma glucose concentrations are strongly correlated with insulin secretion in normal or early diabetic populations.

Diacylglycerol kinase ζ is a positive insulin secretion regulator in pancreatic β-cell line MIN6

Some isoforms of diacylglycerol (DAG) kinase (DGK), an enzyme converting DAG into phosphatidic acid, i.e., DGKα, γ and δ, have been reportedly involved in the regulation of pancreatic β-cell function. DGKζ has also been reported to be expressed in rat pancreatic β-cells. However, its function in pancreatic β-cells remains unknown. The present study aimed to elucidate the function of DGKζ in pancreatic β-cells. The expression of DGKζ was detected in the β-cell line MIN6B and mouse pancreatic islets and in the cytoplasmic fraction from MIN6B cells. The knockdown of DGKζ with siRNA significantly decreased glucose-induced insulin secretion in MIN6B cells. The induction of DGKζ expression in MIN6CEon1 cells with a doxycycline-inducible stable expression system significantly increased glucose-induced insulin secretion. In contrast, glucose-induced insulin secretion was not changed when a kinase-dead DGKζ mutant (G356D) was overexpressed in MIN6CEon1 cells, indicating that a mechanism dependent on its kinase activity mediates the facilitatory effect of DGKζ on glucose-induced insulin secretion. Additionally, we revealed that DGKζ overexpression exhibited no effect on cell cycle of MIN6 cells. These results suggest that DGKζ plays a facilitatory role in insulin secretion in pancreatic β-cells.

A dissociated glucocorticoid receptor modulator mitigates glucolipotoxicity in the endocrine pancreas and peripheral tissues: Preclinical data from a mouse model of diet-induced type 2 diabetes.

Type 2 diabetes (T2D) is a prevalent metabolic disease linked to obesity and metabolic syndrome (MS). The glucolipotoxic environment (GLT) impacts tissues causing low-grade inflammation, insulin resistance and the gradual loss of pancreatic β-cell function, leading to hyperglycemia. We have previously shown that Compound A (CpdA), a plant-derived dissociative glucocorticoid receptor-modulator with inflammation-suppressive activity, displays protective effects on β-cells in type 1 diabetes murine models. This study aimed to evaluate whether the administration of CpdA can attenuate GLT effects and improve pathophysiological parameters in a murine model of T2D/MS. Eight-week-old male C57BL/6NCrl mice were fed either a standard chow diet or a high-fat/high-sucrose diet (HFHS) for 15weeks. From week 5 of feeding, each group received i.p. injections of CpdA (2.5μg/g) or vehicle three times a week. We also examined CpdA in vitro effect against GLT using the insulinoma cell line INS-1E and naïve isolated mouse islets. CpdA administration in HFHS fed mice improved glucose homeostasis and insulin sensitivity with no apparent side effects. CpdA treatment also preserved pancreatic islet architecture and insulin expression, while reducing hepatic steatosis and visceral adipose tissue inflammation induced by HFHS diet. In vitro assays in INS-1E cells and naïve isolated mouse islets demonstrated that CpdA counteracted GLT-induced inhibition of glucose-stimulated insulin secretion and supported the expression of key β-cell identity genes under GLT conditions. These findings highlight the potential protective effect of CpdA in preserving β-cell functionality and peripheral tissue physiology in the context of T2D/MS.

Baihu Jia Renshen Decoction may improve skeletal muscle and adipose tissue functions of type I diabetic rats by affecting pancreatic β-cell function.

Baihu Jia Renshen Decoction (BJRD) is used for diabetes mellitus (DM) management in clinics. To elucidate the potential mechanism of BJRD in treating type 1 DM (T1DM). T1DM models were established via intraperitoneal injection of streptozotocin (STZ). Rats were subsequently randomly divided into the normal control (NC), model (MOD), insulin (INS), INS + BJRD-medium dose (MID), and INS + BJRD-high dose (HIGH) groups. The rats' body weight was measured. Transcriptome sequencing was performed to detect differentially expressed genes (DEGs) in the muscle and adipose tissues. Quantitative real-time polymerase chain reaction was utilized to verify the DEG levels. Body weights of MOD, INS, MID, and HIGH groups were significantly reduced as compared to those of NC group. Compared with NC group, MOD group showed significant Hspa1b and Notch3 downregulation and Camkk2 level elevation. Compared with MOD group, INS group showed further downregulation of the Hspa1b level, whereas MID group exhibited an increase. The Camkk2 levels in INS, MID, and HIGH groups were further reduced. The Notch3 levels did not significantly change in INS and MID groups, whereas that of HIGH group increased. Additionally, compared with NC group, MOD group demonstrated upregulation of the Myl1, Mylpf, Acacb, and Pygm levels and downregulation of Fasn level. Compared with MOD group, Myl1, Mylpf, and Pygm levels in INS, MID, and HIGH groups were down-regulated, whereas Fasn and Acacb levels were up-regulated. BJRD may influence pancreatic β-cell function, thereby enhancing the function of the skeletal muscle and adipose tissues in a T1DM rat model.

