[show abstract][hide abstract] ABSTRACT: Diabetes frequently develops in patients with pancreatic disorders. We aimed to determine the lower threshold of beta cell area for diabetes manifestation as well as the impact of insulin sensitivity on glucose homoeostasis in patients with pancreatic diabetes.
Eighty-two patients undergoing pancreatic surgery underwent pre-operative oral glucose challenge. Fractional pancreatic beta cell area was determined, and indices of insulin sensitivity and beta cell function were calculated.
HbA1c and glucose levels were similar in patients with high and intermediate beta cell area, but were significantly higher in those with the lowest beta cell area (p < 0.0001). Insulin secretion was reduced only in patients with the lowest beta cell area (p < 0.001). The relative beta cell deficits at the onset of diabetes and impaired glucose tolerance were 64% and 21%, respectively, based on 2 h glucose levels. Deteriorating insulin sensitivity was associated with a small increase in the incidence of diabetes.
In conclusion, pancreatic diabetes probably develops after a reduction in beta cell area of ~65%. Post-challenge glucose excursions are much more closely related to pancreatic beta cell area than to fasting glycaemia, thereby underlining the usefulness of the OGTT in patients with pancreatic disorders.
[show abstract][hide abstract] ABSTRACT: Mitochondrial dysfunction plays a central role in the general pathogenesis of non-alcoholic fatty liver disease (NAFLD), increasing the risk of developing steatosis and subsequent hepatocellular inflammation. We aimed to assess hepatic mitochondrial function by a non-invasive (13)C-methionine breath test (MeBT) in patients with histologically proven NAFLD.
118 NAFLD-patients and 18 healthy controls were examined by MeBT. Liver biopsy specimens were evaluated according to the NASH scoring system. Results: Higher grades of NASH activity and fibrosis were independently associated with a significant decrease in cumulative (13)C-exhalation (expressed as cPDR(%)). cPDR (1.5h) was markedly declined in patients with NASH and NASH cirrhosis compared to patients with simple steatosis or borderline diagnosis (cPDR1.5h: 3.24 ± 1.12% and 1.32 ± 0.94% vs. 6.36 ± 0.56% and 4.80 ± 0.88% respectively; p<0.001). (13)C-exhalation further declined in the presence of advanced fibrosis which was correlated with NASH activity (r = 0.36). The area under the ROC curve (AUROC) for NASH diagnosis was estimated to be 0.87 in the total cohort and 0.83 in patients with no or mild fibrosis (F0-1).
The (13)C-methionine breath test indicates mitochondrial dysfunction in non-alcoholic fatty liver disease and predicts higher stages of disease activity. It may, therefore, be a valuable diagnostic addition for longitudinal monitoring of hepatic (mitochondrial) function in non-alcoholic fatty liver disease.
European journal of medical research 06/2011; 16(6):258-64. · 1.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mitoxantrone is highly efficacious in the treatment of severe multiple sclerosis (MS). Mitoxantrone therapy-related acute leukemia (TRAL) has recently become the focus of interest.
A case report of fatal TRAL following mitoxantrone therapy is presented with a discussion on the differential diagnosis and risk factors. The interdisciplinary development of diagnostic and therapeutic algorithms is presented from a haematological and neurological point of view.
We describe the case of a 34-year-old MS patient who developed TRAL following mitoxantrone therapy (cumulative dose 45 mg/m(2) body surface). The patient died from endocarditis. TRAL is a rare but potentially fatal complication of mitoxantrone therapy with a wide variation of reported incidence. Thus far, no specific risk factors relating for example to preceding therapy and treatment regimens have been identified. Frequent laboratory controls and early bone marrow aspiration are mandatory for suspected TRAL as the condition is potentially curable.
TRAL needs to be considered in the risk-benefit assessment of mitoxantrone therapy, however, the exact incidence and risk factors (e.g. dosage, treatment regimen) are still unclear. The risks are controllable under close surveillance and early diagnosis is important for prognosis. Future investigations need to concentrate on identification of potential risk factors.
Der Nervenarzt 11/2010; 81(12):1483-9. · 0.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: Diabetes frequently develops in patients with chronic pancreatitis (CP). Partial pancreatectomy has emerged as a treatment option for such patients. We addressed whether the development of diabetes in CP patients is related to pancreatic beta cell area or clinical variables, and which factors predict the diabetes risk after partial pancreatectomy.
Fractional beta cell area was determined in pancreatic tissue samples obtained from 114 CP patients undergoing pancreatic surgery and related to measures of glucose control, as well as clinical and anthropometric data. Seventy-four patients without diabetes at the time of surgery were contacted again 2.5 +/- 1.0 years after partial pancreatectomy in order to obtain information about the post-operative development of diabetes.
