Metabolomic Characteristics of Fatty Pancreas

Abstract

Objective Pancreatic steatosis is associated with impaired beta cell function in patients with prediabetes. The pathomechanisms underlying this association still remain to be elucidated. Recent data show that adipocytes are situated within the pancreatic parenchyma and therefore give raise to hypothesize that pancreatic fat together with known and unknown metabolites such as hepatokines affect insulin secretion. Applying a targeted metabolomic approach we investigated possible circulating markers of pancreatic fat in order to better understand its role in the pathophysiology of impaired beta cell function.

Methods We included 361 Caucasians, at increased risk of type 2 diabetes, from the Tübingen Family Study. All participants underwent a frequently sampled oral glucose tolerance test to assess insulin secretion and a magnetic resonance imaging to quantify pancreatic fat content, total body fat and visceral fat. Among the 152 subjects with prediabetes (IFG and/or IGT), two groups each with 20 individuals, having the lowest and highest pancreatic fat content were selected. The groups were matched for sex, age, BMI, total fat content, visceral fat content, liver fat content and insulin sensitivity. Metabolites were analyzed using the AbsoluteIDQ^® p400 HR Kit by Biocrates.

Results Pancreatic fat content of all 152 subjects with prediabetes was negatively associated with insulin secretion represented by AUC_{C-peptide 0–120}/AUC_{Glucose 0–120} (p=0.04; β=− 3.24). Furthermore, pancreatic fat content was positively associated with BMI, total body and visceral fat (all p<0.005). Levels of aminoacids, biogenic amines and monosaccharides were similar between the groups with high/low pancreatic fat content (p>0.90). Also, levels of polar lipids such as lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides did not differ significantly between the groups (p>0.90). Investigating the levels of neutral lipids such as aclycarnitines, diglycerides, triglycerides and cholesteryl esters also revealed no differences between the groups (p>0.90).

Conclusion The amount of pancreatic fat is not associated with the metabolomic pattern in individuals with prediabetes. This might be due to the relatively low pancreatic fat content compared to the total amount of fat stored in other depots. The impact of pancreatic steatosis on insulin secretion might be mediated by paracrine effects which cannot be detected in the circulation.

Key words

prediabetes - type 2 diabetes - pancreatic fat - non-alcoholic fatty pancreas disease - NAFPD - metabolomics - insulin secretion - insulin sensitivity

