Usefulness of urinary trypsinogen-2 and trypsinogen activation peptide in acute pancreatitis: A multicenter study in Japan.

BACKGROUND: Rapid urinary trypsinogen-2 dipstick test and levels of urinary trypsinogen-2 and trypsinogen activation peptide (TAP) concentration have been reported as prognostic markers for the diagnosis of acute pancreatitis. AIM: To reconfirm the validity of all these markers in the diagnosis of acute pancreatitis by undertaking a multi-center study in Japan. METHODS: Patients with acute abdominal pain were recruited from 17 medical institutions in Japan from April 2009 to December 2012. Urinary and serum samples were collected twice, at enrollment and on the following day for measuring target markers. The diagnosis and severity assessment of acute pancreatitis were assessed based on prognostic factors and computed tomography (CT) Grade of the Japanese Ministry of Health, Labour, and Welfare criteria. RESULTS: A total of 94 patients were enrolled during the study period. The trypsinogen-2 dipstick test was positive in 57 of 78 patients with acute pancreatitis (sensitivity, 73.1%) and in 6 of 16 patients with abdominal pain but without any evidence of acute pancreatitis (specificity, 62.5%). The area under the curve (AUC) score of urinary trypsinogen-2 according to prognostic factors was 0.704, which was highest in all parameter. The AUC scores of urinary trypsinogen-2 and TAP according to CT Grade were 0.701 and 0.692, respectively, which shows higher than other pancreatic enzymes. The levels of urinary trypsinogen-2 and TAP were significantly higher in patients with extended extra-pancreatic inflammation as evaluated by CT Grade. CONCLUSION: We reconfirmed urinary trypsinogen-2 dipstick test is useful as a marker for the diagnosis of acute pancreatitis. Urinary trypsinogen-2 and TAP may be considered as useful markers to determine extra-pancreatic inflammation in acute pancreatitis.

Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune pancreatitis.

OBJECTIVE: Corticosteroid has been established as the standard therapy for autoimmune pancreatitis (AIP), but the requirement for maintenance corticosteroid therapy is controversial. We conducted a randomised controlled trial to clarify the efficacy of maintenance corticosteroid therapy in patients with AIP. DESIGN: We conducted a multicentre, tertiary setting, randomised controlled trial. After the induction of remission with the initial oral prednisolone (PSL) treatment, maintenance therapy with PSL at 5-7.5 mg/day was continued for 3 years or withdrawn at 26 weeks. The primary endpoint was relapse-free survival over 3 years and the secondary endpoint was serious corticosteroid-related complications. All analyses were performed on an intention-to-treat basis. RESULTS: Between April 2009 and March 2012, 49 patients with AIP were randomly assigned to the maintenance therapy group (n=30) or the cessation group (n=19). Baseline characteristics were not different between the two groups. Relapses occurred within 3 years in 11 out of 19 (57.9%) patients assigned to the cessation group, and in 7 of 30 (23.3%) patients in the maintenance therapy group. The relapse rate over 3 years was significantly lower in the maintenance therapy group than that in the cessation group (p=0.011). The relapse-free survival was significantly longer in the maintenance therapy group than that in the cessation group (p=0.007). No serious corticosteroid-related complications requiring discontinuation of PSL were observed. CONCLUSIONS: Maintenance corticosteroid therapy for 3 years may decrease relapses in patients with AIP compared with those who discontinued the therapy at 26 weeks. TRIAL REGISTRATION NUMBER: UMIN000001818; Results.

Clinicopathological Features of Type 2 Autoimmune Pancreatitis in Japan: Results of a Multicenter Survey.

