Islet Β-cell Apoptosis Research Articles

Taurine alleviates high-fat-high-glucose-induced pancreatic islet β-cell oxidative stress and apoptosis in rat

The effect of taurine (TAU) as a specific regulatory mediator on pancreatic function in obese rats induced by a high-fat-high-glucose (HFHG) diet was investigated. We fed male Sprague-Dawley rats under different conditions, namely the control, HFHG, TAU, and HFHG + TAU treatment groups for 4 months. Compared with the HFHG group, TAU supplementation significantly reduced malondialdehyde levels and increased superoxide dismutase, total antioxidant capacity, and glutathione levels in the rat pancreas. In addition, TAU significantly decreased the level of reactive oxygen species, and markedly increased the activity of heme oxygenase 1 (HO-1), Kelch-like ECH-associated protein 1 (KEAP-1), and nuclear factor erythrocyte-2-related factor 2 (Nrf2) in the rat pancreas. Notably, HFHG diet could induce pancreatic injury in the rats through the Nrf2/HO-1 signaling pathway and activate the mitochondrial channel-mediated apoptotic signaling pathway. The addition of TAU significantly improved the pancreatic tissue injury induced by the HFHG diet in the rats and reduced the protein expression of Caspase-3, Cleaved-caspase-3, Caspase-9 and Bcl-2 associated protein X (BAX), and increased the protein expression of B-cell lymphoma-2 (Bcl-2). In conclusion, this experiment confirmed that TAU could alleviate the oxidative stress and apoptosis induced by the HFHG diet in rat pancreatic β-cells.

Downregulation of mTORC1 and Mcl-1 by lipid-oversupply contributes to islet β-cell apoptosis and dysfunction

Pancreatic β-cell apoptosis is a key feature of diabetes and can be induced by chronic exposure to saturated fatty acids (FAs). However, the underlying mechanisms remain poorly understood. We presently evaluated the role of Mcl-1 and mTOR in mice fed with high-fat-diet (HFD) and β-cells exposed to the overloaded palmitic acid (PA). Compared with normal-chow-diet (NCD)-fed mice, HFD group showed impaired glucose tolerance after two months. Along with the diabetes progression, pancreatic islets first became hypertrophic and then atrophic, the ratio of β-cell:α-cell increased in the islets of four months HFD-fed mice while decreased after six months. This process was accompanied by significantly increased β-cell apoptosis and AMPK activity, and decreased Mcl-1 expression and mTOR activity. Consistently, glucose-induced insulin secretion dropped. In terms of mechanism, PA with lipotoxic dose could activate AMPK, which in turn inhibited ERK-stimulated Mcl-1Thr163 phosphorylation. Meanwhile, AMPK blocked Akt activity to release Akt inhibition on GSK3β, followed by GSK3β-initiated Mcl-1Ser159 phosphorylation. The context of Mcl-1 phosphorylation finally led to its degradation by ubiquitination. Also, AMPK inhibited the activity of mTORC1, resulting in a lower level of Mcl-1. Suppression of mTORC1 activity and Mcl-1 expression positively related to β-cell failure. Alteration of Mcl-1 or mTOR expression rendered different tolerance of β-cell to different dose of PA. In conclusion, lipid oversupply-induced dual modulation of mTORC1 and Mcl-1 finally led to β-cell apoptosis and impaired insulin secretion. The study may help further understand the pathogenesis of β-cell dysfunction in case of dyslipidemia, and provide promising therapeutic targets for diabetes.

The therapeutic mechanism of Yuye decoctionon type 2 diabetes mellitusbasedon network pharmacology and experimental verification.

