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After an attack of pancreatitis, individuals may develop metabolic sequelae (eg, new-onset diabetes) and/or pancreatic cancer. These new-onset morbidities are, at least in part, driven by low-grade inflammation. The aim was to study the profiles of cytokines/chemokines in individuals after an attack of pancreatitis. A commercially available panel including 31 cytokines/chemokines was investigated. Random forest classifier and unsupervised hierarchical clustering were applied to study participants (who had no persistent organ failure and did not require ICU admission) according to their cytokine/chemokine profiles. Pancreatitis-related characteristics, detailed body composition (determined using 3.0 T magnetic resonance imaging), markers of glucose, lipid, and iron metabolism, gut and pancreatic hormones, as well as liver and pancreatic enzymes, were compared between clusters. Bootstrap validation was employed. A total of 160 participants, including 107 postpancreatitis individuals (investigated at a median of 18 months after the last attack of pancreatitis) and 53 healthy volunteers, were studied. Twenty-two cytokines/chemokines were significantly different between postpancreatitis and health. Two distinct endotypes of individuals after an attack of pancreatitis were identified-‟inflammatory" and ‟noninflammatory." Sixteen cytokines/chemokines were significantly higher in the inflammatory endotype compared with the noninflammatory endotype. No cytokine/chemokine was significantly higher in the noninflammatory endotype. The inflammatory endotype was characterized by significantly elevated insulin (P= 0.001), glucose-dependent insulinotropic peptide (P = 0.001), peptide YY (P = 0.017), and ghrelin (P = 0.014). The noninflammatory endotype was characterized by significantly elevated hepcidin (P= 0.016). Pancreatitis-related factors, body composition, and other studied parameters did not differ significantly between the 2 endotypes. Individuals with a similar phenotype and clinical course of pancreatitis have differing cytokine/chemokine profiles after clinical resolution of the disease. People with the inflammatory endotype have distinct changes in the pancreatic and gut hormones known to be involved in the pathogenesis of new-onset morbidities after an attack of pancreatitis.

To investigate the factors associated with the circulating levels of oxyntomodulin in healthy individuals and individuals after an episode of acute pancreatitis (AP).Blood samples were collected from all participants after an overnight fast and analyzed for 28 biomarkers. Participants also underwent comprehensive body composition analysis on a 3-T magnetic resonance imaging scanner. Regression analyses were done to investigate the associations between oxyntomodulin and the studied factors.The study included 105 individuals who had a primary diagnosis of AP and 58 healthy individuals. Peptide YY (B coefficient, 0.094; 95% confidence interval [95% CI], 0.164-0.123), pancreatic polypeptide (0.048; 95% CI, 0.030-0.066), and leptin (0.394; 95% CI, 0.128-0.661) had significant associations with oxyntomodulin in healthy individuals. Peptide YY was the most prominent factor associated with oxyntomodulin, explaining 60% of its variance in health. Cholecystokinin (0.014; 95% CI, 0.010-0.018), amylin (-0.107; 95% CI, -0.192 to -0.021), and glycated hemoglobin (-0.761; 95% CI, -1.249 to -0.273) had significant associations with oxyntomodulin in individuals after AP. Cholecystokinin was the most prominent factor associated with oxyntomodulin, explaining 44% of its variance after AP.Factors affecting the circulating levels of oxyntomodulin are different in health and after AP. These insights will enable the determination of populations that benefit from oxyntomodulin therapeutics in the future.

Growing body of evidence suggests that intra-pancreatic fat is associated with diabetes but whether distribution of intra-pancreatic fat across the regions of the pancreas has a pathophysiologic role is unknown. The study aimed to investigate the differences in intra-pancreatic fat deposition between the head, body, and tail of the pancreas, as well as the relationship between regional intra-pancreatic fat deposition and diabetes status and insulin traits. A total of 368 adults from the general population underwent magnetic resonance imaging on a 3 T scanner and intra-pancreatic fat was manually quantified in duplicate. Statistical models were adjusted for age, sex, ethnicity, body mass index, and liver fat. Intra-pancreatic fat deposition in the head, body, and tail of the pancreas did not differ significantly in adjusted models, in both the overall cohort and the three subgroups based on diabetes status. HOMA-IR and fasting insulin were significantly positively associated with fat in the tail and body of the pancreas. There was no significant association between regional intra-pancreatic fat and HOMA-β. The association of increased intra-pancreatic fat deposition in the tail and body regions with increased insulin resistance may have an important role in the early identification of patients at risk for developing insulin resistance and diseases that stem from it.