OBJECTIVE: The aim of the study was to clarify clinicopathological features of type 2 autoimmune pancreatitis (AIP) in Japan; a multicenter survey was carried out. METHODS: The first screening collected patients with pancreatitis whose pancreatic tissue samples were available and who fulfilled at least 1 of the following 3 criteria as possible type 2 AIP: (1) histological presence of granulocytic epithelial lesion, (2) age of 50 years or younger, and (3) association of ulcerative colitis, Sjogren syndrome, and/or primary biliary cirrhosis. Patients with histologically confirmed type 1 AIP were also collected as a control. Clinical information was gathered by questionnaire. RESULTS: A histological re-evaluation identified 8 patients with type 2 AIP and 20 with type 1 AIP. Three of the latter had intralobular neutrophilic infiltration. Factors more frequent in type 2 included age younger than 40 years, abdominal pain, and elevation of serum amylase and lipase, whereas patients with type 1 more frequently showed jaundice, elevated serum IgG and IgG4, presence of autoantibodies, association of IgG4-related disease, sclerosing cholangitis and diabetes mellitus, and imaging findings of intrapancreatic biliary stenosis and extrapancreatic biliary dilatation. CONCLUSIONS: The clinical features of type 2 AIP in Japan were similar to those of western countries. Intralobular neutrophilic infiltration in type 1 is a potential pitfall, especially in the biopsy-based diagnosis.

Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2011.

OBJECTIVES: To clarify the clinicoepidemiological features of autoimmune pancreatitis (AIP) in Japan, a nationwide epidemiological survey was conducted. METHODS: Patients with AIP who had visited selected hospitals in 2011 were surveyed. Autoimmune pancreatitis was diagnosed according to the revised clinical diagnostic criteria for AIP (Japan Pancreas Society 2011). The study consisted of 2 stage surveys; the number of patients with AIP was estimated by the first questionnaire, and their clinical features were assessed by the second questionnaire. RESULTS: The estimated total number of AIP patients in 2011 was 5745 (95% confidence interval, 5325-6164), with an overall prevalence rate of 4.6 per 100,000 population. The number of patients who were newly diagnosed as AIP was estimated to be 1808 (95% confidence interval, 1597-2018), with an annual incidence rate of 1.4 per 100,000 population. The sex ratio (male to female) was 3.2, and the mean age was 66.3 (11.5). Among the 936 patients whose detailed clinical information was obtained, 86.4% of the patients presented high serum immunoglobulin G4 levels (≥135 mg/dL), and 82.3% received steroid therapy. CONCLUSIONS: The data represent the current clinical features of AIP in Japan.

Heterotopic pancreas in the common bile duct, with a review of the literature.

A 65-year-old man presented with upper abdominal pain and was suspected of having choledocholithiasis. Endoscopic extraction of the stone was performed; however, a round filling defect in the common bile duct (CBD) persisted. Subsequent cholangioscopy showed the presence of a papillary tumor in the CBD, and the lesion was removed via the Whipple procedure. Microscopically, the papillary lesion was composed of pancreatic tissue in the submucosal layer of the CBD and therefore diagnosed as reflective of heterotopic pancreas. This is only the seventh case of heterotopic pancreas in the CBD reported in the English literature.

Sulfonamide inhibition studies of two ß-carbonic anhydrases from the bacterial pathogen Legionella pneumophila.

Two ß-carbonic anhydrases (CAs, EC 4.2.1.1) were identified, cloned and purified in the pathogenic bacterium Legionella pneumophila, denominated LpCA1 and LpCA2. They efficiently catalyze CO2 hydration to bicarbonate and protons, with kcat in the range of (3.4-8.3) × 10(5)s(-1) and kcat/Km of (4.7-8.5) × 10(7)M(-1)s(-1), and are inhibited by sulfonamides and sulfamates. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide(KIs in the range of 40.3-90.5 nM). The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide and dichlorophenamide (KIs in the range of 25.2-88.5 nM). As these enzymes may be involved in pH regulation in the phagosome during Legionella infection, their inhibition may lead to antibacterials with a novel mechanism of action.

Amendment of the Japanese Consensus Guidelines for Autoimmune Pancreatitis, 2013 I. Concept and diagnosis of autoimmune pancreatitis.

BACKGROUND: In response to the proposal of the international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP) and the Japanese diagnostic criteria in 2011, the 2009 Japanese consensus guidelines for managing AIP required revision. METHODS: Three committees [the professional committee for making clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators] were organized. Fifteen specialists for AIP extracted the specific clinical statements from 1,843 articles published between 1963 and 2012 (obtained from Pub Med and a secondary database, and developed the CQs and statements. The expert panel individually rated the clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than seven on a nine-point scale from the panel was regarded as valid. RESULTS: The professional committee created 13 CQs and statements for the current concept and diagnosis of AIP, 6 for extra-pancreatic lesions, 6 for differential diagnosis, and 11 for treatment. CONCLUSION: After evaluation by the moderators, amendments to the Japanese consensus guidelines for AIP have been proposed for 2013.