Yuye decoction (YYD) has been widely used as a folk Chinese herbal formula in clinical treatment of type 2 diabetes mellitus(T2DM) for many years. However, its mechanism is still unclear. The aim of this study was to explore the potential mechanism of YYD against T2DM initially by UHPLC-MS/MS combining with network pharmacology, molecular docking techniques and experimental validation. The main ingredients in the water extract of YYD were initially identified using UHPLC-MS/MS analysis. Combined with network pharmacology and molecular docking techniques, the YYD key compounds-core targets-key signaling pathways network was constructed and the binding activity of key components to core targets was validated. The T2DM rat model was induced by Streptozotocin combined with high glucose and high fat diets. The apoptosis cell model of mouse islet β-cell of Min6 was induced by high-glucose and palmitic acid. Histopathological and immunofluorescence satining were used to evaluate pancreatic islet β-cell function and apoptosis in rats. Min6 cell viability and apoptosis ratio were evaluated by CCK-8 and TUNEL staining. The predicted targets and pathways were validated by experiments in vitro and in vivo. The 56 compounds from YYD were identified by UHPLC-MS/MS. The potential targets of the above compounds were predicted by online compound target database, among of which 362 targets were associated with T2DM. Protein-protein interaction analysis identified the main targets such as SRC, MAPK1, PIK3R1, AKT1, HRAS and HSP90AA1, which were considered as the therapeutic targets of YYD on against T2DM. Functional enrichment analysis revealed that PI3K/AKT, FoxO and apoptosis signaling pathways were significantly enriched. Molecular docking results showed that compounds of monolinolein, neomangiferin, mangiferin, pelargonidin-3-O-glucoside and acacetin from YYD had high binding activities to PIK3R1, AKT1, Sirt1 and FoxO1. Therefore, PI3K/AKT1, Sirt1/FoxO1 and apoptotic signaling pathways were considered as predicted targets for experimental validation study. Animal experiments showed that YYD reduced blood glucose levels, improved pancreatic dysfunction and pancreatic islet β-cells apoptosis in T2DM rats which contributed to the activation of AKT1 and FoxO1 and their related signaling molecules. These results were confirmed in Min6 cell model induced by high-glucose and palmitic acid. In summary, this study systematically visualized the possible therapeutic effects and mechanisms of YYD on T2DM through the network pharmacology approach and experimental study. The results indicated that YYD could prevent pancreatic islet dysfunction and reverse islet of β-cells apoptosis possibly via PI3K/AKT1, Sirt1/FoxO1 signaling pathways.

Taurine reduces apoptosis mediated by endoplasmic reticulum stress in islet β-cells induced by high-fat and -glucose diets.

Poor eating habits, especially high-fat and -glucose diets intake, can lead to endoplasmic reticulum (ER) stress in islet β-cells, insulin resistance, and islet β-cell dysfunction and cause islet β-cell apoptosis, which leads to type 2 diabetes mellitus (T2DM). Taurine is a crucial amino acid in the human body. In this study, we aimed to explore the mechanism through which taurine reduces glycolipid toxicity. INS-1 islet β-cell lines were cultured with a high concentration of fat and glucose. SD rats were fed a high-fat and -glucose diet. MTS, Transmission electron microscopy, Flow cytometry, Hematoxylin-eosin, TUNEL, Western blotting analysis and other methods were used to detect relevant indicators. The research found that taurine increases the cell activity, reduces the apoptosis rate, alleviates the structural changes of ER under high-fat and -glucose exposure models. In addition, taurine improves blood lipid content and islets pathological changes, regulates the relative protein expression in ER stress and apoptosis, increases the insulin sensitivity index (HOMA-IS), and reduces the insulin resistance index (HOMAC-IR) of SD rats fed with a high-fat and -glucose diet.

TFP5 attenuates cyclin-dependent kinase 5-mediated islet β-cell damage in diabetes.

Islet β-cell damage and dysfunction represent the pathophysiological basis of diabetes. Excessive activation of cyclin-dependent kinase 5 (CDK5) is involved in the pathogenesis of type 2 diabetes mellitus (T2DM), although the exact mechanism remains unclear. Therefore, this study investigated the role of a CDK5 inhibitor (TFP5) in islet β-cell damage under diabetic conditions by regulating the expression of CDK5 in vitro and in vivo. CDK5 was upregulated under high glucose conditions in vivo and in vitro, which resulted in inflammation, oxidative stress, and apoptosis of islet β-cells, thereby decreasing insulin secretion. However, TFP5 treatment inhibited the overexpression of CDK5; reduced the inflammatory response, oxidative stress, and apoptosis of islet β cells; and restored insulin secretion. In conclusion, CDK5 is involved in islet β-cell damage under high glucose conditions, and TFP5 may represent a promising candidate for the development of treatments for T2DM.