Acute pancreatitis (AP) is the largest contributor to diabetes of the exocrine pancreas. However, there is no accurate predictor at the time of hospitalisation for AP to identify individuals at high risk for new-onset diabetes.To investigate the accuracy of indices of glucose variability (GV) during the early course of AP in predicting the glycated haemoglobin (HbA1c) trajectories during follow-up.This was a prospective longitudinal cohort study of patients without diabetes at the time of hospitalisation for AP. Fasting blood glucose was regularly measured over the first 72 h of hospital admission. The study endpoint was the HbA1c trajectories - high-increasing, moderate-stable, normal-stable - over two years of follow-up. Multinomial logistic regression analyses were conducted to investigate the associations between several common GV indices and the HbA1c trajectories, adjusting for covariates (age, sex, and body mass index). A sensitivity analysis constrained to patients with non-necrotising AP was conducted.A total of 120 consecutive patients were studied. All patients in the high-increasing HbA1c trajectory group had new-onset diabetes at 18 and 24 months of follow-up. Glycaemic lability index had the strongest significant direct association (adjusted odds ratio = 13.69; p = 0.040) with the high-increasing HbA1c trajectory. High admission blood glucose, standard deviation of blood glucose, and average real variability significantly increased the patients' odds of taking the high-increasing HbA1c trajectory by at least two-times. Admission blood glucose, but not the other GV indices, had a significant direct association (adjusted odds ratio = 1.46; p = 0.034) with the moderate-stable HbA1c trajectory. The above findings did not change materially in patients with non-necrotising AP alone.High GV during the early course of AP gives a prescient warning of worsening HbA1c pattern and new-onset diabetes after hospital discharge. Determining GV during hospitalisation could be a relatively straightforward approach to early identification of individuals at high risk for new-onset diabetes after AP.

Insulin resistance is a well-known derangement after an attack of pancreatitis but the role of dietary fat intake and intra-pancreatic fat deposition (IPFD) in it is unknown. We aimed to investigate the relationship of dietary fat intake with markers of insulin resistance in individuals after acute pancreatitis, taking into account IPFD.This was a cross-sectional study. The EPIC-Norfolk food frequency questionnaire was used to determine the habitual intake of saturated, monounsaturated, polyunsaturated fatty acids. The studied markers of insulin resistance were fasting insulin, HOMA-IR, and METS-IR. 3 T magnetic resonance imaging was used to quantify IPFD. Linear regression analysis, with adjustment for possible confounders, was performed.A total of 111 individuals after acute pancreatitis (33 low IPFD, 40 moderate IPFD, and 38 high IPFD) were included. In the high IPFD group, intake of monounsaturated fatty acids was inversely associated with both fasting insulin, and HOMA-IR, and METS-IR in the unadjusted (β = -65.405, p 0.001; β = -15.762, p 0.001; β = -0.760, p = 0.041, respectively) and fully adjusted models (β = -155.620, p 0.001; β = -34.656, p 0.001, β = -2.008, p = 0.018, respectively). Intake of polyunsaturated or saturated fatty acids did not have a consistently significant pattern of associations with the three markers of insulin resistance. None of the above associations was significant in the low IPFD and moderate IPFD groups.Habitual dietary fat intake is associated with insulin resistance only in individuals after an attack of pancreatitis who have high IPFD. These indviduals may benefit from a calorically balanced diet that is rich in monounsaturated fatty acids.