Amendment of the Japanese Consensus Guidelines for Autoimmune Pancreatitis, 2013 III. Treatment and prognosis of autoimmune pancreatitis.

The standard treatment for autoimmune pancreatitis (AIP) is steroid therapy, although some patients improve spontaneously. Indications for steroid therapy in AIP patients are symptoms such as obstructive jaundice, abdominal pain, back pain, and the presence of symptomatic extrapancreatic lesions. Prior to steroid therapy, obstructive jaundice should be managed by biliary drainage, and blood glucose levels should be controlled in patients with diabetes mellitus. The recommended initial oral prednisolone dose for induction of remission is 0.6 mg/kg/day, which is administered for 2-4 weeks. The dose is then tapered by 5 mg every 1-2 weeks, based on changes in clinical manifestations, biochemical blood tests (such as liver enzymes and IgG or IgG4 levels), and repeated imaging findings (US, CT, MRCP, ERCP, etc.). The dose is tapered to a maintenance dose (2.5-5 mg/day) over a period of 2-3 months. Cessation of steroid therapy should be based on the disease activity in each case. Termination of maintenance therapy should be planned within 3 years in cases with radiological and serological improvement. Re-administration or dose-up of steroid is effective for treating AIP relapse. Application of immunomodulatory drugs is considered for AIP patients who prove resistant to steroid therapy. The prognosis of AIP appears to be good over the short-term with steroid therapy. The long-term outcome is less clear, as there are many unknown factors, such as relapse, pancreatic exocrine or endocrine dysfunction, and associated malignancy.

Anion inhibition studies of two new ß-carbonic anhydrases from the bacterial pathogen Legionella pneumophila.

We investigated the cloning, catalytic activity and anion inhibition of the ß-class carbonic anhydrases (CAs, EC 4.2.1.1) from the bacterial pathogen Legionella pneumophila. Two such enzymes, lpCA1 and lpCA2, were found in the genome of this pathogen. These enzymes were determined to be efficient catalysts for CO2 hydration, with kcat values in the range of (3.4-8.3)×10(5) s(-1) and kcat/KM values of (4.7-8.5)×10(7) M(-1) s(-1). A set of inorganic anions and small molecules was investigated to identify inhibitors of these enzymes. Perchlorate and tetrafluoroborate were not acting as inhibitors (KI >200 mM), whereas sulfate was a very weak inhibitor for both lpCA1 and lpCA2 (KI values of 77.9-96.5 mM). The most potent lpCA1 inhibitors were cyanide, azide, hydrogen sulfide, diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid and phenylarsonic acid, with KI values ranging from 6 to 94 µM. The most potent lpCA2 inhibitors were diethyldithiocarbamate, sulfamide, sulfamate, phenylboronic acid and phenylarsonic acid, with KI values ranging from 2 to 13 µM. As these enzymes seem to be involved in regulation of phagosome pH during Legionella infection, inhibition of these targets may lead to antibacterial agents with a novel mechanism of action.

Pancreatic involvement in Japanese patients with von Hippel-Lindau disease: results of a nationwide survey.

BACKGROUND: The frequency and prognosis of pancreatic endocrine tumors (PNET)/pancreatic cystic tumors (PCT) in Japanese patients with von Hippel-Lindau disease (VHL) are still open to question. METHODS: We conducted the first nationwide epidemiological study of VHL disease in Japan to elucidate this question. Data on 377 VHL patients (PNET, 53; PCT, 152) were reported, and then their clinical characteristics were analyzed. RESULTS: PNET was found in 14.1 % and PCT in 40.3 %; 4.5 % had both. The onset of PNET and PCT mostly occurred at 30-39 years of age (median ages, 34 and 33 years, respectively). Metastasis was observed in 7.5 % of PNET patients at diagnosis, and 64.2 % underwent surgery including enucleation, partial and total pancreatectomy, and bypass surgery. Two patients received non-surgical therapies. No PNET-related deaths were observed. In PCT patients, no metastasis was observed at diagnosis, and 9.2 % underwent surgery or drainage. According to the classification system without or with adrenal pheochromocytoma, the VHL patients studied herein were subdivided into 313 (83 %) with VHL type 1 and 64 (17 %) with VHL type 2; 29 (9.3 %) and 24 (37.5 %) patients had PNET with VHL type 1 and 2, suggesting that patients with VHL type 2 were significantly more related to PNET than those with VHL type 1 (P < 0.01). CONCLUSIONS: This study showed no significant difference in the epidemiology of pancreatic involvement between Japanese and non-Japanese VHL patients. Concerning the prognosis, follow-up study is needed.

