Islet cell transplantation has considerable potential as a cure for type 1 diabetes, but recurrent autoimmunity and allograft rejection in which both cytokines play an important role are major obstacles. Using a new approach considering confounders by regression analysis, we investigated circulating cytokines and their association with graft function in type 1 diabetes patients who underwent either simultaneous islet kidney (SIK) or islet after kidney (IAK) transplantation. After transplantation, interleukin (IL)-10 was lower in SIK recipients with subsequent loss of graft function in comparison to recipients maintaining graft function. Before transplantation, high IL-13 and IL-18 concentrations were prospectively associated for subsequent loss of graft function in IAK recipients, whereas in SIK recipients, high macrophage migration inhibitory factor (MIF) concentrations were associated with subsequent loss of graft function. Circulating cytokines are associated with islet graft function in patients with long-standing type 1 diabetes when considering confounders.

Our primary objective in this study was to determine the effect of two different transplantation sites (renal capsule vs. portal vein) on islet xenograft survival and graft morphology. 59 chemically induced diabetic C57BL/6J mice were transplanted either intraportally (n = 30) or under the left renal capsule (n = 29) receiving 300-350 either freshly isolated or culture pretreated (37 degrees C or 22 degrees C) Lewis rat islets without any immunosuppressive therapy. Histology was performed by immunohistochemical staining to examine the morphologic pattern after rejection or after post-transplant normoglycemia for more than 120 days. Life table analysis revealed a significant (p < 0.001) prolongation of xenograft survival using the renal capsule as transplantation site. 75% graft rejection occurred 56 days after transplantation when the renal capsule was used, compared to 19.5 days intraportal. The intriguing finding was that graft morphology was different depending on the transplantation site. After transplantation under the renal capsule we observed predominantly a more periinsular infiltration with focal aggregates of mononuclear cells at the periphery of the graft. This pattern was more consistent with a non-destructive type of insulitis. In contrast, we found direct infiltration of the transplanted islets following intraportal transplantation reflecting a more destructive type of insulitis. In summary, we could demonstrate a significant prolongation of islet xenograft survival by using the renal capsule as transplantation site in contrast to intraportal transplantation. The morphological pattern possibly indicates two different mechanisms of rejection depending on the transplantation site.