Background New-onset prediabetes/diabetes after acute pancreatitis (NODAP) is the most common sequela of pancreatitis, and it differs from type 2 prediabetes/diabetes mellitus (T2DM). Aim To study the associations between circulating levels of pancreatic amylase, pancreatic lipase, chymotrypsin and fat phenotypes in NODAP, T2DM, and health. Methods Individuals with NODAP (n = 30), T2DM (n = 30), and sex-matched healthy individuals (n = 30) were included. Five fat phenotypes (intra-pancreatic fat, liver fat, skeletal muscle fat, visceral fat, and subcutaneous fat) were determined using the same magnetic resonance imaging protocol and scanner magnet strength for all participants. One-way analysis of covariance, linear regression analysis, and relative importance analysis were conducted. Results Intra-pancreatic fat deposition (IPFD) was higher in NODAP (9.4% ± 1.8%) and T2DM (9.8% ± 1.1%) compared with healthy controls (7.8% ± 1.9%) after adjusting for covariates (P = 0.003). Similar findings were observed in regards to visceral fat volume (P = 0.005), but not subcutaneous fat volume, liver fat, or skeletal muscle fat. Both IPFD (β = -2.201, P = 0.023) and visceral fat volume (β = -0.004, P = 0.028) were significantly associated with circulating levels of pancreatic amylase in NODAP, but not in T2DM or healthy individuals. Of the five fat phenotypes, IPFD explained the highest amount of variance in pancreatic amylase concentration (R 2 = 15.3% out of 41.2%). None of the phenotypes contributed meaningfully to the variance in pancreatic lipase or chymotrypsin. Conclusion Both NODAP and T2DM are characterized by increased IPFD and visceral fat volume. However, only NODAP is characterized by significant inverse associations between the two fat phenotypes and pancreatic amylase.

Summary Background and aims Exogenous ketone supplementation is emerging as a nutritional intervention that beneficially affects blood glucose control. We hypothesized that varying abdominal fat phenotypes play a role in the effect of exogenously induced ketosis. The aim was to investigate whether intra-abdominal fat distribution modulates the effect of exogenous ketones on glucoregulatory peptides in new-onset prediabetes. Methods Eighteen individuals with new-onset prediabetes after acute pancreatitis were randomized to receive a ketone monoester supplement or placebo in a crossover fashion. All participants underwent magnetic resonance imaging on a 3T scanner to determine their abdominal fat phenotypes. They were non-exclusively categorized as low adiposity or high adiposity phenotypes based on their abdominal and ectopic fat distribution (regardless of body mass index and waist circumference). Blood samples were analyzed for glucoregulatory peptides. Total area under the curve (AUC) over 150 min was calculated for each analyte. Results The total AUCs for insulin and C-peptide were significantly higher after ketone supplementation in individuals with high intra-pancreatic fat deposition, skeletal muscle fat deposition, and subcutaneous fat volume; and low visceral fat volume and intra-hepatic fat deposition. The total AUC for glucose-dependent insulinotropic peptide was significantly higher after ketone supplementation in individuals with high intra-pancreatic fat deposition, skeletal muscle fat deposition, subcutaneous fat volume, and visceral fat volume. The total AUC for glucagon-like peptide-1 was not associated with any adiposity phenotype. Conclusions Individuals with high depositions of intra-pancreatic fat, skeletal muscle fat, subcutaneous fat may not achieve favorable outcomes of blood glucose control following ketone supplementation. Abdominal fat distribution is an important factor in the pathogenesis of new-onset prediabetes and it may influence the effectiveness of nutritional strategies designed for these individuals. Registered under ClinicalTrials.gov identifier no NCT03889210.

