diabetes mellitus and chronic pancreatitis

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1 Gut, 1966, 7, 277 Exocrine and endocrine pancreatic function in diabetes mellitus and chronic pancreatitis N. PETERS1, A. P. DCK, C. N. HALES, D. H. ORRELL, AND MARTN SARNER1 From Addenbrooke's Hospital and the University Department of Biochemistry, Cambridge EDTORAL SYNOPSS Endocrine and exocrine pancreatic function was studied in a small group of controlled patients and in patients with chronic pancreatitis and with mild diabetes mellitus. Patients with chronic pancreatitis showed impaired production of pancreatic enzyme and inadequate production of insulin but no close correlation between exocrine and endocrine function could be demonstrated. Patients with diabetes mellitus show normal exocrine function but plasma insulin concentration was equal to or greater than normal. The exocrine function of the pancreas has been extensively studied in chronic pancreatitis (Burton, Evans, Harper, Howat, Oleesky, Scott, and Varley, 196; Sun and Shay, 196) but little is known of endocrine pancreatic function in this condition. n a recent study, Marks, Banks, and Jackson (1964) found that diabetes mellitus occurred in over 25% of 25 patients with chronic pancreatitis and if pancreatic calcification was present diabetes was found in 75 % of the patients. The glucose tolerance test was impaired in over 7% of all their patients with chronic pancreatitis and it could be abnormal even when the duodenal intubation tests were normal. The study of exocrine pancreatic function in patients with diabetes mellitus has produced conflicting results. Joslin, Root, White, and Marble (1959) quote work carried out on diabetics, in 29 of whom the pancreatic juice was normal; the remaining six cases had impaired pancreatic function but all had pancreatic calculi and a history suggestive of chronic pancreatitis. Conversely, of 5 diabetics, selected at random, studied by Chey, Shay, and Shuman (1961), had an abnormal duodenal intubation test; these workers also studied six cases of juvenile diabetes and found abnormal exocrine pancreatic function in all of them. The introduction of an immuno-assay method for the estimation of the plasma insulin concentration (Yalow and Berson, 196) and its modification by Hales and Randle (1963a) has enabled the plasma insulin to be measured accurately and more simply than has hitherto been possible. The object of this Present address: St. George's Hospital, London, S.W. 1. preliminary study has been to ascertain the nature of the endocrine disturbance in chronic pancreatitis and to compare this with the changes found in untreated diabetes mellitus; our second object has been to study the relationship between the endocrine and exocrine disturbances in chronic pancreatitis. For this purpose we have investigated three groups of patients: normal controls, patients with chronic pancreatitis, and patients having mild diabetes mellitus. CASE MATERAL 1 CONTROL SUBJECTS These were patients with abdominal pain in whom pancreatic disease was suspected, but excluded on further investigation. Those suffering from any condition in which the plasma insulin concentration was likely to be abnormal, e.g., diabetes mellitus, obesity, restricted intake of carbohydrate, and myocardial infarction, were excluded. Four patients were studied, aged from 2 to 65 years. 2 CHRONC PANCREATTS Five patients, aged from 55 to 8 years, with undoubted clinical evidence of chronic pancreatitis, were studied. All had steatorrhoea improved by pancreatin, and four of the five had pancreatic calcification. n no case did a follow-through barium meal show any significant abnormality, and none of the patients had a family history of diabetes. 3 DABETES MELLTUS Five patients were studied, aged from 58 to 79. They were all newly diagnosed mild diabetics who were, at the time, untreated. METHODS EXOCRNE FUNCTON The patient was intubated with an Abbott-Rawson double-lumen tube, having been starved 277 Gut: first published as 1.36/gut on 1 June Downloaded from on 4 October 2 by guest. Protected by copyright.

