Exp Clin Endocrinol Diabetes 2020; 128(01): 43-51
DOI: 10.1055/a-0859-7168
Article
© Georg Thieme Verlag KG Stuttgart · New York

Elevated Circulating Levels of Motilin are Associated with Diabetes in Individuals after Acute Pancreatitis

Fuchsia D. Gold-Smith
1   School of Medicine, University of Auckland, Auckland, New Zealand
,
Ruma G. Singh
1   School of Medicine, University of Auckland, Auckland, New Zealand
,
Maxim S. Petrov
1   School of Medicine, University of Auckland, Auckland, New Zealand
› Author Affiliations
Acknowledgement: This study was part of the Clinical and epidemiological inveStigations in Metabolism, nutrition, and pancreatic diseaseS (COSMOS) programme. COSMOS is supported in part by the Auckland Medical Research Foundation (grant 1116021 to Associate Professor Max Petrov), which played no role in the study design; collection, analysis, or interpretation of data; or writing of the manuscript.
Further Information

Publication History

received 21 November 2018
revised 14 January 2019

accepted 18 February 2019

Publication Date:
14 March 2019 (online)

Abstract

Aim The study aimed to investigate the associations between glycaemic control after acute pancreatitis and gastrointestinal motility, using plasma motilin concentration and gastroparesis cardinal symptom index score as proxies.

Methods This cross-sectional study recruited a total of 93 individuals after acute pancreatitis. Gastroparesis cardinal index scores, demographic and anthropometric factors, as well as pancreatitis-related factors were analysed. Fasting venous blood was collected to measure motilin, glycated haemoglobin, and fasting blood glucose. Linear regression analyses were conducted to investigate the associations between glycaemic control and gastrointestinal motility in unadjusted and adjusted models.

Results Motilin was significantly higher in individuals with diabetes across all adjusted models, with the highest ß-coefficient (95% confidence interval) of 588.89 (138.50, 1039.28); P=0.010. Fasting blood glucose was significantly associated with motilin across all models, with the highest ß-coefficient (95% confidence interval) of 156.30 (55.49, 257.10); P=0.002. Glycated haemoglobin was significantly associated with motilin in one adjusted model with ß-coefficient (95% confidence interval) of 18.78 (1.53, 36.02); P=0.033. Gastroparesis cardinal symptom index was not significantly associated with any measure of glycaemic control.

Conclusions Diabetes in individuals after acute pancreatitis appears to be characterised by elevated plasma motilin but not gastroparesis cardinal symptom index. The role of motilin in this setting warrants further investigations.