BACKGROUND The potential of a ketone monoester (β-hydroxybutyrate; KEβHB) supplement to rapidly mimic a state of nutritional ketosis offers a new therapeutic possibility for diabetes prevention and management. While KEβHB supplementation has a glucose-lowering effect in adults with obesity, its impact on glucose control in other insulin-resistant states is unknown. OBJECTIVES The primary objective was to investigate the effect of KEβHB-supplemented drink on plasma glucose in adults with prediabetes. The secondary objective was to determine its impact on plasma glucoregulatory peptides. METHODS This randomized controlled trial [called CETUS (Cross-over randomizEd Trial of β-hydroxybUtyrate in prediabeteS)] included 18 adults [67% men, mean age = 55 y, mean BMI (kg/m2) = 28.4] with prediabetes (glycated hemoglobin between 5.7% and 6.4% and/or fasting plasma glucose between 100 and 125 mg/dL). Participants were randomly assigned to receive KEβHB-supplemented and placebo drinks in a crossover sequence (washout period of 7-10 d between the drinks). Blood samples were collected from 0 to 150 min, at intervals of 30 min. Paired-samples t tests were used to investigate the change in the outcome variables [β-hydroxybutyrate (βHB), glucose, and glucoregulatory peptides] after both drinks. Repeated measures analyses were conducted to determine the change in concentrations of the prespecified outcomes over time. RESULTS Blood βHB concentrations increased to 3.5 mmol/L within 30 minutes after KEβHB supplementation. Plasma glucose AUC was significantly lower after KEβHB supplementation than after the placebo [mean difference (95% CI): -59 (-85.3, -32.3) mmol/L × min]. Compared with the placebo, KEβHB supplementation led to significantly greater AUCs for plasma insulin [0.237 (0.044, 0.429) nmol/L × min], C-peptide [0.259 (0.114, 0.403) nmol/L × min], and glucose-dependent insulinotropic peptide [0.243 (0.085, 0.401) nmol/L × min], with no significant differences in the AUCs for amylin, glucagon, and glucagon-like peptide 1. CONCLUSIONS Ingestion of the KEβHB-supplemented drink acutely increased the blood βHB concentrations and lowered the plasma glucose concentrations in adults with prediabetes. Further research is needed to investigate the dynamics of repeated ingestions of a KEβHB supplement by individuals with prediabetes, with a view to preventing new-onset diabetes. This trial was registered at www.clinicaltrials.gov as NCT03889210.

Current knowledge of the link between dietary carbohydrate intake and insulin regulation in individuals after an attack of pancreatitis is limited. We aimed to investigate the associations between dietary carbohydrate intake and insulin traits in post-pancreatitis versus healthy individuals, taking into account intrapancreatic fat deposition (IPFD).All participants underwent magnetic resonance imaging (using the same protocol and 3T scanner) to quantify IPFD. Dietary carbohydrate intake was assessed using a validated 131-item food frequency questionnaire. Insulin, HOMA-IR, HOMA-β were determined in the fasted state. Linear regression and effect modification analyses were conducted in unadjusted and adjusted models (accounting for age, sex, body mass index, daily energy intake, use of anti-diabetic medications, and recurrence of acute pancreatitis).The study included 111 post-pancreatitis individuals (categorized into low IPFD (n = 33), moderate IPFD (n = 40), high IPFD (n = 38)) and 47 healthy controls. In the high IPFD group, starch intake was negatively associated with fasting insulin and HOMA-β in both the unadjusted (p 0.001 both) and fully adjusted models (p 0.001 both); and with HOMA-IR in the fully adjusted model (p 0.001) only. Total sugar intake was positively associated with fasting insulin (p = 0.015) and HOMA-β (p = 0.007) in the fully adjusted model but not associated with HOMA-IR. None of the above associations was statistically significant in the low IPFD, moderate IPFD, and healthy controls groups. The studied associations were more pronounced in the high IPFD group but not in the moderate IPFD or low IPFD groups (when compared with the healthy controls group).Dietary carbohydrate intake is differentially associated with insulin traits in individuals after an attack of pancreatitis and the associations are modified by IPFD. These findings will be helpful for the development of dietary guidelines specifically for individuals after an attack of pancreatitis.

Innate-like CD5+ B1a cells localized in serous cavities are activated by innate stimuli, such as lipopolysaccharide (LPS), leading to T cell-independent antibody responses. Although ion channels play crucial roles in the homeostasis and activation of immune cells, the electrophysiological properties of B1a cells have not been investigated to date. Previously, in the mouse B cell lymphoma cells, we found that the voltage-independent two-pore-domain potassium (K2P) channels generate a negative membrane potential and drive Ca2+ influx. Here, we newly compared the expression and activities of K2P channels in mouse splenic follicular B (FoB), marginal zone B (MZB), and peritoneal B1a cells. Next-generation sequencing analysis showed higher levels of transcripts for TREK-2 and TWIK-2 in B1a cells than those in FoB or MZB cells. Electrophysiological analysis, using patch clamp technique, revealed higher activity of TREK-2 with the characteristic large unitary conductance (~ 250 pS) in B1a than that in FoB or MZB cells. TREK-2 activity was further increased by LPS treatment (>2 h), which was more prominent in B1a than that in MZB or FoB cells. The cytosolic Ca2+ concentration of B cells was decreased by high-K+-induced depolarization (ΔRKCl (%)), suggesting the basal Ca2+ influx to be driven by negative membrane potential. The LPS treatment significantly increased the ΔRKCl (%) in B1a, though not in FoB and MZB cells. Our study was the first to compare the K2P channels in mouse primary B cell subsets, elucidating the functional upregulation of TREK-2 and augmentation of Ca2+ influx by the stimulation of Toll-like receptor 4 in B1a cells.

