Motozumi Okamoto

High Prevalence of Autoantibodies Against Carbonic Anhydrase II and Lactoferrin in Type 1 Diabetes : Concept of Autoimmune Exocrinopathy and Endocrinopathy of the Pancreas

Introduction Dysfunction of the exocrine as well as the endocrine pancreas has been reported in type 1 diabetes. Lymphocytic infiltration of the exocrine pancreas is observed in approximately half of Japanese type 1 diabetic patients. Aims To investigate the involvement of autoimmunity against the exocrine pancreas in type 1 diabetes. Methodology We examined autoantibodies against human carbonic anhydrase II (ACA) and lactoferrin (ALF), antigens in the pancreatic duct cells and the pancreatic acinus, respectively, in 43 type 1 diabetic patients and 20 type 2 diabetic patients using the enzyme-linked immunosorbent assay method. Results Of 43 type 1 diabetic patients, ACA was detected in 28 patients (65%) and ALF was detected in 29 patients (67%). One or both of the antibodies were detected in 33 type 1 diabetic patients (77%). In contrast, neither ACA nor ALF were detected in type 2 diabetic patients. Conclusions The high prevalence of both ACA and ALF strongly suggests the involvement of autoimmunity against the exocrine pancreas as well as the endocrine pancreas in some type 1 diabetic patients. We propose that these conditions be referred to as autoimmune exocrinopathy and endocrinopathy of the pancreas.

Autoimmune pancreatitis detected as a mass in the tail of the pancreas

A mass in the tail of the pancreas was detected in a 62‐year‐old male patient who had hypergammaglobulinaemia, and was positive for antinuclear antigen and anti‐SS‐A antibody. Endoscopic retrograde pancreatography revealed focal irregular narrowing of the main pancreatic duct in the tail of the pancreas. Dynamic computed tomography showed swelling of the pancreatic tail, which was enhanced on delayed phase. Autoimmune pancreatitis was suspected and corticosteroid therapy was commenced. This led to significant resolution of the pancreatic stricture. It is important to recognize this clinical entity as corticosteroid therapy may avoid unnecessary surgery.

Diffusion-weighted magnetic resonance imaging in autoimmune pancreatitis

PurposeThe aim of this study was to investigate the usefulness of diffusion-weighted magnetic resonance imaging (DWI MRI) for the diagnosis and evaluation of autoimmune pancreatitis (AIP).Materials and methodsA total of 4 consecutive patients with AIP, 5 patients with chronic alcoholic pancreatitis (CP), and 13 patients without pancreatic disease (controls) were studied. DWI was performed in the axial plane with spin-echo echo-planar imaging single-shot sequence. Apparent diffusion coefficients (ADCs) were measured in circular regions of interest in the pancreas. In AIP patients, abdominal MRI was performed before, and 2–4 weeks after steroid treatment. Follow-up study was performed chronologically for up to 11 months in two patients. The correlation between ADCs of the pancreas and the immunoglobulin G4 (IgG4) index (serum IgG4 value/serum IgG4 value before steroid treatment) was evaluated.ResultsIn the AIP patients, DWI of the pancreas showed high signal intensity, and the ADCs of the pancreas (mean ± SD: 0.97 ± 0.18 × 10−3 mm2/s) were significantly lower than those in patients with CP (1.45 ± 0.10 × 10−3 mm2/s) or the controls (1.45 ± 0.16 × 10−3 mm2/s) (Mann-Whitney U-test, P < 0.05). In one AIP patient with focal swelling of the pancreas head that appeared to be a mass, DWI showed high signal intensity throughout the pancreas, indicating diffuse involvement. The ADCs of the pancreas and IgG4 index were significantly inversely correlated (Spearman’s rank correlation coefficient, rs = −0.80, P < 0.05).ConclusionAutoimmune pancreatitis showed high signal intensity on DWI, which improved after steroid treatment. ADCs reflected disease activity. Thus, diffusion-weighted MRI might be useful for diagnosing AIP, determining the affected area, and evaluating the effect of treatment.

Regulation of glucose-transporter gene expression by insulin in cultured human fibroblasts.

To clarify the effect of insulin on glucose-transporter (GT) biosynthesis, we determined GT mRNA levels in human cultured skin fibroblasts, using HepG2 GT cDNA as a probe. Insulin specifically increased the GT mRNA level in a time- and dose-dependent manner. Time-course study demonstrated that the mRNA level peaked within 3 h of insulin (1 × 10−7 M) addition. After remaining elevated for several hours, mRNA decreased and returned to the basal level after 24 h. In the cell strains from seven normal subjects, the mean (±SE) GT mRNA level determined after 3 h of treatment with 1 × 10−7 M insulin was 164.3 ± 8.5% of the level found in untreated control cells. The insulin dose-response curve of GT mRNA levels showed that the maximum stimulation was elicited at 1 × 10−7 M, and the half-maximum stimulation occurred at ∼5 × 10−10 M. Degradation rates of GT mRNA determined in the presence of actinomycin D were not different between insulin-treated and untreated cells. These results suggest that insulin increases GT gene expression in cultured human fibroblasts.

Autoimmune pancreatitis detected as a mass in the head of the pancreas without hypergammaglobulinemia, which relapsed after surgery: case report and review of the literature.

Autoimmune pancreatitis is a recently proposed clinical entity characterized by diffuse swelling of the pancreas, irregular narrowing of the main pancreatic duct on endoscopic retrograde pancreatography, hypergammaglobulinemia, and the presence of autoantibodies, together with responsiveness to corticosteroid therapy (1, 2). There are some reports of cases with focal swelling, which simulates pancreatic cancer or lymphoma (3–6), as well as cases that begin with focal swelling and progress to diffuse swelling (7–10 ). Here, we report a case of autoimmune pancreatitis that presented with obstructive jaundice and a mass in the head of the pancreas, which progressed to diffuse swelling 4 months after surgery. We also review the clinical features of reported cases of autoimmune pancreatitis.

