Disentangling the relationship between intra-pancreatic fat deposition and pancreatitis

Abstract

Background: The clinical significance of intra-pancreatic fat deposition (IPFD) is increasingly recognised. However, the pathophysiological mechanisms of IPFD, the inter-relationship between IPFD and

metabolic derangements, the contributing factors to

IPFD and the associated metabolic sequelae after acute pancreatitis (AP) (such as new onset prediabetes and diabetes) are poorly understood. The overall goal of this doctoralresearch was to comprehensively investigate the role of IPFD in pancreatitis and health.

Methods: Study participants underwent abdominal magnetic resonance imaging (MRI) on the same 3T scanner and intra-pancreatic fat, liver fat, skeletal muscle fat, visceral and subcutaneous fat, total pancreas volume and the pancreas diameters were measured using previously published protocols. Fasting venous blood was collected to measure glycated haemoglobin, fasting plasma glucose, fasting insulin, liver enzymes, and lipid profiles. The MILLIPLEX® MAP or ELISA techniques were used to measure incretins and pancreatic hormones. Habitual dietary intake was determined using the EPIC-Norfolk Food Frequency Questionnaire. A series of linear and binary logistic regression analyses

were conducted, adjusting for covariates (age, sex, body mass index, daily energy intake, use of anti-diabetic medications, recurrence of AP, alcohol consumption and tobacco smoking, as well as the presence of pancreatic necrosis). Also, complex analytical methods (such as interaction and effect modification analyses) were used. Besides, a systematic review on the associations between IPFD (and other metabolic disorders) and exocrine pancreatic dysfunction was carried out. Pooled estimates analysis and standardised effect size meta-analysis were conducted.

Results: In the MRI study, one unit increase in IPFD was significantly associated with a 1.31-times (95% CI: 1.05, 1.64; p < 0.02) increased chance of developing AP (regardless of age, sex, body mass index, and fasting plasma glucose); IPFD was associated with elevated circulating levels of periostin in individuals with chronic pancreatitis (p = 0.034) and reduced pancreas tail diameter, which in turn was associated with reduced levels of pancreatic amylase in individuals with AP (p = 0.042). In the meta-analysis, people with

type 2 diabetes, metabolic syndrome, and overweight/obesity had significantly lower serum levels of amylase compared with healthy individuals. Both individuals with type 1 diabetes and those with type 2 diabetes mellitus had significantly lower serum levels of lipase than healthy individuals. In the MRI study, individuals with post-pancreatitis diabetes had a significantly higher IPFD than healthy individuals (p = 0.003) and IPFD was associated with circulating levels of pancreatic amylase (but not in type 2 prediabetes/diabetes or healthy individuals) and was also significantly associated with indices of insulin sensitivity (i.e., HOMA-IS, Matsuda index, Raynaud index) (but not in type 2 prediabetes/diabetes or healthy individuals). It was also found that in the mediation analysis that fasting plasma glucose, HDL cholesterol, and triglycerides mediated 6.8%, 17.9%, and 24.2%, respectively, of the direct association between liver fat and IPFD, whereas HbA1c, fasting insulin, ALT, AST, ALP, and GGT did not mediate the

association between liver fat and IPFD. The effect modification analysis showed that, in individuals with high IPFD, dietary intake of carbohydrate and fat was significantly associated with insulin traits. 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.

Conclusion: This doctoral research uncovered a number of novel both simple and complex associations involving IPFD. It has the potential to form the basis for future research on early detection and prevention strategies in individuals with high IPFD.