ORIGINAL ARTICLE Early Alterations in Glycemic Control and Pancreatic Endocrine Function in Nondiabetic Patients With Chronic Pancreatitis Rachel Lundberg, BS,* Gregory J. Beilman, MD,† Ty B. Dunn, MD,† Tim L. Pruett, MD,† Martin L. Freeman, MD,‡ Peggy E. Ptacek, CMA,* Katherine Louise Berry, RN,† R. Paul Robertson, MD,‡ Antoinette Moran, MD,* and Melena D. Bellin, MD*† disease to clinical attention, diabetes mellitus (DM) is an impor- Objectives: – Diabetes mellitus is a frequent consequence of chronic pan- tant and frequent consequence.1 5 The lifelong risk of developing creatitis (CP). Little is known about pancreatic endocrine function before DM in the setting of CP is estimated at 25% to 75%6–9 and de- the development of diabetes mellitus in CP,particularly in females, or those pends in part on previous surgical resection, etiology of disease, without calcific and/or alcoholic pancreatitis. and extent of pancreatic damage, with exocrine insufficiency Methods: – Twenty-five nondiabetic adult patients with CP (19 female; and calcifications as important markers of the latter.7 11 mean [SE] age, 34.2 [2.4] years) were compared with 25 healthy controls Compared with type 1 and type 2 DM, very few clinical stud- matched for age, sex, and body mass index. Subjects underwent frequent ies exist to characterize the pathophysiology and natural history of sample intravenous glucose tolerance testing (FSIVGTT) and mixed meal DM in CP.Impaired insulin responses to oral and intravenous (IV) tolerance testing (MMTT). 6,10,12 Results: secretagogues have been observed in those with DM and CP Mean (SE) fasting glucose was higher in patients with CP and in a handful of patients with normal glucose tolerance and (89.5 [2.3] mg/dL) than in controls (84.4 [1.2] mg/dL, P = 0.04). On CP.10 However, these studies included nearly all male patients, MMTT, patients with CP had a higher area under the curve (AUC) glu- usually with alcohol-induced pancreatitis and with late calcific ≤ cose and AUC glucagon compared with controls (P 0.01). The AUC CP.More than half of CP cases are due to causes other than alco- C-peptide was equivalent (P = 0.6) but stimulated C-peptide at 30 minutes hol, and women are frequently affected.13 This important demo- was lower in patients with CP (P = 0.04). Mean insulin sensitivity index graphic has been overlooked. Moreover, glucose homeostasis is calculated from the FSIVGTT was lower in CP group, indicating reduced regulated by multiple other factors; mixed data exist on the role ≤ insulin sensitivity (P 0.01). Disposition index (insulin secretion of glucagon and prandial incretin responses as well as insulin adjusted for insulin sensitivity on FSIVGTT) was lower in patients with sensitivity in metabolic control in this population.4,6,14–20 CP (P = 0.01). Conclusions: Little is known about the natural history of pancreatic endo- Patients with CP had higher fasting and MMTT glucose crine function in CP before the onset of DM. It has been proposed levels, without a compensatory increase in insulin secretion suggesting that inflammation and an altered pancreatic milieu may cause subtle early islet dysfunction. Our cohort had relative hyperglucagonemia β-cell dysfunction early in the disease course, with progressive and was less insulin sensitive than controls. loss of β cells leading to frank diabetic mellitus in a subset of Key Words: β cell, pancreatitis, diabetes, patients.21,22 The aim of this study was to advance our current total pancreatectomy and islet autotransplantation, pancreatectomy, islet understanding of the development of endocrine insufficiency – in CP. Insulin secretion in response to oral and IV secretagogues, (Pancreas 2016;45: 565 571) postprandial glucagon suppression, and the incretin axis were assessed in nondiabetic patients with CP and compared with the hronic pancreatitis (CP) is an inflammatory condition that well-matched healthy controls. Moreover, we enriched our CP C causes permanent structural damage to the pancreas. Al- cohort with patients who have been underrepresented in earlier though it is severe abdominal pain that generally brings the studies, including those with nonalcoholic disease, females, and patients who had not yet developed pancreatic calcifica- tions. Better understanding of the progression from endocrine † ‡ From the Departments *Pediatrics, Surgery, and Medicine, University of dysfunction to DM is critical to develop screening tools for Minnesota, Minneapolis, MN. Received for publication January 13, 2015; accepted June 12, 2015. early detection and intervention. Reprints: Melena D. Bellin, MD, University of Minnesota Children’sHospital, East Bldg, Room MB-671, 2450 Riverside Ave, Minneapolis, MN 55454 (e‐mail: [email protected]). MATERIALS AND METHODS This study was supported in part by the American Diabetes Association (No. 1-11-CT-06) and the National Pancreas Foundation. M.D.B and R.P.R received support from the National Institute for