Pancreatic Β-cell Insulin Research Articles

Characterization of insulin crystalline form in isolated β-cell secretory granules.

Insulin is stored in vivo inside the pancreatic β-cell insulin secretory granules. In vitro studies have led to an assumption that high insulin and Zn2+ concentrations inside the pancreatic β-cell insulin secretory granules should promote insulin crystalline state in the form of Zn2+-stabilized hexamers. Electron microscopic images of thin sections of the pancreatic β-cells often show a dense, regular pattern core, suggesting the presence of insulin crystals. However, the structural features of the storage forms of insulin in native preparations of secretory granules are unknown, because of their small size, fragile character and difficult handling. We isolated and investigated the secretory granules from MIN6 cells under near-native conditions, using cryo-electron microscopic (Cryo-EM) techniques. The analysis of these data from multiple intra-granular crystals revealed two different rhomboidal crystal lattices. The minor lattice has unit cell parameters (a ≃ b ≃ 84.0 Å, c ≃ 35.2 Å), similar to in vitro crystallized human 4Zn2+-insulin hexamer, whereas the largely prevalent unit cell has more than double c-axis (a ≃ b ≃ c ≃ 96.5 Å) that probably corresponds to two or three insulin hexamers in the asymmetric unit. Our experimental data show that insulin can be present in pancreatic MIN6 cell granules in a microcrystalline form, probably consisting of 4Zn2+-hexamers of this hormone.

Stress Etiology of Type 2 Diabetes.

Stress creates disharmony in the body's natural environment and thus causes an imbalance in the normal physiological system. The term diabetes describes a group of metabolic disorders, characterized and identified by the presence of hyperglycemia. Essential factors identified to initiate hyperglycemia are excess body weight, high cholesterol, high blood pressure, and lifestyle changes like stress, genetics, etc. Different types of stress and related conditions like depression, anxiety, etc., cause pancreatic β-cell dysfunction and insulin resistance, the prime risk factors in the progression of type 2 diabetes. The neuroendocrine system plays a pivotal role in countering psychological stress is the hypothalamus-pituitary-adrenal (HPA) axis, which secretes glucocorticoids (GCs), e.g., cortisol is the principal stress-responsive natural steroid hormone. The stress system essentially hampers the body's homeostasis and develops serious clinical manifestations. Glucocorticoids exert a strong physiological impact on glucose metabolism directly or indirectly, cause hyperglycemic effect and play an important role in the development of type 2 diabetes observed in patients suffering from chronic stress, Cushing's syndrome, or patients on long term GCs therapy. This review provides a clear outline on the pathways and mechanisms of stress-linked type 2 diabetes.

Evaluation of Insulin Resistance and Glutathione-S-transferase in Iraqi Patients with Type 2 Diabetes Mellitus and Diabetic Peripheral Neuropathy

Diabetes mellitus type 2 (T2DM) is a metabolic disorder that influences above 450 million individuals around the world. Type 2 diabetes is a lack of insulin due to pancreatic β-cell malfunction and insulin resistance. This study aimed to detect insulin resistance using homeostasis model assessment (HOMA IR) and determined the correlation with glutathione-s-transferase (GST) activity in T2DM and neuropathy patients as a predictor of oxidative stress, which occurs when the oxidation-antioxidant equilibrium is disrupted. Reactive oxygen species causes vascular injury and a series of inflammation. In the present study, the results show there is no significant difference in diabetic patients (DM) and neuropathy patients (NU) versus healthy people in insulin resistance (p> 0.05). GST activity significantly differs between the patients and healthy groups (p≤0.05). Moreover, this study has reported an improvement in insulin resistance and high activity of GST in the patient's group as a warning sign of excessive oxidative stress. There was no evidence revealing a link between insulin resistance and GST. The present study has demonstrated that HOMA-IR had a positive relationship with fasting blood sugar and insulin in the neuropathy group and diabetic group and a negative relationship with high-density lipoprotein (HDL).

