Pancreapedia: Exocrine Pancreas Knowledge Base, DOI: 10.3998/panc.2015.7
Despite being described anatomically almost 2,000 years ago the physiological function of the pancreas and its role in diseases remained more or less unknown until the 19th century. Performing pancreatectomies in dogs, von Mehring and Minkowski realised that the animals developed diabetes that could be cured by pancreas transplantation (26). Ever since these studies it has been accepted that pancreatic diseases or diseases involving the exocrine pancreas can induce diabetes mellitus. The American Diabetes Association (ADA) diabetes classification published in 1998 therefore includes pancreatic diabetes as “type 3c” that can be caused by pancreatic neoplasms, acute or chronic pancreatitis, hemochromatosis, cystic fibrosis or pancreatic surgery (37). When the role of insulin was established in the early 20st century, physicians were aware that patients with diabetes mellitus – most of them having type 1 diabetes at the time – also suffered from malnutrition. While prior to the discovery of insulin this malnutrition was a consequence of failure of nutrient storage rather than digestion, physicians nonetheless suspected that the digestive function of the pancreas might be reduced in patients with diabetes mellitus and several groups started to investigate exocrine pancreatic function in diabetes mellitus once pancreatic function tests became available.
2. Studies of Exocrine Pancreatic Function in Diabetes Mellitus
Direct function tests
The first exocrine pancreatic function tests available in specialized centres were direct function tests using cholecystokinin (CCK) and/or secretin stimulation to measure pancreatic enzyme output in duodenal juice. Despite being rather invasive and complicated, these tests remained the gold standard for scientific evaluation of exocrine pancreatic function until today. Pollard et al. reported as early as 1943 that the secretin stimulated lipase and amylase output in a small series of patients with diabetes mellitus was reduced in 62% of all cases (31). Several studies in the 1970s and up to today reported similar findings (Table 1). On average, pancreatic exocrine insufficiency (PEI) was described in 67% of the patients investigated with direct function tests, most of them being classified as insulin dependent diabetes mellitus (“IDDM”) or type 1 diabetes where absolute insulin deficiency leads to pancreas gland atrophy.
Indirect function tests
Later on, when indirect function tests became available, fecal chymotrypsin activity and fecal elastase 1 concentrations (FEC) were used to measure exocrine pancreatic function. Since these tests did not depend on specialized centers, it was possible to involve larger series of patients with diabetes mellitus. The largest trial was carried out as a multi-center trial in Germany and included 323 patients classified as “type 1 diabetes mellitus” and 697 patients classified as “type 2” diabetes mellitus. The prevalence of exocrine pancreatic insufficiency (FEC < 200 µg/g) was reported to be 51% and 35% respectively (15). Other studies reported very similar results – an overview of the available studies is given in Table 2. While the relevance of these findings is still under debate, it can be summarized that the coincidence of exocrine and endocrine pancreatic insufficiency has been accepted to be very frequent. Furthermore it has been shown in autopsy studies and imaging studies that pancreas anatomy frequently shows alterations in patients with diabetes mellitus (16).
Several national and international associations have discussed and published special considerations concerning exocrine insufficiency in diabetes mellitus and type 3c diabetes mellitus (1, 13, 33, 40).
3. Fat Exertion in Diabetes Mellitus
Fat digestion in patients with diabetes mellitus and low fecal elastase 1 levels have been studied by at least two different centers. Hardt et al. reported that about 60% of the patients (type 1 or type 2) with FEC < 100 µg/g had steatorrhea (14) and Cavalot et al. reported that 29% of type 1 patients had steatorrhea. In this study there was a significant inverse correlation between FEC and the amount of fat excretion (4). Despite this surprising finding (steatorrhea is believed to exist only if pancreatic lipase secretion is below 10% of normal activity) it did not receive much attention.
This neglect might be explained by the fact that most diabetic patients do not report classical symptoms of exocrine insufficiency – unless they are asked about it. If asked, they report a slightly increased number of stools, bloating and loose stools as compared to patients without PEI. Major pain episodes are rare.
4. Pathophysiological Concepts
A number of different pathophysiological concepts that try to explain pancreatic exocrine insufficiency in diabetes mellitus have been discussed in the past (1):
- A lack of local insulin levels (as in type 1 diabetes) might cause an atrophy of acinar tissue since insulin is a relevant local trophic factor (insulin-acinar portal system)
- Regulatory functions of other islet hormones on exocrine tissue might be impaired in diabetes mellitus or suppress exocrine function (glucagon, pancreatic polypeptide, somatostatin etc.)