Diabetic MedicineVolume 26, Issue 12 p. 1309-1310 Effect of combined oral proteases and flavonoid treatment in subjects at risk of Type 1 diabetes K. Kempf, K. Kempf Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Düsseldorf West-German Centre of Diabetes and Health, Sana Hospital Gerresheim, Sana Clinics Düsseldorf GmbH, DüsseldorfSearch for more papers by this authorG. Manzo, G. Manzo Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, DüsseldorfSearch for more papers by this authorP. Hanifi-Moghaddam, P. Hanifi-Moghaddam Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, DüsseldorfSearch for more papers by this authorS. Kappler, S. Kappler Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, DüsseldorfSearch for more papers by this authorJ. Seissler, J. Seissler Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Düsseldorf Diabetes Centre, Medical Clinic Innenstadt, Ludwig-Maximilians-University Munich, MunichSearch for more papers by this authorC. Jaeger, C. Jaeger Third Medical Department, University Hospital Giessen and Marburg, GiessenSearch for more papers by this authorB. Boehm, B. Boehm Division of Endocrinology and Diabetes, Graduate School Molecular Endocrinology and Diabetes, Ulm University, UlmSearch for more papers by this authorM. Roden, M. Roden Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Düsseldorf Department of Medicine/Metabolic Diseases, University Hospital Düsseldorf, Düsseldorf, GermanySearch for more papers by this authorH. Kolb, H. Kolb Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, DüsseldorfSearch for more papers by this authorS. Martin, S. Martin Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Düsseldorf West-German Centre of Diabetes and Health, Sana Hospital Gerresheim, Sana Clinics Düsseldorf GmbH, DüsseldorfSearch for more papers by this authorN. C. Schloot, N. C. Schloot Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Düsseldorf Department of Medicine/Metabolic Diseases, University Hospital Düsseldorf, Düsseldorf, GermanySearch for more papers by this authorfor the PRODIAB Study Group, for the PRODIAB Study Group Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, DüsseldorfSearch for more papers by this author K. Kempf, K. Kempf Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Düsseldorf West-German Centre of Diabetes and Health, Sana Hospital Gerresheim, Sana Clinics Düsseldorf GmbH, DüsseldorfSearch for more papers by this authorG. Manzo, G. Manzo Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, DüsseldorfSearch for more papers by this authorP. Hanifi-Moghaddam, P. Hanifi-Moghaddam Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, DüsseldorfSearch for more papers by this authorS. Kappler, S. Kappler Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, DüsseldorfSearch for more papers by this authorJ. Seissler, J. Seissler Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Düsseldorf Diabetes Centre, Medical Clinic Innenstadt, Ludwig-Maximilians-University Munich, MunichSearch for more papers by this authorC. Jaeger, C. Jaeger Third Medical Department, University Hospital Giessen and Marburg, GiessenSearch for more papers by this authorB. Boehm, B. Boehm Division of Endocrinology and Diabetes, Graduate School Molecular Endocrinology and Diabetes, Ulm University, UlmSearch for more papers by this authorM. Roden, M. Roden Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Düsseldorf Department of Medicine/Metabolic Diseases, University Hospital Düsseldorf, Düsseldorf, GermanySearch for more papers by this authorH. Kolb, H. Kolb Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, DüsseldorfSearch for more papers by this authorS. Martin, S. Martin Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Düsseldorf West-German Centre of Diabetes and Health, Sana Hospital Gerresheim, Sana Clinics Düsseldorf GmbH, DüsseldorfSearch for more papers by this authorN. C. Schloot, N. C. Schloot Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Düsseldorf Department of Medicine/Metabolic Diseases, University Hospital Düsseldorf, Düsseldorf, GermanySearch for more papers by this authorfor the PRODIAB Study Group, for the PRODIAB Study Group Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at the Heinrich-Heine-University Düsseldorf, DüsseldorfSearch for more papers by this author First published: 24 November 2009 https://doi.org/10.1111/j.1464-5491.2009.02879.xCitations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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Context Histopathological analysis has demonstrated lymphocytic infiltration in both the endocrine and the exocrine pancreas in some patients with type 1 diabetes and nonalcoholic chronic pancreatitis, suggesting an immune-mediated mechanism which affects both diabetes mellitus and chronic pancreatitis.Objective The examination of exocrine pancreatic humoral markers in Caucasian patients with respect to the interactions between exocrine and endocrine pancreatic diseases.Patients One hundred and thirty-six European Caucasian subjects subdivided into three groups: type 1 diabetes (n=48); non-alcoholic chronic pancreatitis (n=48); controls (n=40).Main outcome measure Autoantibodies against carbonic anhydrase II (CAIIAb) and lactoferrin (LACAb) (both of which are exocrine pancreatic antigens) were analyzed by enzyme-linked immunosorbent assay.Results No positivity for CAIIAb and LACAb were found in the controls. Patients with type 1 diabetes had a significantly higher prevalence of CAIIAb (25.0%) than the controls while the prevalence of LACAb (8.3%) was not significantly higher than the controls. The prevalence of CAIIAb (12.5%) and LACAb (20.8%) in the patients with nonalcoholic chronic pancreatitis was significantly higher than that in the controls. A significantly higher prevalence of CAIIAb and/or LACAb was found in patients with type 1 diabetes (29.2%) and non-alcoholic chronic pancreatitis (22.9%) compared to that in the controls (0%). There was a significant association between CAIIAb and LACAb titers both in patients with type 1 diabetes (P=0.042) and in patients with non-alcoholic chronic pancreatitis (P<0.001).Conclusion We have clearly demonstrated that some European Caucasian patients with type 1 diabetes and non-alcoholic chronic pancreatitis have autoantibodies against the exocrine pancreatic antigens CAIIAb and LACAb.