Patients whose tumors harbor oncogene amplification on extrachromosomal DNA (ecDNA) fail to respond to targeted or immune therapy and have poor prognosis. ecDNA are cancer-specific circular fragments of genomic DNA engendered with unique properties, including open chromatin architecture associated with hyper transcription and a predilection for structural variation. In addition, ecDNA+ tumors have tremendous copy number heterogeneity mediated through acentric, non-Mendelian segregation. These properties afford ecDNA+ tumors with unparalleled genomic plasticity permitting circumvention of therapeutic pressure. However, these features also confer heightened levels of DNA replication stress (RS), and we have found that ecDNA amplified tumor cells are hyper-reliant on CHK1, a master regulator of the cellular RS response. We identified CHK1 as an ecDNA essential target in a CRISPR genetic screen using a methotrexate-induced ecDNA amplification model in HeLa cancer cells. ecDNA-dependent cell fitness assessment of CHK1 was confirmed using a flow cytometry-based CRISPR competition assay. The target was further validated using a CHK1 inhibitor (CHK1i) tool compound in MYC-amplified COLO320 isogenic cell lines that demonstrated a 10-fold enhanced cytotoxicity in the ecDNA amplified setting.Based on these results, we developed a highly potent, selective, and orally bioavailable CHK1i optimized as an ecDNA-directed therapeutic (ecDTx). An advanced lead, BBI-cmpd1, robustly induced RS biomarkers (e.g., pRPA) in ecDNA+ COLO320 tumor cells as compared to matched chromosomally-amplified (ecDNA-) COLO320 cells, consistent with the increased reliance on CHK1 to manage elevated RS in the ecDNA amplified setting. BBI-cmpd1 demonstrated potent anti-proliferative activity against a panel of ecDNA+ oncogene amplified tumor lines as compared to non-amplified lines demonstrating oncogene and indication agnostic efficacy in ecDNA-based tumors. Oral administration of BBI-cmpd1 resulted in on-target activity against CHK1 and anti-tumor activity in an ecDNA oncogene amplified tumor model in vivo. These findings support the clinical utility of potent, selective, and oral CHK1i to address the significant unmet need driven by ecDNA oncogene amplified cancers. Citation Format: Sudhir Chowdhry, Snezana Milutinovic, Edison Tse, Salvador Garcia, Dean Perusse, Melissa Ritland, Juyeon Ko, Deepti Wilkinson, Kristen Turner, Auzon Steffy, Joshua Plum, Ben Norman, AnnMarie Pferdekamper, Todd Meyer, Debbie Liao, Rachelle Elsdon, Joshua Lange, Anthony Pinkerton, Ryan Hansen, Christian Hassig, Shailaja Kasibhatla. Tumors driven by oncogene amplified extrachromosomal DNA (ecDNA) demonstrate enhanced sensitivity to cell cycle checkpoint kinase 1 (CHK1) inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1626.

Functional food ingredients from natural sources are gaining popularity for treating chronic inflammation associated with metabolic diseases (e.g., diabetes, hypertension, and obesity) due to their lower toxicity and no severe side effects. Pigmented rice is a natural food source in Korea commonly consumed in the whole grain form to improve the immune system. In particular, pigmented rice bran contains various nutritional components involved in the immune benefits. Of many nutrients in pigmented rice bran, anthocyanins, gamma-oryzanol, and arabinoxylan have notably shown to enhance natural killer cell activity and reduce pro-inflammatory cytokines. Especially, pigmented rice has higher amounts of anthocyanins and gamma-oryzanol than white rice. In this review, to provide further insight into the immune effects of the pigmented rice, we have focused on the immune benefits of bioactive substances (e.g., anthocyanins, gamma-oryzanol, and arabinoxylan) from pigmented rice compared to white rice. The pigmented rice has potential effects on immunity, and it can be used as a functional food.

