The Pharmacological Landscape for Fatty Change of the Pancreas.

The quest for medications to reduce intra-pancreatic fat deposition is now quarter a century old. While no specific medication has been approved for the treatment of fatty change of the pancreas, drug repurposing shows promise in reducing the burden of the most common disorder of the pancreas. This leading article outlines the 12 classes of medications that have been investigated to date with a view to reducing intra-pancreatic fat deposition. Information is presented hierarchically-from preclinical studies to retrospective findings in humans to prospective interventional studies to randomised controlled trials. This lays the grounds for shepherding the most propitious drugs into medical practice through well-designed basic science studies and adequately powered randomised controlled trials.

Intra-pancreatic fat is associated with continuous glucose monitoring metrics.

AIM: To investigate the relationship of fat in the pancreas with time spent in different glycaemic ranges. METHODS: Abdominal magnetic resonance imaging at 3.0 Tesla was used to quantify fat in the pancreas as both continuous [i.e. intra-pancreatic fat deposition (IPFD)] and binary (i.e. fatty change of the pancreas vs. normal pancreas) variables. Dexcom G6 devices were used to collect continuous glucose monitoring data every 5 min over a continuous 7-day period. Time above range (TAR), time in range (TIR) and time below range were computed. Statistical models were built to adjust for age, sex, body composition, and other covariates in linear regression analysis and analysis of covariance. RESULTS: In total, 38 individuals were studied. IPFD was significantly associated with TAR (p = .036) and TIR (p = .042) after adjustment for covariates. For every 1% increase in IPFD, there was a 0.3 unit increase in TAR and a decrease in TIR. Individuals with fatty change of the pancreas, when compared with those with normal pancreas, had significantly higher TAR (p = .034) and lower TIR (p = .047) after adjustment for covariates. Neither IPFD (p = .805) nor fatty change of the pancreas (p = .555) was associated with time below range after adjustment for covariates. CONCLUSION: Increased fat in the pancreas is associated with excessive glycaemic variability. Fatty change of the pancreas may contribute to heightening the risk of cardiovascular diseases.

Dietary Fibre for the Prevention of Post-Pancreatitis Diabetes Mellitus: A Review of the Literature and Future Research Directions.

Post-pancreatitis diabetes mellitus-the most common sequela of pancreatitis-leads to poorer glycaemic control compared with type 2 diabetes. Because post-pancreatitis diabetes mellitus is an exemplar of secondary diabetes (with a clear underlying cause), much post-pancreatitis diabetes mellitus is preventable or treatable early. Earlier literature established the important role of dietary fibre in reducing plasma glucose in individuals with type 2 diabetes. The present review benchmarks available evidence on the role of habitual dietary fibre intake in pancreatitis and post-pancreatitis diabetes mellitus. It also paves the way for future research on the use of dietary fibre in the post-pancreatitis setting.

Fateful fat: Intra-pancreatic lipids cause pancreatic cancer.

In a Mendelian randomization and prospective cohort study,1 intra-pancreatic fat increases the risk of pancreatic cancer. This provides persuasive human evidence of causal relation between lipids and cancer in the pancreas, which confirms a prediction of the PANDORA hypothesis.

Relationship of Liver Blood Tests and T1 Relaxation Time With Intra-pancreatic Fat Deposition.

Background: Liver is well recognised as a metabolically active organ. While intra-pancreatic fat deposition (IPFD) is emerging as an important player in the whole-body metabolism, the interplay between the liver and IPFD has been poorly investigated. This study aimed to investigate the associations of liver blood tests and non-invasive tests for hepatic fibrosis with IPFD. Methods: Participants underwent a 3.0 Tesla magnetic resonance imaging to measure IPFD and map liver T1 (longitudinal relaxation time). Four liver tests were done on the same sample of blood. Hepatic fibrosis risk score (BARD) was calculated. Linear regression models were built, accounting for age, sex, visceral-to-subcutaneous fat ratio, and other covariates. Results: A total of 143 individuals were studied. In the most adjusted model, alkaline phosphatase (P < 0.001), alanine aminotransferase (P < 0.001), and γ-glutamyl transferase (P = 0.042) were significantly positively associated with IPFD. The BARD score was not significantly associated with IPFD in the most adjusted model (P = 0.295). T1 relaxation time of the liver was not significantly associated with IPFD in the most adjusted model (P = 0.782). Conclusions: Elevated alkaline phosphatase, alanine aminotransferase, and γ-glutamyl transferase are associated with increased IPFD. Hepatic fibrosis does not appear to be associated with IPFD.

