Pancreatic Dysfunction Research Articles

Surfactin Mitigates a High-Fat Diet and Streptozotocin-Induced Type 2 Diabetes through Improving Pancreatic Dysfunction and Inhibiting Inflammatory Response.

Surfactin from Bacillus amyloliquefaciens fmb50 was utilized to treat mice with type 2 diabetes (T2DM) induced by a high-fat diet/streptozotocin (HFD/STZ). Our group’s earlier research indicated that surfactin could lower blood glucose and mitigate liver dysfunction to further improve HFD/STZ-induced T2DM through modulating intestinal microbiota. Thus, we further investigated the effects of surfactin on the pancreas and colon in mice with T2DM to elucidate the detailed mechanism. In the present study, mice with HFD/STZ-induced T2DM had their pancreatic and colon inflammation, oxidative stress, and endoplasmic reticulum stress (ERS) reduced when given oral surfactin at a dose of 80 mg/kg body weight. According to further research, surfactin also improved glucose metabolism by activating the phosphatidylinositol kinase (PI3K)/protein kinase B (Akt) signaling pathway, further protecting islets β-cell, promoting insulin secretion, inhibiting glucagon release and mitigating pancreas dysfunction. Additionally, after surfactin treatment, the colon levels of the tight junction proteins Occludin and Claudin-1 of T2DM mice were considerably increased by 130.64% and by 36.40%, respectively. These findings revealed that surfactin not only ameliorated HFD/STZ-induced pancreas inflammation and dysfunction and preserved intestinal barrier dysfunction and gut microbiota homeostasis but also enhanced insulin sensitivity and glucose homeostasis in T2DM mice. Finally, in the further experiment, we were able to demonstrate that early surfactin intervention might delay the development of T2DM caused by HFD/STZ, according to critical biochemical parameters in serum.

Clinical, metabolic, and immunological characterisation of adult Ugandan patients with new-onset diabetes and low vitamin D status

BackgroundLow vitamin D concentrations are associated with metabolic derangements, notably insulin resistance and pancreatic beta-cell dysfunction in Caucasian populations. Studies on its association with the clinical, metabolic, and immunologic characteristics in black African adult populations with new-onset diabetes are limited. This study aimed to describe the clinical, metabolic, and immunologic characteristics of a black Ugandan adult population with recently diagnosed diabetes and hypovitaminosis D.MethodsSerum vitamin D concentrations were measured in 327 participants with recently diagnosed diabetes. Vitamin D deficiency, vitamin D insufficiency, and normal vitamin D status were defined as serum 25 hydroxyvitamin D levels of < 20 ng/ml, 21–29 ng/ml, and ≥ 30 ng/ml, respectively.ResultsThe median (IQR) age, glycated haemoglobin, and serum vitamin D concentration of the participants were 48 years (39–58), 11% (8–13) or 96 mmol/mol (67–115), and 24 ng/ml (18–30), respectively. Vitamin D deficiency, vitamin D insufficiency, and normal vitamin D status were noted in 105 participants (32.1%), 140 participants (42.8%), and 82 participants (25.1%), respectively.Compared with those having normal serum vitamin D levels, participants with vitamin D deficiency and insufficiency had higher circulating concentrations of interleukin (IL) 6 (29 [16–45] pg/ml, 23 [14–40] pg/ml vs 18 [14–32] pg/ml, p = 0.01), and IL-8 (24 [86–655] pg/ml, 207 [81–853] pg/ml vs 98 [67–224], p = 0.03). No statistically significant differences were noted in the markers of body adiposity, insulin resistance, and pancreatic beta-cell function between both groups.ConclusionVitamin D deficiency and insufficiency were highly prevalent in our study population and were associated with increased circulating concentrations of pro-inflammatory cytokines. The absence of an association between pancreatic beta-cell function, insulin resistance, and low vitamin D status may indicate that the latter does not play a significant role in the pathogenesis of type 2 diabetes in our adult Ugandan population.

Antihypertensive treatment improves glycemic control in patients with newly diagnosed type 2 diabetes mellitus: A prospective cohort study.