MiR-124 is upregulated in diabetic mice and inhibits proliferation and promotes apoptosis of high-glucose-induced β-cells by targeting EZH2.

Diabetes is a chronic metabolic disease, and a variety of miRNA are involved in the occurrence and development of diabetes. In clinical studies, miR-124 is highly expressed in the serum of patients with diabetes and in pancreatic islet β-cells. However, few reports exist concerning the role and mechanism of action of miR-124 in diabetes. To investigate the expression of miR-124 in diabetic mice and the potential mechanism of action in islet β-cells. The expression levels of miR-124 and enhancer of zeste homolog 2 (EZH2) in pancreatic tissues of diabetic mice were detected. The targeted relationship between miR-124 and EZH2 was predicted by Targetscan software and verified by a double luciferase reporter assay. Mouse islet β-cells Min6 were grown in a high glucose (HG) medium to mimic a diabetes model. The insulin secretion, proliferation, cell cycle and apoptosis of HG-induced Min6 cells were detected after interference of miR-124a and/or EZH2. The expression of miR-124 was upregulated and EZH2 was downregulated in the pancreatic tissue of diabetic mice compared with control mice, and the expression of miR-124 was negatively correlated with that of EZH2. miR-124 was highly expressed in HG-induced Min6 cells. Inhibition of miR-124 promoted insulin secretion and cell proliferation, induced the transition from the G0/G1 phase to the S phase of the cell cycle, and inhibited cell apoptosis in HG-induced Min6 cells. EZH2 was one of the targets of miR-124. Co-transfection of miR-124 inhibitor and siRNA-EZH2 could reverse the effects of the miR-124 inhibitor in HG-induced Min6 cells. miR-124 is highly expressed in diabetic mice and HG-induced Min6 cells and regulates insulin secretion, proliferation and apoptosis of islet β-cells by targeting EZH2.

Circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis in obesity

Pancreatic β-cell compensation is a major mechanism in delaying T2DM progression. Here we report the abnormal high expression of circGlis3 in islets of male mice with obesity and serum of people with obesity. Increasing circGlis3 is regulated by Quaking (QKI)-mediated splicing circularization. circGlis3 overexpression enhances insulin secretion and inhibits obesity-induced apoptosis in vitro and in vivo. Mechanistically, circGlis3 promotes insulin secretion by up-regulating NeuroD1 and Creb1 via sponging miR-124-3p and decreases apoptosis via interacting with the pro-apoptotic factor SCOTIN. The RNA binding protein FUS recruits circGlis3 and collectively assemble abnormal stable cytoplasmic stress granules (SG) in response to cellular stress. These findings highlight a physiological role for circRNAs in β-cell compensation and indicate that modulation of circGlis3 expression may represent a potential strategy to prevent β-cell dysfunction and apoptosis after obesity.

N-3 PUFA Deficiency Aggravates Streptozotocin-Induced Pancreatic Injury in Mice but Dietary Supplementation with DHA/EPA Protects the Pancreas via Suppressing Inflammation, Oxidative Stress and Apoptosis.

It has been reported that dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential for the preservation of functional β-cell mass. However, the effect of dietary n-3 PUFA deficiency on pancreatic injury and whether the supplementation of n-3 PUFA could prevent the development of pancreatic injury are still not clear. In the present study, an n-3 PUFA deficiency mouse model was established by feeding them with n-3 PUFA deficiency diets for 30 days. Results showed that n-3 PUFA deficiency aggravated streptozotocin (STZ)-induced pancreas injury by reducing the insulin level by 18.21% and the HOMA β-cell indices by 31.13% and the area of islet by 52.58% compared with the STZ group. Moreover, pre-intervention with DHA and EPA for 15 days could alleviate STZ-induced pancreas damage by increasing the insulin level by 55.26% and 44.33%, the HOMA β-cell indices by 118.81% and 157.26% and reversed the area of islet by 196.75% and 205.57% compared to the n-3 Def group, and the effects were significant compared to γ-linolenic acid (GLA) and alpha-linolenic acid (ALA) treatment. The possible underlying mechanisms indicated that EPA and DHA significantly reduced the ration of n-6 PUFA to n-3 PUFA and then inhibited oxidative stress, inflammation and islet β-cell apoptosis levels in pancreas tissue. The results might provide insights into the prevention and alleviation of pancreas injury by dietary intervention with PUFAs and provide a theoretical basis for their application in functional foods.

