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Defects in Α-Cell Function in Patients with Diabetes Due to Chronic

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Defects in Α-Cell Function in Patients with Diabetes Due to Chronic Diabetes Care 1 Lena Mumme,1 Thomas G.K. Breuer,1 Defects in -Cell Function in CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL a Stephan Rohrer,1 Nina Schenker,1 Patients With Diabetes Due to Bjorn¨ A. Menge,1 Jens J. Holst,2 Michael A. Nauck,1 and Juris J. Meier1 Chronic Pancreatitis Compared With Patients With Type 2 Diabetes and Healthy Individuals https://doi.org/10.2337/dc17-0792 OBJECTIVE Diabetes frequently develops in patients with chronic pancreatitis. We examined the alterations in the glucagon response to hypoglycemia and to oral glucose adminis- tration in patients with diabetes due to chronic pancreatitis. RESEARCH DESIGN AND METHODS Ten patients with diabetes secondary to chronic pancreatitis were compared with 13 patients with type 2 diabetes and 10 healthy control subjects. A stepwise hypo- glycemic clamp and an oral glucose tolerance test (OGTT) were performed. RESULTS Glucose levels during the OGTT were higher in patients with diabetes and chronic pancreatitis and lower in control subjects (P < 0.0001). Insulin and C-peptide levels were reduced, and the glucose-induced suppression of glucagon was impaired in both groups with diabetes (all P < 0.0001 vs. control subjects). During hypoglycemia, glucagon concentrations were reduced in patients with chronic pancreatitis and with type 2 diabetes (P < 0.05). The increase in glucagon during the clamp was inversely related to the glucose-induced glucagon suppression and positively related to b-cell function. Growth hormone responses to hypoglycemia were lower in patients with type 2 diabetes (P = 0.0002) but not in patients with chronic pancreatitis. 1Diabetes Division, Department of Medicine I, CONCLUSIONS St. Josef Hospital (Ruhr-University Bochum), Bochum, Germany a-Cell responses to oral glucose ingestion and to hypoglycemia are disturbed in 2Department of Biomedical Sciences, Panum In- patients with diabetes and chronic pancreatitis and in patients with type 2 diabetes. stitute, University of Copenhagen, Copenhagen, The similarities between these defects suggest a common etiology. Denmark Corresponding author: Juris J. Meier, juris.meier@ rub.de. Chronic pancreatitis is frequently complicated by the development of diabetes (1,2). Received 20 April 2017 and accepted 3 July 2017. This typically occurs at the advanced stages of the disease, alongside with pancreatic This article contains Supplementary Data online atrophy and fibrosis (2–4). Phenotypically, diabetes in patients with chronic pancrea- at http://care.diabetesjournals.org/lookup/ titis is often characterized by insulin deficiency, while insulin resistance is held to be less suppl/doi:10.2337/dc17-0792/-/DC1. prevalent (5). Furthermore, obesity is far less common in patients with diabetes sec- © 2017 by the American Diabetes Association. ondary to chronic pancreatitis than in patients with type 2 diabetes, owing to the Readers may use this article as long as the work is properly cited, the use is educational and not malnutrition resulting from the loss of exocrine tissue (1,6). The etiology of diabetes for profit, and the work is not altered. More infor- in patients with chronic pancreatitis mainly involves a loss of endocrine b-cells, which mation is available at http://www.diabetesjournals likely results from inflammatory destruction (4,7). We have previously demonstrated .org/content/license. Diabetes Care Publish Ahead of Print, published online July 27, 2017 2 Hypoglycemia Counterregulation in Pancreatitis Diabetes Care that pancreatic b-cell mass was reduced seems to be relatively high (15). Because of acute myocardial infarction, percuta- by ;45% in a group of patients with glucagon is the major safeguard against neous coronary angioplasty or coronary chronic pancreatitis, whereas the reduc- the development of hypoglycemia (16), artery bypass graft, hemoglobinopathies tion in a-cell mass was less pronounced in an impairment in hypoglycemia-induced or anemia (hemoglobin ,9 g/dL), sys- this group (;35%) (4). Interestingly, the glucagon secretion might be found in temic treatment with glucocorticoids, loss of b-cells seems to occur relatively such patients. C-reactive protein .100 mg/dL (normal late during the course of the disease. Therefore, in the current study, the value ,5 mg/dL), previous pancreatic Thus, it appears that the endocrine islets hormonal counterregulatory response to resective surgery, current infections exhibit greater resistance to the self- hypoglycemia was examined in patients (fever), a history of seizures, or unwilling- destruction of the pancreas than acinar with diabetes secondary to chronic pan- ness or lack of competence to comply with or ductal cells. This observation