Diabetes, Digestive, and Subjects Kidney diseases (1K23DK084315 and R01-39994, respectively). The authors declare no conflict of interest. Twenty-five nondiabetic patients with CP and 25 healthy vol- R.L. and M.D.B. constructed the design of the study, collected and analyzed unteers were studied in a matched case-control cross-sectional data, and wrote the manuscript. G.J.B. constructed the design of the study analysis. Patients with CP were recruited from a cohort of adult and revised the manuscript. T.B.D., T.L.P.,K.L.B., and P.E.P.participated in patients, aged 18 years or older, scheduled for total pancrea- participant care, data collection for the study, and approval of final manuscript. M.L.F., R.P.R., and A.M. contributed to data interpretation, tectomy and islet autotransplantation (TP-IAT) at the University revised, and approved the manuscript. R.L. and M.D.B. had full access to all of Minnesota from 2010 to 2012. All patients with CP were partic- of the data in the study and take responsibility for the integrity of the data ipants in a clinical trial, which included metabolic testing per- and the accuracy of the data analysis. formed within 2 weeks before TP-IAT. Patients were considered Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions ineligible for study participation if they had a previous diagnosis of this article on the journal’s Web site (www.pancreasjournal.com). of DM, if they were using any antidiabetic medications at the Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. time of study enrollment, if fasting blood glucose level was Pancreas • Volume 45, Number 4, April 2016 www.pancreasjournal.com 565 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Lundberg et al Pancreas • Volume 45, Number 4, April 2016 greater than 115 mg/dL, or if hemoglobin A1c (HbA1c)level difficult to maintain in some patients with CP and hemolysis wasmorethan6.0%. can compromise the accuracy of insulin immunoassay measures, All patients with CP were seen in consultation and clinical we excluded patients with CP and their matched controls for re- history was reviewed by a multidisciplinary team. The CP diagno- spective analyses of AIRglu and/or SI if lacking adequate samples sis before TP-IATwas based on at least one of the following, as for insulin measures during necessary time points (resulting in previously described1: documented episodes of recurrent acute matched pairs, n = 20 for AIRglu, n = 21 for SI). pancreatitis (amylase/lipase > 3 times upper limit of normal) with The mixed meal tolerance test required placement of 1 pe- progression to characteristic chronic abdominal pain2;imaging ripheral IV 30 minutes before the first blood draw. At time 0, or functional studies supporting CP (at least 2 tests abnormal the patient consumed 6 mL/kg Boost HP to a maximum of among abnormal magnetic resonance cholangiopancreatography, 360 mL within 5 minutes. Patients on pancreatic enzyme therapy ≥4 criteria on endoscopic ultrasound, or abnormal secretin- were instructed to take their usual dose with the Boost HP. Glu- stimulated pancreatic function tests)3; pancreatic calcifications cose, insulin, C-peptide, glucagon, gastric inhibitory peptide on computed tomography scan4; or histopathology-confirmed (GIP), and active glucagon-like peptide 1 (GLP-1) were measured CP at time of previous surgery (if done). at −1, +30, +60, +90, and +120 minutes. Area AUC for C-peptide Healthy control subjects were recruited from 2012 to 2013 (AUC C-peptide) and glucose (AUC glucose) were calculated through fliers and advertisements displayed around the community. using the trapezoidal method. One patient in the CP group Interested subjects were screened by phone or through e-mail for was unable to complete the MMTT because of vomiting and eligibility. Eligible healthy controls were matched to patients with was excluded from the MMTT analyses. The earliest 5 patients CP on the basis of sex, age (±3 years), and body mass index in our CP cohort did not have glucagon collected (n = 20 case- (BMI) (±3 kg/m2). Subjects were excluded if they had a history of control pairs for AUC glucagon). any of the following: past or present use of insulin or oral antidia- Plasma glucose levels were measured by glucose oxidase betic mediation, DM, diagnosis of acute or CP, chronic unexplained assay, and plasma C-peptide levels were measured by Siemen abdominal pain, or use of corticosteroids in the past 6 months. immunolite 2000 chemiluminescent immunoassay. Insulin Screening fasting glucose was obtained at time of informed consent. levels were measured by 2-site immunoenzymometric assay The University of Minnesota Institutional Review Board (IRB) on a TOSOH 2000 autoanalyzer.26,27 Glucagon was measured reviewed and approved the protocols (IRB Number 1006M83756 by radioimmunoassay, active GLP-1 and GIP by ELISA fluores- for CP group, IRB Number 1203M11602 for healthy control cent sandwich immunoassay (EMD Millipore Corp, Billerica, group).