2 278 N. Peters, A. P. Dick, C. N. Hales, D. H. Orrell, and Martin Sarner for the previous hours. The weighted end of the tube was passed into the second part of the duodenum under radioscopic control using an image intensifier. When necessary, Gastrografin was injected down the inner tube to assist in defining its position and the position of the tube was checked at intervals during the test. The secretin-pancreozymin test was carried out according to the method of Burton et al. (196), duodenal contents being aspirated for two 1-minute control periods, followed by three 1-minute periods after the intravenous injection of secretin, and a further three 1- minute periods after the intravenous injection of pancreozymin. The biochemical methods used for the analysis of the duodenal aspirate were as described in their paper. Amylase alone was estimated in view of their finding that no advantage was gained from the simultaneous estimation of trypsin and lipase. ENDOCRNE FUNCTON A standard two and a half hour oral glucose tolerance test was carried out, the dose of glucose being 5 g. glucose was estimated by the glucose oxidase method on the Technicon Auto- Analyzer (Wincey and Marks, 1961). insulin concentrations were estimated using the immuno-assay described by Hales and Randle (1963a). RESULTS AND DSCUSSON The results for each patient are shown in Tables - together with the glucose tolerance tests and plasma insulin concentrations. n the secretinpancreozymin test no consistent difference was found in any of the parameters measured between each of the two 1-minute samples collected in Subject the control period. Nor was any consistent dliterence demonstrated between each of the three samples collected in the post-secretin period or between each of the three samples collected in the postpancreozymin period. values are therefore given for the control, post-secretin, and postpancreozymin periods in respect of volumes, and bicarbonate and amylase levels, and these are shown in Figure 1. As in the study of Burton et al. (196), patients with chronic pancreatitis show a limited ability to secrete an alkaline, enzyme-rich pancreatic juice, either at rest or following stimulation with secretin or pancreozymin. However, the mean volume of pancreatic juice in these patients is no less than that of the control and diabetic groups. Exocrine pancreatic function in the diabetic group does not differ appreciably from that in the control group. values for the blood glucose and plasma insulin concentrations are shown in Figure 2. Accepting Conn's (1958) criterion of mild diabetes as a failure of the blood glucose to fall below mg.% at one and a half hours after an oral glucose load of 5 g., the mean glucose tolerance curve for the chronic pancreatitis group is mildly diabetic. The mean fasting insulin concentration for this group is normal but there is a failure of response to the glucose load. t appears that the islets are still able to produce some insulin but have no reserve to respond to a glucose stimulus. One patient (case 1) who failed to produce any detectable LE CONTROL PATENTS Sex Volume Bicarbonate (ml./1 min.) Concentration (mm/.) 1 65 M Control 4 P-S' p_p F Control 2-2 P-S P-P F Control 5 5 P-S 19 P-P 4 3 M Control 8 P-S P-P 'Post secretin 2Post pancreozymin Amylase Concentration Glucose nsulin Hr. Mg. % Hr. Microunits /ml. 1* Gut: first published as 1.36/gut on 1 June Downloaded from on 4 October 2 by guest. Protected by copyright.

3 Subject Exocrine and endocrine pancreatic function in diabetes mellitus and chronic pancreatitis TABLE CHRONC PANCREATTS PATENTS Sex Volume Bicarbonate Amylase 1 61 M Control 8 P-S1 P-P' 2 69 F Control 48 P-S 22 P-P M Control S P-S 2 P-p 4 8 M Control 15 P-S 29 P-P M Control 13 P-S 38 P-P 2 'Post secretin 'Post pancreozymin Subject (ml./1 min.) Concentration Concentration (mm/i.) TABLE DABETES MELLTUS PATENTS Sex Volume Bicarbonate Amylase (ml./1 min.) Concentration Concentration (mm/.) 1 58 F Control 1 P-S' p-ps M Control 3-3 P-S 2 P-P 3 79 F Control 8 P-S 42 P-P M Control 3 P-S P-P F Control S P-S 17 P-P 1 'P-S Post secretin 'P-P Post pancreozymin 7 5 nsuff Glucose nsulin Hr. Mg % Hr. Microunits ml. 7 * 29 i i 1* * * 2* 2* 93 * * 1 1 1i 13 1i 2* 58 2* 66 * 3 * 1 1 1* 1 2* 96 2* 7 i 95 * * 95 1* 2* 75 2* Glucose nsulin Hr. Mg. % Hr. Microunits /ml * * 36 1* 2* 29 2* 2 * * 4 1* 2* 2* 2 i 3 i * 349 1* 2* 2* * 3 1* 2* 27 2* * 2 1* 2* 132 2* Gut: first published as 1.36/gut on 1 June Downloaded from on 4 October 2 by guest. Protected by copyright.