- Diabetic autonomic neuropathy may cause problems in the enteropancreatic interaction and may result in exocrine pancreatic dysfunction
- Diabetic angiopathy may cause pancreatic fibrosis and atrophy
- Simultaneous damage of exocrine and endocrine pancreatic tissue may result from:
- infections (e.g. viral infections)
- autoimmunity (e.g. autoimmune pancreatitis)
- genetic mutations (e.g. CEL mutation)
- Pancreatic diabetes (type 3c) might be more common than previously believed
- Beta-cell regeneration from exocrine and ductal tissue might be altered in pancreatic diseases
- Inflammatory alterations and/or altered cytokine expression (e.g. TGFb1, TGFa,TNFa, etc.) in metabolic syndrome and obesity may lead to the described comorbidity
When taking into consideration that in most studies the finding of PEI did not depend on the duration of diabetes mellitus, it seems rather unlikely that PEI is a complication of diabetes mellitus. There are other findings – e.g. some type 1 diabetes patients do not suffer from PEI despite complete lack of local insulin – suggesting that type 3c diabetes might be underdiagnosed and much more frequent than previously believed (9).
5. Clinical Relevance
The clinical relevance of PEI in diabetes mellitus is still under debate. Nevertheless, the high prevalence of coexisting pathological findings in endocrine and exocrine pancreas has stimulated several national and international expert committees to discuss and publish guidelines on PEI in diabetes mellitus and diagnosis and management of diabetes mellitus in pancreatic diseases. These guidelines try to summarize the current knowledge. So far, they have proposed the evaluation of exocrine function in patients with known diabetes mellitus and symptoms suggestive of PEI. Furthermore treatment of PEI, if present, is suggested. However, before reasonable advice can be given, there is still need for prospective trials to determine the true prevalence of type 3c diabetes mellitus and its clinical relevance.
Impact on qualitative nutrition
The maldigestion due to PEI can lead to a relevant qualitative malnutrition concerning e.g. the absorption of fat-soluble vitamins (A, D, E, and K), especially vitamin D. A significant correlation of low fecal elastase 1 levels and low vitamin D levels has been demonstrated e.g. in osteoporosis and alterations of bone metabolism have been shown in patients with PEI (25, 35). A recent German study of 248 patients with PEI due to different reasons (e.g. chronic pancreatitis, pancreatic carcinoma, etc.) showed vitamin D deficiency in 93% of those patients. Supplementation with high doses of vitamin D resulted in normalization of serum concentrations (19). Considering the important role of vitamin D in the regulation of the immune system, the possible role of vitamin D deficiency in the pathogenesis of type 1 diabetes and the highly interesting association of low vitamin D levels and poor glycemic control, qualitative malnutrition of vitamin D in patients with PEI and diabetes mellitus may be of great clinical importance. Measuring serum 25-hydroxyvitamin D levels and supplementing patients with low levels should therefore be considered in these patients. However, up to date randomized, controlled trials are still missing and are strongly encouraged.
Impact on glycemic control
Since the secretion of incretins (regarded as a major factor regulating insulin secretion and action) largely depends on normal fat and protein digestion, PEI might play a critical role in quite a number of patients. As early as in 1980, exocrine pancreatic insufficiency has been shown to prevent the normal release of GIP in response to oral feeding and that this effect can be abolished by enzyme replacement therapy (6). Other recent studies emphasize the important role of unimpaired fat hydrolysis in regulating GLP-1 secretion (2) and document a reversal of impaired GLP-1 secretion by pancreatic enzyme supplementation in patients with exocrine pancreatic insufficiency due to cystic fibrosis (21).
Since the incretin axis has become a major target in modern diabetology, it is of utmost importance to learn about the clinical implications of exocrine pancreatic insufficiency in diabetic patients.
However, there are hardly any studies addressing the impact of PEI on glycemic control in diabetes mellitus. This is rather astonishing considering the fact, that due to the above described reasons one would expect a rather important impact of restoring proper fat digestion in those patients.