Kinetic and data-driven modeling of pancreatic β-cell central carbon metabolism and insulin secretion.

Pancreatic β-cells respond to increased extracellular glucose levels by initiating a metabolic shift. That change in metabolism is part of the process of glucose-stimulated insulin secretion and is of particular interest in the context of diabetes. However, we do not fully understand how the coordinated changes in metabolic pathways and metabolite products influence insulin secretion. In this work, we apply systems biology approaches to develop a detailed kinetic model of the intracellular central carbon metabolic pathways in pancreatic β-cells upon stimulation with high levels of glucose. The model is calibrated to published metabolomics datasets for the INS1 823/13 cell line, accurately capturing the measured metabolite fold-changes. We first employed the calibrated mechanistic model to estimate the stimulated cell's fluxome. We then used the predicted network fluxes in a data-driven approach to build a partial least squares regression model. By developing the combined kinetic and data-driven modeling framework, we gain insights into the link between β-cell metabolism and glucose-stimulated insulin secretion. The combined modeling framework was used to predict the effects of common anti-diabetic pharmacological interventions on metabolite levels, flux through the metabolic network, and insulin secretion. Our simulations reveal targets that can be modulated to enhance insulin secretion. The model is a promising tool to contextualize and extend the usefulness of metabolomics data and to predict dynamics and metabolite levels that are difficult to measure in vitro. In addition, the modeling framework can be applied to identify, explain, and assess novel and clinically-relevant interventions that may be particularly valuable in diabetes treatment.

Network Pharmacology and Transcriptomics Reveal the Mechanism of GuaLouQuMaiWan in Treatment of Type 2 Diabetes and Its Active Small Molecular Compound.

The main pathophysiological abnormalities in type 2 diabetes (T2D) include pancreatic β-cell dysfunction and insulin resistance. Due to hyperglycemia, patients receive long-term treatment. However, side effects and drug tolerance usually lead to treatment failure. GuaLouQuMaiWan (GLQMW), a common traditional Chinese medicine (TCM) prescription, has positive effects on controlling blood sugar and improving quality of life, but the mechanism is still unclear. To decipher their molecular mechanisms, we used a novel computational systems pharmacology-based approach consisting of bioinformatics analysis, network pharmacology, and drug similarity comparison. We divided the participants into nondisease (ND), impaired glucose tolerance (IGT), and type 2 diabetes groups according to the WHO's recommendations for diabetes. By analyzing the gene expression profile of the ND-IGT-T2D (ND to IGT to T2D) process, we found that the function of downregulated genes in the whole process was mainly related to insulin secretion, while the upregulated genes were related to inflammation. Furthermore, other genes in the ND-IGT (ND to IGT) process are mainly related to inflammation and lipid metabolic disorders. We speculate that 17 genes with a consistent trend may play a key role in the process of ND-IGT-T2D. We further performed target prediction for 50 compounds in GLQMW that met the screening criteria and intersected the differentially expressed genes of the T2D process with the compounds of GLQMW; a total of 18 proteins proved potential targets for GLQMW. Among these, RBP4 is considerably related to insulin resistance. GO/KEGG enrichment analyses of the target genes of GLQMW showed enrichment in inflammation- and T2D therapy-related pathways. Based on the RDKit tool and the DrugBank database, we speculate that (-)-taxifolin, dialoside A_qt, spinasterol, isofucosterol, and 11,14-eicosadienoic acid can be used as potential drugs for T2D via molecular docking and drug similarity comparison.

Overexpression of TRIM32 promotes pancreatic β-cell autophagic cell death through Akt/mTOR pathway under high glucose conditions.