 
  • References

  • 1 Xiao AY, Tan ML, Wu LM. et al. Global incidence and mortality of pancreatic diseases: A systematic review, meta-analysis, and meta-regression of population-based cohort studies. Lancet Gastroenterol Hepatol 2016; 1: 45-55
  • 2 Peery AF, Crockett SD, Barritt AS. et al. Burden of gastrointestinal, liver, and pancreatic diseases in the United States. Gastroenterology 2015; 149: 1731-1741
  • 3 Chand SK, Singh RG, Pendharkar SA. et al. Iron: A strong element in the pathogenesis of chronic hyperglycaemia after acute pancreatitis. Biol Trace Elem Res. 2017: 1-9
  • 4 Gillies NA, Pendharkar SA, Singh RG. et al. Lipid metabolism in patients with chronic hyperglycemia after an episode of acute pancreatitis. Diabetes Metab Syndr 2016; 11: S233-S241
  • 5 Gillies NA, Pendharkar SA, Singh RG. et al. Fasting levels of insulin and amylin after acute pancreatitis are associated with pro-inflammatory cytokines. Arch Physiol Biochem 2017; 123: 238-248
  • 6 Pendharkar SA, Asrani VM, Xiao AY. et al. Relationship between pancreatic hormones and glucose metabolism: a cross-sectional study in patients after acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 2016; 311: G50-G58
  • 7 Pendharkar SA, Drury M, Walia M. et al. Gastrin-releasing peptide and glucose metabolism following pancreatitis. Gastroenterology Res 2017; 10: 224-234
  • 8 Bharmal SH, Pendharkar SA, Singh RG. et al. Relationship between circulating levels of pancreatic proteolytic enzymes and pancreatic hormones. Pancreatology 2017; 17: 876-883
  • 9 Das SL, Singh PP, Phillips AR. et al. Newly diagnosed diabetes mellitus after acute pancreatitis: A systematic review and meta-analysis. Gut 2014; 63: 818
  • 10 Párniczky A, Kui B, Szentesi A. et al. Prospective, multicentre, nationwide clinical data from 600 cases of acute pancreatitis. PLoS One 2016; 11: e0165309
  • 11 Zimmet P, Alberti KG, Magliano DJ. et al. Diabetes mellitus statistics on prevalence and mortality: facts and fallacies. Nat Rev Endocrinol 2016; 12: 616-622
  • 12 WHO. Global report on diabetes. World Health Organization; 2016
  • 13 Pendharkar SA, Asrani VM, Murphy R. et al. The Role of gut-brain axis in regulating glucose metabolism after acute pancreatitis. Clin Transl Gastroenterol 2017; 8: 1-10
  • 14 Pendharkar SA, Singh RG, Petrov MS. Cross-talk between innate cytokines and the pancreatic polypeptide family in acute pancreatitis. Cytokine 2017; 90: 161-168
  • 15 Chand SK, Singh RG, Pendharkar SA. et al. Interplay between innate immunity and iron metabolism after acute pancreatitis. Cytokine 2018; 103: 90-98
  • 16 Singh RG, Pendharkar SA, Gillies NA. et al. Associations between circulating levels of adipocytokines and abdominal adiposity in patients after acute pancreatitis. Clin Exp Med 2017; 17: 477-487
  • 17 Singh RG, Pendharkar SA, Plank LD. et al. Role of human lipocalin proteins in abdominal obesity after acute pancreatitis. Peptides 2017; 91: 1-7
  • 18 Tack J, Rotondo A, Meulemans A. et al. Randomized clinical trial: A controlled pilot trial of the 5-HT4 receptor agonist revexepride in patients with symptoms suggestive of gastroparesis. Neurogastroenterol Motil 2016; 28: 487-497
  • 19 Pasricha PJ, Yates KP, Nguyen L. et al. Outcomes and factors associated with reduced symptoms in patients with gastroparesis. Gastroenterology 2015; 149: 1762-1774
  • 20 Kofod-Andersen K, Tarnow L. Prevalence of gastroparesis-related symptoms in an unselected cohort of patients with type 1 diabetes. J Diabetes Complications 2012; 26: 89-93
  • 21 Shin A, Camilleri M, Busciglio I. et al. Randomized controlled phase Ib study of ghrelin agonist, RM-131, in type 2 diabetic women with delayed gastric emptying pharmacokinetics and pharmacodynamics. Diabetes Care 2013; 36: 41-48
  • 22 Shin A, Camilleri M, Busciglio I. et al. The ghrelin agonist RM-131 accelerates gastric emptying of solids and reduces symptoms in patients with type 1 diabetes mellitus. Clin Gastroenterol Hepatol 2013; 11: 1453-1459
  • 23 Gebel E. Diabetes 101. Gastroparesis. Feeling full. This nerve disorder can leave your stomach out of sync. Diabetes Forecast 2009; 62: 39-40
  • 24 Gold-Smith FD, Chand SK, Petrov MS. Post-pancreatitis diabetes mellitus: towards understanding the role of gastrointestinal motility. Minerva Gastroenterol Dietol 2018; 64: 363-375
  • 25 Wu LM, Sankaran SJ, Plank LD. et al. Meta-analysis of gut barrier dysfunction in patients with acute pancreatitis. Br J Surg 2014; 101: 1644-1656