∆nFGF1 Protects β-Cells against High Glucose-Induced Apoptosis via the AMPK/SIRT1/PGC-1α Axis.

Long-term exposure to high glucose leads to β-cell dysfunction and death. Fibroblast growth factor 1 (FGF1) has emerged as a promising diabetes treatment, but its pharmaceutical role and mechanism against glucolipotoxicity-induced β-cell dysfunction remain uncharacterized. Wild-type FGF1 (FGF1WT) may exhibit in vivo mitogenicity, but deletion of N-terminal residues 1-27 gives a nonmitogenic variant, ∆nFGF1, that does not promote cell proliferation and still retains the metabolic activity of FGF1WT. To investigate the roles of ∆nFGF1 on glucose regulation and potential islet β-cell dysfunction, db/db mice were used as a model of type 2 diabetes. The results showed that insulin secretion and apoptosis of islet β-cells were dramatically improved in ∆nFGF1-treated db/db mice. To further test the effects of ∆nFGF1 treatment, pancreatic β-cell (MIN6) cells were exposed to a mixture of palmitic acid (PA) and high glucose (HG) to mimic glucolipotoxic conditions in vitro. Treatment with ∆nFGF1 significantly inhibited glucolipotoxicity-induced apoptosis. Mechanistically, ∆nFGF1 exerts a protective effect on β-cells via activation of the AMPK/SIRT1/PGC-1α signaling pathway. These findings demonstrate that ∆nFGF1 protects pancreatic β-cells against glucolipotoxicity-induced dysfunction and apoptosis.

Decreased Sirt3 contributes to cyclic production of reactive oxygen species and islet β-cell apoptosis in high glucose conditions.

Reactive oxygen species (ROS) plays a vital role in the apoptosis of islet β-cells in type 2 diabetes mellitus (T2DM). Sirt3 (Sirtuin 3, a deacetylase) and FoxO1 (a transcription factor) might be involved in ROS production. This study was to investigate mechanism of ROS production and β-cell apoptosis in T2DM. Oxidative stress and apoptosis in islets of db/db mice and high glucose cultured β-cells were observed by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay and western blotting. Then, H2O2 was used to ascertain the effect of ROS on the expression of Sirt3. Meanwhile, FoxO1, antioxidant enzymes - catalase (CAT) and manganese superoxide dismutase (MnSOD) and β-cell apoptosis were also determined by western blotting. Finally, Sirt3 was knocked down to evaluate the effect on oxidative stress and apoptosis of β-cells. Under high glucose environment, enhanced ROS made a decrease of Sirt3 expression, which increased acetylation of FoxO1, thus reduced the expression of its target proteins -MnSOD and CAT, and further significantly increased ROS levels. Increased ROS finally led to the apoptosis of β-cells. Down-regulation of Sirt3 plays an important role in the cyclic production of ROS and β-cell apoptosis. Targeting Sirt3 may be favorable for the treatment of T2DM.

Targeting Ceramides and Adiponectin Receptors in the Islet of Langerhans for Treating Diabetes.

Ceramides belong to the sphingolipid family and represent the central hub of the sphingolipid network. In obesity, oversupply of saturated fatty acids including palmitate raises ceramide levels which can be detrimental to cells. Elevated ceramides can cause insulin resistance, endoplasmic reticulum stress, and mitochondrial dysfunction. Studies over the last few decades have highlighted the role played by ceramides in pancreatic islet β-cell apoptosis, especially under glucolipotoxic and inflammatory conditions. This review focuses on ceramides and adiponectin receptor signaling, summarizing recent advancements in our understanding of their roles in islet β-cells and the discovery of zinc-dependent lipid hydrolase (ceramidase) activity of adiponectin receptors. The therapeutic potential of targeting these events to prevent islet β-cell loss for treating diabetes is discussed.