Clinical, Endocrine and Metabolic Aspects of the Werner Syndrome Compared with Those of Normal Aging

Data on the clinical features of the Werner syndrome in 102 patients in Japan were collected by sending questionnaires to major hospitals and analyzed. The male-to-female ratio was 3 to 2 and the incidences of consanguinity and familial occurrence were 51% and 39.4%, respectively. These patients were divided into 3 subgroups; group 1, 2, and 3 lacked short stature, cataract, and hypogonadism, respectively. Each group had somewhat different clinical features. Endocrine and metabolic abnormalities in the Werner syndrome patients were compared with those in normal aged subjects. Impaired plasma growth-hormone responses to insulin and arginine were more common and impaired plasma thyrotropin responses to TRH were less common in the Werner syndrome patients than in aged subjects. Plasma LH and FSH levels were higher in most patients than those in age- and sex-matched controls; also, their serum testosterone concentrations were lower than those in age-matched controls and testicular biopsy revealed more marked atrophy than in aged subjects. Serum triiodothyronine levels tended to be lower than in age-matched controls. Oral glucose tolerance test revealed diabetic glucose tolerance in 55% and impaired glucose tolerance in 22%, although fasting blood glucose levels were elevated only in 20%. Plasma insulin response to glucose was more exaggerated in those with the Werner syndrome than in normal aged subjects. The euglycemic glucose clamp method revealed lower glucose disposal rates and insulin sensitivity indices in the Werner syndrome than in normal subjects of similar age. The number of erythrocyte insulin-binding sites was normal in the Werner syndrome patients. These results suggest a postreceptor defect in insulin resistance in the Werner syndrome.

CASE REPORT: Autoimmune Pancreatitis Detected as a Mass in the Head of the Pancreas with Contiguous Fibrosis Around the Superior Mesenteric Artery

Several cases of chronic pancreatitis associated with autoimmunity have been reported (1–3), and the concept of autoimmune pancreatitis was recently proposed (4, 5). This clinical entity is characterized by diffuse or focal swelling of the pancreas, irregular narrowing of the main pancreatic duct on endoscopic retrograde pancreatography (ERP), hypergammaglobulinemia, and the presence of autoantibodies, together with remarkable responsiveness to corticosteroid therapy. Some cases showing focal swelling or multiple focal masses that simulate pancreatic cancer or lymphoma have been reported by us and others (3, 6–10). Here, we report a case of autoimmune pancreatitis, detected as a mass in the head of the pancreas with a contiguous mass around the superior mesenteric artery, that was treated successfully with corticosteroid.

Effects of a high-fat diet on insulin receptor kinase and the glucose transporter in rats

Abstract A high-fat (HF) diet causes insulin resistance. To characterize this type of insulin resistance, autophosphorylation of the insulin receptor (IR) in vitro and in vivo, phosphorylation of its endogenous substrates (pp190, pp175), and the amount of glucose transporters (GLUT-2, GLUT-4) were determined using muscles and liver from rats fed a HF-diet. Hyperinsulinemia and insulin resistance were observed by oral glucose tolerance test in the HF group. The levels of insulin binding to wheat germ agglutinin-purified insulin receptors from both muscles and liver were similar to those of the controls. Autophosphorylation of IR on tyrosine residues in vitro was decreased both in muscles and liver. Tyrosine-phosphorylation of both IR and an endogenous substrate (pp175) in response to insulin injection in vivo was decreased in the liver. However, a decrease in the phosphorylation of pp190 in muscles was not found. The levels of both GLUT-4 from muscles and GLUT-2 from liver in the crude membrane were comparable to those of the controls. These data suggest that insulin resistance in rats fed a HF-diet is a post-receptor defect in muscles, although tyrosine-phosphorylation of both IR and its endogenous substrate (pp175) were decreased in liver.

Insulin resistance in werner's syndrome

Insulin resistance in Werners syndrome (WS) was studied using the glucose clamp technique, and compared with physiologically aged and young subjects. Fasting immuno-reactive insulin (IRI) was increased in patients with Werners syndrome compared with aged and young subjects. Metabolic clearance rate (MCR) of glucose was decreased in the aged and WS. A rightward shift of the dose-response curves of insulin and MCR of glucose was observed in the aged and WS with a more pronounced shift in the latter. MCR of insulin was also decreased in WS. [125I]insulin binding to erythrocytes was similar in the three groups. These results suggest that insulin resistance associated with WS is due to a post-binding defect manifested by a rightward shift of the dose-response curve of insulin-induced glucose disposal and a decrease in insulin clearance rate.

Effects of insulin secretagogues and inhibitors on phospholipid metabolism in Langerhans' islets of rat pancreas

Glucose stimulation of [32P]-prelabelled pancreatic islets induced an increased incorporation of radioactivity into phosphatidylinositol. Glucagon and agents that increases cAMP in the islet did not affect phosphatidylinositol turnover, in spite of increased release of insulin. Furthermore, the potent inhibitor of insulin release, somatostatin did not alter phospholipid metabolism. Colchicine inhibited glucose-stimulated turnover of phosphatidylinositol as well as insulin release. These results may suggest that: (1) cAMP and phosphatidylinositol turnover are involved in different transmembrane control system for regulating insulin release; and (2) the function of microtubules modulate phospholipid metabolism.