Type 2 diabetes mellitus (T2DM) is a growing worldwide epidemic and is characterized by progressive pancreatic β-cell dysfunction and insulin resistance. Tripartite motif protein 32 (TRIM32) belongs to the TRIM family protein and has been shown to be involve in insulin resistance in skeletal muscle and the liver. However, the effect of TRIM32 on pancreatic β-cell dysfunction and its mechanism remains unknown. In the current study, we found that serum TRIM32 concentrations of T2DM in patients were significantly elevated compared to those in healthy controls, which indicated that TRIM32 might be used as a diagnostic biomarker in T2DM patients. In INS-1 cells, exposure to high glucose (HG) conditions caused a significant elevation in TRIM32 expression and TRIM32 was located in the nucleus. Overexpression of TRIM32 in INS-1 cells exacerbated the effects of HG-induced autophagy and impaired insulin secretion. In contrast, the silencing of TRIM32 produced the opposite effect. Furthermore, TRIM32 overexpression decreased the phosphorylation levels of Akt and mTOR under HG conditions. However, the activation of Akt/mTOR by MHY1485 reversed the effects of TRIM32 on HG-treated INS-1 cells. Collectively, the present results suggested that TRIM32 participates in the development of T2DM by modulating autophagic cell death and insulin secretion, which might occur through the Akt/mTOR pathway. Thus, TRIM32 might be a promising target in T2DM therapy.

The p66Shc Protein Mediates Insulin Resistance and Secretory Dysfunction in Pancreatic β-Cells Under Lipotoxic Conditions.

We evaluated the role of the p66Shc redox adaptor protein in pancreatic β-cell insulin resistance that develops under lipotoxic conditions and with excess body fat. Prolonged exposure to palmitate in vitro or the presence of overweight/obesity augmented p66Shc expression levels and caused an impaired ability of exogenous insulin to increase cellular insulin content and secreted C-peptide levels in INS-1E cells and human and murine islets. In INS-1E cells, p66Shc knockdown resulted in enhanced insulin-induced augmentation of insulin content and C-peptide secretion and prevented the ability of palmitate to impair these effects of insulin. Conversely, p66Shc overexpression impaired insulin-induced augmentation of insulin content and C-peptide secretion in both the absence and presence of palmitate. Under lipotoxic condition, the effects of p66Shc are mediated by a p53-induced increase in p66Shc protein levels and JNK-induced p66Shc phosphorylation at Ser36 and appear to involve the phosphorylation of the ribosomal protein S6 kinase at Thr389 and of insulin receptor substrate 1 at Ser307, resulting in the inhibition of insulin-stimulated protein kinase B phosphorylation at Ser473. Thus, the p66Shc protein mediates the impaired β-cell function and insulin resistance induced by saturated fatty acids and excess body fat.

Curcuma longa modulates Islet β-cell function and insulin resistance in diabetic rat.

Objective: To analyze modulating effect of Curcuma longa on Pancreatic Islet β-cell function and insulin resistance in alloxan induced diabetic rat model. Study Design: Experimental study. Setting: Department of Anatomy, Pharmacology and Pathology, SRMCH, T. Adam. Period: February 2019 to January 2020. Material & Methods: One hundred adult male rats were selected according to criteria and grouped A to E. Group A and B was negative and positive control rats, and C –E were diabetic experimental rats. Alloxan (120 mg/Kg body weight) was injected intraperitoneally (i.p) to induce diabetes mellitus. Curcuma longa was used in doses of 200, 300 and 500 mg/d for 28 days. Body weight, blood glucose, HbA1c, insulin and C-peptide were estimated. Insulin resistance (HOMA-IR) and β- cell function (HOMA-β) were calculated by formulae. Data was analyzed on SPSS package ver. 21.0 (IBM, incorporation, USA) (p≤ 0.05). Results: Twenty eight days therapy of Curcuma longa extract ameliorates blood glucose, A1C, serum Insulin levels and C-peptide levels. Insulin resistance (HOMA-IR) was found improved and β- cell function (HOMA-β) was augmented in in Curcuma longa treated experimental rats (P=0.0001). Conclusion: Administration of Curcuma longa positively modulates the Islet β-cell function and insulin resistance in alloxan induced diabetic rats.

Oral fat tolerance testing identifies abnormal pancreatic β-cell function and insulin resistance in individuals with normal glucose tolerance.