In the surgical samples in the whole cohort, pancreatic beta cell area was 0.40 +/- 0.06% in patients with and 0.64 +/- 0.06% in those without previously known diabetes (p = 0.039). There was an inverse non-linear relationship between pancreatic beta cell area and fasting glucose concentrations (r = 0.29) as well as HbA(1c) levels (r = 0.36). Nineteen out of 74 previously normoglycaemic patients (26%) developed diabetes over an average period of 2.5 years of follow-up. Pre-operative fasting glucose levels, HbA(1c) and BMI were identified as predictors of diabetes after partial pancreatectomy. However, pancreatic beta cell area did not differ in those who subsequently developed diabetes (0.66 +/- 0.15%) and those who did not (0.62 +/- 0.08%, p = 0.45).
Hyperglycaemia in CP patients is associated with reduced beta cell area. However, reduced beta cell area does not predict the development of diabetes, suggesting that other factors are more important determinants of alterations in glucose metabolism in patients with CP.
[show abstract][hide abstract] ABSTRACT: Zusammenfassung
Hintergrund Aufgrund seiner hohen Effektivität in der Behandlung der schubförmig progressiven sowie sekundär progredienten Multiplen Sklerose
(MS) hat Mitoxantron einen hohen Stellenwert in der Eskalationstherapie. Die therapieassoziierte akute Leukämie („therapy
related acute leukemia“, TRAL) nach Mitoxantron-Applikation ist rezent in den Blickpunkt des Interesses gerückt.
Methodik Der Fallbericht einer TRAL mit hämatologisch-onkologischer Differenzialdiagnostik wird aufgearbeitet und mögliche Risikofaktoren
diskutiert. Die interdisziplinäre hämatologisch-onkologische sowie neurologische Entwicklung diagnostischer und therapeutischer
Algorithmen bei unklarer Zytopenie unter Mitoxantron wird erörtert.
Ergebnisse Wir beschreiben den Fall eines 34-jährigen MS-Patienten mit einer TRAL nach einer kumulativen Gesamtdosis von 45 mg/m2 Körperoberfläche Mitoxantron. Der Patient verstarb an einer Endokarditis. TRAL sind seltene aber schwerwiegende Komplikationen
einer Mitoxantron-Therapie, allerdings mit einer breiten Streuung der berichteten Inzidenz. In der Literatur sind bislang
keine sicheren Risikofaktoren und Abhängigkeiten von Vortherapien und von Therapieschemata identifiziert. Engmaschige Laborkontrollen
sowie frühzeitige Knochenmarkpunktionen sind bei Verdacht auf eine TRAL essenziell, da die TRAL prinzipiell kurativ therapierbar
Schlussfolgerung Das Risiko einer TRAL ist bei der Indikationsstellung für eine Eskalationstherapie mit Mitoxantron zu berücksichtigen, wobei
die exakte Inzidenz sowie Risikofaktoren (Dosierung, Therapieschema) noch unklar sind. Unter engmaschigem Monitoring sind
die Risiken allerdings beherrschbar. Künftige Untersuchungen müssen auf die Identifizierung von Risikofaktoren von TRAL unter
Der Nervenarzt 01/2010; 81(12):1483-1489. · 0.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: Infection with Helicobacter pylori (H. pylori) leads to the initiation of innate immune responses with increased antimicrobial peptide (AMP) expression in the gastric epithelium. This study aimed to determine the expression of the novel peptides beta-defensin 4 (hBD-4) and RNase 7 in infectious and non-infectious gastritis. Furthermore, pattern recognition receptors and mechanisms of regulation were characterized.
Expression of AMPs was quantified by real-time PCR in biopsies obtained from healthy individuals and patients with infectious and non-infectious gastritis as well as in AGS gastric epithelial cells infected with H. pylori. Distribution of hBD-4 in the gastric mucosa was characterized by in-situ hybridisation and immunohistochemistry. The role of Toll-like receptors (TLRs) 2 and 4 and associated signalling pathways was addressed.
hBD-4 was expressed at low levels in gastric epithelial cells and was significantly upregulated in infectious and non-infectious gastritis. Standard eradication but not acid suppression therapy significantly decreased hBD-4 expression. Cytotoxin associated gene (cag)A positive H. pylori significantly increased the expression of hBD-4 whereas cagA negative organisms, non-viable bacteria or culture supernatants had no significant effect. Overexpression and downregulation of TLRs was not associated with an altered hBD-4 expression. However, blocking experiments revealed an essential role for the p38 mitogen-activated protein kinase. RNase7 was inconsistently expressed in biopsies and not significantly upregulated by H. pylori.
hBD-4 may play a significant role in H. pylori associated gastritis. Inconsistent expression of RNase 7 does not support a pivotal role for this peptide in response to infection with H. pylori.
European Journal of Clinical Investigation 03/2009; 39(2):126-38. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Partial pancreatectomy is frequently performed in patients with pancreatic tumours or chronic pancreatitis, but little is known about the metabolic impact of this intervention. We examined the effects of approximately 50% partial pancreatectomy on glucose homeostasis and insulin secretion.
Fourteen patients with chronic pancreatitis, ten patients with pancreatic carcinoma and 13 patients with benign pancreatic tumours or extra-pancreatic masses (control group) underwent 240 min oral glucose tolerance tests before and after pancreatic tail-resection (n = 12), duodenopancreatectomy (n = 19) or duodenum-preserving pancreatic-head resection (n = 6).