BackgroundType 2 diabetes mellitus (T2DM) is a chronic metabolic disorder involving progressive pancreatic dysfunction. A substantial proportion of patients with T2DM cannot achieve euglycemia despite pharmacologic therapy. Preceding clinical studies have shown that hypertension contributes to glucose dysregulation, and investigators in this study hypothesized that antihypertensive treatment may improve glycemic control in patients with T2DM.MethodsThis prospective cohort study investigates the effect of adding the antihypertensive drug Amlodipine to standard diabetes therapy on serum glycosylated hemoglobin A1c (HbA1c) and lipid profile in patients with newly diagnosed T2DM. The study enrolled a total of 168 participants with newly diagnosed T2DM.ResultsRecipients of additional antihypertensive drug Amlodipine demonstrated significantly lower serum HbA1c (6.62% vs. 7.01%, P = 0.01), systolic blood pressure (132 mm Hg vs. 143 mm Hg, P < 0.001), and diastolic blood pressure (78.9 mm Hg vs. 86.0 mm Hg, P <0.001) compared to recipients of standard diabetes therapy after 24 weeks.ConclusionAntihypertensive treatment with Amlodipine in addition to standard diabetes therapy improves glycemic control in patients with T2DM and may be an appropriate option in people with diabetes and concomitant hypertension to help maintain euglycemia.

Irisin Ameliorates Oxidative Stress-Induced Injury in Pancreatic Beta-Cells by Inhibiting Txnip and Inducing Stat3-Trx2 Pathway Activation.

Lipotoxicity can lead to beta-cell dysfunction and apoptosis because it induces oxidative stress. Recent studies have found that Irisin prevents pancreatic beta-cell dysfunction induced by palmitic acid (PA). However, an association between the protection against oxidative stress conferred by Irisin and beta-cell dysfunction has not been fully elucidated. In this study, we observed that Irisin treatment prevented INS-1 cell apoptosis induced by PA treatment and preserved the insulin-secreting function of INS-1 cells in vitro. These effects probably resulted from the Irisin-induced decrease in intracellular ROS levels triggered by PA treatment. In addition, PA treatment induced oxidative stress partially by inhibiting the activation of thioredoxin 2 (Trx2) through its increase of thioredoxin-interacting protein (Txnip) expression. However, Irisin administration blocked the increase in Txnip expression, which reversed the PA-induced inactivation of Trx2. Irisin also increased the nuclear translocation of Stat3, and the inhibition of Stat3 by siRNAs blocked Irisin-induced Trx2 expression, indicating that both Txnip and Stat3 are involved in Irisin-induced activation of Trx2. Furthermore, blockade of Stat3 by siRNAs led to the decreased gene expression of MafA and Ins and to cessation of glucose-induced insulin secretion that had been enhanced by Irisin. In vivo, HFD treatment led to reduced glucose tolerance and an increase in the level of the oxidative marker malondialdehyde (MDA) compared to that in the control group. However, these effects were ameliorated by Irisin injection due to the inhibition of beta-cell apoptosis and the activation of Trx2, probably through Txnip inhibition and Stat3 activation. In conclusion, our results reveal a possible mechanism for Irisin-induced beta-cell protection, which is mediated through Txnip inhibition and activation of the Stat3-Trx2 pathway.

Long Noncoding RNA-5657 Inhibits the Proliferation of Pancreatic Cells and Insulin Secretion in Gestational Diabetes by Inhibiting the NADPH Oxidase 4 (NOX4)

Multiple comorbidities are observed during pregnancy and there are many challenges for pregnant women with a previous history of diabetes. Pancreatic β-cell dysfunction is associated with gestational diabetes mellitus (GDM). This study intends to explore LncRNA-5657’s effect on proapoptotic cell proliferation and insulin secretion in gestational diabetes. Real-time quantitative fluorescence PCR measured LncRNA-5657 expression in GDM patient placental tissues along with analysis of cell activity, proliferation and insulin secretion by MTT assay, BrdU staining and ELISA. The relation between LncRNA-5657 and NOX4 was assessed by dual luciferase reporter assay. LncRNA-5657 was overexpressed in placental tissue of GDM patients compared to normal pregnant women. LncRNA-5657 overexpression promoted cell proliferation and insulin secretion, which was reversed by LncRNA-5657 downregulation. In addition, LncRNA-5657 negatively regulated NOX4 expression. Overexpression of NOX4 abolished the effect of LncRNA-5657 mimics on pancreatic β-cells, and knockdown of LncRNA-5657 promoted insulin secretion by upregulating NOX4 expression. In conclusion, LncRNA-5657 inhibits insulin secretion and β-cell proliferation by targeting NOX4, indicating that LncRNA-5657 might be a novel target for the treatment of GDM.