Associations of pancreas fat content and size with markers of iron metabolism.

OBJECTIVE: To comprehensively investigate the associations of pancreas fat content and size with circulating markers of iron metabolism. METHODS: A total of 116 individuals underwent magnetic resonance imaging and spectroscopy on a 3.0 Tesla scanner, exclusively for the purpose of the COSMOS research programme. Intra-pancreatic fat deposition, total pancreas volume, liver fat content, visceral and subcutaneous fat volumes were quantified. Plasma levels of hepcidin and ferritin were measured. Multiple linear regression analysis was conducted, adjusting for body mass index, age, and sex. RESULTS: Total intra-pancreatic fat deposition was inversely associated with hepcidin (ß = -0.54, 95 % confidence interval -1.02 to -0.07) whereas total pancreas volume was not associated with hepcidin (ß = 0.36, 95 % confidence interval -7.12 to 7.84) in the most adjusted model. Neither total intra-pancreatic fat deposition (ß = -0.03, 95 % confidence interval -0.39 to 0.33) nor total pancreas volume (ß = -1.02, 95 % confidence interval -6.67 to 4.63) was associated with ferritin in the most adjusted model. Subcutaneous fat, visceral fat, and liver fat were not associated with hepcidin. Subcutaneous fat was inversely associated with ferritin (ß = -0.06, 95 % CI -0.11 to -0.01) whereas visceral fat (ß = 0.05, 95 % CI -0.01 to 0.14) and liver fat (ß = 0.09, 95 % CI -0.04 to 0.34) were not associated with ferritin in the most adjusted model. CONCLUSIONS: Increased intra-pancreatic fat deposition, but not other fat depots, is associated with reduced circulating levels of hepcidin. Deranged iron metabolism may play a role in the pathogenesis of fatty change of the pancreas.

Comprehensive analysis of dyslipidemia states associated with fat in the pancreas.

BACKGROUND: The global burden of cardiovascular diseases continues to rise, and it is increasingly acknowledged that guidelines based on traditional risk factors fail to identify a substantial fraction of people who develop cardiovascular diseases. Fat in the pancreas could be one of the unappreciated risk factors. This study aimed to investigate the associations of dyslipidemia states with fat in the pancreas. METHODS: All participants underwent magnetic resonance imaging on the same 3.0 T scanner for quantification of fat in the pancreas, analyzed as both binary (i.e., fatty change of the pancreas) and continuous (i.e., intra-pancreatic fat deposition) variables. Statistical analyses were adjusted for body mass index, glycated hemoglobin, fasting insulin, ethnicity, age, and sex. RESULTS: There were 346 participants studied. On most adjusted analyses, high-density lipoprotein cholesterol dyslipidemia was significantly associated with both fatty change of the pancreas (p = 0.010) and intra-pancreatic fat deposition (p = 0.008). Neither low-density lipoprotein cholesterol dyslipidemia nor triglyceride dyslipidemia were significantly associated with fatty change of the pancreas and intra-pancreatic fat deposition. The absence of any dyslipidemia was inversely associated with both fatty change of the pancreas (p = 0.016) and intra-pancreatic fat deposition (p < 0.001). CONCLUSIONS: Dyslipidemias are uncoupled when it comes to the relationship with fat in the pancreas, with only high-density lipoprotein cholesterol dyslipidemia having a consistent and strong link with it. The residual cardiovascular diseases risk may be attributed to fatty change of the pancreas.

Relationship of Iron Intake, Ferritin, and Hepcidin with the Transverse Relaxation Rate of Water Protons in the Pancreas.