Most studies address glycemic control in patients with type 3c diabetes mellitus due to chronic pancreatitis or cystic fibrosis (11, 27, 29, 30). Even those studies show very inconsistent results. Some report more stable glucose control, some less stable control, and some no impact of enzyme replacement therapy on glycemic control. To our knowledge there is only one study so far addressing the impact of pancreatic enzyme replacement therapy on glycemic control in patients with diabetes mellitus and PEI. In this multicenter study no positive effect on HbA1c, C-peptide levels or blood glucose levels could be found. There was a slight trend towards fewer hypoglycemic episodes in the pancreatic enzyme treated group, yet it was not statistically significant (8). Yet, taking a closer look at the study, one must admit that it bears several flaws. The study included insulin dependent diabetes mellitus patients and did not differentiate between type 1, type 2 or type 3c diabetes mellitus. Furthermore the follow up of 16 weeks was rather short.
Several studies describe a major impact of an adequately restored fat digestion on incretin action and therefore on glycemic control (2, 6, 20, 21). Thus, a well-designed randomized controlled trial on pancreatic enzyme replacement therapy in patients with diabetes mellitus and PEI is urgently needed. One might speculate that pancreatic enzyme replacement therapy would be a beneficial therapeutic option concerning glucose control.
It is evident that there is a frequent comorbidity of endocrine and exocrine pancreatic pathology. Alterations in exocrine pancreatic function in diabetes mellitus can be found quite frequently. Although there are many interesting pathophysiological concepts trying to explain those consistent findings, none of the raised hypotheses have been proven so far. Probably several of the described pathophysiological hypotheses contribute to the phenomenon to a certain degree.
The relevance of the finding of a frequent comorbidity of exocrine and endocrine pancreatic disease is still under controversial debate. Unfortunately randomized controlled trials are very rare in this research area. A very interesting field might be the qualitative malnutrition (e.g. vitamin D, lipid digestion) in these patients and the impact it might have on diabetes mellitus. Furthermore the impact of fat and protein maldigestion (and therefore impaired incretin secretion) on glycemic control is unclear due to the lack of larger clinical studies.
- Andren-Sandberg A, Hardt PD. Second Giessen International Workshop on Interactions of Exocrine and Endocrine Pancreatic Diseases. Castle of Rauischholzhausen of the Justus-Liebig-University, Giessen, Germany. March 7-8, 2008. JOP 9: 541-575, 2008. PMID: 18648151
- Beglinger S, Drewe J, Schirra J, Göke B, D'Amato M, Beglinger C. Role of fat hydrolysis in regulating glucagon-like Peptide-1 secretion. J Clin Endocrinol Metab 95: 879-886, 2010. PMID: 19837920
- Bretzke G. [Diabetes mellitus and exocrine pancreas function]. Z Gesamte Inn Med. 39: 388-390, 1984. PMID: 6506812
- Cavalot F, Bonomo K, Fiora E, Bacillo E, Salacone P, Chirio M, Gaia E, Trovati M. Does pancreatic elastase-1 in stools predict steatorrhea in type 1 diabetes? Diabetes Care 29: 719-721, 2006. PMID: 16505538
- Chey WY, Shay H, Shuman CR .External pancreatic secretion in diabetes mellitus. Ann Intern Med 59: 812-821, 1963. PMID: 14082733
- Ebert R, Creutzfeldt W. Reversal of impaired GIP and insulin secretion in patients with pancreatogenic steatorrhea following enzyme substitution. Diabetologia 19: 198-204, 1980. PMID: 6997121
- El Ne Wihi H, Dooley CP, Saad C. Impaired exocrine pancreatic function in diabetics with diarrhoea and peripheral neuropathy. Dig Dis Sci 33: 705-710, 1988. PMID: 2897272
- Ewald N, Bretzel RG, Fantus IG, Hollenhorst M, Kloer HU, Hardt PD; S-2453110 Study Group. Pancreatin therapy in patients with insulin-treated diabetes mellitus and exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations. Results of a prospective multi-centre trial. Diabetes Metab Res Rev 23: 386-391, 2007. PMID: 17103488
- Ewald N, Kaufmann C, Raspe A, Kloer HU, Bretzel RG, Hardt PD. Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c). Diabetes Metab Res Rev 28: 338-342, 2012. PMID: 22121010
- Frier BM, Saunders JHB, Wormsley KG Bouchier IAD. Exocrine pancreatic function in juvenile-onset diabetes mellitus. Gut 17: 685-691, 1976. PMID: 976808
- Glasbrenner B, Malfertheiner P, Kerner W, Scherbaum WA, Ditschuneit H. [Effect of pancreatin on diabetes mellitus in chronic pancreatitis]. Z Gastroenterol 28: 275-279, 1990. PMID: 2238755
- Harano Y, Kim CI, Kang M, Shichiri M, Shimizu Y, Li H, Yoshida M, Shigeta Y, Abe H. External pancreatic dysfunction associated with diabetes mellitus. J Lab Clin Med. 91:780-90, 1978. PMID: 641400
- Hardt P, Hammer H, Abrahamian H, Ebenbichler C, Hummel M, Matthaei S, Schnell O, Spinas G, Weitgasser R, Wiesli P, Philippe J. Diagnostik und Therapie der exokrinen Insuffizienz bei Diabetes mellitus. Diabetes, Stoffwechsel und Herz 20: 185-190, 2011.