Background: People with prediabetes often have altered iron metabolism and may benefit from mild exogenous ketosis, which can now be successfully achieved thanks to recent developments in chemistry of food components. Objective: The objective was to investigate the effect of acute exogenous ketone monoester (β-hydroxybutyrate) on plasma levels of markers of iron metabolism in people with prediabetes. Methods: Eighteen participants with new-onset prediabetes after acute pancreatitis aged 18 years or above took part in randomised controlled cross-over trial in Auckland, New Zealand. After an overnight fast, participants consumed the exogenous ketone supplement or placebo. Blood samples were collected in the fasted state (0 minutes) and then serially every 30 minutes for 150 minutes. Both participants and study personnel were blinded to the intervention/placebo allocation. Repeated measures analysis of variance was performed using total area under the curve to determine the change in hepcidin and ferritin over time after consumption of the exogenous ketone supplement and placebo. Results: Consumption of the exogenous ketone supplement significantly elevated blood levels of β-hydroxybutyrate from 0.20 mmol L-1 at baseline to 3.50 mmol L-1 at 30 minutes (p < 0.05) and remained significantly elevated for the duration of the trial. The total area under the curve of hepcidin was 340.5 ± 121.1 ng mL-1 after the exogenous ketone supplementation as compared with 343.2 ± 119.6 ng mL-1 min-1 after the use of placebo (p = 0.91). The total area under the curve of ferritin was 786.7 ± 129.1 ng mL-1 min-1 after the exogenous ketone supplementation as compared with 776.9 ± 131.4 ng mL-1 min-1 after the use of placebo (p = 0.10). Conclusion: Acute supplementation of β-hydroxybutyrate did not significantly affect the circulating levels of hepcidin or ferritin in people with prediabetes. Long-term effects of β-hydroxybutyrate warrant investigations in the future.

Aims/hypothesis The clinical importance of fat deposition in the liver and pancreas is increasingly recognised. However, to what extent deposition of fat in these two depots is affected by intermediate variables is unknown. The aim of this work was to conduct a mediation analysis with a view to uncovering the metabolic traits that underlie the relationship between liver fat and intrapancreatic fat deposition (IPFD) and quantifying their effect. Methods All participants underwent MRI/magnetic resonance spectroscopy on the same 3.0 T scanner to determine liver fat and IPFD. IPFD of all participants was quantified manually by two independent raters in duplicate. A total of 16 metabolic traits (representing markers of glucose metabolism, incretins, lipid panel, liver enzymes, pancreatic hormones and their derivatives) were measured in blood. Mediation analysis was conducted, taking into account age, sex, ethnicity and BMI. Significance of mediation was tested by computing bias-corrected bootstrap CIs with 5000 repetitions. Results A total of 353 individuals were studied. Plasma glucose, HDL-cholesterol and triacylglycerol mediated 6.8%, 17.9% and 24.3%, respectively, of the association between liver fat and IPFD. Total cholesterol, LDL-cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, insulin, glucagon, amylin, C-peptide, HbA1c, glucagon-like peptide-1 and gastric inhibitory peptide did not mediate the association between liver fat and IPFD. Conclusions/interpretation At least one-quarter of the association between liver fat and IPFD is mediated by specific blood biomarkers (triacylglycerol, HDL-cholesterol and glucose), after accounting for potential confounding by age, sex, ethnicity and BMI. This unveils the complexity of the association between the two fat depots and presents specific targets for intervention. Graphical abstract