Polysaccharide from Hovenia dulcis (Guaizao) improves pancreatic injury and regulates liver glycometabolism to alleviate STZ-induced type 1 diabetes mellitus in rats

Hovenia dulcis is a traditional medicinal and edible plant and has a major geographical presence in China. In this study, a polysaccharide purified from H. dulcis (HDPs-2A) was found to ameliorate type 1 diabetes mellitus (T1DM) in streptozotocin-induced diabetic rat. HDPs-2A treatment resulted in significantly lower fasting blood glucose levels, but higher body weight, plasma insulin, and liver glycogen levels. Moreover, HDPs-2A improved dyslipidemia, pancreatic oxidative stress, and reduced serum pro-inflammatory factors. In addition, HDPs-2A up-regulated PDX-1, activated and up-regulated IRS2 expression, and regulated apoptosis and regeneration of islet β cells to recover islet β-cell function injury in TIDM rats. HDPs-2A also up-regulated the expression of pancreatic GK and GLUT2 to improve insulin secretion ability of islet β-cells, ultimately improving the glucose metabolism disorder of T1DM rats. Moreover, HDPs-2A significantly up-regulated the expression of GK and down-regulated the expression of G6Pase in liver to improve liver glycogen synthesis, inhibit liver gluconiogenesis, and improve liver glucose metabolism disorder of T1DM rats. In summary, the hypoglycemic mechanisms of HDPs-2A may include regulating the regeneration and apoptosis of islet β-cells and activating liver glycometabolism-related signaling pathways in T1DM rats.

Effect of sodium butyrate on glucose and lipid metabolism, insulin expression and apoptosis of β-cells in obese pregnant rats


 
 
 
 Purpose: To study the influence of sodium butyrate on the metabolism of lipid and glucose, insulin expression and apoptosis of β-cells in obese pregnant rats.
 Methods: Three groups of one hundred and twenty 4-week-old female C5BL/6J mice were used: control, high-fat diet and sodium butyrate groups. Insulin, triglycerides and total cholesterol were evaluated by enzyme-linked immunosorbent assay (ELISA). Insulin levels, as well as area and quality of islet β-cells were assessed using Image Pro Plus software. The number of DAPI-positive islet cells, positive expression of bcl-2 in each islet cell, and apoptosis of islet β-cells in each group were determined.
 Results: The expression levels of insulin in high-fat diet group and butyrate group were significantly reduced, relative to control, but insulin expression level in Na butyrate group increased, relative to high- fat diet mice (p < 0.01). The area and quality of islet β-cells in high-fat diet and sodium butyrate groups were markedly higher in sodium butyrate group than in high-fat diet group (p < 0.01). The bcl-2 expression in islet β-cells rose in mice given high-fat diet, relative to control and sodium butyrate groups (p < 0.01).
 Conclusion: Sodium butyrate facilitates glucose and lipid metabolism, but increases insulin expression, and effectively inhibits apoptosis of islet β-cells in obese pregnant mice. Thus, sodium butyrate may be useful in the prevention and treatment of metabolic disorders due to diabetes mellitus (DM).
 
 
 

Neu-P11 - a novel melatonin receptor agonist, could improve the features of type-2 diabetes mellitus in rats.

