Pancreatic Islet Beta Cell Function Research Articles

Advances in research on ferroptosis and pancreatic islet beta-cell function

正常的胰岛功能是维持体内糖代谢稳态的必要因素。铁死亡作为一种由脂质过氧化物及活性氧累积驱动的铁依赖性细胞死亡形式，与多种疾病的发生相关，且在形态学、发生机制以及调控机制等方面显示与其他细胞死亡方式不同的特征。近年研究表明，胰岛β细胞对铁死亡具有易感性。铁死亡通过不同途径对胰岛β细胞的功能和存活产生影响，甚至诱导糖尿病的发生。本文就铁死亡与胰岛β细胞功能的相关研究进行综述。.

Non-invasive quantification of pancreatic islet beta-cell function in people with type 1 diabetes mellitus

Non-invasive quantification of pancreatic islet beta-cell function in people with type 1 diabetes mellitus

Association between plasma homocysteine levels and pancreatic islet beta-cell function in the patients with type 2 diabetes mellitus: a cross-sectional study from China.

This study sought to investigate the association between plasma homocysteine (HCY) levels and pancreatic islet beta-cell function in type 2 diabetes mellitus (T2DM) patients. 430 hospitalized T2DM patients were enrolled in this cross-sectional study from December 2013 to December 2016. All participants were requested to complete a detailed questionnaire and undergo anthropometric measurements. Blood samples were collected from all participants. A 75-g oral glucose tolerance test (OGTT) was performed to diagnose T2DM in each individual, and an insulin releasing test (IRT) was used to calculate selected parameters for glucose, insulin, and C-peptide. Linear correlation and multivariate regression analyses were performed to assess the association between serum HCY concentration and these parameters. Patients were divided into the following subgroups based on quartiles of serum HCY levels: Group Q1: <17.03 µmol/L; Group Q2: 17.03-19.50 µmol/L; Group Q3: 19.5-24.7 µmol/L; and Group Q4: >24.7 µmol/L. The levels of fasting blood glucose (FBG), 2 h postprandial blood glucose (2hPBG), glycated hemoglobin A1c (HbA1c), fasting C-peptide and fasting insulin increased significantly as HCY levels increased (P<0.05). The area under the curves (AUCs) of serum glucose and insulin in IRT increased significantly and that of serum C-peptide decreased as HCY levels increased (P<0.05). The levels of Homeostasis Model Assessment-β (HOMA-β), Modified Beta-cell function Index (MBCI), Disposal Index (DI), C-peptide immunoreactivity (CPR), Insulinogenic Index 30 (IGI 30), and Secretory Units of Islets in Transplantation (SUIT) decreased as HCY levels increased. An inverse linear correlation was found between HOMA-β, MBCI, DI, CPR, IGI 30, SUIT 0 h, and HCY plasma concentration (R2, 0.539, 0.569, 0.500, 0.676, 0.579, and 0.588, respectively; P<0.001), and this association was independent of many confounders, such as age, gender, body mass index, glucose and insulin levels, and HbA1c. Serum HCY levels were inversely related to the parameters for pancreatic islet beta-cell function. Thus, the insulin releasing function of beta cells in the pancreas can be well elucidated by plasma HCY concentration.

Increased inflammation is associated with islet autoimmunity and type 1 diabetes in the Diabetes Autoimmunity Study in the Young (DAISY).

BackgroundType 1 diabetes (TID) is characterized by a loss of pancreatic islet beta cell function resulting in loss of insulin production. Genetic and environmental factors may trigger immune responses targeting beta cells thus generating islet antibodies (IA). Immune response pathways involve a cascade of events, initiated by cytokines and chemokines, producing inflammation which can result in tissue damage.MethodsA nested case-control study was performed to identify temporal changes in cytokine levels in 75 DAISY subjects: 25 diagnosed T1D, 25 persistent IA, and 25 controls. Serum samples were selected at four time points: (T1) earliest, (T2) just prior to IA, (T3) just after IA, and (T4) prior to T1D diagnosis or most recent. Cytokines (IFN-α2a, IL-6, IL-17, IL-1β, IP-10, MCP-1, IFN-γ, IL-1α, and IL-1ra) were measured using the Meso Scale Discovery system Human Custom Cytokine 9-Plex assay.ResultsMultivariate mixed models adjusting for HLA risk, first-degree relative status, age, and gender, showed MCP-1 and IFN-үto be significantly higher at T3 in T1D compared to IA subjects. At T4, IP-10 was significantly higher in IA subjects than controls.ConclusionsThis repeated measures nested case-control study identified increased inflammatory markers in IA children who developed T1D compared to IA children who had not progressed to clinical disease. It also showed increased inflammation in both T1D and IA children when compared to controls. Results suggest inflammation may be related to both the development of IA and progression to T1D.

