Exocrine pancreas in type 1

Although most histologic changes are limited to the islets of Langerhans, some changes are also observed in the exocrine pancreas. These changes relate mainly to a decreased pancreatic weight and increased amounts of interlobular connective tissue in patients with chronic disease and to inflammatory lesions in the exocrine tissue in acute cases. More recent evidence shows that exocrine pancreatic volume/weight is also reduced in recent onset type 1 diabetes, and potentially in islet autoantibody-positive non-diabetic individuals, suggesting that the exocrine pancreas is affected at an early stage of the type 1 disease process. The mechanism is currently unclear but deserves further investigation.

The pancreas has a reduced size in patients with long-standing type 1 DM.

Chronic type 1 diabetes is associated with a significant decrease in pancreatic volume and weight [1]. An autopsy study found that the volume of pancreases obtained from patients with a disease duration of 20-30 years was reduced by 50% when compared to those of non-diabetic individuals of similar age (43 vs 86 ml). The decrease in volume was due to atrophy of the individual acinar cells that had become small in size and showed only few secretory granules[2]. This cellular atrophy may explain why many patients with long-standing type 1 diabetes show decreased pancreatic exocrine function[3]. The reason why acinar cells become atrophic is not clear, most evidence points to an important role of insulin as a trophic agent, although other factors including autoimmunity against exocrine tissue and vascular damage (microangiopathy) cannot be excluded. Insulin can exert its trophic effects on acinar cells because of the presence of a portal system between the endocrine and the exocrine tissue. Islets are supplied by arterial blood via arterioles that branch into the islet capillary network. Insulin released by the beta cells will pass through the fenestrated wall of the capillaries directly into the circulation. Islet capillaries fuse into one or more venules that leave the islets and either empty into the exocrine capillary network or into collecting veins. Exocrine tissue surrounding the islets will thus be exposed to high hormone concentrations. Insulin receptors on the surface of acinar cells mediate the hormone’s effects on cellular growth and enzyme synthesis. Autoimmune beta cell destruction will result in decreased insulin levels in the islet venous outflow and reduced trophic effects.

Changes in recent onset type 1 diabetes

In recent onset cases the degree of atrophy differs markedly per region, depending on the relative amount of pseudoatrophic islets and islets that still contain beta cells, either with or without an inflammatory infiltrate[4]. The natural history of pancreatic atrophy is still poorly defined, with no prospective studies of pancreas size in diabetes. One ultrasound study reported a reduction in pancreas size in children within 2 years of diagnosis, but this finding still requires confirmation. Two studies have measured pancreatic volume in recent-onset adult cases using magnetic resonance imaging. The first study, which investigated 10 patients with a mean disease duration of 3.4 months (mean age 29 years) and 11 controls (mean age 31 years), found a 31% reduction in pancreatic volume in patients after adjustment for body surface area[5]. The second study of 20 patients with a median disease duration of 3.8 months (median age 27 years,) and 24 healthy individuals (median age 27 years) found that pancreatic volume in patients was reduced by 26% , after correction for body weight[6].

A recent study examined donor pancreases obtained via nPOD (network for Pancreatic Organ Donors). The study group consisted of 23 pancreases from previously healthy donors, 8 from people without diabetes but positive for single islet autoantibodies, and 20 from patients with established type 1 diabetes (mean duration of 18 years). The mean pancreatic weights were 81.4 g for the controls, 61.3 for the antibody positive group, and 44.9 g for those with diabetes[7]. These studies, taken together, provide a striking indication that the disease process leading to type 1 diabetes can produce pathophysiological changes in the exocrine pancreas before the onset of hyperglycaemia, opening up a fascinating new area for research. There is a large inter-individual variation in pancreas size, but it has been suggested that such changes might be used to aid prediction of type 1 diabetes through prospective monitoring of pancreas size in individuals considered at high risk of disease[6].

Pancreatic exocrine function is reduced in type 1 DM

Reduced pancreatic exocrine function is a common finding in chronic type 1 diabetes[3]. This reduction in exocrine function has again been ascribed to loss of the trophic effects of insulin on the acinar cells, but evidence is lacking. Pancreatic enzyme output and bicarbonate production are both reduced in type 1 diabetes, but rarely result in malabsorption that is severe enough to cause clinical concern[8]. Indirect markers of exocrine insufficiency such as faecal elastase or chymotrypsin indicated reduced levels of pancreatic function in 30 to 40% of patients with established type 1 diabetes compared to 20% of patients with type 2 diabetes[3].

Fibrosis is common in chronic type 1 DM

A relative increase in the amount of connective tissue (fibrosis) surrounding the pancreatic lobes and, to a lesser extent, also the exocrine acini is a regular finding in chronic type 1 DM.

Inflammation is also present in the exocrine pancreas

Inflammatory infiltrates are relatively common in acute onset diabetes; in addition to the focal lesions that specifically affect (part of) the islets, they may be found in the connective tissue close to the islets and around the vasculature (fig 1) and the ductal system. Leucocytic infiltration around the exocrine vasculare as demonstrated by immunohistochemistry for Leucocyte Common Antigen (LCA) in brown.
Leucocytic infiltration around the exocrine vasculare as demonstrated by immunohistochemistry for Leucocyte Common Antigen (LCA) in brown.
Focal or diffuse lesions of acute pancreatitis may be found throughout the pancreas, although it has been suggested that such lesions may represent terminal complications in comatose patients (ref 1) rather than being the result of an autoimmune process. A diffuse T-cell infiltration of the exocrine pancreas is considered to be a hallmark of a special fulminant form of type 1 diabetes in Japanese patients in which no autoantibody-positivity or insulitis can be found[7].

References

  1. ^ Gepts W, Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 619-633, 1965

  2. ^ M Löhr and Klöppel G, Residual insulin positivity and pancreatic atrophy in relation to duration of chronic type 1 (insulin-dependent) diabetes mellitus and microangiopathy. Diabetologia 757-762, 1987.

  3. ^ Larger E, Philippe MF, Barbot-Trystam L, Radu A, Rotariu M, Nobécourt E, Boitard C. Pancreatic exocrine function in patients with diabetes. Diabetic Medicine 29:1047-1054, 2012.

  4. ^ Foulis AK and Stewart JA. The pancreas in recent-onset Type 1 (insulin-dependent) diabetes mellitus: insulin content of islets, insulitis and associated changes in the exocrine tissue. Diabetologia 26:456-461, 1984

  5. ^ Gaglia JL, Guimaraes AR, Harisinghani M, Turvey SE, Jackson R, Benoist C, Mathis D, Weissleder R. Noninvasive imaging of pancreatic islet inflammation in type 1A diabetes patients. The Journal of Clinical Investigation 121:442-445, 2011

  6. ^ Williams AJK et al. Pancreatic volume is reduced in adult patients with recently diagnosed type 1 diabetes. J Clin Endocrinol Metab 2012;97(11):E2109-2113

  7. ^ Campbell-Thompson et al. Pancreas organ weight in individuals with disease-associated autoantibodies at risk for type 1 diabetes. JAMA 2012;30(22)2337-9

  8. ^ Hahn JU, Kerner W, Maisonneuve P, Lowenfels AB, Lankisch PG. Low fecal elastase 1 levels do not indicate exocrine pancreatic insufficiency in type-1 diabetes mellitus. Pancreas. 2008 Apr;36(3):274-8

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