Background and Study Aims: We present ten patients who developed secondary sclerosing cholangitis following long-term treatment in an intensive care unit (ICU) between 1999 and 2004.Patients and Methods: Ten consecutive patients who had no evidence suggestive of pre-existing hepatobiliary disease were admitted to an ICU because of trauma (n = 5), intracerebral hemorrhage (n = 3), or nonabdominal postsurgical complications (n = 2). All the patients had required treatment with long-term ventilation, catecholamines, total parenteral nutrition, and several antimicrobial agents.Results: Cholestasis was first noted within 11 days after the initial insult. Endoscopic retrograde cholangiopancreatography (ERCP), performed after a median follow-up of 69 days, revealed multifocal stricturing and beading of the intrahepatic bile ducts, and attenuation of the peripheral branches. In all the patients, the bile ducts were partially filled by black-pigmented thrombotic material. All the patients underwent endotherapy, which comprised sphincterotomy and removal of the occluding material, in an attempt to improve biliary drainage; the treatment had to be repeated in seven of the ten patients. After a median follow-up period of 21 months, despite transient clinical improvement following endotherapy, complete recovery has not been achieved in any of the patients and so far one patient has had to undergo orthotopic liver transplantation as a result of end-stage liver disease.Conclusions: The development of secondary sclerosing cholangitis in patients who have received long-term treatment in an ICU is a rare event of unknown pathophysiology, but patients demonstrate characteristic findings on ERCP. It is not known whether endotherapy can delay the progress of the condition in the long term.

Einleitung: In seltenen Fällen tritt als Komplikation nach intensivmedizinischer Langzeitbehandlung eine sekundär sklerosierende Cholangitis (SSC) bei bis dahin lebergesunden Patienten auf. Zwischen 1999–2004 wurden in den HSK Wiesbaden 10 Patienten mit dieser seltenen Form der SSC nach intensivmedizinischer Langzeitbehandlung diagnostiziert.

Early duodenal carcinoma is a rare entity. Most duodenal carcinomas are diagnosed at a more advanced stage. This report describes the case of a 59-year-old lady with an early duodenal adenocarcinoma diagnosed at check-up gastroduodenoscopy in an outpatient clinic who was referred to us for further investigation and management. The initial upper endoscopy at our department revealed a type IIa+c lesion in the proximal duodenum (10 - 12 mm diameter, flat elevated lesion with central depression). Using chromoendoscopy and magnification endoscopy the lesion could be well demarcated and neoplastic changes in the architecture of the intestinal villi could be detected. After submucosal epinephrine-saline injection, the lesion was removed by endoscopic resection without complications. Histopathological examination revealed the rare entity of an early duodenal carcinoma arising from incomplete-type gastric metaplasia in the duodenum. In summary, the presented paper describes a case of successful endoscopic treatment of an early duodenal carcinoma arising from incomplete gastric metaplasia.

This report describes the case of a 62-year-old man with tonsillar carcinoma who had undergone esophagectomy due to an esophageal metastasis. Subsequently, a second metastasis occurred in the residual esophagus, and he presented for evaluation for local endoscopic therapy. The initial upper endoscopy revealed a type IIa - c lesion at 21 cm from the incisors, within a segment suspicious for Barrett's mucosa. As part of the complex treatment approach in this patient, endoscopic resection of the lesion was carried out using the suck-and-cut technique with ligation. Histology showed that the lesion was a metastasis from a squamous-cell carcinoma, with focal infiltration of the upper submucosal layer and vascular invasion consistent with the hypothesis of hematogenous spread from the preceding tonsillar carcinoma. The resection margins were tumor-free. At the time of writing, the patient had been recurrence-free for more than 9 months. In summary, the present paper describes a unique case of successful endoscopic resection of an esophageal metastasis associated with an antecedent tonsillar carcinoma.