Evaluation of Ki-67 index in EUS-FNA specimens for the assessment of malignancy risk in pancreatic neuroendocrine tumors.

BACKGROUND AND STUDY AIM: Malignancy in pancreatic neuroendocrine tumors (PNETs) is graded by assessing the resected specimens according to the World Health Organization (WHO) 2010 criteria. The feasibility of such grading using endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens remains unclear. The aim of this study was to ascertain the optimal method of measuring the Ki-67 index in EUS-FNA specimens, using resected specimens as the criterion standard. PATIENTS AND METHODS: A total of 58 consecutive patients diagnosed with PNETs between March 1998 and May 2011 were included. The study measured intratumoral Ki-67 index heterogeneity, concordance rates of PNET grading by EUS-FNA with grade of the resected tumor, optimal method of measuring the Ki-67 index in EUS-FNA specimens, and survival analysis based on EUS-FNA specimen grading. RESULTS: Intratumoral dispersion of Ki-67 index in resected specimens was 0.033 for Grade 1 and 0.782 for Grade 2 tumors (P<0.001). Concordance rates for WHO classification between EUS-FNA and resected specimens were 74.0% using the mean Ki-67 index in EUS-FNA specimens and 77.8% using the highest Ki-67 index. The concordance rate rose to 90% when EUS-FNA samples with less than 2000 tumor cells were excluded (26% of EUS-FNA cases). The Kaplan-Meier survival curves were significantly stratified by the EUS-FNA grading of PNETs with 5-year survival rates of 100%, 58.3%, and 0%, for Grade 1, Grade 2, and neuroendocrine carcinoma (NEC) tumors, respectively. CONCLUSIONS: Grading of PNETs by the highest Ki-67 index in EUS-FNA specimens with adequate cellularity has a high concordance with grading of resected specimens, and can predict long term patient survival with high accuracy.

Invasive carcinoma derived from branch duct-type IPMN may be a more aggressive neoplasm than that derived from main duct-type IPMN.

The present study aimed to evaluate the long-term follow-up results of patients with intraductal papillary mucinous neoplasm (IPMN) and to estimate the degree of IPMN malignancy based on pathological and molecular features of resected specimens. The detection rate of IPMN has increased over the last decade; however, the management of this neoplasm remains controversial. This is particularly so for branch duct-type IPMN, which carries a high potential for malignancy and risk of recurrence. We retrospectively reviewed a single institution's prospective pancreatic resection database to identify IPMN patients who underwent pancreatectomy with curative intent. The clinicopathological variables of 100 patients resected for IPMN were analyzed with a detailed review of histopathological results (borderline lesions, non-invasive carcinoma and invasive carcinoma) to determine the grade of IPMN malignancy based on transforming growth factor (TGF)-ß/SMAD4 signaling. The incidence of malignant change was significantly higher in patients with main duct-type IPMN (69.7%) compared with branch duct-type IPMN cases (17.9%). However, patients with an invasive carcinoma had a significantly worse outcome if it was derived from branch duct-type IPMN compared with those derived from main duct-type IPMN, and TGF-ß mRNA expression was significantly increased in the former patient group. Immunohistochemistry also showed higher numbers of SMAD4-positive cells in patients with carcinoma derived from branch duct-type IPMN. Our results demonstrated that invasive carcinoma derived from branch duct-type IPMN is more aggressive than that derived from main duct-type IPMN, once invasive morphological change takes place. Determining TGF-ß and/or SMAD4 status at initial diagnosis may be useful for stratifying IPMN patients into treatment regimens.