(1) Background: There is a paucity of markers of iron metabolism in health and disease. The aim was to investigate the associations of iron metabolism with pancreas transverse water proton relaxation rate (R2water) in healthy individuals and people after an attack of pancreatitis. (2) Methods: All participants underwent a 3.0 T magnetic resonance imaging of the abdomen on the same scanner. High-speed T2-corrected multi-echo (HISTO) acquisition at single-voxel magnetic resonance spectroscopy and inline processing were used to quantify pancreas R2water. Habitual dietary intake of iron was determined using the EPIC-Norfolk food frequency questionnaire. Circulating levels of ferritin and hepcidin were measured. Generalised additive models were used, adjusting for age, sex, body mass index, and haemoglobin A1c. (3) Results: A total of 139 individuals (47 healthy individuals, 54 individuals after acute pancreatitis, and 38 individuals after chronic pancreatitis) were included. Total dietary intake of iron was significantly associated with pancreas R2water, consistently in healthy individuals (p < 0.001), individuals after acute pancreatitis (p < 0.001), and individuals after chronic pancreatitis (p < 0.001) across all the statistical models. Ferritin was significantly associated with pancreas R2water, consistently in healthy individuals (p < 0.001), individuals after acute pancreatitis (p < 0.001), and individuals after chronic pancreatitis (p = 0.01) across all adjusted models. Hepcidin was significantly associated with pancreas R2water in individuals after acute pancreatitis (p < 0.001) and individuals after chronic pancreatitis (p = 0.04) in the most adjusted model. (4) Conclusions: Pancreas R2water, corrected for T2, is related to iron metabolism in both health and pancreatitis. This non-invasive marker could be used for automated in vivo identification of intra-pancreatic iron deposition.

Remnant cholesterol, but not low-density lipoprotein cholesterol, is associated with intra-pancreatic fat deposition.

AIM: To investigate the associations of components of the lipid panel (and its derivatives) with intra-pancreatic fat deposition (IPFD). METHODS: All participants underwent abdominal magnetic resonance imaging on the same 3.0-Tesla scanner and IPFD was quantified. Blood samples were collected in the fasted state for analysis of lipid panel components. A series of linear regression analyses was conducted, adjusting for age, sex, ethnicity, body mass index, fasting plasma glucose, homeostatic model assessment of insulin resistance, and liver fat deposition. RESULTS: A total of 348 participants were included. Remnant cholesterol (P = 0.010) and triglyceride levels (P = 0.008) were positively, and high-density lipoprotein cholesterol level (P = 0.001) was negatively, associated with total IPFD in the most adjusted model. Low-density lipoprotein cholesterol and total cholesterol were not significantly associated with total IPFD. Of the lipid panel components investigated, remnant cholesterol explained the greatest proportion (9.9%) of the variance in total IPFD. CONCLUSION: Components of the lipid panel have different associations with IPFD. This may open up new opportunities for improving outcomes in people at high risk for cardiovascular diseases (who have normal low-density lipoprotein cholesterol) by reducing IPFD.

Relationship of Serum Bile Acids with Fat Deposition in the Pancreas, Liver, and Skeletal Muscle.

Introduction: Ectopic fat deposition is well appreciated as a key contributor to digestive and liver diseases. Bile acids have emerged as pleiotropic signalling molecules involved in numerous metabolic pathways. The aim was to study the associations of bile acids with ectopic fat deposition and lipid panel. Methods: A single 3.0 Tesla magnetic resonance imaging scanner was employed to measure fat deposition in the pancreas, liver, and skeletal muscle in 76 adults. Blood samples were drawn to determine total bile acids and lipid panel. Linear regression analyses were run, taking into account age, sex, body mass index, and other covariates. Results: The studied ectopic fat depots were not significantly associated with levels of total bile acids in serum. Total bile acids were significantly associated high-density lipoprotein cholesterol - consistently in both the unadjusted (p = 0.018) and all adjusted models (p = 0.012 in the most adjusted model). Low-density lipoprotein cholesterol, total cholesterol, and triglycerides were not significantly associated with total bile acids in both the unadjusted and all adjusted models. Conclusion: Fat deposition in the pancreas, liver, and skeletal muscle is not associated with circulating levels of total bile acids. High-density lipoprotein cholesterol is the only component of lipid panel that is associated with total bile acids.

Metabolic Sequelae: The Pancreatitis Zeitgeist of the 21st Century.