Immune mediated complications associated with subcutaneous insulin therapy such as insulin neutralizing antibodies and/or skin reactions are rare conditions since human insulin is in general use. Nevertheless, if it occurs, a stepwise diagnostic approach is essential for differential diagnosis and consecutive treatment of these complications. Here we suggest a diagnostic algorithm to deal with e.g. insulin antibody formation of the IgG and/or IgE type and/or severe skin reactions resulting in poor metabolic control and often "brittle diabetes" in affected patients. This diagnostic algorithm includes step 1: Intradermal skin testing with positive and negative controls, additives and different insulin preparations; step 2: Quantification of insulin specific IgG and IgE in the serum, and step 3: Analysis of the time dependent binding/dissociation curves of the insulin neutralizing antibodies in an ex vivo/in vitro assay to assess the clinical significance of these antibodies. Based on 158 insulin treated control subjects and four patients with typical symptoms and signs representing the spectrum of immune-mediated complications subsequent to subcutaneous insulin therapy we demonstrate that the proposed stepwise approach leads to a definite diagnosis as a prerequisite for individual and successful therapy.

Background. Alloimmunity, autoimmunity, and nonspecific inflammation are known to be potential determinants for long-term islet survival and insulin independence. Sufficient islet mass is a key determinant. But islet engraftment and posttransplant survival may also depend on functional characteristics of the graft. This study investigated the significance of current product release criteria for the transplantation outcome.Methods. Fourty five consecutive transplanted human islet preparations and their functional outcomes were analyzed. Islet mass was determined according to standard criteria: purity by light microscopy, viability by dye exclusion and Insulin secretory response to static glucose incubation. Islet graft function was monitored for greater than or equal to1 year. Islet function was defined as full (FF), partial (PF), or nonfunction (NF) based on serum C-peptide levels and insulin independence.Results. All islet grafts displayed primary function. Islet mass [IEQ/kg BW]: 7331.3 +/- 679.7 (FF), 5821.3 +/- 546.7 (PF), 6468.6 +/- 658.5 (NF), (FF vs PF p =.032) Purity [%] 86.9 +/- 3.1 (FF), 76.0 +/- 2.87 (PF), 88.2 +/- 2.3 (NF) (FF vs PF P =.045, PF vs NF, P = 0.01). (4) Viability [%]:89.2 +/- 2 (FF), 86.2 +/- 1.7 (PF), 87.3 +/- 1.8 (NF) (ns). Stimulation index (SI): 20 +/- 6.3 (FF), 80.2 +/- 2 8.2 (PF), 21.6 +/- 3.5 (NF) (ns) No correlation was observed between SI and any other parameter nor between SI and C-peptide levels. Islet mass significantly correlated with C-peptide levels at 6 and 12 months after transplantation for functioning grafts.Conclusions. Stringent product release criteria allow identification of islet preparations suitable for clinical transplantation. However, currently used parameters are not predictive of long-term graft function, indicating that further refined quality assessments including apoptosis and resistance to early inflammation, are required to assess the primary engrafted islet mass.

Impaired exocrine pancreatic secretion has been frequently observed in diabetic patients by different methods, including direct function tests. However, the clinical importance remained unclear. In the present study, the fecal fat excretion in patients with type 1 or type 2 diabetes mellitus and exocrine dysfunction according to fecal elastase 1 concentrations <100 μg/g was investigated. Subjects with a history of gastrointestinal cancer, gastrointestinal surgery, alcohol abuse, or inflammatory diseases were excluded. In 101 patients the mean (±SD) fat excretion was 9.19 ± 5.39 g. Only 41 patients (40.6%) had normal fat excretion <7 g/day. In 40 patients (39.6%), it was higher than 10 g/day, indicating relevant steatorrhea. The fat excretion did not correlate with diabetes type, duration, or clinical symptoms. This finding is of some clinical importance and might influence pathophysiological concepts and the management of diabetic patients.