Voluntary Physical Activity Prevents Pancreatic Cancer Cachexia, Immobility, And Dysfunction

Voluntary Physical Activity Prevents Pancreatic Cancer Cachexia, Immobility, And Dysfunction

343.9: Longitudinal Monitoring of Pancreas and Kidney Transplant Recipients Using Donor-Derived Cell-Free DNA

Introduction: Donor-derived cell-free DNA (dd-cfDNA) is validated for allograft surveillance in kidney transplant recipients; however, the utility in patients undergoing pancreas and kidney (PTx) transplantation has not been well studied. Pancreatic rejection remains a major clinical concern, yet diagnosis relies on pancreatic biopsy which is associated with significant risk of procedural complications. Early identification of allograft injury is imperative to optimize treatment and intervention. Here, we describe dd-cfDNA levels in PTx transplant recipients in the setting of clinical stability and immunological events. Methods: PTx recipients were monitored longitudinally with dd-cfDNA (AlloSure, CareDx) at the discretion of the treating physician. dd-cfDNA was collected in tandem with standard of care laboratory testing including serum creatinine, amylase, lipase, DSA and BK PCR. Pancreatic graft dysfunction was defined by elevations in serum amylase/lipase or dysregulated glucose control. The reference population was defined by stable allograft function in the absence of immunological or clinical events. Immunological events were defined as clinically suspected allograft rejection or documented subtherapeutic immunosuppression. Results: A total of 16 PTx patients were monitored longitudinally with dd-cfDNA, including 15 SPK recipients and 1 pancreas after kidney transplant (Table 1). 12 patients met criteria for the stable reference population with a median dd-cfDNA level of 0.22% (IQR 0.12 – 0.36%, n=248). There was a trend towards increased variability in dd-cfDNA levels in the first 2 months post-transplant, after which there was no significant difference in dd-cfDNA stratified by time (Figure 1A). 4 patients developed 6 independent immunological events, which were associated with a significantly increased median dd-cfDNA level of 1.15% (IQR 0.15 – 1.85%) compared to 0.22% in the reference population (p = 0.03, Figure 1B). Conclusions: In stable PTx recipients, dd-cfDNA levels remain low post-transplant and reflect the reference ranges validated in kidney transplant alone. Early variability in dd-cfDNA levels may be explained by recovery from ischemia reperfusion injury. Significant increases in dd-cfDNA were associated with immunological events including clinically suspected allograft rejection, highlighting its utility in longitudinal graft surveillance.

Angiotensin-(1–7) Restores Microcirculation Profiles in Acute Pancreatitis

The aim of this study was to investigate whether angiotensin (Ang)-(1-7)-mediated restoration of pancreatic microcirculation profiles and endothelial injury is associated with the expression of telomerase reverse transcriptase (TERT). Wild-type, TERT transgene, and TERT knockdown mice were used in this study, and acute pancreatitis model was induced by intraperitoneal injection of cerulein and lipopolysaccharide (LPS). Pancreatitis was confirmed by histopathology and serum amylase levels. Pancreatic microcirculation function was assessed by laser Doppler. Endothelial injury model was established by exposing endothelial cells to LPS. Proinflammatory cytokines were detected using enzyme-linked immunosorbent assay, endothelial permeability was detected using transwell assay, and mitochondrial dysfunction and mitochondrial reactive oxygen species (mtROS) were determined by performing confocal microscopy. The effects of Ang-(1-7) in the treatment of pancreatic microcirculation dysfunction were associated with TERT expression. In addition, Ang-(1-7) protected against endothelial cell lesions via inhibiting the increase in endothelial cell permeability and release of proinflammatory cytokines in a TERT-dependent manner. Furthermore, TERT was involved in Ang-(1-7)-mediated attenuation of mitochondrial dysfunction and mtROS in LPS-induced endothelial cells. Angiotensin-(1-7) restores pancreatic microcirculation profiles and reverses endothelial injury by inhibiting mtROS production and mitochondrial dysfunction in a TERT-dependent manner.

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.

Inflammatory Cytokines Rewire the Proinsulin Interaction Network in Human Islets.