Holistic management of pancreatitis means that gastroenterologists in the 21st Century should think beyond improving in-hospital outcomes of pancreatitis alone. In particular, there is considerable room for optimizing the management of new-onset diabetes, exocrine pancreatic insufficiency, and other metabolic sequelae of pancreatitis. The present article provides state-of-the-art information on classification, terminology, and burden of the common sequelae of pancreatitis. A high-risk group of patients with pancreatitis is identified, which is positioned to benefit the most from the metabolic sequelae surveillance program introduced in this article. The program involves continuous follow-up after pancreatitis diagnosis, with the focus on early identification of new-onset diabetes after pancreatitis and exocrine pancreatic insufficiency. The metabolic sequelae surveillance program is scalable and has the potential to reduce the burden of pancreatitis through tertiary prevention in the decades to come.

Diabetes of the Exocrine Pancreas: Implications for Pharmacological Management.

Post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes are often underappreciated. As a result, a substantial proportion of people with these sub-types of diabetes receive antidiabetic medications that may be suboptimal, if not harmful, in the context of their underlying disease of the exocrine pancreas. The present article delineates both classical (biguanides, insulin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, and meglitinides) and newer (glucagon-like peptide-1 receptor agonists, amylin analogs, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, D2 receptor agonists, bile acid sequestrants, and dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor co-agonists) therapies and provides recommendations for managing people with diabetes of the exocrine pancreas based on the most up-to-date clinical evidence. Also, several emerging directions (lipid-enriched pathways, Y4 receptor agonism, glucagon-like peptide-1 and glucagon receptor co-agonism) are presented with a view to informing the process of new drug discovery and development.

Fatty change of the pancreas: the Pandora's box of pancreatology.

Prevention of common diseases of the pancreas or interception of their progression is as attractive in theory as it is elusive in practice. The fundamental challenge has been an incomplete understanding of targets coupled with a multitude of intertwined factors that are associated with the development of pancreatic diseases. Evidence over the past decade has shown unique morphological features, distinctive biomarkers, and complex relationships of intrapancreatic fat deposition. Fatty change of the pancreas has also been shown to affect at least 16% of the global population. This knowledge has solidified the pivotal role of fatty change of the pancreas in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. The pancreatic diseases originating from intrapancreatic fat (PANDORA) hypothesis advanced in this Personal View cuts across traditional disciplinary boundaries with a view to tackling these diseases. New holistic understanding of pancreatic diseases is well positioned to propel pancreatology through lasting research breakthroughs and clinical advances.

Intra-pancreatic fat deposition across the pancreatitis spectrum and the influence of gut hormones.

BACKGROUND AND AIMS: Acute pancreatitis (AP) and chronic pancreatitis (CP) often represent parts of the spectrum of disease. While growing evidence indicates that intra-pancreatic fat deposition (IPFD) plays an important role in the pathogenesis of pancreatitis, no study of living individuals has investigated IPFD in both AP and CP. Further, the associations between IPFD and gut hormones remain to be elucidated. The aims were to investigate the associations of IPFD with AP, CP, and health; and to study whether gut hormones affect these associations. METHODS: Magnetic resonance imaging on the same 3.0 Tesla scanner was used to determine IPFD in 201 study participants. These participants were arranged into the health, AP, and CP groups. Gut hormones (ghrelin, glucagon-like peptide-1, gastric inhibitory peptide, peptide YY, and oxyntomodulin) were measured in blood, both after an 8-hour overnight fasting and after ingestion of a standardised mixed meal. A series of linear regression analyses was run, accounting for age, sex, ethnicity, body mass index, glycated haemoglobin, and triglycerides. RESULTS: Both the AP group and CP group had significantly higher IPFD in comparison with the health group, consistently across all models (p for trend 0.027 in the most adjusted model). Ghrelin in the fasted state had a significant positive association with IPFD in the AP group (but not the CP or health group), consistently across all models (p = 0.019 in the most adjusted model). None of the studied gut hormones in the postprandial state was significantly associated with IPFD. CONCLUSION: Fat deposition in the pancreas is similarly high in individuals with AP and those with CP. The gut-brain axis, and more specifically overexpression of ghrelin, may contribute to increased IPFD in individuals with AP.