Insulin sensitivity and β-cell function are affected by lipid metabolism disorders, even before the onset of type 2 diabetes. People are in the postprandial state most of the time. Therefore, identifying postprandial hyperlipemia is important. This study aimed to assess patients with abnormalities in lipid metabolism, but with normal glucose tolerance, using oral fat tolerance testing (OFTT) to identify defects in insulin sensitivity and β-cell function. We included 248 volunteers with normal glucose tolerance who underwent OFTT. They were divided into three groups in accordance with their fasting and 4-h postprandial triglyceride (TG) concentrations. Their lipid concentrations during OFTT were compared. The disposition index (DI) was applied to estimate β-cell function, and the Matsuda insulin sensitivity index (ISIM ) was used to assess insulin sensitivity. We used multiple linear regression analysis to estimate the relationships of fasting and postprandial TG concentrations with β-cell function and insulin sensitivity . The changes in TG concentrations during OFTT were more marked than those in low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol or total cholesterol concentrations. As lipid metabolism deteriorated, the ISIM and the DI gradually decreased. Multiple linear regression analysis showed that fasting and 4-h postprandial TG concentrations affected LnISIM and LnDI. In individuals with normal glucose tolerance, β-cell function and insulin sensitivity gradually decrease with a deterioration in the lipid profile. Not only fasting TG, but also postprandial TG concentrations are independent risk factors for impaired β-cell function and insulin resistance.

اكتشاف جين جديد يساهم في الإصابة بمرض السكري ويؤثر في استقلاب الغلوكوز

الملخص المقدمة وهدف الدراسة: يعدّ مرض السكري من النوع الثاني مرضًا متعدد العوامل والجينات. وقد تم اكتشاف أكثر من 140 متغيرًا جينيًا وراثيًا مرتبطًا بسببية المرض، ولكنها تفسر فقط 10% من الأسباب الوراثية للسكري. لهذا، تسعى هذه الدراسة إلى استخدام نهج جديد تُحدَّد من خلاله جينات جديدة مشارِكة في فسيولوجية مرض السكري وإفراز الإنسولين. طريقة البحث: تم تحليل بيانات تسلسل الحمض النووي الريبوزي من جزر البنكرياس البشرية جُمعت من 89 متبرعًا. كما أُجريت سلسلة من التجارب الوظيفية في خلايا بيتا الحيوانية (INS-1) من الفئران للتحقق من الدور المحتمل للجين المرشح بما في ذلك تثبيط نشاطه، وإفراز الإنسولين، وحيوية الخلية، وموت الخلية المبرمج، والتعبير الجيني. النتائج: قد أظهر تحليل التعبير الجيني التفاضلي لبيانات تسلسل الحمض النووي الريبوزي أن 231 جينًا كان لها تعبير منخفض على نحو ملحوظ في جزر البنكرياس من المتبرعين المرضى بالسكري مقارنة بالأصحاء. وتم خفض عدد الجينات إلى 37 من جراء تطبيق قطع إحصائي أكثر صرامة. ومن بين تلك الجينات، تم اختيار (PPP1R1A) كجين مرشح بسبب ارتباطه القوي مع معدل السكري التراكمي، وتعبيره الجيني المرتفع في جزر البنكرياس البشرية مقارنة بباقي الجينات. وأيضًا، وُجد أن تعبير الجينات الوظيفية المهمة في خلايا بيتا مثل (INS) و(PDX1) و(GLUT2) و(INSR) انخفض على نحو كبير في الخلايا التي ثُبّط فيها نشاط (PPP1R1A). وخلصت الدراسة إلى أن (PPP1R1A) جين منظّم لوظيفة خلايا بيتا وإفراز الإنسولين، كما سلطت الضوء على قائمة من الجينات التي قد يكون لها دور وتأثير في مرض السكري. Background: Type 2 diabetes (T2D) is a multifactorial polygenic disease with an unclear causative mechanism. Close to 140 genetic variants are associated with T2D, but they only explain 10% of the heritability. Aim: In this study, we employed a novel approach to identify novel genes involved in the pathophysiology of T2D and insulin secretion. Methods: We analyzed RNA-sequencing data from human pancreatic islets at a global level. Furthermore, we performed a serial of functional experiments in rat pancreatic β-cells to validate the potential role of the candidate gene including siRNA silencing, insulin secretion, cell viability, apoptosis, QPCR, and western blot expression of the key molecule in β-cells. Results: Differential expression analysis reveals those 231 genes are significantly (P<0.05) downregulated in diabetic islets compared to nondiabetics. However, the number of genes was restricted to 37 genes by applying a cutoff of (P<0.01). Of these genes, PPP1R1A was selected as a candidate gene due to its strong correlation with HbA1c and high expression in human pancreatic islets. Silencing of PPP1R1A in INS-1 cells was markedly reduced, insulin secretion while cell viability and apoptosis were not affected. In addition, the expression of Insulin, PDX1, GLUT2, and INSR was significantly down-regulated in PPP1R1A-silenced cells. Expression of NEUROD1 and GCK was not affected. Conclusion: The study identifies PPP1R1A as a novel regulator of pancreatic β-cell function and insulin secretion. Moreover, it introduces a list of potential genes to be explored for their role in the pathogenesis of T2D.