Background: There have been numerous reports on pancreatic exocrine dysfunction in diabetes mellitus using either direct or indirect function tests. The measurement of fecal elastase 1 concentrations (FEC) has been used as a screening tool for exocrine pancreatic disease in different patient groups indicating a high prevalence of exocrine dysfunction in diabetic populations. In this study we had the opportunity to study more than 1,000 diabetic patients to confirm recent observations in smaller populations. Methods: FEC were measured by ELISA in 323 patients with type 1 and 697 type 2 diabetes mellitus. Subjects with a history of alcohol abuse, gastrointestinal surgery, cancer or inflammatory diseases were not included. Diabetes history and clinical data were recorded using a standard case report form. Findings: 1,021 patients (334 female, 687 male; mean age 50 years; mean diabetes duration 11 years; mean age at onset of diabetes 39 years) were studied. FEC was normal (> 200 μg/g) in 59.3% and severely reduced (< 100 μ/g) in 22.9%. There were significant differences between type 1 and type 2 patients as well as between insulin-treated and non-insulin-treated patients. Furthermore, there were weak associations between FEC and diabetes duration, age at onset of diabetes and body mass index, respectively. Interpretation: We could confirm that both type 1 and type 2 diabetic patients show pathological exocrine function in high prevalence. Exocrine insufficiency seems to be correlated to early onset of endocrine failure, long-lasting diabetes mellitus and low body mass index levels.

We could confirm that both type 1 and type 2 diabetic patients show pathological exocrine function in high prevalence. Exocrine insufficiency seems to be correlated to early onset of endocrine failure, long-lasting diabetes mellitus and low body mass index levels.

OBJECTIVE:In type 1 diabetes the coexistence with other endocrine diseases and organ-specific autoantibodies has been frequently reported leading to the concept of autoimmune polyendocrine syndrome (APS). In addition, an association of type 1 diabetes with celiac disease has been described. These disorders share a similar genetic background, and first-degree relatives of type 1 diabetic patients may also be affected significantly. Screening for specific antibodies allows early diagnosis of these disorders.RESEARCH DESIGN AND METHODS:In the present cross-sectional study, we analyzed sera from 197 recent-onset type 1 diabetic patients at the time of diagnosis, 882 first-degree relatives, and sera of 150 healthy control subjects for prevalence and co-occurence of the following antibodies (method): insulin autoantibodies (radioimmunoassay); GAD and IA-2 antibodies (radioligand assay); islet cell antibody, anti-adrenal cortex antibodies, and anti-gastric parietal cell antibodies (indirect immunofluorescence); anti-thyroglobulin and anti-thyroid peroxidase antibodies; and gliadin IgG/A and tissue-transglutaminase IgA (enzyme-linked immunosorbent assay).RESULTS:The overall frequency of gastric patietal cell antibodies and adrenal antibodies did not differ significantly among groups. In contrast, type 1 diabetes-associated antibodies and thyroid antibodies were significantly more frequent both in recent-onset type 1 diabetic patients and in the group of first-degree relatives (P < 0.05). The prevalence of gliadin IgG/IgA and transglutaminase IgA was significantly higher in the group of recent-onset type 1 diabetic patients (P < 0.05), but the difference between first-degree relatives and control subjects did not reach statistical significance. Focusing on the coexistence of antibodies, the group of recentonset type 1 diabetic patients presented with 27.4% of the subjects testing antibody-positive-specific for two or more of the envisaged disorders (i.e., type 1 diabetes, autoimmune thyroiditis, and celiac disease) compared with 3.1% in the group of first-degree relatives and 0 of 150 in the control population (P < 0.05).CONCLUSIONS:We conclude that, in an active case-finding strategy, recent-onset type 1 diabetic patients should be routinely screened at least for concomitant autoimmune thyroid disease and additionally for celiac disease. Screening in their first-degree relatives should include at a minimum the search for thyroid autoimmunity in addition to screening for pre-type 1 diabetes.

Beta-cell replacement either by pancreatic organ or islet cell transplantation is the only treatment to achieve an insulin-independent, normoglycemic state and to avoid hypoglycemic episodes in patients with type 1 diabetes mellitus. This article will review the state-of-the-art in clinical islet cell transplantation at the dawn of the new millennium and will provide an outlook on the basis of extended personal experience.