A Novel Pathway for Regulation of Insulin Secretion by Fractalkine and CX3CR1 System (LB772)

Fractalkine (FKN) (CX3CL1) and its receptor CX3CR1 mediate cell‐to‐cell interactions in different tissues. Here, we demonstrate that the FKN/CX3CR1 system represents a novel regulatory mechanism for pancreatic islet beta cell function and insulin secretion. CX3CR1 KO mice exhibit glucose intolerance with normal insulin sensitivity, due to a marked beta cell defect in glucose and GLP1‐stimulated insulin secretion. The defect in insulin secretion was also observed in vitro in isolated islets from CX3CR1 KO mice. In vivo administration of FKN improved glucose tolerance with an increase in insulin secretion. In vitro treatment of islets with FKN increased intracellular Ca2+ level and potentiated insulin secretion. The KO islets exhibited reduced expression of a set of genes which are necessary for the fully functional, differentiated beta cell state, whereas, treatment of WT islets with FKN leads to increased expression of these genes. Lastly, expression of FKN in islets was decreased by aging and HFD/obesity, suggesting that decreased fractalkine/CX3CR1 signaling could be a mechanism underlying beta cell dysfunction in type 2 diabetes.

Epistasis of Transcriptomes Reveals Synergism between Transcriptional Activators Hnf1α and Hnf4α

The transcription of individual genes is determined by combinatorial interactions between DNA–binding transcription factors. The current challenge is to understand how such combinatorial interactions regulate broad genetic programs that underlie cellular functions and disease. The transcription factors Hnf1α and Hnf4α control pancreatic islet β-cell function and growth, and mutations in their genes cause closely related forms of diabetes. We have now exploited genetic epistasis to examine how Hnf1α and Hnf4α functionally interact in pancreatic islets. Expression profiling in islets from either Hnf1a+/− or pancreas-specific Hnf4a mutant mice showed that the two transcription factors regulate a strikingly similar set of genes. We integrated expression and genomic binding studies and show that the shared transcriptional phenotype of these two mutant models is linked to common direct targets, rather than to known effects of Hnf1α on Hnf4a gene transcription. Epistasis analysis with transcriptomes of single- and double-mutant islets revealed that Hnf1α and Hnf4α regulate common targets synergistically. Hnf1α binding in Hnf4a-deficient islets was decreased in selected targets, but remained unaltered in others, thus suggesting that the mechanisms for synergistic regulation are gene-specific. These findings provide an in vivo strategy to study combinatorial gene regulation and reveal how Hnf1α and Hnf4α control a common islet-cell regulatory program that is defective in human monogenic diabetes.

Impairment of pancreatic islet beta cell function induced by intermittent high glucose through oxidative and endoplasmic reticulum stress: experiment with rat pancreatic islet beta cells

To investigate the effect of intermittent high glucose (IHG) on the pancreatic islet beta-cell function and mechanism thereof. Rat pancreatic islet p-cells of the line INS-1 were cultured and randomly divided into 3 groups: IHG group exposed to fluctuating concentrations of glucose, stable high glucose (SHG) group exposed to 16. 7 mmol/L glucose, and control group exposed to normal concentration (5.5 mmol/L) glucose. 24, 48, and 72 hours later radioimmunoassay was used to detect the insulin secretion index (ISI). 72 h later, the concentration of insulin in the cells was detected with radioimmunoassay. The contents of oxidative stress markers, nitrotyrosine (NT) and 8-hydroxy-2-deoxyguanosine (8-OHdG) were detected. Real-time PCR was used to detect the mRNA expression of peroxiredoxin 1 (PDX-1), ATF-4, one of the transcription factors of the family bZIP, and insulin. Western blotting was used to detect the protein expression of ATF-4. The ISI of the IHG and SHG groups decreased time-dependently, The ISI of IHG and SHG groups were 0.64 +/- 0.11 and 1.31 +/- 0. 04 respectively, both significantly lower than that of the control group (1.67 +/- 0.23, both P < 0.05). The intracellular insulin contents of the IHG and SHG groups were (10.91 +/- 0.14) and (11.08 +/- 0.03) +/- U/microg respectively, both significantly lower than that of the control group [(12.37 +/- 0.37) microU/microg, both P < 0.05]. The intracellular concentrations of 8-OHdG and NT of the SHG and IHG groups, were significantly higher than those of the control group (all P < 0.01), and those of the IHG group were significantly higher than those of the SHG group (both P < 0.05). The mRNA and protein expression levels of ATF-4 of the IHG group were all significantly higher than those of the control group (all P < 0.05) and those of the IHG group were significantly higher than those of the SHG group (both P < 0.05). IHG and SHG induce severe impairment in pancreatic islet beta cell functions, especially IHG, which is closely associated with the aggravation of oxidative stress and endoplasmic reticulum stress triggered by intermittent high glucose.

Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in Type 2 diabetes

Type 2 diabetes is characterized by a relentless decline in pancreatic islet beta cell function and worsening hyperglycemia despite optimal medical treatment. Our central hypothesis is that residual hyperglycemia, especially after meals, generates reactive oxygen species (ROS), which in turn causes chronic oxidative stress on the beta cell. This hypothesis is supported by several observations. Exposure of isolated islets to high glucose concentrations induces increases in intracellular peroxide levels. The beta cell has very low intrinsic levels of antioxidant proteins and activities and thus is very vulnerable to ROS. Treatment with antioxidants protects animal models of type 2 diabetes against complete development of phenotypic hyperglycemia. The molecular mechanisms responsible for the glucose toxic effect on beta cell function involves disappearance of two important regulators of insulin promoter activity, PDX-1 and MafA. Antioxidant treatment in vitro prevents disappearance of these two transcription factors and normalizes insulin gene expression. These observations suggest that the ancillary treatment with antioxidants may improve outcomes of standard therapy of type 2 diabetes in humans.

Pathophysiology of insulin secretion

Defects in pancreatic islet beta-cell function play a major role in the development of diabetes mellitus. Type 1 diabetes is caused by a more or less rapid destruction of pancreatic beta cells, and the autoimmune process begins years before the beta-cell destruction becomes complete, thereby providing a window of opportunity for intervention. During the preclinical period and early after diagnosis, much of the insulin deficiency may be the result of functional inhibition of insulin secretion that may be at least partially and transiently reversible. Type 2 diabetes is characterized by a progressive loss of beta-cell function throughout the course of the disease. The pattern of loss is an initial (probably of genetic origin) defect in acute or first-phase insulin secretion, followed by a decreasing maximal capacity of insulin secretion. Last, a defective steady-state and basal insulin secretion develops, leading to almost complete beta-cell failure requiring insulin treatment. Because of the reciprocal relation between insulin secretion and insulin sensitivity, valid representation of beta-cell function requires interpretation of insulin responses in the context of the prevailing degree of insulin sensitivity. This appropriate approach highlights defects in insulin secretion at the various stages of the natural history of type 2 diabetes and already present in individuals at risk to develop the disease. To date none of the available therapies can stop the progressive beta-cell defect and the progression of the metabolic disorder. The better understanding of the pathophysiology of the disease should lead to the development of new strategies to preserve beta-cell function in both type 1 and type 2 diabetes mellitus.

Two-photon NAD(P)H and one-photon Flavoprotein autofluorescence imaging to examine the metabolic mechanisms of pancreatic islet beta-cell function

Two-photon NAD(P)H and one-photon Flavoprotein autofluorescence imaging to examine the metabolic mechanisms of pancreatic islet beta-cell function

Effect of α-phenyl-N-tert-butylnitrone on diabetes and lipid peroxidation in BB rats

Oxygen free radicals have been shown to interfere with pancreatic islet beta cell function and integrity, and have been implicated in autoimmune type 1 diabetes. We hypothesized that the spontaneous autoimmune type 1 diabetes of the BB rat would be prevented by in vivo administration of a free-radical spin trap, alpha-phenyl-N-tert-butylnitrone (PBN). Twenty-eight diabetes-prone (BBdp) and 13 non-diabetes-prone (BBn) rats received PBN (10 mg/kg) subcutaneously twice daily, and 27 BBdp and 12 BBn rats received saline as controls. Rats were treated from age 47 +/- 6 days until diabetes onset or age 118 +/- 7 days. PBN caused no growth, biochemical, or hematological side effects. Sixteen control BBdp rats became diabetic (BBd, mean age 77 +/- 6 days) and six demonstrated impaired glucose tolerance (IGT rats). The incidence of diabetes and IGT was not different in PBN-treated BBdp rats. Saline-treated rats showed no differences in pancreatic malondialdehyde (MDA) contents of BBd, IGT rats, and the BBdp that did not develop diabetes, versus BBn rats (2.38 +/- 0.35 nmoL/g). Among rats receiving PBN, BBn had lower pancreatic MDA than BBd and IGT rats (1.38 +/- 0.15 vs. 1.88 +/- 0.15 and 2.02 +/- 0.24 nmoL/g, p < 0.05), but not than BBdp rats (1.78 +/- 0.12 nmoL/g, ns). BBn rats receiving PBN also had lower pancreatic MDA than the saline controls (p < 0.05). Thus, PBN is remarkably nontoxic and is able to decrease MDA in the absence of the autoimmune process, but does not prevent diabetes. A combination of PBN with other complementary antioxidant agents may hold better promise for disease prevention.

Intravenous glucose tolerance and pancreatic islet beta-cell function in patients with multiple sclerosis during 2-yr treatment with cyclosporin

Intravenous glucose tolerance and pancreatic islet beta-cell function in patients with multiple sclerosis during 2-yr treatment with cyclosporin