Increased intrapancreatic fat deposition (IPFD) has emerged as a harbinger of pancreatic cancer and chronic pancreatitis. Although it is well recognized that diseases of the exocrine pancreas often lie on a continuum (with acute pancreatitis preceding the development of chronic pancreatitis and/or pancreatic cancer), whether increased IPFD predisposes to acute pancreatitis is unknown. This study aimed to compare fat depositions in the pancreas (as well as the liver and skeletal muscle) between individuals who developed first attack of acute pancreatitis and healthy individuals.This was a matched case-control study nested into population-based cohort. MRI on a single 3 T scanner was used to quantify intrapancreatic, liver, and skeletal muscle fat depositions using the same protocols in all study participants. Binary logistic regression with adjustment for body mass index and other possible confounders was performed.Fifty individuals with first attack of nonnecrotizing acute pancreatitis comprised the case group and 100 healthy individuals comprised the control group. A 1% increase in IPFD (but not the other fat depositions) was significantly associated with a more than 30% higher chance of developing first attack of acute pancreatitis, consistently in both the unadjusted ( P = 0.004) and all adjusted models. Furthermore, a 1% increase in IPFD (but not the other fat depositions) was significantly associated with up to a 27% higher chance of developing first attack of acute pancreatitis in individuals with normotriglyceridemia, consistently in both the unadjusted ( P = 0.030) and all adjusted models.Increased IPFD may predispose to the development of acute pancreatitis. This opens up opportunities for reducing the burden of acute pancreatitis by means of primary prevention.

The TMEM16 family of calcium-activated membrane proteins includes ten mammalian paralogs (TMEM16A-K) playing distinct physiological roles with some implicated in cancer and airway diseases. Their modulators with therapeutic potential include 1PBC, a potent inhibitor with anti-tumoral properties, and the FDA-approved drug niclosamide that targets TMEM16F to inhibit syncytia formation induced by SARS-CoV-2 infection. Here, we report cryo-EM structures of TMEM16F associated with 1PBC and niclosamide, revealing that both molecules bind the same drug binding pocket. We functionally and computationally validate this binding pocket in TMEM16A as well as TMEM16F, thereby showing that drug modulation also involves residues that are not conserved between TMEM16A and TMEM16F. This study establishes a much-needed structural framework for the development of more potent and more specific drug molecules targeting TMEM16 proteins.

Background: Periostin is a matricellular protein that induces fibrillogenesis and activates cell migration. It is overexpressed in common fibrotic diseases and is also associated with abdominal adiposity/ectopic fat phenotypes. The study aimed to investigate circulating levels of periostin in health and after an attack of pancreatitis, as well as their associations with abdominal adiposity/ectopic fat phenotypes. Methods: Blood samples were obtained from healthy controls, as well as definite chronic pancreatitis (CP) and acute pancreatitis (AP) individuals during follow-up visits. Fat depositions in the pancreas, liver, skeletal muscle, as well as visceral and subcutaneous fat volumes, were quantified with the use of magnetic resonance imaging. A series of multivariable analyses were conducted, accounting for possible confounders. Results: A total of 121 individuals were included. Periostin levels were significantly higher in the CP group compared with the other groups in both unadjusted (F = 3.211, P = 0.044) and all adjusted models (F = 4.165, P = 0.019 in the most adjusted model). Intra-pancreatic fat deposition (but not the other fat phenotypes) was significantly associated with periostin concentration in the CP group (beta = 49.63, P = 0.034) and explained most of its variance (32.0%). Conclusions: Individuals with CP, but not healthy individuals or those after clinical resolution of AP, are characterized by elevated circulating levels of periostin that are positively associated with intra-pancreatic fat deposition. J Clin Med Res. 2020;12(9):568-578 doi: https://doi.org/10.14740/jocmr4279

New-onset diabetes is the most common sequela of acute pancreatitis (AP). Yet, prospective changes in glycaemia over time have never been investigated comprehensively in this study population. The primary aim was to determine the cumulative incidence of new-onset prediabetes and new-onset diabetes after AP over 24 months of follow-up in a prospective cohort study. The secondary aim was to identify trajectories of glycaemia during follow-up and their predictors at the time of hospitalisation. Patients with a prospective diagnosis of AP and no diabetes based on the American Diabetes Association criteria were followed up every 6 months up to 24 months after hospital discharge. Incidence of new-onset prediabetes/diabetes over each follow-up period was calculated. Group-based trajectory modelling was used to identify common changes in glycaemia. Multinomial regression analyses were conducted to investigate the associations between a wide array of routinely available demographic, anthropometric, laboratory, imaging, and clinical factors and membership in the trajectory groups. A total of 152 patients without diabetes were followed up. The cumulative incidence of new-onset prediabetes and diabetes was 20% at 6 months after hospitalisation and 43% over 24 months of follow-up (p trend