Effects of FGFR2b-ligand signaling on pancreatic branching morphogenesis and postnatal islet function.

Pancreatic development is a complex process vital for maintaining metabolic balance, requiring intricate interactions among different cell types and signaling pathways. Fibroblast growth factor receptors 2b (FGFR2b)-ligands signaling from adjacent mesenchymal cells is crucial in initiating pancreatic development and differentiating exocrine and endocrine cells through a paracrine mechanism. However, the precise critical time window that affects pancreatic development remains unclear. To explore the roles of FGFR2b-ligands and identify the narrow window of time during which FGFR2b-ligand signaling affects pancreatic development, we used an inducible mouse model to control the expression of soluble dominant-negative FGFR2b (sFGFR2b) at various stages of pancreatic development. Our findings revealed a significant effect of FGFR2b-ligand signaling on epithelial morphology, lumen formation, and pancreatic branching during primary and secondary transition stages. Additionally, sFGFR2b expression reduced the number of Pdx1+ progenitor cells and altered the pancreatic islet structure. Furthermore, we examined the effect of mutation in FGF10, an FGFR2b ligand, on embryonic pancreatic β-cell function. FGF10 null mutant embryos exhibited reduced pancreatic size and a decrease number of islet-like structure. Although neonatal mice with haploinsufficiency for FGF10 exhibited abnormal glucose tolerance test results, indicating a potential diabetes predisposition, these abnormalities normalized with age, aligning with observations in wild type mice. Our study underscores the critical role of FGFR2b-ligand signaling in pancreatic development and postnatal islet function, offering insights into potential therapeutic targets for pancreatic disorders.

The Causal Role of Ectopic Fat Deposition in the Pathogenesis of Metabolic Syndrome.

Consuming a "modern" Western diet and overnutrition may increase insulin secretion. Additionally, nutrition-mediated hyperinsulinemia is a major driver of ectopic fat deposition. The global prevalence of metabolic syndrome is high and growing. Within this context, people with congenital lipodystrophy often experience a severe form of metabolic syndrome. Evidence is increasingly supporting that subtle partial lipodystrophy plays an important role in the development of metabolic syndrome in the general population. In individuals in the general population with subtle partial lipodystrophy, as well as in those with congenital lipodystrophy, the subcutaneous adipose tissues are unable to accommodate surplus energy intake. In both conditions, (excess) fat is directed toward the liver, pancreas, and muscles, where it is deposited as ectopic fat, as this fat can no longer be stored in the "safe" subcutaneous fat depots. Ectopic fat depositions cause insulin resistance in the liver and muscles, as well as β-cell dysfunction in the pancreas. Support of a direct pathological role of ectopic fat deposition in this condition is further provided by the rapid normalization of hepatic insulin sensitivity and improvement in pancreatic β-cell function after marked reductions in ectopic fat depositions. Thus, ectopic fat deposition in the liver, pancreas, and muscles may play a causal role in the pathogenesis of metabolic syndrome even in the general population. As such, the prevention of ectopic fat deposition may reduce the risk of metabolic syndrome and mitigate its effects.

Chloroquine-induced proinsulin misfolding in the endoplasmic reticulum underlies the attenuation of mature insulin synthesis.

Chloroquine (CQ), initially introduced for the clinical treatment of malaria, has subsequently been found to exhibit beneficial effects in combating diabetes mellitus. The anti-hyperglycemic properties of chloroquine may be attributed to its anti-inflammatory response and its ability to activate the insulin signaling pathway. However, both animal and clinical studies have yielded mixed results. Moreover, the impact of chloroquine on pancreatic β-cells, the key player of glycemic control, was not known. To fill this knowledge gap, we investigated the effects of chloroquine on pancreatic β-cell functions. Our findings revealed that while chloroquine did not alter proinsulin expression, it interfered with the conversion of proinsulin to insulin, resulting in reduced insulin levels. Using multiple independent approaches, we further showed that chloroquine disrupted proinsulin oxidative folding in the endoplasmic reticulum (ER) and impaired proinsulin trafficking from ER to Golgi, leading to ER stress and decreased insulin production. Notably, the elevated ER stress observed in chloroquine-treated β-cells was reversed upon knockout of insulin genes, indicating that chloroquine-induced β-cell ER stress primarily through the accumulation of misfolded proinsulin, rather than directly affecting ER homeostasis. Further investigation into the mechanisms underlying chloroquine-induced proinsulin misfolding revealed that the accumulation of misfolded proinsulin was not caused by autophagy inhibition or the alkaline pH of chloroquine. Instead, it was primarily due to the disruption of the interaction between proinsulin and protein disulfide isomerase (PDI). Our findings unveiled new mechanisms of chloroquine treatment and raised important safety considerations regarding the use of chloroquine in diabetes treatment.