Melatonin (Mel) and its receptors are promising for glycaemic control in patients with type 2 diabetes mellitus (T2DM) and its complications, but there is significant heterogeneity among studies. This study aims to investigate the effects of Mel receptor agonist Neu-P11 on glucose metabolism, immunity, and islet function in T2DM rats. In this study, SD rats were treated with a high-fat diet and streptozotocin (STZ) to establish a T2DM model. The glucose oxidase method was used to measure blood glucose levels. Glucose and insulin tolerance tests were used to assess glucose metabolism. Haematoxylin-eosin staining was used to observe pancreatic tissue injury. The apoptosis of isletβ cells was analysed by TUNEL and insulin staining. Reactive oxygen species (ROS) levels and immune cell expression were analysed by flow cytometry. IF was used to analyse the activation of microglia. The immunoglobulins: IgA, IgG, IgM, tumour necrosis factorα (TNF-α), interleukins IL-10 and IL-1β, interferonγ (IFN-γ), C-peptide, and insulin levels were determined by ELISA. The expression of CD11b, CD86, cleaved caspase 3, p21, and P16 proteins were analysed by western blot. The results showed that the blood glucose level increased, insulin resistance occurred, spleen coefficient and ROS levels increased, humoral immunity in peripheral blood decreased, and inflammation increased in the model group compared to the control group. After Mel and Neu-P11 treatment, the blood glucose level decreased significantly, insulin sensitivity improved, spleen coefficient and ROS levels decreased, humoral immunity in peripheral blood was enhanced, and inflammation improved in T2DM rats. Brain functional analysis of T2DM rats showed that microglia cells were activated, TNF-α and IL-β levels were increased, and IL-10 levels were decreased. Mel and Neu-P11 treatment reversed these indexes. Functional analysis of islets in T2DM rats showed that islet structure inflammation was impaired, isletβ cells were apoptotic, p21 and p16 protein expressions were increased, and blood C-peptide and insulin were decreased. Mel and Neu-P11 treatment restored the function of pancreatic b cells and improved the damage of pancreatic tissue. Melatonin and its receptor Neu-P11 can reduce the blood glucose level, enhance humoral and cellular immunity, inhibit microglia activation and inflammation, and repair isletβ cell function, and this improve the characterization of T2DM-related diseases.

Evaluating the antidiabetic effects of R-verapamil in type 1 and type 2 diabetes mellitus mouse models.

The global incidence of diabetes mellitus (DM) is increasing. Types 1 and 2 DM are associated with declining β-cell function. Verapamil (50% S-verapamil and 50% R-verapamil) can treat DM by downregulating thioredoxin-interacting protein (TXNIP), which induces islet β-cell apoptosis. However, it may also induce cardiovascular side effects as S-verapamil is negatively inotropic. In contrast, R-verapamil only weakly induces adverse cardiac effects. In this study, we aimed to determine the antidiabetic efficacy and cardiovascular safety of R-verapamil. We examined R- and S-verapamil binding through in vitro studies. Streptozotocin-induced type 1 and db/db type 2 DM mouse models were used to assess the antidiabetic efficacy of verapamil. IL-6, blood glucose (BG), Txnip expression, and β-cells were evaluated in streptozotocin-induced diabetic mice, while body weight, BG, and serum insulin were measured in the db/db mice. In the type 1 DM study, 100 mg/kg/day R-verapamil and racemic verapamil lowered BG, downregulated Txnip expression, and reduced β-cell apoptosis. In the type 2 DM study, the optimal R-verapamil dosage was 60 mg/kg/day and it lowered BG and raised serum insulin. However, efficacy did not increase with R-verapamil dosage. R-verapamil combined with metformin/acarbose improved BG and serum insulin more effectively than metformin/acarbose alone or verapamil combined with acarbose. R-verapamil had weaker cardiovascular side effects than S-verapamil. R-verapamil was 9.0× and 3.4× less effective than S-verapamil at inhibiting atrial inotropy and ileal contractility, respectively. It was also 8.7× weaker than S-verapamil as an agonist of somatostatin receptor type 2 (SSTR2), inhibiting ileal neurogenic contraction. Hence, R-verapamil may be an optimal DM treatment as it is safe, improves glycemic control, and preserves β-cell function both as monotherapy and in combination with metformin or acarbose. R-Verapamil has potential for delaying or arresting DM progression and improving patients’ quality of life.

MiR-139-5p mediates the palmitate-induced inhibition of insulin secretion by targeting neuronal pentraxin 1 in INS-1 cells.