- Hardt PD, Hauenschild A, Jaeger C, Teichmann J, Bretzel RG, Kloer HU, S2453112/S2453113 Study Group. High prevalence of steatorrhea in 101 diabetic patients likely to suffer from exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations: a prospective multicenter study. Dig Dis Sci 48:1688-1692, 2003. PMID: 14560984
- Hardt PD, Hauenschild A, Nalop J, Marzeion AM, Jaeger C, Teichmann J, Bretzel RG, Hollenhorst M, Kloer HU; S2453112/S2453113 Study Group. High prevalence of exocrine pancreatic insufficiency in diabetes mellitus. A multicenter study screening fecal elastase 1 concentrations in 1,021 diabetic patients. Pancreatology 3: 395-402, 2003. PMID: 14526149
- Hardt PD, Kloer HU, Brendel MD, Bretzel RG. Is pancreatic (type 3c) diabetes underdiagnosed and misdiagnosed? Diabetes Care 31(S2): 165–169, 2008. PMID: 18227480
- Hardt PD, Krauss A, Bretz L, Porsch-Oezcueruemez M, Schnell-Kretschmer H, Mäser E, Bretzel RG, Zekorn T, Klör HU. Pancreatic exocrine function in patients with type-1 and type-2 diabetes mellitus. Acta Diabetologia 37: 105-110, 2000. PMID: 11277309
- Icks A, Haastert B, Giani G, Rathmann W. Low fecal elastase 1 in type 1 diabetes mellitus. Z Gastroenterol 39: 823-830, 2001. PMID: 11605150
- Klapdor S, Richter E, Klapdor R. Vitamin D status and per-oral vitamin D supplementation in patients suffering from chronic pancreatitis and pancreatic cancer disease. Anticancer Res 32: 1991–1998, 2012. PMID: 22593477
- Knop FK, Vilsbøll T, Larsen S, Højberg PV, Vølund A, Madsbad S, Holst JJ, Krarup T. Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution. Am J Physiol Endocrinol Metab 292: E324-330, 2007. PMID: 16954337
- Kuo P, Stevens JE, Russo A, Maddox A, Wishart JM, Jones KL, Greville H, Hetzel D, Chapman I, Horowitz M, Rayner CK. Gastric emptying, incretin hormone secretion, and postprandial glycemia in cystic fibrosis--effects of pancreatic enzyme supplementation. J Clin Endocrinol Metab 96: E851-855, 2011. PMID: 21389144
- Lankisch PG, Manthey G, Otto J, Talaulicar M, Willms B, Creutzfeldt W. Exocrine pancreatic function in insulin-dependent diabetes mellitus. Digestion 25: 210-216, 1982. PMID: 6186557
- Larger E, Philippe MF, Barbot-Trystram L, Radu A, Rotariu M, Nobécourt E, Boitard C. Pancreatic exocrine function in patients with diabetes. Diabet Med 29: 1047-1054, 2012. PMID: 22273174
- Mancilla AC, Hurtado HC, Tobar AE, Orellana NI, Pineda BP, Castillo MI, Ledezma RR, Berger FZ. [Pancreatic exocrine function in diabetes mellitus. Determination of fecal elastase]. Rev Med Chil 134: 407-414, 2006. PMID: 16758074
- Mann ST, Mann V, Stracke H, Lange U, Klör HU, Hardt P, Teichmann J. Fecal elastase 1 and vitamin D3 in patients with osteoporotic bone fractures. Eur J Med Res 13: 68–72, 2008. PMID: 18424365
- Mering J v, Minkowski O. Diabetes mellitus nach Pankreasextirpation. Arch Exp Pathol Pharmakol 26: 37, 1890.
