Onset of diabetessecondary topancreatic disorder (%)
Pancreatic endocrine tumor
Pancreatic cystic tumor
Previously, we demonstrated for the first time that endocrine pancreas showed the dysfunction of both insulin secretion from beta cells and glucagon secretion from alpha cells in patients with AIP . These findings mean that endocrine dysfunction in AIP is a secondary pancreatic diabetes mellitus, unlike primary diabetes mellitus, in which glucagon secretion is preserved . Furthermore, the results of histological findings in AIP showed markedly that fibrosis and lymphoplasmacytic cell infiltration were observed strongly around the islet cell, but the islet cell was revealed to be almost intact . Therefore, the onset mechanism of endocrine dysfunction in AIP is considered to be as follows: At first, rapid inflammatory cell infiltration and fibrosis induce the reduction in blood flow in exocrine pancreas, and subsequently, islet cells fall into ischemia because of the reduction in blood flow, and then circulation failure causes the dysfunction of hormone secretion from islet cells, such as alpha cells and beta cells. However, interestingly, Tanaka et al.  reported that the volume of beta cells was reduced in patients with AIP, but the volume of alpha cells in AIP did not differ from that of type 2 diabetes by immunohistologic examination. Accordingly, exocrine dysfunction in AIP, especially insulin secretion from beta cells, may be induced not only by circulation failure in islet cells but also by the reduction in the number of beta cells. However, details need to be clarified in the future. After all, the mechanism of pathogenesis of diabetes mellitus is assumed to be affected by both of the following disorders [11, 28]: obstructed blood flow to the endocrine glands (islets of Langerhans) associated with the fibrosis of the exocrine glands and damaged islets of Langerhans due to the spreading of inflammation [11, 28].
Exocrine Dysfunction Associated with Type 1 AIP
AIP is in many cases associated with pancreatic exocrine dysfunction. According to the nationwide survey conducted in Japan in 2000, 80.6 % of patients with AIP showed abnormal pancreatic exocrine function in which the abnormality is defined as 70 % or lower secretion in the BT-PABA (PFD test), and 70.0 % of the cases showed exocrine dysfunction (as determined by the secretin test), comparable to that in confirmed cases of chronic pancreatitis . From our detailed examination of secretin test, differences of results between chronic pancreatitis and AIP were clarified . Patients with chronic pancreatic exocrine dysfunction examined by secretin test revealed especially the reduction in bicarbonate concentration, whereas main reductions in patients with AIP were in volume and amylase output. The reason for these differences between chronic pancreatitis and AIP was determined by histological examination as follows: Destruction of the basement membranes of the pancreatic duct in chronic pancreatitis was observed. Therefore, as pancreatic ducts assume the responsibility of bicarbonate secretion, bicarbonate secretion in chronic pancreatitis by secretin test may be reduced. On the other hand, most basement membranes in AIP were intact, so bicarbonate secretion was preserved. However, stenoses of pancreatic ducts cause disturbances in pancreatic juice flow in AIP, and therefore, volume and amylase output by secretin test may be reduced. Of course, if the basement membranes were destroyed, bicarbonate secretion would diminish even in AIP. On this point, Otsuki et al.  and Yamaguchi et al. [30, 31] reported certain interesting facts. They examined 2 models of pancreatitis in rats – irreversible pancreatitis induced by intraductal infusion of oleic acid and reversible pancreatitis induced by retrograde intraductal infusion of sodium taurocholate – and noted that the difference between irreversible pancreatitis and reversible pancreatitis depended on the degree of injury of the pancreatic duct, especially injury of the pancreatic ductal basement membranes [29–31]. These experimental studies have clearly indicated that the difference between reversible and irreversible pancreatitis depended on the degree of damage of the duct epithelium where pancreatic progenitor cells exist. If the epithelial cells were severely injured, the pancreas could not regenerate [29–31]. Furthermore, Song et al.  reported that the pattern of fibrosis was mainly loose fibrosis with stromal edema in AIP, whereas it was dense fibrosis in CP. Taken together, it is considered that exocrine function in AIP is reversible to some extent by steroid therapy if the basement membranes of the pancreatic ducts are not destroyed, because the pancreatic ducts are compressed and stenosed by lymphoplasmacytic cell infiltration, which extended from the pancreatic parenchyma to the ducts in most AIP.
After all, in AIP, the mechanism of pathogenesis of pancreatic exocrine dysfunction is assumed to involve the following: decreased secretion of pancreatic enzymes associated with collapsed acinar cells caused by pronounced cellular infiltration mainly of plasmacytes and fibrosis and obstructed flow of pancreatic juice due to inflammatory cell infiltration around the pancreatic ducts and subsequent narrowing of the pancreatic ducts [11, 25, 26, 28]. A recent study suggested that mislocalization of cystic fibrosis transmembrane conductance regulator (CFTR), which plays a central role in pancreatic duct HCO3− secretion, and upregulation of aquaporin-1 (AQP1) on the plasma membrane and in the cytoplasm of pancreatic duct cells may be involved in the development of AIP . Corticosteroids reduce inflammation and restore both digestive enzyme and HCO3− secretion in patients with AIP by regenerating acinar cells and correcting CFTR localization in pancreatic duct cells .
Pancreatic Exocrine and Endocrine Functions After Steroid Therapy in AIP
Many AIP patients have associated pancreatic exocrine and endocrine dysfunction [11, 24–27, 34]. It has been reported that improvement of pancreatic exocrine and endocrine function was detected after steroid therapy in 38 % –50 %  and 25 % –45 %  of AIP patients, respectively. It has also been suggested as a mechanism of improvement in pancreatic exocrine and endocrine functions after steroid therapy that steroid suppresses lymphoplasmacytic cell infiltration and fibrosis, permitting the attenuation of blood flow  and further regenerating islet cells by suppression of cytokine production . A recent study about the changes in pancreatic tissue before and after steroid therapy in AIP patients revealed regeneration of acinar cells by steroids and suggested that acinar cell regeneration might be associated with CD133-positive pancreatic progenitor cells . Diabetes mellitus control worsens in 75 % of AIP patients with type 2 diabetes mellitus before AIP onset after steroid therapy . DM also develops after steroid therapy in some AIP patients [11, 26]. We should therefore take occurrence of DM into consideration in patients who continuously undergo steroid therapy.