  • 26 Bevan MG, Asrani VM, Pendharkar SA. et al. Nomogram for predicting oral feeding intolerance in patients with acute pancreatitis. Nutrition 2017; 36: 41-45
  • 27 Wu LM, Pendharkar SA, Asrani VM. et al. Effect of intravenous fluids and analgesia on dysmotility in patients with acute pancreatitis: A prospective cohort study. Pancreas 2017; 46: 858-866
  • 28 Wu LM, Premkumar R, Phillips AR. et al. Ghrelin and gastroparesis as early predictors of clinical outcomes in acute pancreatitis. Pancreatology 2016; 16: 181-188
  • 29 Ma J, Pendharkar SA, O’Grady G. et al. Effect of nasogastric tube feeding vs nil per os on dysmotility in acute pancreatitis: Results of a randomized controlled trial. Nutr Clin Pract 2016; 31: 99-104
  • 30 Petrov MS. The nescience and nascence of gastrointestinal motility research in acute pancreatitis. Scand J Gastroenterol 2017; 52: 615-616
  • 31 Revicki DA, Camilleri M, Kuo B. et al. Evaluating symptom outcomes in gastroparesis clinical trials: Validity and responsiveness of the Gastroparesis Cardinal Symptom Index-Daily Diary (GCSI-DD). Neurogastroenterol Motil 2012; 24: 456-463
  • 32 Revicki DA, Rentz AM, Dubois D. et al. Gastroparesis Cardinal Symptom Index (GCSI): Development and validation of a patient reported assessment of severity of gastroparesis symptoms. Qual Life Res 2004; 13: 833-844
  • 33 Cassilly DW, Wang YR, Friedenberg FK. et al. Symptoms of gastroparesis: use of the gastroparesis cardinal symptom index in symptomatic patients referred for gastric emptying scintigraphy. Digestion 2008; 78: 144-151
  • 34 Revicki D, Rentz A, Dubois D. et al. Development and validation of a patient-assessed gastroparesis symptom severity measure: The Gastroparesis Cardinal Symptom Index. Aliment Pharmacol Ther 2003; 18: 141-150
  • 35 Revicki DA, Camilleri M, Kuo B. et al. Development and content validity of a gastroparesis cardinal symptom index daily diary. Aliment Pharmacol Ther 2009; 30: 670-680
  • 36 Ohno T, Mochiki E, Kuwano H. The roles of motilin and ghrelin in gastrointestinal motility. Int J Pept 2010 2010; 1-6
  • 37 Poitras P. Motilin is a digestive hormone in the dog. Gastroenterology 1984; 87: 909-913
  • 38 Luiking YC, Peeters TL, Stolk MF. et al. Motilin induces gall bladder emptying and antral contractions in the fasted state in humans. Gut 1998; 42: 830-835
  • 39 Kamerling I, Van Haarst A, Burggraaf J. et al. Dose-related effects of motilin on proximal gastrointestinal motility. Aliment Pharmacol Ther 2002; 16: 129-135
  • 40 Deloose E, Vos R, Corsetti M. et al. Endogenous motilin, but not ghrelin plasma levels fluctuate in accordance with gastric phase III activity of the migrating motor complex in man. Neurogastroenterol Motil 2015; 27: 63-71
  • 41 Wang X, Gong Z, Wu K. et al. Gastrointestinal dysmotility in patients with acute pancreatitis. J Gastroenterol Hepatol 2003; 18: 57-62
  • 42 Imura H, Seino Y, Mori K. et al. Plasma motilin levels in normal subjects and patients with diabetes mellitus and certain other diseases. Fasting levels and responses to food and glucose. Endocrinol Jpn 1980; 27: 151-155
  • 43 Fiorucci S, Scionti L, Bosso R. et al. Effect of erythromycin on gallbladder emptying in diabetic patients with and without autonomic neuropathy and high levels of motilin. Dig Dis Sci 1992; 37: 1671-1677
  • 44 Kawagishi T, Nishizawa Y, Okuno Y. et al. Effect of cisapride on gastric emptying of indigestible solids and plasma motilin concentration in diabetic autonomic neuropathy. Am J Gastroenterol 1993; 88: 933-938
  • 45 Achem-Karam SR, Funakoshi A, Vinik AI. et al. Plasma motilin concentration and interdigestive migrating motor complex in diabetic gastroparesis: effect of metoclopramide. Gastroenterology 1985; 88: 492-499
  • 46 Maravi-Poma E, Zubia Olascoaga F, Petrov MS. et al. SEMICYUC 2012. Recommendations for intensive care management of acute pancreatitis. Med Intensiva 2013; 37: 163-179
  • 47 Gillies NA, Pendharkar SA, Asrani VM. et al. Interleukin-6 is associated with chronic hyperglycemia and insulin resistance in patients after acute pancreatitis. Pancreatology 2016; 16: 748-755
  • 48 Petrov MS. Diabetes of the exocrine pancreas: American Diabetes Association-compliant lexicon. Pancreatology 2017; 17: 523-526
  • 49 Eibl G, Cruz-Monserrate Z, Korc M. et al. Diabetes mellitus and obesity as risk factors for pancreatic cancer. J Acad Nutr Diet 2018; 118: 555-567