Aberrant biosynthesis and secretion of the insulin precursor proinsulin occurs in both type I and type II diabetes. Inflammatory cytokines are implicated in pancreatic islet stress and dysfunction in both forms of diabetes, but the mechanisms remain unclear. We sought to determine the effect of the diabetes-associated cytokines on proinsulin folding, trafficking, secretion, and β-cell function. Human islets were treated with interleukin-1β and interferon-γ for 48 hours, followed by analysis of interleukin-6, nitrite, proinsulin and insulin release, RNA sequencing, and unbiased profiling of the proinsulin interactome by affinity purification-mass spectrometry. Cytokine treatment induced secretion of interleukin-6, nitrites, and insulin, as well as aberrant release of proinsulin. RNA sequencing showed that cytokines upregulated genes involved in endoplasmic reticulum stress, and, consistent with this, affinity purification-mass spectrometry revealed cytokine induced proinsulin binding to multiple endoplasmic reticulum chaperones and oxidoreductases. Moreover, increased binding to the chaperone immunoglobulin binding protein was required to maintain proper proinsulin folding in the inflammatory environment. Cytokines also regulated novel interactions between proinsulin and type 1 and type 2 diabetes genome-wide association studies candidate proteins not previously known to interact with proinsulin (eg, Ataxin-2). Finally, cytokines induced proinsulin interactions with a cluster of microtubule motor proteins and chemical destabilization of microtubules with Nocodazole exacerbated cytokine induced proinsulin secretion. Together, the data shed new light on mechanisms by which diabetes-associated cytokines dysregulate β-cell function. For the first time, we show that even short-term exposure to an inflammatory environment reshapes proinsulin interactions with critical chaperones and regulators of the secretory pathway.

Adiponectin gene therapy prevents islet loss after transplantation

Significant pancreatic islet dysfunction and loss shortly after transplantation to the liver limit the widespread implementation of this procedure in the clinic. Nonimmune factors such as reactive oxygen species and inflammation have been considered as the primary driving force for graft failure. The adipokine adiponectin plays potent roles against inflammation and oxidative stress. Previous studies have demonstrated that systemic administration of adiponectin significantly prevented islet loss and enhanced islet function at post‐transplantation period. In vitro studies indicate that adiponectin protects islets from hypoxia/reoxygenation injury, oxidative stress as well as TNF‐α‐induced injury. By applying adenovirus mediated transfection, we now engineered islet cells to express exogenous adiponectin gene prior to islet transplantation. Adenovirus‐mediated adiponectin transfer to a syngeneic suboptimal islet graft transplanted under kidney capsule markedly prevented inflammation, preserved islet graft mass and improved islet transplant outcomes. These results suggest that adenovirus‐mediated adiponectin gene therapy would be a beneficial clinical engineering approach for islet preservation in islet transplantation.

Characterisation of an Atrx Conditional Knockout Mouse Model: Atrx Loss Causes Endocrine Dysfunction Rather Than Pancreatic Neuroendocrine Tumour.

Simple SummaryATRX and DAXX mutations occur in 30–40% of pancreatic neuroendocrine tumours (PanNETs), and there are no reports in the literature of any genetically engineered mouse model (GEMM) evaluating the effect of Atrx disruption as a putative driver event on PanNET initiation. We created a novel GEMM with Atrx conditional disruption in β cells. We observed that this genetic alteration, per se, was not tumourigenic, but we reported novel roles of Atrx on endocrine function, which resulted in dysglycaemia and the exacerbation of inflammageing (increased pancreatic inflammation and hepatic steatosis).ATRX is a chromatin remodeller that maintains telomere homeostasis. Loss of ATRX is described in approximately 10% of pancreatic neuroendocrine tumours (PanNETs) and associated with poorer prognostic features. Here, we present a genetically engineered mouse model (GEMM) addressing the role of Atrx loss (AtrxKO) in pancreatic β cells, evaluating a large cohort of ageing mice (for up to 24 months (mo.)). Atrx loss did not cause PanNET formation but rather resulted in worsening of ageing-related pancreatic inflammation and endocrine dysfunction in the first year of life. Histopathological evaluation highlighted an exacerbated prevalence and intensity of pancreatic inflammation, ageing features, and hepatic steatosis in AtrxKO mice. Homozygous floxed mice presented hyperglycaemia, increased weights, and glucose intolerance after 6 months, but alterations in insulinaemia were not detected. Floxed individuals presented an improper growth of their pancreatic endocrine fraction that may explain such an endocrine imbalance. A pilot study of BRACO-19 administration to AtrxKO mice resulted in telomere instability, reinforcing the involvement of Atrx in the maintenance of β cell telomere homeostasis. Thereby, a non-obese dysglycaemic GEMM of disrupted Atrx is here presented as potentially useful for metabolic studies and putative candidate for inserting additional tumourigenic genetic events.