High fatty acid reduces insulin secretion in pancreatic β-cells and miR-139-5p is increased in diabetic pancreatic tissues and induces islet β-cell apoptosis. However, to date, there is no study exploring whether or not miR-139-5p is involved in high fatty acid-induced insulin secretion. In the present study, INS-1 cells were exposed to different concentrations (0.1, 0.2, and 0.4 mM) of palmitate for different time periods (12, 24, and 48 h). The expression levels of miR-139-5p and neuronal pentraxin 1 (NPTX1) were evaluated by real-time PCR and western blot analysis. The regulation of NPTX1 by miR-139-5p was examined by luciferase assay. Cell transfection was conducted using Lipo8000 or Lipofectamine RNAiMAX. Potassium or glucose-stimulated insulin secretion levels were used to verify the function of miR-139-5p or NPTX1 in insulin secretion. Insulin secretion levels were detected by radioimmunoassay. We found that miR-139-5p was increased in INS-1 cells stimulated with palmitate. In addition, miR-139-5p was also elevated in islets of high-fat diet-fed mice and db/db mice compared to those in islets of normal diet-fed mice and wild-type mice. Knockdown of miR-139-5p could reverse high fatty acid-induced insulin secretion defects in INS-1 cells. Furthermore, we demonstrated that NPTX1 is a target of miR-139-5p. miR-139-5p mediated palmitate-induced insulin secretion defects by targeting NPTX1. Moreover, palmitate treatment declined the expression of NPTX1 and the NPTX1 expression was also decreased in islets of high-fat diet-fed mice and db/db mice. Impaired NPTX1 expression is involved in fatty acid-induced insulin secretion defects. Collectively, our results illustrate that the induction of β-cell insulin secretion defects by fatty acids is mediated, at least in part, by miR-139-5p via downregulation of NPTX1 expression.

An Immediate and Long-Term Complication of COVID-19 May Be Type 2 Diabetes Mellitus: The Central Role of β-Cell Dysfunction, Apoptosis and Exploration of Possible Mechanisms.

The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was declared a pandemic by the WHO on 19 March 2020. This pandemic is associated with markedly elevated blood glucose levels and a remarkable degree of insulin resistance, which suggests pancreatic islet β-cell dysfunction or apoptosis and insulin’s inability to dispose of glucose into cellular tissues. Diabetes is known to be one of the top pre-existing co-morbidities associated with the severity of COVID-19 along with hypertension, cardiocerebrovascular disease, advanced age, male gender, and recently obesity. This review focuses on how COVID-19 may be responsible for the accelerated development of type 2 diabetes mellitus (T2DM) as one of its acute and suspected long-term complications. These observations implicate an active role of metabolic syndrome, systemic and tissue islet renin–angiotensin–aldosterone system, redox stress, inflammation, islet fibrosis, amyloid deposition along with β-cell dysfunction and apoptosis in those who develop T2DM. Utilizing light and electron microscopy in preclinical rodent models and human islets may help to better understand how COVID-19 accelerates islet and β-cell injury and remodeling to result in the long-term complications of T2DM.

Tectorigenin enhances PDX1 expression and protects pancreatic β-cells by activating ERK and reducing ER stress

Pancreas/duodenum homeobox protein 1 (PDX1) is an important transcription factor that regulates islet β-cell proliferation, differentiation, and function. Reduced expression of PDX1 is thought to contribute to β-cell loss and dysfunction in diabetes. Thus, promoting PDX1 expression can be an effective strategy to preserve β-cell mass and function. Previously, we established a PDX1 promoter-dependent luciferase system to screen agents that can promote PDX1 expression. Natural compound tectorigenin (TG) was identified as a promising candidate that could enhance the activity of the promoter for the PDX1 gene. In this study, we first demonstrated that TG could promote the expression of PDX1 in β-cells via activating extracellular signal-related kinase (ERK), as indicated by increased phosphorylation of ERK; this effect was observed under either normal or glucotoxic/lipotoxic conditions. We then found that TG could suppress induced apoptosis and improved the viability of β-cells under glucotoxicity and lipotoxicity by activation of ERK and reduction of reactive oxygen species and endoplasmic reticulum (ER) stress. These effects held true in vivo as well: prophylactic or therapeutic use of TG could obviously inhibit ER stress and decrease islet β-cell apoptosis in the pancreas of mice given a high-fat/high-sucrose diet (HFHSD), thus dramatically maintaining or restoring β-cell mass and islet size, respectively. Accordingly, both prophylactic and therapeutic use of TG improved HFHSD-impaired glucose metabolism in mice, as evidenced by ameliorating hyperglycemia and glucose intolerance. Taken together, TG, as an agent promoting PDX1 expression exhibits strong protective effects on islet β-cells both in vitro and in vivo.

