Optimising the management of new-onset prediabetes/diabetes after acute pancreatitis

Abstract

Background: New-onset prediabetes/diabetes after acute pancreatitis (NOPAP/NODAP) is recognised as a clinically distinct entity, yet individuals with NOPAP/NODAP are often misclassified as type 2 diabetes mellitus. Further, given its until recent nosologic dereliction, there is not only a lack of predictive biomarkers to identify individuals at high risk for NOPAP/NODAP, but specific treatment options are also sparingly investigated. This doctoral research aimed to investigate biomarkers specific to NOPAP/NODAP, identify biomarkers that predicted individuals at high risk for NOPAP/NODAP, and assess intervention strategies in NOPAP to prevent progression to NODAP. Methods: The studies conducted as a part of this thesis are divided into three parts. The first part includes studies that investigated the gut hormone profile after a mixed-meal test to identify a distinguishing biomarker for NOPAP/NODAP (comparator groups - type 2 prediabetes/diabetes and health), and the factors associated with that biomarker. The second part includes studies that were part of a longitudinal prospective cohort project that investigated glycaemic changes over 24 months of follow-up. The accuracy of markers of glucose variability, pancreatic and gut hormones, and cytokines/chemokines at baseline as predictors for NOPAP/NODAP during follow-up were investigated. The third part includes studies that were part of a randomised controlled trial that investigated the effect of exogenous ketones (a ketone monoester supplement) on markers of glucose metabolism in NOPAP. The studied analytes were measured using multiplex assays and enzyme-linked immunosorbent assays. Participants underwent abdominal magnetic resonance imaging to quantify abdominal and ectopic fat distribution. Statistical analyses were conducted using a series of linear regression, binary logistic regression, multinomial regression, repeated ii measures analyses using unadjusted and adjusted models (for patient-, pancreatitis-, and metabolic-related characteristics). Results: Oxyntomodulin levels were significantly low in NOPAP. Cholecystokinin was the most prominent factor (R2 = 44%) associated with oxyntomodulin after acute pancreatitis. In the prospective cohort of 152 acute pancreatitis patients, at least one out of five patients developed NOPAP/NODAP at six months of follow-up and more than four out of 10 in the first 24 months. Three discrete glycaemic trajectories were seen over 24 months of follow-up: normal-stable glycaemia, moderate-stable glycaemia, and high-increasing glycaemia. A high glycaemic lability index at baseline increased the odds of taking the high-increasing trajectory by 13-fold. Elevated insulin levels at baseline significantly increased the odds of progression from normoglycaemia to NOPAP by 90%, glucagon by 240%, interleukin-1β by 9%, and interferon γ by 9%. Nutritional ketosis achieved after ingesting the ketone monoester supplement lowered glucose levels by 14.5% in individuals with NOPAP. The ketone supplement also had a large effect on levels of insulin (Cohen’s d = 0.61), C-peptide (d = 0.89), and glucose-dependent insulinotropic peptide-1 (d = 0.77). The presence/absence of excessive fat in the abdominal regions modulated the metabolic effect of the ketone supplement. Conclusions: The findings suggested that oxyntomodulin may serve to be a promising biomarker for distinguishing NOPAP/NODAP. High glucose variability, elevated pancreatic hormones, and cytokines could be good predictors for screening AP individuals at increased risk for NOPAP/NODAP. Ketomimetics might be potential candidates for treating NOPAP/NODAP.