- Mohan V, Poongothai S, Pitchumoni CS. Oral pancreatic enzyme therapy in the control of diabetes mellitus in tropical calculous pancreatitis. Int J Pancreatol 24: 19-22, 1998. PMID: 9746885
- Nunes AC, Pontes JM, Rosa A, Gomes L, Carvalheiro M, Freitas D. Screening for pancreatic exocrine insufficiency in patients with diabetes mellitus. Am J Gastroenterol 98: 2672-2675, 2003. PMID: 14687815
- O'Keefe SJ, Cariem AK, Levy M. The exacerbation of pancreatic endocrine dysfunction by potent pancreatic exocrine supplements in patients with chronic pancreatitis. J Clin Gastroenterol 32: 319-323, 2001. PMID: 11276275
- Perano SJ, Couper JJ, Horowitz M, Martin AJ, Kritas S, Sullivan T, Rayner CK. Pancreatic enzyme supplementation improves the incretin hormone response and attenuates postprandial glycemia in adolescents with cystic fibrosis: a randomized crossover trial. J Clin Endocrinol Metab 99: 2486-2493, 2014. PMID: 24670086
- Pollard H, Miller L, Brewer W. External secretion of the pancreas and diabetes (study of secretin test). Amer J Dig Dis 10: 20, 1943.
- Rathmann W, Haastert B, Icks A, Giani G, Hennings S, Mitchell J, Curren S, Wareham NJ. Low fecal elastase 1 concentrations in Type 2 diabetes. Scand J Gastroenterol 36: 1056-1061, 2001. PMID: 11589378
- Rickels MR, Bellin M, Toledo FGS, Robertson RP, Andersen DK, Chari ST, Brand R, Frulloni L, Anderson MA, Whitcomb DC for the PancreasFest Recommendation Conference Participant. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: Recommendations from PancreasFest 2012. Pancreatology 13: 336-342, 2013. PMID: 23890130
- Semakula C, Vandewalle CL, Van Schravendijk CF, Sodoyez JC, Schuit FC, Foriers A, Falorni A, Craen M, Decraene P, Pipeleers DG, Gorus FK. Abnormal circulating pancreatic enzyme activities in more than twenty-five percent of recent-onset insulin-dependent diabetic patients: association of hyperlipasemia with high-titer islet cell antibodies. Belgian Diabetes Registry. Pancreas 12: 321-33, 1996. PMID: 8740397
- Teichmann J, Mann ST, Stracke H, Lange U, Hardt PD, Kloer HU, Bretzel RG. Alterations of vitamin D3 metabolism in young women with various grades of chronic pancreatitis. Eur J Med Res 12: 347–350, 2007. PMID: 17933711
- Terzin V, Várkonyi T, Szabolcs A, Lengyel C, Takács T, Zsóri G, Stájer A, Palkó A, Wittmann T, Pálinkás A, Czakó L. Prevalence of exocrine pancreatic insufficiency in type 2 diabetes mellitus with poor glycemic control. Pancreatology 14: 356-360, 2014. PMID: 25278304
- The Expert Committee on the diagnosis and classification of Diabetes mellitus. Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 21; Suppl 1: 5-19, 1998.
- Vacca JB, Henke WJ, Knight WA. The exocrine pancreas in diabetes mellitus. Ann Intern Med 61: 242-247, 1964. PMID: 14204860
- Vujasinovic M, Zaletel J, Tepes B, Popic B, Makuc J, Epsek Lenart M, Predikaka M, Rudolf S. Low prevalence of exocrine pancreatic insufficiency in patients with diabetes mellitus. Pancreatology 13: 343-346, 2013. PMID: 23890131
- Weitgasser R, Abrahamian H, Clodi M, Fortunat W, Hammer H. Positionspapier: Exokrine Pankreasinsuffizienz und Diabetes mellitus. Wien Klin Wochenschr 124 [Suppl 2]: 100–103, 2012. PMID: 23250472
- Yilmaztepe A, Ulukaya E, Ersoy C, Yilmaz M, Tokullugil HA. Investigation of fecal pancreatic elastase-1 levels in type 2 diabetic patients. Turk J Gastroenterol 16: 75-80, 2005. PMID: 16252196