  • 50 Petrov MS, Windsor JA. Conceptual framework for classifying the severity of acute pancreatitis. Clin Res Hepatol Gastroenterol 2012; 36: 341-344
  • 51 Meyers LS, Gamst G, Guarino AJ. Applied multivariate research: Design and interpretation. Sage publications; 2016
  • 52 Das SL, Kennedy JI, Murphy R. et al. Relationship between the exocrine and endocrine pancreas after acute pancreatitis. World J Gastroenterol 2014; 20: 17196-17205
  • 53 Dellinger EP, Forsmark CE, Layer P. et al. Determinant-based classification of acute pancreatitis severity: An international multidisciplinary consultation. Ann Surg 2012; 256: 875-880
  • 54 Camilleri M, Bharucha AE, Farrugia G. Epidemiology, mechanisms, and management of diabetic gastroparesis. Clin Gastroenterol Hepatol 2011; 9: 5-12
  • 55 Parkman HP, Yates K, Hasler WL. et al. Similarities and differences between diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol 2011; 9: 1056-1064
  • 56 Singh RG, Nguyen NN, DeSouza SV. et al. Comprehensive analysis of body composition and insulin traits associated with intra-pancreatic fat deposition in healthy individuals and people with new-onset prediabetes/diabetes after acute pancreatitis. Diabetes Obes Metab 2019; 21: 417-423
  • 57 DeSouza SV, Singh RG, Yoon HD. et al. Pancreas volume in health and disease: A systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 2018; 12: 757-766
  • 58 Pendleton H, Ekman R, Olsson R. et al. Motilin concentrations in relation to gastro intestinal dysmotility in diabetes mellitus. Eur J Intern Med 2009; 20: 654-659
  • 59 Peeters TL, Muls E, Janssens J. et al. Effect of motilin on gastric emptying in patients with diabetic gastroparesis. Gastroenterology 1992; 102: 97-101
  • 60 Chiu YC, Kuo MC, Rayner CK. et al. Decreased gastric motility in type II diabetic patients. Biomed Res Int 2014 2014; 1-6
  • 61 Brown JC, Cook MA, Dryburgh JR. Motilin, a gastric motor activity-stimulating polypeptide: final purification, amino acid composition, and C-terminal residues. Gastroenterology 1972; 62: 401-404
  • 62 Miegueu P, Cianflone K, Richard D. et al. Motilin stimulates preadipocyte proliferation and differentiation and adipocyte lipid storage. Am J Physiol Endocrinol Metab 2011; 301: E758-E766
  • 63 Suzuki H, Kuwano H, Mochiki E. et al. Effect of motilin on endogenous release of insulin in conscious dogs in the fed state. Dig Dis Sci 2003; 48: 2263-2270
  • 64 Hanson M, Almér LO, Ekman R. et al. Motilin response to a glucose load aberrant in smokers. Scand J Gastroenterol 1987; 22: 809-812
  • 65 Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. N Engl J Med 1978; 299: 926-930
  • 66 Pendharkar SA, Singh RG, Cervantes A et al. Gut hormone responses to mixed meal test in new-onset prediabetes/diabetes after acute pancreatitis. Horm Metab Res 2018 [Epub ahead of print]
  • 67 Bharmal SH, Pendharkar SA, Singh RG. et al. Associations between gastrointestinal humoral factors and pancreatic proteolytic enzymes in alcohol-related versus non-alcohol-related pancreatitis. Alcohol 2019; 76: 1-10
  • 68 Petrov MS, Yadav D. Global epidemiology and holistic prevention of pancreatitis. Nat Rev Gastroenterol Hepatol 2019; 16: 175-184
  • 69 Pendharkar SA, Singh RG, Bharmal SH et al. Pancreatic hormone responses to mixed meal test in new-onset prediabetes/diabetes after non-necrotizing acute pancreatitis. J Clin Gastroenterol 2018 [Epub ahead of print]
  • 70 Bharmal SH, Pendharkar SA, Singh RG et al. Associations between ketone bodies and fasting plasma glucose in individuals with post-pancreatitis prediabetes. Arch Physiol Biochem 2018 [Epub ahead of print]
  • 71 Singh RG, Pendharkar SA, Cervantes A. et al. Abdominal obesity and insulin resistance after an episode of acute pancreatitis. Dig Liver Dis 2018; 50: 1081-1087
  • 72 Cervantes A, Singh RG, Pendharkar SA. et al. Profile of gut hormones, pancreatic hormones and pro-inflammatory cytokines in New Zealand Maori. Gastroenterol Res 2018; 11: 280-289
  • 73 Pendharkar SA, Singh RG, Chand SK. et al. Pro-inflammatory cytokines after an episode of acute pancreatitis: associations with fasting gut hormone profile. Inflamm Res 2018; 67: 339-350
  • 74 Collins SM, Lewis TD, Fox JE. et al. Changes in plasma motilin concentration in response to manipulation of intragastric and intraduoduenal contents in man. Can J Physiol Pharmacol 1981; 59: 188-194