Jiedutongluotiaogan formula restores pancreatic function by suppressing excessive autophagy and endoplasmic reticulum stress

Context Jiedutongluotiaogan formula (JTTF), a traditional Chinese medicine (TCM), could promote islet function. However, the potential effect of JTTF on endoplasmic reticulum stress (ERS) and autophagy have not been reported. Objective This study explores the potential effect of JTTF on ERS and autophagy in the pancreas. Materials and methods The Zucker diabetic fatty (ZDF) rats were randomised into five groups, control, model, JTTF (1, 3, 5 g/kg/day for 12 weeks). LPS induced pancreatic β-cells were treated with JTTF (50, 100, 200 μg/mL). LPS was used to induce pancreatic β-cell injury, with cell viability and insulin secretion evaluated using MTT, glucose-stimulated insulin secretion (GSIS) assays, and PCR. Intracellular Ca2+ concentration was measured using flow cytometry, while ERS and autophagy levels were monitored via Western blotting and/or immunostaining. Results Compared with the model group, body weight, FGB, HbA1c, IPGTT, FINs, and HOMA-IR in JTTF treatment groups were significantly reduced. In islets cells treated with JTTF, the pancreatic islet cells in the JTTF group were increased, lipid droplets were reduced, and there was a decrease in Ca2+ (16.67%). After JTTF intervention, PERK, p-PERK, IRE1α, p- IRE1α, ATF6, eIF2α, GRP78, p-ULK1, LC3 and p62 expression decreased, whereas Beclin1and p-mTOR expression increased. In addition, the expression of proteins related to apoptosis in the JTTF groups were lower than those in the control group. Discussion and conclusions JTTF may alleviate pancreatic β-cell injury by inhibiting ER stress and excessive autophagy in diabetic rats. This provides a new direction for treating diabetes and restoring pancreatic dysfunction by TCM.

Swietenine and swietenolide from Swietenia macrophylla king improve insulin secretion and attenuate apoptosis in H2 O2 induced INS-1 cells.

Oxidative stress is an important factor that causes pancreatic β-cell dysfunction leading to the development and aggravation of diabetes. Swietenine (Stn) and swietenolide (Std) were isolated from the fruits of Swietenia macrophylla King and had the potential effects on treatment and prevention of diabetes. The aim of this study is to investigate the effects of Stn and Std on insulin secretion and apoptosis in H2 O2 induced insulinoma cell line (INS-1) cells. In the present study, INS-1 cells were treated with 300 μM H2 O2 for 4h to establish the oxidative damage model. Cell apoptosis, insulin secretion, reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels, and Caspase-3 enzyme activity were measured via corresponding methods. Finally, pancreatic duodenal home box factor-1 (PDX-1), B cell lymphoma-2 (Bcl-2), and Bax protein expression were detected by western blot. Experimental results showed that Stn and Std could significantly improve the INS-1 cell viability, increase the secretion of insulin and reduce the ROS level in H2 O2 induced INS-1 cells. Furthermore, the SOD and GSH levels increased, and the MDA levels decreased compared with the model group after Stn and Std treatment. In addition, after treated with Stn and Std, cell apoptosis was improved, and the activity of Caspase 3 was also significantly inhibited. Meanwhile, Western blot results showed that Stn and Std could up-regulate the expression of PDX-1 protein, and affect the cell apoptosis pathway by up-regulating the expression of Bcl-2 protein and down-regulating the expression of Bax protein. In conclusion, Stn and Std can signifcantly improve the insulin secretion function, protect oxidative stress injury, and reduce apoptosis in H2 O2 induced INS-1 cells, which provides a research basis for Stn and Std to be new drug candidates for the treatment and prevention of diabetes.