Pancreatitis often represents a continuous inflammatory process, from the first episode of acute pancreatitis (FAP) to recurrent acute pancreatitis (RAP) to chronic pancreatitis (CP). Psoas muscle size is a validated surrogate for global skeletal mass, changes in which are associated with inflammation. The objective was to investigate psoas muscle size in individuals following FAP, RAP, and CP, as well as its associations with pro-inflammatory cytokines. Individuals following pancreatitis and healthy individuals were recruited. All participants underwent magnetic resonance imaging, from which psoas muscle volume was derived independently by two raters in a blinded fashion. Circulating levels of four major cytokines (interleukin-6, tumour necrosis factor-α, C-C motif chemokine ligand 2, and leptin) were measured. Five linear regression additive models were built to adjust for possible confounders (age, sex, body composition, physical activity, tobacco smoking, alcohol consumption, comorbidities, and endocrine and exocrine pancreatic functions). A total of 145 participants were enrolled. A significant downward trend in psoas muscle volume was observed between healthy controls and individuals following FAP, RAP, and CP in all adjusted models (p = 0.047, 0.005, 0.004, and

Radiomics of the pancreas has the potential to personalize the management of patients with diseases that are characterized by diffuse involvement of the pancreas. However, to date, radiomics features that are both clinically useful and reproducible have not been reported.Individuals with definite chronic pancreatitis and healthy individuals, matched on sex and age, were prospectively recruited and underwent T1-weighted magnetic resonance imaging of the pancreas at 3T. A total of 107 radiomics features (shape, first-order texture, and second-order texture) were extracted using PyRadiomics and compared between the two groups, taking into account false discovery rate. Stability of significant texture features was investigated by subjecting magnetic resonance images of the pancreas to two core non-overlapping image pre-processing methods - intensity normalization and intensity discretisation.Thirty-one (28.9%) radiomics features were significantly different between the two groups. These included 6 shape features, 6 first-order texture features, and 19 second-order texture features. 'Kurtosis' was significantly different between the two groups after both intensity normalization and intensity discretisation. 'Total energy', 'energy', 'mean', 'root mean squared', '10th percentile', and 'GLCM correlation' were significantly different between the two groups after intensity discretisation.The identified radiomics features that are both accurate in characterizing definite diffuse changes in the pancreas morphology and stable irrespective of computational settings (and, therefore, reproducible) are positioned well to form the basis for development of a robust radiomics signature in diffuse diseases of the pancreas.

Markers of iron metabolism are altered in new-onset diabetes, but their relationship with metabolic signals involved in the maintenance of energy balance is poorly understood. The primary aim was to explore the associations between markers of iron metabolism (hepcidin and ferritin) and markers of energy balance (leptin, ghrelin, and the leptin/ghrelin ratio) in both the fasted and postprandial states. These associations were also studied in the sub-groups stratified by diabetes status. This was a cross-sectional study of individuals without disorders of iron metabolism who were investigated after an overnight fast and, in addition, some of these individuals underwent a mixed meal test to determine postprandial responses of metabolic signals. The associations between hepcidin, ferritin, and leptin, ghrelin, leptin/ghrelin ratio were studied using several multiple linear regression models. A total of 76 individuals in the fasted state and 34 individuals in the postprandial state were included. In the overall cohort, hepcidin was significantly inversely associated with leptin (in the most adjusted model, the β coefficient ± SE was −883.45 ± 400.94, p = 0.031) and the leptin/ghrelin ratio (in the most adjusted model, the β coefficient ± SE was −148.26 ± 61.20, p = 0.018) in the fasted state. The same associations were not statistically significant in the postprandial state. In individuals with new-onset prediabetes or diabetes (but not in those with normoglycaemia or longstanding prediabetes or diabetes), hepcidin was significantly inversely associated with leptin (in the most adjusted model, the β coefficient ± SE was −806.09 ± 395.44, p = 0.050) and the leptin/ghrelin ratio (in the most adjusted model, the β coefficient ± SE was −129.40 ± 59.14, p = 0.037). Leptin appears to be a mediator in the link between iron metabolism and new-onset diabetes mellitus. These findings add to the growing understanding of mechanisms underlying the derangements of glucose metabolism.