Super-conserved receptors expressed in the brain: biology and medicinal chemistry efforts.

The super-conserved receptors expressed in the brain (SREB) constitute a family of orphan G protein-coupled receptors that include GPR27 (SREB1), GPR85 (SREB2) and GPR173 (SREB3). Their sequences are highly conserved in vertebrates, and they are almost exclusively expressed in the central nervous system. This family of receptors has attracted much attention due to their putative physiological functions and their potential as novel drug targets. The SREB family has been postulated to play important roles in a wide range of different diseases, including pancreatic β-cell insulin secretion and regulation, schizophrenia, autism and atherosclerosis. This review intends to provide a comprehensive overview of the SREB family and its recent advances in biology and medicinal chemistry.

Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function.

Impaired pancreatic β-cell function and insulin secretion are hallmarks of type 2 diabetes. miRNAs are short, noncoding RNAs that silence gene expression vital for the development and function of β cells. We have previously shown that β cell-specific deletion of the important energy sensor AMP-activated protein kinase (AMPK) results in increased miR-125b-5p levels. Nevertheless, the function of this miRNA in β cells is unclear. We hypothesized that miR-125b-5p expression is regulated by glucose and that this miRNA mediates some of the deleterious effects of hyperglycemia in β cells. Here, we show that islet miR-125b-5p expression is upregulated by glucose in an AMPK-dependent manner and that short-term miR-125b-5p overexpression impairs glucose-stimulated insulin secretion (GSIS) in the mouse insulinoma MIN6 cells and in human islets. An unbiased, high-throughput screen in MIN6 cells identified multiple miR-125b-5p targets, including the transporter of lysosomal hydrolases M6pr and the mitochondrial fission regulator Mtfp1. Inactivation of miR-125b-5p in the human β-cell line EndoCβ-H1 shortened mitochondria and enhanced GSIS, whereas mice overexpressing miR-125b-5p selectively in β cells (MIR125B-Tg) were hyperglycemic and glucose intolerant. MIR125B-Tg β cells contained enlarged lysosomal structures and had reduced insulin content and secretion. Collectively, we identify miR-125b as a glucose-controlled regulator of organelle dynamics that modulates insulin secretion.

Roles of mTOR in the Regulation of Pancreatic β-Cell Mass and Insulin Secretion.

Pancreatic β-cells are the only type of cells that can control glycemic levels via insulin secretion. Thus, to explore the mechanisms underlying pancreatic β-cell failure, many reports have clarified the roles of important molecules, such as the mechanistic target of rapamycin (mTOR), which is a central regulator of metabolic and nutrient cues. Studies have uncovered the roles of mTOR in the function of β-cells and the progression of diabetes, and they suggest that mTOR has both positive and negative effects on pancreatic β-cells in the development of diabetes.