Publikationsverlauf

Eingereicht: 12. Dezember 2018
Eingereicht: 08. April 2019

Angenommen: 17. April 2019

Artikel online veröffentlicht:
16. Mai 2019

• Literature

• 1 Gerst F, Wagner R, Kaiser G. et al. Metabolic crosstalk between fatty pancreas and fatty liver: Effects on local inflammation and insulin secretion. Diabetologia 2017; 1-12
• 2 Khoury T, Asombang AW, Berzin TM. et al. The clinical implications of fatty pancreas: A concise review. Dig Dis Sci 2017; 62: 2658-2667
• 3 Takahashi M, Hori M, Ishigamori R et al. Fatty pancreas: A possible risk factor for pancreatic cancer in animals and humans. Cancer Sci 2018
• 4 Hori M, Takahashi M, Hiraoka N. et al. Association of pancreatic fatty infiltration with pancreatic ductal adenocarcinoma. Clin Transl Gastroenterol 2014; 5: e53
• 5 Gaborit B, Abdesselam I, Kober F. et al. Ectopic fat storage in the pancreas using 1H-MRS: Importance of diabetic status and modulation with bariatric surgery-induced weight loss. Int J Obes 2014; 39: ijo2014126
• 6 Dong Z, Luo Y, Cai H. et al. Noninvasive fat quantification of the liver and pancreas may provide potential biomarkers of impaired glucose tolerance and type 2 diabetes. Medicine (Baltimore) 2016; 95: e3858
• 7 Patel NS, Peterson MR, Lin GY. et al. Insulin resistance increases mri-estimated pancreatic fat in nonalcoholic fatty liver disease and normal controls. Gastroenterol Res Pract 2013; 2013: 498296
• 8 Saisho Y, Butler AE, Meier JJ. et al. Pancreas volumes in humans from birth to age one hundred taking into account sex, obesity, and presence of type-2 diabetes. Clin Anat 2007; 20: 933-942
• 9 Gaborit B, Abdesselam I, Kober F. et al. Ectopic fat storage in the pancreas using 1H-MRS: Importance of diabetic status and modulation with bariatric surgery-induced weight loss. Int J Obes 2015; 39: 480-487
• 10 Murakami R, Saisho Y, Watanabe Y. et al. Pancreas fat and β cell mass in humans with and without diabetes: An analysis in the Japanese population. J Clin Endocrinol Metab 2017; 102: 3251-3260
• 11 Steven S, Hollingsworth KG, Small PK. et al. Weight loss decreases excess pancreatic triacylglycerol specifically in type 2 diabetes. Diabetes Care 2016; 39: 158-165
• 12 Taylor R, Al-Mrabeh A, Zhyzhneuskaya S. et al. Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for β cell recovery. Cell Metab 2018; 28: 547-556.e3
• 13 Umemura A, Sasaki A, Nitta H. et al. Pancreas volume reduction and metabolic effects in Japanese patients with severe obesity following laparoscopic sleeve gastrectomy. Endocr J 2017; 64: 487-498
• 14 Lim EL, Hollingsworth KG, Aribisala BS. et al. Reversal of type 2 diabetes: Normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011; 54: 2506-2514
• 15 Hannukainen JC, Borra R, Linderborg K. et al. Liver and pancreatic fat content and metabolism in healthy monozygotic twins with discordant physical activity. J Hepatol 2011; 54: 545-552
• 16 Heiskanen MA, Motiani KK, Mari A. et al. Exercise training decreases pancreatic fat content and improves beta cell function regardless of baseline glucose tolerance: A randomised controlled trial. Diabetologia 2018; 1-12
• 17 Heni M, Machann J, Staiger H. et al. Pancreatic fat is negatively associated with insulin secretion in individuals with impaired fasting glucose and/or impaired glucose tolerance: A nuclear magnetic resonance study. Diabetes Metab Res Rev 2010; 26: 200-205
• 18 Zijl van der JN, Goossens GH. et al. Ectopic fat storage in the pancreas, liver, and abdominal fat depots: Impact on β-cell function in individuals with impaired glucose metabolism. J Clin Endocrinol Metab 2011; 96: 459-467
• 19 Tushuizen ME, Bunck MC, Pouwels PJ. et al. Pancreatic fat content and β-cell function in men with and without type 2 diabetes. Diabetes Care 2007; 30: 2916-2921
• 20 Garcia TS, Rech TH, Leitão CB. Pancreatic size and fat content in diabetes: A systematic review and meta-analysis of imaging studies. PLOS ONE 2017; 12: e0180911
• 21 Wang C-Y, Ou H-Y, Chen M-F. et al. Enigmatic ectopic fat: Prevalence of nonalcoholic fatty pancreas disease and its associated factors in a Chinese population. J Am Heart Assoc 2014; 3: e000297
• 22 Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 2003; 46: 3-19
• 23 Lee JS, Kim SH, Jun DW. et al. Clinical implications of fatty pancreas: Correlations between fatty pancreas and metabolic syndrome. World J Gastroenterol WJG 2009; 15: 1869-1875
• 24 Haffner SM, Miettinen H, Stern MP. The Homeostasis Model in the San Antonio Heart Study. Diabetes Care 1997; 20: 1087-1092
• 25 Wong VW-S, Wong GL-H, Yeung DK-W. et al. Fatty pancreas, insulin resistance, and β-cell function: A population study using fat-water magnetic resonance imaging. Am J Gastroenterol 2014; 109: 589-597
• 26 Lê K-A, Ventura EE, Fisher JQ. et al. Ethnic differences in pancreatic fat accumulation and its relationship with other fat depots and inflammatory markers. Diabetes Care 2011; 34: 485-490
• 27 Begovatz P, Koliaki C, Weber K. et al. Pancreatic adipose tissue infiltration, parenchymal steatosis and beta cell function in humans. Diabetologia 2015; 58: 1646-1655
• 28 Yamazaki H, Tsuboya T, Katanuma A. et al. Lack of independent association between fatty pancreas and incidence of type 2 diabetes: 5-Year Japanese cohort study. Diabetes Care 2016; 39: 1677-1683
• 29 Machann J, Thamer C, Stefan N. et al. Follow-up whole-body assessment of adipose tissue compartments during a lifestyle intervention in a large cohort at increased risk for type 2 diabetes. Radiology 2010; 257: 353-363
• 30 Schwenzer NF, Machann J, Martirosian P. et al. Quantification of pancreatic lipomatosis and liver steatosis by MRI: Comparison of in/opposed-phase and spectral-spatial excitation techniques. Invest Radiol 2008; 43: 330-337
• 31 Singh RG, Yoon HD, Poppitt SD et al. Ectopic fat accumulation in the pancreas and its biomarkers: A systematic review and meta-analysis. Diabetes Metab Res Rev 2017; 33:
• 32 Lehmann R, Franken H, Dammeier S. et al. Circulating lysophosphatidylcholines are markers of a metabolically benign nonalcoholic fatty liver. Diabetes Care 2013; 36: 2331-2338
• 33 Wagner R, Hakaste LH, Ahlqvist E. et al. Nonsuppressed glucagon after glucose challenge as a potential predictor for glucose tolerance. Diabetes 2017; 66: 1373-1379
• 34 DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia 2010; 53: 1270-1287
• 35 Würslin C, Machann J, Rempp H. et al. Topography mapping of whole body adipose tissue using a fully automated and standardized procedure. J Magn Reson Imaging JMRI 2010; 31: 430-439
• 36 Miller AJ, Joseph PM. The use of power images to perform quantitative analysis on low SNR MR images. Magn Reson Imaging 1993; 11: 1051-1056
• 37 Stefan N, Kantartzis K, Häring H-U. Causes and metabolic consequences of fatty liver. Endocr. Rev 2008; 29: 939-960
• 38 Stefan N, Schick F, Häring H-U. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. Cell Metab 2017; 26: 292-300
• 39 van Geenen EM, Smits MM, Schreuder m a TC. et al. Nonalcoholic fatty liver disease is related to nonalcoholic fatty pancreas disease. Pancreas 2010; 39: 1185-1190
• 40 Targher G, Rossi AP, Zamboni GA. et al. Pancreatic fat accumulation and its relationship with liver fat content and other fat depots in obese individuals. J Endocrinol Invest 2012; 35: 748-753