Effect of D-ß-hydroxybutyrate-(R)-1,3 butanediol on plasma levels of asprosin and leptin: results from a randomised controlled trial.

Background: D-ß-Hydroxybutyrate-(R)-1,3 butanediol - a non-racemic ketone monoester for ingestion - has emerged as an effective way to achieve acute nutritional ketosis. Whether white adipose tissue plays a role in effects of acute nutritional ketosis is largely unknown. Objective: To investigate the effects of acute nutritional ketosis on plasma levels of asprosin and leptin and if they are affected by abdominal fat phenotypes. Methods: The design was a randomised crossover trial. Participants received either the D-ß-hydroxybutyrate-(R)-1,3 butanediol monoester (KEßHB) drink or placebo drink. Blood samples were collected at baseline, 30, 60, 90, 120, and 150 minutes. 3.0 Tesla magnetic resonance imaging was used to measure visceral and subcutaneous fat volumes (VFV and SFV, respectively), intra-hepatic fat deposition (IHFD), and intra-pancreatic fat deposition (IPFD). Results: A total of 18 adults were randomised, with no drop-outs. There were no significant differences in plasma levels of asprosin and leptin (p = 0.808 and p = 0.907, respectively) between the KEßHB and placebo drinks. There was no effect of time, treatment, or interaction between time and treatment on asprosin and leptin. After stratification by the VFV/SFV ratio, IHFD, and IPFD, there were no differences in asprosin and leptin between the KEßHB and placebo drinks. Conclusion: Plasma levels of asprosin and leptin were not significantly affected by acute nutritional ketosis. Abdominal fat phenotypes did not significantly affect circulating levels of the two hormones. White adipose tissue does not appear to play a role in altering hormone levels during acute nutritional ketosis. The clinical trial registry number is NCT03889210 (https://clinicaltrials.gov).

When to Stop Surveillance: Pancreatic Cysts.

Surveillance of mucinous pancreatic cysts is a key to reducing pancreatic cancer risk and detecting malignancy early. However, while the management of cysts with high-risk and worrisome features is fairly straightforward, surveillance of patients with low-risk branch-duct intraductal papillary mucinous neoplasms has long presented gastroenterologists with the challenging question of discontinuation of surveillance. Up-to-date evidence supports the cessation of follow-up in these patients depending on both interval stability of the cyst and cyst size. Based on these criteria, discontinuation of surveillance at either 5 years or 10 years is recommended. Oversurveillance of patients with pancreatic cysts in the absence of high-risk and worrisome features is discouraged.

Identifying endotypes of individuals after an attack of pancreatitis based on unsupervised machine learning of multiplex cytokine profiles.

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.

Effect of d-ß-Hydroxybutyrate-(R)-1,3 Butanediol on Appetite Regulation in People with Prediabetes.

SCOPE: The main aim of the present study is to study the effect of acute ketosis on parameters of appetite regulation in prediabetes. METHODS AND RESULTS: This is a randomized controlled trial registered under ClinicalTrials.gov identifier NCT03889210. After an overnight fast, 18 adults with prediabetes are assigned to consume a ketone monoester (d-ß-hydroxybutyrate-(R)-1,3 butanediol) drink and a placebo drink in cross-over fashion. Blood samples are collected every 30 min, from baseline to 150 min. Paired t test is used to compare the total area under the curve (AUC) for the changes in parameters of appetite regulation (acylated ghrelin, peptide YY [PYY], and hunger) following both drinks. Significant elevation in blood ß-hydroxybutyrate from 0.2 to 3.5 mmol L-1 (p < 0.001) is achieved within 30 min. Acute ketosis does not result in statistically significant differences in the AUCs for ghrelin, PYY, and hunger. CONCLUSION: Acute ketosis consistently does not affect both objective and subjective parameters of appetite regulation in prediabetes.

Metabolic traits affecting the relationship between liver fat and intrapancreatic fat: a mediation analysis.

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.

Factors Affecting the Circulating Levels of Oxyntomodulin in Health and After Acute Pancreatitis.

OBJECTIVES: To investigate the factors associated with the circulating levels of oxyntomodulin in healthy individuals and individuals after an episode of acute pancreatitis (AP). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.