Potential Identification of Type 2 Diabetes with Elevated Insulin Clearance

BackgroundDecreased blood insulin concentrations resulting from reduced pancreatic β-cell insulin secretion and elevated insulin clearance (IC) could be involved in impaired glucose metabolism in diabetes. Recently, we reported a patient with type 2 diabetes mellitus (T2DM) who had decreased blood insulin concentrations and elevated IC.MethodsFor this study, we recruited patients with newly diagnosed, treatment-naïve T2DM and measured the metabolic clearance rate of insulin (MCRI) determined by a hyperinsulinemic-euglycemic clamp examination. We defined elevated IC as an MCRI of more than 700 ml/min/m2. Using this tentative cutoff, we identified patients with T2DM with elevated IC and investigated their clinical characteristics.ResultsWe enrolled 101 patients in this study; 78.2% were men. Patients had a mean age of 54.1 years, a median body-mass index (BMI) of 25.1 kg/m2 (interquartile range [IQR], 22.9 to 28.4 kg/m2), a median hemoglobin A1c of 10.0% (IQR, 8.0 to 12.3%), and a median MCRI of 655 ml/min/m2 (IQR, 562 to 810 ml/min/m2). Our case definition for elevated IC was met by 44 patients whose median MCRI was 842 ml/min/m2 (IQR, 747 to 975 ml/min/m2) compared with those without elevated IC (570 ml/min/m2; IQR, 500 to 628 ml/min/m2). On the basis of this division, fasting blood glucose and insulin levels were 178 mg/dl (IQR, 140 to 218 mg/dl) and 4.2 mU/l (IQR, 2.7 to 5.5 mU/l), respectively, in patients with elevated IC compared with 146 mg/dl (IQR, 128 to 188 mg/dl) and 9.6 mU/l (IQR, 6.6 to 14.9 mU/l), respectively, in patients without elevated IC. The BMI of patients with elevated IC was 22.9 kg/m2 (IQR, 20.7 to 24.2 kg/m2) compared with 27.3 kg/m2 (IQR, 25.2 to 29.4 kg/m2) in patients who did not have elevated IC. There were no clinically significant differences in renal or hepatic function test results.ConclusionsOur data suggest that there is a group of patients with T2DM with elevated IC, and that they are nonobese and have decreased blood insulin concentrations. If confirmed, this novel form of T2DM could affect the treatment of such patients. (UMIN Clinical Trials Registry number, UMIN000032014.)

Relationships Between Urinary Metals and Diabetes Traits Among Mexican Americans in Starr County, Texas, USA.

Hispanics/Latinos have higher rates of type 2 diabetes (T2D), and the origins of these disparities are poorly understood. Environmental endocrine-disrupting chemicals (EDCs), including some metals and metalloids, are implicated as diabetes risk factors. Data indicate that Hispanics/Latinos may be disproportionately exposed to EDCs, yet they remain understudied with respect to environmental exposures and diabetes. The objective of this study is to determine how metal exposures contribute to T2D progression by evaluating the associations between 8 urinary metals and measures of glycemic status in 414 normoglycemic or prediabetic adults living in Starr County, Texas, a Hispanic/Latino community with high rates of diabetes and diabetes-associated mortality. We used multivariable linear regression to quantify the differences in homeostatic model assessments for pancreatic β-cell function, insulin resistance, and insulin sensitivity (HOMA-β, HOMA-IR, HOMA-S, respectively), plasma insulin, plasma glucose, and hemoglobin A1c (HbA1c) associated with increasing urinary metal concentrations. Quantile-based g-computation was utilized to assess mixture effects. After multivariable adjustment, urinary arsenic and molybdenum were associated with lower HOMA-β, HOMA-IR, and plasma insulin levels and higher HOMA-S. Additionally, higher urinary copper levels were associated with a reduced HOMA-β. Lastly, a higher concentration of the 8 metal mixtures was associated with lower HOMA-β, HOMA-IR, and plasma insulin levels as well as higher HOMA-S. Our data indicate that arsenic, molybdenum, copper, and this metal mixture are associated with alterations in measures of glucose homeostasis among non-diabetics in Starr County. This study is one of the first to comprehensively evaluate associations of urinary metals with glycemic measures in a high-risk Mexican American population.