is further creatitis, patients with type 2 diabetes, the requirements of the study protocol. supported by the fact that the endocrine and control subjects without diabetes. In Study Design islets are more resistant against the enzy- addition, the glucagon response to oral glu- In all participating subjects, a screening matic digestion of the pancreas during cose ingestion was examined and related to examination including the determination the process of islet isolation for transplan- glucagon secretion during hypoglycemia. of a standard laboratory profile (hemo- tation (8). globin, leukocytes, transaminases [ALAT/ Although the impairment of insulin se- RESEARCH DESIGN AND METHODS ASAT], g-glutamyl transpeptidase, creati- cretion in patients with diabetes due to Study Protocol, Ethics Committee nine, sodium, potassium, and C-reactive chronic pancreatitis is relatively well es- Approval protein) was performed. If subjects met tablished (7,9), much less is known about The study protocol was approved by the the inclusion criteria, they were invited to potential alterations in a-cell function. A ethics committee of the Medical Faculty, participate in two experiments: 1) a hy- recent study suggested higher rises of glu- Ruhr-University Bochum (registration perinsulinemic, sequentially euglycemic cagon after a mixed-meal challenge in pa- number 4134–11). Written informed con- and hypoglycemic clamp experiment tients with chronic pancreatitis, thought sent was obtained from all participants. and 2) an oral glucose tolerance test to be a consequence of the loss of insulin- (OGTT) over 240 min. b-Blockers and mediated inhibition of glucagon secretion Patients With Diabetes Due to Chronic oral glucose-lowering agents were dis- (10). In contrast, glucagon secretion after Pancreatitis, Patients With Type 2 continued for at least 3 days before the arginine stimulation was found to be re- Diabetes, and Healthy Control Subjects date of the clamp experiment. Long-acting duced in patients without diabetes with Three groups of subjects were recruited insulin preparations were last allowed in chronic pancreatitis (11). However, very into the current study: 1) patients with the morning of the previous day, and little information is yet available about diabetes due to chronic pancreatitis, 2) short-acting insulin preparations were other physiological functions of glucagon, patients with type 2 diabetes and no chronic last allowed for dinner of the day before such as the counterregulatory response pancreatitis, and 3) normal glucose- the experimental days. to hypoglycemia (12,13). Furthermore, it tolerant subjects without chronic pancre- is not known to what extent the abnor- atitis. Chronic pancreatitis was diagnosed Experimental Procedures malities in glucagon secretion in patients after clinical workup based on the pres- OGTT with diabetes secondary to chronic pan- ence of pancreatic calcifications, dilated After an overnight fast of at least 10 h, a creatitis resemble those typically found in pancreatic ducts, septation/lobulation large forearm vein was cannulated, and patients with type 2 diabetes. due to fibrotic changes, exocrine pancre- the cannula was kept patent by a slow In clinical practice, glucose-lowering atic atrophy (all demonstrated by appro- drip of 0.9% saline. The body position treatment of patients with diabetes sec- priate imaging procedures) (for details, was semirecumbent, with the body ondary to chronic pancreatitis can be see Supplementary Table 1), and pancre- ;30° upright. After drawing basal blood challenging (2). This is partly due to the atic exocrine insufficiency requiring pan- samples at 25 and 0 min, an oral glucose fact that oral glucose-lowering agents creas enzyme replacement therapy. The drink (75 g glucose in 300 mL) was admin- that act to improve insulin sensitivity absence of chronic pancreatitis in the istered, and venous blood samples were (e.g., metformin) may not address the control groups (normal glucose-tolerant collected over 240 min. key pathophysiological problems, and and type 2 diabetes) was verified by the Hyperinsulinemic, Stepwise Hypoglycemic other drugs (DPP-4 inhibitors and GLP-1 absence of clinical signs and symptoms of Clamp receptor agonists) are even contraindi- chronic pancreatitis. The hyperinsulinemic, stepwise hypogly- cated because of a potentially increased For all three groups, the following cemic clamp was commenced in the risk of pancreatitis (14). On the other inclusion criteria were used: both sexes, morning after an overnight (.10 h) fast. hand, the use of insulinotropic agents, age 18–75 years (inclusive), and BMI One large vein on each forearm was can- such as the sulphonylureas, or exogenous 17–45 kg/m2 (inclusive). Exclusion criteria nulated, and the cannulas were kept patent insulin replacement therapy is often af- were as follows: pregnancy or breastfeed-
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