4 28 Mea n Volumes (m/ lo min Bicarbonate (mm/.) Amylase (units/ ml). ~~~~~~~,v N. Peters, A. P. Dick, C. N. Hales, D. H. Orrell, and Martin Sarner PS PP,/ 1,Y ' 3-25 Glucose g ~~~~~~- _.~~~~ (mg.,) -' 9. so PS p p 7 6 so / 4 3 / 2~ = PS PP 3 ' 2 X nsulin units/ml.) FG. 1. FG. 2. KEY _-_---. Control -- Diabetes & *Chronic Mellitus Pancreatitis PS -Post Secretin PP-Post Pancreozymin 1 5O 71 6 so '.. Hours!i k 2k2 Hours FG. 1. volumes, mean bicarbonate concentrations, and mean amylase concentrations ofpancreatic juice during secretin-pancreozymin tests. FG. 2. orally s 15 o s blood glucose and mean plasma insulin concentrations during glucose tolerance tests using 5 g. glucose insulin during the glucose tolerance test was subsequently re-tested during treatment with chlorpropamide, at which time his glucose tolerance curve was still abnormal. On this occasion a fasting plasma insulin concentration of 22 microunits/ml. was found but again there was no appreciable rise after a glucose load. The mean insulin curve for the diabetic group shows a high fasting concentration, with a delayed rise and a failure of the insulin to return to normal levels, a type of response which compares well with the observations of Hales and Randle (1963b) in a similar group of diabetics. n contrast to the chronic pancreatitis patients, the diabetics in our study were c able to increase their output of insulin in response to a glucose stimulus. Their more abnormal glucose tolerance curve indicates a failure of action of this insulin, suggesting the presence of insulin antagonism. There does not appear to be a direct relation between the degree of disturbance of the two parameters of pancreatic function in the patients with chronic pancreatitis. For example the patient, (case 1), in whom there was no detectable plasma insulin, was able to secrete small amounts of pancreatic juice containing both bicarbonate and amylase. This contrasts with the patient (case 4) in whom the duodenal aspirate contained no detectable Gut: first published as 1.36/gut on 1 June Downloaded from on 4 October 2 by guest. Protected by copyright.

5 Exocrine and endocrine pancreatic function in diabetes mellitus and chronic pancreatitis 281 amylase and only small quantities of bicarbonate, although this patient was able to produce appreciable quantities of insulin. n this preliminary study, the mild diabetes of chronic pancreatitis is shown to be associated with an impaired production of insulin; this is in contrast to the liberal insulin production found in postmature diabetics. No close relationship has been found between the impairment of exocrine and endocrine pancreatic function in this small series of patients with chronic pancreatitis, but exocrine pancreatic function in the post-mature diabetics was normal. SUMMARY Endocrine and exocrine pancreatic function tests have been carried out on four control patients, five patients with chronic pancreatitis, and five patients with mild diabetes mellitus. The patients with chronic pancreatitis showed impaired production of pancreatic ferments and an inadequate production of insulin; they were all mildy diabetic. There was no close correlation between disturbance of exocrine and endocrine function in this group. The patients with diabetes mellitus had normal exocrine pancreatic function and their plasma insulin concentration was equal to or greater than normal. We would like to thank the British Diabetic Association for a grant to one of us (C.N.H.) REFFRENCES Burton, P., Evans, D. G., Harper, A. A., Howat, H. T., Oleesky, S., Scott, J. E., and Varley, H. (196). A test of pancreatic function in man, based on the analysis of duodenal contents after the administration of secretin and pancreozymin. Gut, 1, 1-1. Chey, W. Y., Shay, H., and Shuman, C. R. (1961). External secretory function of the pancreas in diabetes mellitus. J. clin. nvest., 49, 9. Conn, J. W. (1958). The prediabetic state in man. Diabetes, 7, Hales, C. N., and Randle, P. J. (1963a). mmunoassay of insulin with insulin-antibody precipitate. Biochem. J., 88, 1-6. (1963b). Effects of low-carbohydrate diet and diabetes mellitus on plasma concentrations of glucose, non-esterified fatty acid, and insulin during oral glucose-tolerance tests. Lancet, 1, Joslin, E. P., Root, H. F., White, P., and Marble, A. (1959). T/.e Treatment of Diabetes Mellitus, 1th ed. p Kimpton, London. Marks,. N., Banks, S., and Jackson, W. P. U. (1964). Glucose tolerance and chronic pancreatitis in Cape Town. Excerpta med. int. Congr. Ser. (Amst.), 74, 8. Sun, D. C. H., and Shay, H. (196). Pancreozymin-secretin test. The combined study of serum enzymes and duodenal contents in the diagnosis of pancreatic disease. Gastroenterology, 38, Wincey, C., and Marks, V. (1961). A micro-method for measuring glucose using the AutoAnalyzer and glucose-oxidase. J. clin. Path.,, Yalow, R. S., and Berson, S. A. (196). mmunoassay of endogenous plasma insulin in man. J. clin. nvest.,, Gut: first published as 1.36/gut on 1 June Downloaded from on 4 October 2 by guest. Protected by copyright.