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production.

Pancreatic islet β-cells exhibit tremendous plasticity for secretory adaptations that coordinate insulin production and release with nutritional demands. This essential feature of the β-cell can allow for compensatory changes that increase secretory output to overcome insulin resistance early in Type 2 diabetes (T2D). Nutrient-stimulated increases in proinsulin biosynthesis may initiate this β-cell adaptive compensation; however, the molecular regulators of secretory expansion that accommodate the increased biosynthetic burden of packaging and producing additional insulin granules, such as enhanced ER and Golgi functions, remain poorly defined. As these adaptive mechanisms fail and T2D progresses, the β-cell succumbs to metabolic defects resulting in alterations to glucose metabolism and a decline in nutrient-regulated secretory functions, including impaired proinsulin processing and a deficit in mature insulin-containing secretory granules. In this review, we will discuss how the adaptative plasticity of the pancreatic islet β-cell’s secretory program allows insulin production to be carefully matched with nutrient availability and peripheral cues for insulin signaling. Furthermore, we will highlight potential defects in the secretory pathway that limit or delay insulin granule biosynthesis, which may contribute to the decline in β-cell function during the pathogenesis of T2D.

Increased serum cystatin C levels and responses of pancreatic α- and β-cells in type 2 diabetes.

BackgroundIncreased serum cystatin C (CysC) can predict the onset of type 2 diabetes (T2D). Meanwhile, impaired pancreatic α- and β-cell functions get involved in the pathophysiological processes of T2D. So this study was to explore the relationships between serum CysC levels and pancreatic α- and β-cell functions in T2D.MethodsIn this cross-sectional observational study, a total of 2634 patients with T2D were consecutively recruited. Each recruited patient received a serum CysC test and oral glucose tolerance test for synchronous detection of serum C-peptide and plasma glucagon. As components of pancreatic β-cell function, insulin secretion and sensitivity indices were evaluated by C-peptide area under the curve (AUC-CP) and C-peptide-substituted Matsuda’s index (Matsuda-CP), respectively. Fasting glucagon (F-GLA) and post-challenge glucagon calculated by glucagon area under the curve (AUC-GLA) were used to assess pancreatic α-cell function. These skewed indices and were further natural log-transformed (ln).ResultsWith quartiles of serum CysC levels ascending, AUC-CP, F-GLA and AUC-GLA were increased, while Matsuda-CP was decreased (P for trend <0.001). Moreover, serum CysC levels were positively related to lnAUC-CP, lnF-GLA and lnAUC-GLA (r= 0.241, 0.131 and 0.208, respectively, P < 0.001), and inversely related to lnMatsuda-CP (r= –0.195, P < 0.001). Furthermore, after controlling for other relevant variables via multivariable linear regression analysis, serum CysC levels were identified to account for lnAUC-CP (β= 0.178, t= 10.518, P < 0.001), lnMatsuda-CP (β= –0.137, t= –7.118, P < 0.001), lnF-GLA (β= 0.049, t= 2.263, P = 0.024) and lnAUC-GLA (β= 0.121, t= 5.730, P < 0.001).ConclusionsIncreased serum CysC levels may be partly responsible for increased insulin secretion from β-cells, decreased systemic insulin sensitivity, and elevated fasting and postprandial glucagon secretion from α-cells in T2D.