Autophagy modulators in type 2 diabetes: A new perspective.

Type 2 diabetes (T2D) is a chronic metabolic disorder caused by defective insulin signaling, insulin resistance, and impairment of insulin secretion. Autophagy is a conserved lysosomal-dependent catabolic cellular pathway involved in the pathogenesis of T2D and its complications. Basal autophagy regulates pancreatic β-cell function by enhancing insulin release and peripheral insulin sensitivity. Therefore, defective autophagy is associated with impairment of pancreatic β-cell function and the development of insulin rersistance (IR). However, over-activated autophagy increases apoptosis of pancreatic β-cells leading to pancreatic β-cell dysfunction. Hence, autophagy plays a double-edged sword role in T2D. Therefore, the use of autophagy modulators including inhibitors and activators may affect the pathogenesis of T2D. Hence, this review aims to clarify the potential role of autophagy inhibitors and activators in T2D.

Development of MXene Composite Nanofiber-Based 3D Culture System for the Efficient Generation of MSC-Derived Functional Pancreatic β-Cells.

Pancreatic β-cell transplantation is an effective approach for the therapeutic treatment of type I diabetes. However, it has limitations due to the lack of human cadaveric pancreas donors. Stem cells provide an alternative source for the generation of surrogate pancreatic β-cells. Nonetheless, its clinical utility is restricted due to the unavailability of a robust culture system for the generation of large quantities of insulin-responsive pancreatic β-cells. In this study, we fabricated an MXene composite nanofibrous scaffold (PCL 25_Ti2C 5 nanofiber) for the development of a three-dimensional (3D) culture system that can enhance the proliferation and differentiation of stem cell-derived pancreatic β-cells. The fabricated MXene composite nanofibers exhibited a porous nanostructure and increased hydrophilicity due to a large number of hydrophilic functional groups. We assessed the biocompatibility and differentiation potential of human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) on a fabricated MXene composite nanofibrous scaffold. MXene composite nanofibers significantly upregulated key pancreatic β-cell markers including PDX-1, MAFA, Insulin, Nkx6.1, and Nkx2.2 and also showed increased production and secretion of insulin in response to glucose stimulation when compared to control (PCL 25 nanofiber), suggesting enhanced differentiation of hWJ-MSCs into functional pancreatic β-cells. Overall, the results suggest that MXene nanofiber-based cell therapy has therapeutic potential for diabetes treatment.

Relationship between metabolomics of T2DM patients and the anti-diabetic effects of Phellodendri Chinensis Cortex-Anemarrhenae Rhizoma herb pair in mice

Ethnopharmacological relevanceType 2 diabetes mellitus (T2DM) poses significant threats to public health. In Traditional Chinese Medicine (TCM), the Phellodendri Chinensis Cortex-Anemarrhenae Rhizoma (PCC/AR) herb pair has long been used for T2DM treatment, although its specific anti-diabetic mechanisms remain unclear. Aim of the studyThis study aimed to elucidate the relationship between metabolomics of T2DM patients and the anti-diabetic effects of PCC/AR herb pair in mice through clinical metabolomics and both in vitro and in vivo experiments. Materials and methodsIn this study, a T2DM mouse model was established via high-fat feeding (HFD) and streptozotocin (STZ) injection. The effects of PCC/AR on blood glucose, lipid metabolism, and inflammatory markers were evaluated. High-performance liquid chromatography-mass spectrometry (HPLC-MS) was performed for metabolomics analysis of T2DM patients. ResultsSerum metabolomics analysis identified significant alterations in metabolites linked to the biosynthesis of unsaturated fatty acids and purine metabolism in T2DM patients, with elevated 2-hydroxyvaleric acid (2HB) levels. In T2DM mice, PCC/AR intervention normalized FBG, GHbA1c, TC, TG, LDL-C, HDL-C, TNF-α and IL-1β levels, while improving insulin sensitivity and pancreatic β-cell function in T2DM mice. Notably, PCC/AR reduced key enzymes in gluconeogenesis and fatty acid synthesis, PEPCK and ACC1. ConclusionPCC/AR herb pair exerts an anti-diabetes effect in T2DM mice by regulating 2HB through ACC1 inhibition, thereby reducing FFA and TG synthesis. Additionally, PCC/AR may also exert its effects by modulating glucose and lipid metabolism and reducing inflammation. These results support further investigation into the PCC/AR herb pair as a complementary therapy for T2DM.