Cadmium induces ferroptosis mediated inflammation by activating Gpx4/Ager/p65 axis in pancreatic β-cells

Cadmium (Cd) is a widely distributed endocrine disruptor and has been reported to be closely correlated to the pathogenesis of diabetes. Since pancreatic β-cells loss and dysfunction are central to pathogenesis of diabetes, studying Cd toxicity on pancreatic β-cells and its molecular mechanism is an important scientific issue. However, less attention has been payed to study how Cd induces pancreatic β-cells death and dysfunction in recent years. Thus, our study aims to explore the toxic mechanism of Cd treatment on pancreatic β-cells using both cellular and animal models. Firstly, it was confirmed that Cd induced decreased cell viability and insulin secretion in a dose-and time-dependent manner in MIN6 cells. To explore the underlying mechanism, transcriptomic analysis was employed to screen the differentially expressed genes and disturbed metabolic pathways. Go and KEGG analysis showed that Cd exposure triggered ferroptosis process in MIN6 cells. We further validated that Cd led to GSH depletion, Gpx4 reduction, lipid peroxidation, mitochondrial membrane potential loss and ultrastructural damage at mitochondrial level. Since immune system process was also perturbed based on GO analysis, we found that Cd activated Ager/Pkc/p65 inflammatory process. Moreover, ferroptosis inhibitor Fer-1 could effectively antagonized the activation of Ager-mediated immune process. It was also revealed that Cd induced iron accumulation as well as decreased Gpx4 expression in mice islets. We also uncovered that Cd led to systemic and pancreatic inflammation as early as third week after Cd exposure. Our study emphasizes the importance of ferroptotic cell death on Cd-induced systemic chronic inflammation. A novel target is provided to prevent Cd-induced pancreatic β-cells dysfunction and improve the chronic inflammatory state for prediabetes prevention.

Fic-mediated AMPylation tempers the unfolded protein response during physiological stress

The proper balance of synthesis, folding, modification, and degradation of proteins, also known as protein homeostasis, is vital to cellular health and function. The unfolded protein response (UPR) is activated when the mechanisms maintaining protein homeostasis in the endoplasmic reticulum become overwhelmed. However, prolonged or strong UPR responses can result in elevated inflammation and cellular damage. Previously, we discovered that the enzyme filamentation induced by cyclic-AMP (Fic)can modulate the UPR response via posttranslational modification of binding immunoglobulin protein (BiP) by AMPylation during homeostasis and deAMPylation during stress. Loss of fic in Drosophila leads to vision defects and altered UPR activation in the fly eye. To investigate the importance of Fic-mediated AMPylation in a mammalian system, we generated a conditional null allele of Fic in mice and characterized the effect of Fic loss on the exocrine pancreas. Compared to controls, Fic-/- mice exhibit elevated serum markers for pancreatic dysfunction and display enhanced UPR signaling in the exocrine pancreas in response to physiological and pharmacological stress. In addition, both fic-/- flies and Fic-/- mice show reduced capacity to recover from damage by stress that triggers the UPR. These findings show that Fic-mediated AMPylation acts as a molecular rheostat that is required to temper the UPR response in the mammalian pancreas during physiological stress. Based on these findings, we propose that repeated physiological stress in differentiated tissues requires this rheostat for tissue resilience and continued function over the lifetime of an animal.

Association of SLC30A8 (rs13266634) and GLIS3 (rs7034200) gene variant in development of type 2 diabetes mellitus in Indian population: A case-control study

ObjectiveType 2 diabetes mellitus (T2DM) is a chronic disorder characterized by pancreatic beta-cell dysfunction and insulin resistance because of unsettled hyperglycemia. The present study was designed to understand the association of genetic variations in SLC30A8 and GLIS3 genes with T2DM. MethodA total of 600 samples were taken with 400 T2DM cases (240 males and 160 females; mean age 42.4 ± 9.3) and 200 control cases (130 males and 70 females; mean age 40.7 ± 8.2) in the study from regions across North India. A genetic study was conducted by PCR-RFLP methods. P parametric and non-parametric tests were used to analyze the data based on the qualitative and quantitative data. ResultsSignificant difference was found in biochemical parameters and sedentary lifestyle compared between T2DM patients and healthy controls such as triglycerides, HbA1c, T-cholesterol, LDL-C, BMI, systolic and diastolic BP, PPG, FPG, weight loss, fatigue, slow wound healing, blur vision, urination, appetite, urination, consumption of alcohol, non-veg, fast food and sugary drink, excessive consumption of calorie, normal and brisk (20 min) walk, prolonged sitting 3 h work, leisure sitting (3 h) and standing work (3 h) while no significant differences were observed in parameters such as HDLC, WHR, family history, household chores and exercise among T2DM patients and controls. In SLC30A8 rs13266634 variant, it was observed that TC and CC genotypes frequencies were significantly higher in T2DM cases as compared to healthy controls (OR- 2.88; 95%CI- 1.93–4.31; p < 0.0001 and OR- 5.6; 95%CI- 2.33–13.55; p = 0.0001). C allele frequency was higher as compared to healthy controls. For the GLIS3 rs7034200 variant, no significant difference was found in allelic frequency in cases and controls (p-0.434). We did not find any significant association of T2DM with GLIS3 gene variant under dominant as well as recessive models. ConclusionPresent study concludes that the association of genetic variations between T2DM cases and control was found to have a significant difference and play a vital role in T2DM risk based on odds ratio. However, the difference in frequency of alleles in the GLIS3 variant was non-significant among T2DM patients and healthy controls.