Cadmium exposure suppresses insulin secretion through mtROS-mediated mitochondrial dysfunction and inflammatory response in pancreatic beta cells

BackgroundCadmium (Cd) exposure is a worldwide environmental threat to the public health and participates in the pathogenesis of multiple diseases. Epidemiologic research have established a direct relation between Cd exposure and diabetes development in humans. Although pancreatic β-cell dysfunction has been considered as the major culprit in the pathogenesis of diabetes, there is a paucity of studies to elucidate the molecular mechanism of Cd toxicity on β-cells. MethodsTo unveil the toxic effect and its underlying mechanism of Cd exposure on β-cells, we used an in vitro MIN6 cell model of environment-relevant Cd exposure to elucidate the crucial role of mtROS-mediated mitochondrial dysfunction and inflammatory response in suppression of pancreatic β-cell insulin secretion. ResultsWe uncovered that Cd treatment suppresses cell viability and induces insulin secretion dysfunction in a dose-dependent manner. Moreover, Cd exposure elicits the inflammatory response, as indicated by increased IL-1β, IL-6 and TNF-α expressions. Significant elevations of intracellular ROS and mitochondrial ROS levels were detected as early as 3 h after Cd treatment. In mitochondrial function analysis, we demonstrated that Cd treatment induced mitochondrial dysfunction and disorder of mitochondrial fission indicated by the significant decline in ATP production, the marked depolarization of mitochondrial membrane potential, the decrease in mtDNA copy numbers, the suppressions of mitochondrial transcription factor A (Tfam) and mitochondrial fission-related gene Drp1 expressions. Pretreatment with TEMPO, a specific mitochondrial ROS (mtROS) scavenger, efficiently antagonizes Cd cytotoxicity, which is indicated by attenuating Cd-induced mitochondrial dysfunction, suppressing IL-1β, IL-6 and TNF-α expressions, ameliorating insulin production dysfunction and preserving cell viability in MIN6 cells. ConclusionOur study demonstrates that Cd exposure induces an inflammatory response through mtROS-mediated mitochondrial dysfunction. Antagonism of mtROS production might be an effective strategy to prevent pancreatic toxicity from environment-relevant Cd exposure.

Molecular mechanisms responsible for the sexual dimorphism in pancreatic β-cell insulin release

In humans, type 2 diabetes mellitus (T2DM) has a higher incidence in males compared to females, a phenotype recapitulated by many rodent models. While the sex difference in insulin sensitivity partially accounts for this phenomenon, hitherto uncharacterized differences in pancreatic β-cell insulin release strongly contribute. Here we show that stepwise increase in extracellular glucose concentration (2, 5, 7.5, 10, 15, 20 mM) induced electrical activity in β-cells of both sexes with similar glucose sensitivity (Female EC50 =9.45±0.15 mM, Male EC50 =9.42±0.16 mM).

Mechanisms and Active Compounds Polysaccharides and Bibenzyls of Medicinal Dendrobiums for Diabetes Management.

BackgroundMedicinal dendrobiums are used popularly in traditional Chinese medicine for the treatment of diabetes, while their active compounds and mechanism remain unclear. This review aimed to evaluate the mechanism and active compounds of medicinal dendrobiums in diabetes management through a systematic approach.MethodsA systematic approach was conducted to search for the mechanism and active phytochemicals in Dendrobium responsible for anti-diabetic actions using databases PubMed, Embase, and SciFinder.ResultsCurrent literature indicates polysaccharides, bibenzyls, phenanthrene, and alkaloids are commonly isolated in Dendrobium genusin which polysaccharides and bibenzyls are most aboundant. Many animal studies have shown that polysaccharides from the species of Dendrobium provide with antidiabetic effects by lowering glucose level and reversing chronic inflammation of T2DM taken orally at 200 mg/kg. Dendrobium polysaccharides protect pancreatic β-cell dysfunction and insulin resistance in liver. Dendrobium polysaccharides up-regulate the abundance of short-chain fatty acid to stimulate GLP-1 secretion through gut microbiota. Bibenzyls also have great potency to inhibit the progression of the chronic inflammation in cellular studies.ConclusionPolysaccharides and bibenzyls are the major active compounds in medicinal dendrobiums for diabetic management through the mechanisms of lowering glucose level and reversing chronic inflammation of T2DM by modulating pancreatic β-cell dysfunction and insulin resistance in liver as a result from gut microbita regulation.