HM-Chromanone Alleviates Hyperglycemia by Activating AMPK and PI3K/AKT Pathways in Mice Fed a High-Fat Diet.

We investigated potential antihyperglycemic effects of HM-chromanone (HMC), a homoisoflavonoid isolated from Portulaca oleracea, in mice fed a high-fat diet (HFD). Five-week-old male C57BL/6J mice (n = 24) were divided into three groups: controls, mice fed an HFD (11 weeks), and HFD-fed mice receiving HMC supplementation (8 weeks). Various analyses assessed liver and skeletal muscle proteins, pancreatic β-cell histology, blood glucose and HbA1c levels, and homeostatic index of insulin resistance (HOMA-IR). HMC supplementation significantly reduced fasting blood glucose and postprandial blood glucose levels in HFD-fed mice. HbA1c and serum insulin levels reduced significantly, and HOMA-IR improved. Compensatory β-cell hyperplasia was reduced, and pancreatic β-cell function improved. AMP-activated protein kinase (AMPK) was significantly activated in skeletal muscle and liver tissues. IRS-1tyr612 expression increased significantly. PI3K activation and Akt phosphorylation in skeletal muscles improved insulin signaling. Forkhead box protein O1 phosphorylation increased through hepatic AMPK activation. Phosphoenolpyruvate carboxykinase and glucose-6-phosphatase expression was inhibited. Glycogen synthase kinase 3β phosphorylation increased. HMC supplementation alleviated hyperglycemia by activating the AMPK and PI3K/Akt pathways in skeletal muscles and the AMPK pathway in the liver of HFD-fed mice.

The immune checkpoint molecule B7-H4 regulates β-cell mass and insulin secretion by modulating cholesterol metabolism through Stat5 signalling

BackgroundB7-H4 (B7S1, B7x, VTCN1) is an important immune checkpoint molecule that maintains immune homeostasis and is also expressed in pancreatic β cells. The polymorphism of B7-H4 influences the prevalence of Type 2 diabetes (T2D), suggesting a potential role of B7-H4 in the physiological function of pancreatic β cells and the pathogenesis of T2D. Methodsβ-cell-specific B7-H4 knockout mice (B7-H4 cKO mice) and their wild-type littermates were used to investigate the in vivo effects of B7-H4 on pancreatic β-cell morphology and function. AAV2/8-ins2-B7H4 and a control virus were infused via the pancreatic intraduct into high-fat diet (HFD)-treated mice to elucidate the therapeutic effect of B7-H4. RNA sequencing was conducted on primary islets. A Luminex assay was used to quantify cytokine changes in B7-H4 cKO mice. Electron microscopy imaging was used to observe insulin secretory vesicles in pancreatic β cells. ResultsLesion of B7-H4 in β cells results in glucose intolerance due to reduced β-cell mass and deficient insulin secretion, whereas overexpression of B7-H4 in β cells ameliorates glucose intolerance in HFD-fed mice. Mechanistically, B7-H4 deficiency activates signal transducer and activator of transcription 5 (Stat5) signalling, which inhibits the expression of apolipoprotein F (Apof), leading to reduced cholesterol efflux and accumulated cholesterol in β cells, thereby impairing insulin processing and secretion. Overexpression of Apof in β cells or intraperitoneal injection of a Stat5 inhibitor reverses the metabolic phenotype and insulin secretion deficiency in B7-H4 cKO mice. ConclusionsOur study demonstrated that B7-H4 plays an important role in regulating β-cell mass and insulin secretion, which may shed new light on the development of novel strategies for T2D treatment.

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.

Comparison of protective effects of teneligliptin and luseogliflozin on pancreatic β-cell function: randomized, parallel-group, multicenter, open-label study (SECRETE-I study).