Ligustilide alleviates the insulin resistance, lipid accumulation, and pathological injury with elevated phosphorylated AMPK level in rats with diabetes mellitus

Background Diabetes mellitus (DM) is one of the major risk factors of disability and death worldwide. Despite of the protective role of ligustilide (LIG) in many cell types, we aimed to investigate whether LIG could be a potential to treat DM. Methods Sprague Dawley rats were randomly assigned to five groups. Rats except control were raised on a high-fat diet (HFD). Streptozotocin was intraperitoneally injected into HFD-fed rats to construct DM model. Rats in the LIG intervention groups received intraperitoneal injection of LIG (10, 20, and 40 mg/kg) post-induction of DM. Blood glucose, plasma insulin (p-insulin), adiponectin, HbA1C%, obesity index, HOMA-IR, and biochemical parameters were estimated. Histopathological analysis and apoptosis in liver and kidney, along with proliferation and apoptosis of islet β-cells, were analyzed. Expression of CPT-1 and ACC, and phosphorylation of Nrf2 and AMPKα1, were finally assessed. Results DM-induced alterations were all relived by LIG intervention. In brief, obesity index, glucose level, P-insulin content, HbA1C, and HOMA-IR were lowered while adiponectin level was elevated. Meanwhile, levels of TC, TG, ALT, and AST were decreased in the LIG intervention groups, along with up-regulated CPT-1 level and down-regulated ACC level. Pathological changes in liver and kidney tissues were alleviated, and apoptotic cells were reduced by LIG treatment. For islet β-cells, LIG up-regulated Ki67 and c-Myc expression, and mitigated ratios of Bax/Bcl-2 and cleaved cas3(9)/cas3(9). Finally, LIG could promote phosphorylation of Nrf2 and AMPKα1. Conclusions LIG alleviated the insulin resistance, lipid accumulation, and pathological injury with the activation of AMPK pathway in DM rats.

Sangguayin preparation prevents palmitate-induced apoptosis by suppressing endoplasmic reticulum stress and autophagy in db/db mice and MIN6 pancreatic β-cells.

Sangguayin preparation (SGY-P) is refined from the traditional Chinese medicinal compound Sangguayin, which "clears heat and promotes fluid" and "tonifies kidney and spleen" for "Xiaoke", commonly known as 'Diabetes mellitus' in clinics. Previous studies have shown that SGY-P could reduce insulin resistance and repair damaged pancreas in db/db mice, but the underlying mechanisms were unclear. Here, we investigated whether treatment with SGY-P could protect pancreatic β-cells from apoptosis and uncovered the underlying mechanisms. db/db mice were used to observe the hypoglycemic and islet protective effect in vivo. Apoptosis was induced in mouse insulinoma 6 (MIN6) cells by palmitate, following which the cells were treated with SGY-P for elucidating the anti-apoptotic mechanism in vitro. Cell viability and nuclear morphology were detected by CCK-8 assay and Hoechst 33258 staining. The expression levels of apoptosis-, endoplasmic reticulum (ER) stress-, and autophagy-related proteins were measured by western blot. The results showed that SGY-P reduced fasting blood glucose, pancreatic pathological changes, and islet β-cell apoptosis in db/db mice. Palmitate-induced apoptosis in MIN6 cells was decreased by SGY-P treatment. Hence, SGY-P therapy exhibited a protective effect on pancreatic β-cells by decreasing the expression of cleaved caspase-3, cleaved PARP and Bax, and increasing Bcl-2 by suppressing ER stress (Bip/XBP1/IRE1α/CHOP/Caspase-12) and autophagy (LC3/p62/Atg5) pathways.2/Atg5) pathways.