Hepatogenous diabetes: Knowledge, evidence, and skepticism.

The diabetogenic potential of liver cirrhosis (LC) has been known for a long time, and the name "hepatogenous diabetes" (HD) was coined in 1906 to define the condition. Diabetes mellitus (DM) that develops as a consequence of LC is referred to as HD. In patients with LC, the prevalence rates of HD have been reported to vary from 21% to 57%. The pathophysiological basis of HD seems to involve insulin resistance (IR) and pancreatic β-cell dysfunction. The neurohormonal changes, endotoxemia, and chronic inflammation of LC initially create IR; however, the toxic effects eventually lead to β-cell dysfunction, which marks the transition from impaired glucose tolerance to HD. In addition, a number of factors, including sarcopenia, sarcopenic obesity, gut dysbiosis, and hyperammonemia, have recently been linked to impaired glucose metabolism in LC. DM is associated with complications and poor outcomes in patients with LC, although the individual impact of each type 2 DM and HD is unknown due to a lack of categorization of diabetes in most published research. In fact, there is much skepticism within scientific organizations over the recognition of HD as a separate disease and a consequence of LC. Currently, T2DM and HD are being treated in a similar manner although no standardized guidelines are available. The different pathophysiological basis of HD may have an impact on treatment options. This review article discusses the existence of HD as a distinct entity with high prevalence rates, a strong pathophysiological basis, clinical and therapeutic implications, as well as widespread skepticism and knowledge gaps.

Congenital etiologies of exocrine pancreatic insufficiency.

Congenital exocrine pancreatic insufficiency is a rare condition. In a vast majority of patients, exocrine dysfunction occurs as part of a multisystemic disease, the most prevalent being cystic fibrosis and Shwachman-Bodian-Diamond syndrome. Recent fundamental studies have increased our understanding of the pathophysiology of these diseases. Exocrine pancreatic dysfunction should be considered in children with failure to thrive and fatty stools. Treatment is mainly supportive and consists of pancreatic enzyme replacement and liposoluble vitamins supplementation.

PKCβ Inhibition Promotes TXNIP Degradation to Ameliorate Pancreatic β-Cell Dysfunction

Introduction: Pancreatic β-cell dysfunction is largely regulated by TXNIP accumulation, we have previously disclosed the role of PKA in TXNIP degradation during β-cell dysfunction. However, whether other kinases (PKCs) still regulate TXNIP is unclear, which is beneficial to alleviate β-cell dysfunction. Methods: Thapsigargin (ER stress inducer) was used to induce β-cell dysfunction. PKC’s inhibitors were screened by Western blotting indicated by TXNIP. Also RT-qPCR and Co-immunoprecipitation were applied for evaluating the β-cell improvement ability of PKC’s inhibitors, and the insulin secretion ability was evaluated by glucose-stimulated insulin secretion assay. Results: PKC’s pan-inhibitor, Ro31-8220, decreased β-cell apoptosis and improved insulin secretion under ER stress or high glucose (HG) conditions. Further studies showed that Ro31-8220 reduced ER stress or HG-induced TXNIP levels. On the other side, PKCβ activation or overexpression could reverse the effect of Ro31-8220 on TXNIP. Also, PKCβ selective inhibitor, ruboxistaurin, induced TXNIP degradation as significantly as Ro31-8220 did. Conclusion: This study reveals the regulating mechanism of PKCβ inhibitor on TXNIP degradation to improve β-cell dysfunction. These data indicated PKCβ inhibitor is a promising agent for ameliorating β-cell dysfunction through TXNIP.