Altered expression of carbonic anhydrase-related protein XI in neuronal cells expressing mutant ataxin-3.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a late-onset neurodegenerative disorder caused by the expansion of a polyglutamine tract within the gene product, ataxin-3. Microarray analysis revealed a dramatic differential expression of carbonic anhydrase-related protein XI (CA-RPXI/CA11) in the presence or absence of mutant ataxin-3. Therefore, we examined the expression and distribution of all three CA-RPs (CA8, 10, and 11) in human neuronal cells that stably express mutant ataxin-3. Compared with the cells containing normal ataxin-3, protein expression of CA8 and CA11 is significantly increased in human neuroblastoma cells harboring mutant ataxin-3. Semi-quantitative RT-PCR demonstrated that all three CA-RPs exhibited significantly higher transcript levels in neuronal cells expressing mutant ataxin-3. Interestingly, CA11 is distributed not only in the cytoplasm but also within the nuclei of the stably transfected mutant cells when compared with the sole cytoplasmic distribution in cells containing normal ataxin-3. In addition, results from transient transfection assays in SK-N-SH and Neuro2a (N2a) cells also confirmed the nuclear localization of CA11 in the presence of truncated ataxin-3. Most importantly, immunohistochemical staining of the MJD transgenic mouse and post-mortem MJD human brain also revealed that CA11 is highly expressed in both cytoplasm and nuclei of the brain cells. Recruitment of CA11 into nuclear inclusions containing mutant ataxin-3 revealed a possible correlation between CA11 and disease progression. Although the exact function of CA-RPs is still undefined in the central nervous system, our findings suggest that CA-RPs, especially CA11, may play specific roles in the pathogenesis of Machado-Joseph disease.

Restoring catalytic activity to the human carbonic anhydrase (CA) related proteins VIII, X and XI affords isoforms with high catalytic efficiency and susceptibility to anion inhibition.

Mutation of amino acid residues 94, 96 and 119 to histidine(s) in the human carbonic anhydrase (CA, EC 4.2.1.1) related proteins CARP VIII, X and XI restored the zinc binding and catalytic activity for the hydration of CO(2) to bicarbonate. CA VIII, X and XI thus obtained showed high catalytic activity (67.3-92.0% of the activity of hCA II and much higher compared to hCA I) and were inhibited in the milli-micromolar range by inorganic anions, sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid. Among the three new isoforms, hCA X was the most efficient enzyme and also showed the highest affinity for anion inhibitors (K(I)s of 3.6-68 µM for phenylboronic acid, sufamic acid, sulfamide, cyanide and azide). hCA VIII was poorly inhibited by halides, cyanate, nitrate and sulfate (K(I)s of 38.4-65.4 mM), whereas CA XI had a behavior intermediate between that of hCA VIII and X, both regarding the catalytic activity and sensitivity to anion inhibitors.

Nationwide epidemiological survey of autoimmune pancreatitis in Japan.

OBJECTIVES: To clarify the clinicoepidemiological features of autoimmune pancreatitis (AIP) in Japan, the nationwide survey was conducted. METHODS: Patients with AIP who had visited the selected hospitals in 2007 were surveyed. Autoimmune pancreatitis was diagnosed according to the Japanese clinical diagnostic criteria 2006. The study consisted of 2-stage surveys: the number of patients with AIP was estimated by the first questionnaire and their clinical features were assessed by the second questionnaire. RESULTS: The estimated total number of AIP patients in 2007 was 2790 (95% confidence interval, 2540-3040), with an overall prevalence rate of 2.2 per 100,000 populations. The number of patients, who were newly diagnosed as AIP, was estimated to be 1120 (95% confidence interval, 1000-1240), with an annual incidence rate of 0.9 per 100,000 populations. Sex ratio (male to female) was 3.7, and the mean (SD) age was 63.0 (11.4) years. Among the 546 patients whose clinical information was obtained, 87.6% of the patients presented high serum immunoglobulin G4 levels (≥ 135 mg/dL), and 83% received steroid therapy. CONCLUSIONS: The data represent the current clinical features of AIP in Japan. From the results, most AIP patients in Japan can be categorized to type 1 AIP according to the recent classification of AIP.