The aim of this study is to directly compare the effects of SGLT2 inhibitors and DPP-4 inhibitors on β-cell function in patients with type 2 diabetes. We conducted a 26-week, randomized, open-label, parallel-group study, including a 1-2 week drug washout period, in patients with type 2 diabetes with HbA1c ≥7.0% and <9.0% and BMI ≥20 kg/m2 despite treatment with a drug naïve or other than DPP-4 inhibitors or SGLT2 inhibitors. A total of 103 subjects were randomly assigned to receive once daily oral luseogliflozin (L) or teneligliptin (T). The primary endpoint was the effect of L vs. T on the change in logarithmus naturalis (Ln) disposition index (DI) (DI 0-120min; combining measures of insulin secretion and sensitivity) from baseline to week 25-26 (post intervention), which was calculated by conducting an oral glucose tolerance test. Ln DI 0-120min were improved in both groups: -0.46 ± 0.68 to -0.20 ± 0.59 (p=0.03) in L group and -0.26 ± 0.60 to -0.05 ± 0.62 (p=0.01) in T group. The change in Ln serum proinsulin/C-peptide ratio, a marker of β-cell dysfunction, was reduced in L group (1.63 ± 0.63 to 1.56 ± 0.68, p=0.16), but rather increased in T group (1.70 ± 0.75 to 1.90 ± 0.51, p=0.01), with significant difference between the two groups (-0.27; p=0.004). Improvement of disposition index in subjects with obese type 2 diabetes was comparable between luseogliflozin and teneligliptin. On the other hand, it is likely that alleviation of β-cell dysfunction is more effective with luseogliflozin compared to tenegliptin. https://rctportal.niph.go.jp/en, identifier jRCTs061190008.

Pancreatic β-Cells, Diabetes and Autophagy.

Pancreatic β-cells play a critical role in regulating plasma insulin levels and glucose metabolism balance, with their dysfunction being a key factor in the progression of diabetes. This review aims to explore the role of autophagy, a vital cellular self-maintenance process, in preserving pancreatic β-cell functionality and its implications in diabetes pathogenesis. We examine the current literature on the role of autophagy in β-cells, highlighting its function in maintaining cell structure, quantity, and function. The review also discusses the effects of both excessive and insufficient autophagy on β-cell dysfunction and glucose metabolism imbalance. Furthermore, we discuss potential therapeutic agents that modulate the autophagy pathway to influence β-cell function, providing insights into therapeutic strategies for diabetes management. Autophagy acts as a self-protective mechanism within pancreatic β-cells, clearing damaged organelles and proteins to maintain cellular stability. Abnormal autophagy activity, either overactive or deficient, can disrupt β-cell function and glucose regulation, contributing to diabetes progression. Autophagy plays a pivotal role in maintaining pancreatic β-cell function, and its dysregulation is implicated in the development of diabetes. Targeting the autophagy pathway offers potential therapeutic strategies for diabetes management, with agents that modulate autophagy showing promise in preserving β-cell function.

Terazosin, a repurposed GPR119 agonist, ameliorates mitophagy and β-cell function in NAFPD by inhibiting MST1-Foxo3a signalling pathway.

GPR119 agonists are being developed to safeguard the function of pancreatic β-cells, especially in the context of non-alcoholic fatty pancreas disease (NAFPD) that is closely associated with β-cell dysfunction. This study aims to employ a drug repurposing strategy to screen GPR119 agonists and explore their potential molecular mechanisms for enhancing β-cell function in the context of NAFPD. MIN6 cells were stimulated with palmitic acid (PA), and a NAFPD model was established in GPR119-/- mice fed with a high-fat diet (HFD). Terazosin, identified through screening, was utilized to assess its impact on enhancing β-cell function via the MST1-Foxo3a pathway and mitophagy. Terazosin selectively activated GPR119, leading to increased cAMP and ATP synthesis, consequently enhancing insulin secretion. Terazosin administration improved high blood glucose, obesity, and impaired pancreatic β-cell function in NAFPD mice. It inhibited the upregulation of MST1-Foxo3a expression in pancreatic tissue and enhanced damaged mitophagy clearance, restoring autophagic flux, and improving mitochondrial quantity and structure in β-cells. Nevertheless, GPR119 deficiency negated the positive impact of terazosin on pancreatic β-cell function in NAFPD mice and abolished its inhibitory effect on the MST1-Foxo3a pathway. Terazosin activates GPR119 on the surface of pancreatic β-cells, enhancing mitophagy and alleviating β-cell dysfunction in the context of NAFPD by suppressing the MST1-Foxo3a signalling pathway. Terazosin could be considered a priority treatment for patients with concomitant NAFPD and hypertension.