Inhibition studies of the ß-carbonic anhydrases from the bacterial pathogen Salmonella enterica serovar Typhimurium with sulfonamides and sulfamates.

The two ß-carbonic anhydrases (CAs, EC 4.2.1.1) from the bacterial pathogen Salmonella enterica serovar Typhimurium, stCA 1 and stCA 2, were investigated for their inhibition with a large panel of sulfonamides and sulfamates. Unlike inorganic anions, which are weak, millimolar inhibitors of the two enzymes [Vullo et al., Bioorg. Med. Chem. Lett.2011, 21, 3591], sulfonamides and sulfamates are effective micro-to nanomolar inhibitors of the two enzymes. Various types of inhibitors have been detected among the 38 investigated sulfonamides/sulfamates, with K(I)s in the range of 31 nM-5.87 µM. The best stCA 1 inhibitors were acetazolamide and benzolamide-based compounds, whereas the best stCA 2 inhibitors were sulfonylated benzenesulfonamides and amino-benzolamide derivatives (K(I)s in the range of 31-90 nM). 3-Fluoro-5-chloro-4-aminobenzolamide showed an inhibition constant of 51 nM against stCA 1 and of 38 nM against stCA 2, being the best inhibitor detected so far for these enzymes. As many strains of S. enterica show extensive resistance to classical antibiotics, inhibition of the ß-CAs investigated here may be useful for developing novel antibacterials, targeting ß-CAs which may be involved in pathogenicity and invasion of some bacteria.

The N-terminal domain of G3BP enhances cell motility and invasion by posttranscriptional regulation of BART.

The regulation of mRNA stability plays an important role in the control of gene expression during cell motility and invasion. We previously reported that GTPase-activating protein [Src homology 3 (SH3) domain] binding protein (G3BP), a marker of cytoplasmic stress granules that are formed in stressed cells and regulate mRNA stability, binds and degrades the mRNA of binder of Arl two (BART) that inhibits retroperitoneal invasion and hepatic metastasis of pancreatic cancer cells. Here, we report that overexpression of the amino (N)-terminal region of G3BP, including the binding region for BART mRNA, dominant-negatively inhibits formation of the complex between endogenous G3BP and BART mRNA, and increases the expression of BART. This, in turn, inhibits the invasiveness of pancreatic cancer cells. On the other hand, the carboxy (C)-terminal region of G3BP is associated with phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) that initiates stress granule assembly but does not modulate the posttranscriptional regulation of BART mRNA. N-terminal G3BP also plays a role in regulating secreted matrix metalloproteinases, transcription factors, and a variety of genes involved in cell adhesion and motility. These results suggest that N-terminal G3BP contributes to posttranscriptional regulation of cell motility and invasive capacity of pancreatic cancer.

Characteristics of pancreatic diabetes in patients with autoimmune pancreatitis.

OBJECTIVE: Although patients with autoimmune pancreatitis (AIP) tend to have concurrent diverse disorders, very few studies have focused on diabetes mellitus (DM) coexisting with AIP. METHODS: In total 102 AIP patients with DM were divided into three groups. Those with DM before the onset of AIP were labeled group A (n=35), those who developed DM and AIP simultaneously were labeled group B (n=58) and those who developed DM after steroid therapy for AIP were labeled group C (n=9). The characteristics of DM among the three groups were evaluated. RESULTS: No significant differences were noted in the age of DM onset among the three groups. However, the mean duration of DM was significantly longer in group A (8.7 years) than in groups B and C. AIP developed 6.8 years after DM onset in group A, whereas it developed 1.8 years after steroid therapy in group C. Group A had the highest rate (25.7%) of family members with a history of AIP. Levels of serum albumin, total cholesterol and triglyceride were significantly lower in group A. No correlations were found between glycated hemoglobin and benzoyl-tyrosyl para-aminobenzoic acid. Hypoglycemia was observed in 20% of patients under insulin therapy. Most of them were habitual drinkers and received no pancreatic enzymes. Group A showed a high prevalence of retinopathy, nephropathy and macrovascular disorders than group B. CONCLUSION: Aspects of AIP-associated pancreatic diabetes were clarified. AIP-associated DM must be controlled by a full assessment of the pancreatic endocrine and exocrine function.