Partial pancreatectomy led to a reduction in post-challenge insulin excursions by 49% in chronic pancreatitis patients, 52% in carcinoma patients and 55% in controls (p < 0.05). Nevertheless, post-challenge glucose concentrations were transiently ameliorated after surgery (p < 0.001). In the control participants, pancreatic-head resection caused a transient reduction of post-challenge glycaemia, whereas pancreatic-tail resection increased both fasting and post-challenge glycaemia (p < 0.05). Insulin sensitivity was highest in chronic pancreatitis patients before surgery (p < 0.01), but remained unchanged by the partial pancreatectomy. High pre-operative body weight and elevated fasting glucose levels were associated with poor glycaemic control after surgery.
Insulin secretion is diminished after pancreatic-head and -tail resection, but post-challenge glucose concentrations can be ameliorated after pancreatic-head resection. These data highlight the unequal impact of different surgical procedures on glucose control and suggest that obesity and high pre-operative glucose levels should be considered as risk factors for the development of hyperglycaemia after pancreatic surgery.
[show abstract][hide abstract] ABSTRACT: An increasing proportion of deaths among human immunodeficiency virus (HIV)-infected persons are due to hepatic complications. Hepatitis coinfection, antiretroviral treatment and co-occurrence of metabolic risk factors contribute to hepatic mitochondrial damage manifesting in hepatic steatosis and steatohepatitis. The aim was to assess disease- and treatment-related predictors on hepatic mitochondrial dysfunction in HIV infection by means of a new (13)C-methionine breath test (MeBT).
148 HIV positive individuals with and without antiretroviral treatment (ART) [44 therapy-naives; 89 patients on combination ART and 15 patients on structured treatment interruption (STI)] and 20 HIV-negative controls were studied prospectively by MeBT.
A decay of (13)C-methionine metabolism, expressed as cumulated percentage dose recovered over 1.5h (cPDR(1.5h)), in the subgroups of treatment-naives and patients on STI compared to controls was detected (cPDR(1.5h): 3.4 +/- 1.3% and 4.0 +/- 2.4% vs. 6.3 +/- 1.2%; p<0.01). Multivariate analyses including metabolic, treatment- and disease-related variables showed that antiretroviral treatment with stavudine, didanosine or zalcitabine and treatment-naivety were best predictors of a reduced MeBT result (cPDR(1.5h)) (beta = -0.56 and -0.50, p<0.05). CD4 count had only a minor association (beta = 0.15, p<0.05). No other variable including disease and treatment duration was associated with MeBT outcome. These factors explained 39% of the variance of MeBT results (p<0.05).
Therapy naivety and treatment with d-drugs were the best predictors of poor MeBT outcome. MeBT may be proposed as a feasible, noninvasive diagnostic instrument for clinical assessment of hepatic mitochondrial function and early detection of drug-induced mitochondriotoxity in chronic HIV infection.
European journal of medical research 09/2008; 13(9):401-8. · 1.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: The understanding of genetic risk factors for chronic pancreatitis increased in the last decade with the discovery of mutations in the cationic trypsinogen gene (PRSS1). The first mutation was detected at the R122 autocleavage site of the protein (R122H) and subsequently two other mutations in this region, R122C and V123M, were described that resulted in a similar phenotype of hereditary pancreatitis. This study reports a novel A121T mutation within this region and characterises the resulting molecular properties at the autocleavage site.
Blood samples of a PRSS1 A121T carrier family were analysed for PRSS1 mutations using melting point curve analysis, restriction endonucleases and DNA sequencing. Conformation dependent properties of the mutated sequence were analysed by molecular modelling. The autodegradation kinetic of the mutated trypsin sequence was measured by a novel fluorescence resonance energy transfer (FRET) assay using designed 11 amino acid peptides from PRSS1 aa 118-aa 127 containing the trypsin cleavage site at aa 122 coupled to a Dabcyl/EDANS FRET system. The kinetic of tryptic peptide cleavage was measured in a fluorescence enzyme linked immunosorbent assay (ELISA) reader.
DNA sequencing revealed a novel G to A transition at position 133279 of the published genomic sequence (#U66061 GenBank). The mutation results in an amino acid substitution of alanine by threonine at position 121 (A121T) of the cationic trypsinogen. Four additional mutation carriers could be identified among the relatives while only the first patient developed chronic pancreatitis. Molecular modelling of PRSS1 A121T revealed a change in the bond pattern between the R122 region and the calcium binding loop, whereas FRET assays showed an increased trypsin cleavage rate with a reaction kinetic elevated by more than 80%.
The novel PRSS1 A121T mutation highlights the surface exposed region PRSS1 A121-R122-V123 as a hotspot for hereditary pancreatitis associated trypsinogen mutations. Molecular modelling and FRET assays provide evidence for an A121T mutation dependent increase in susceptibility to trypsin digestion at the R122 cleavage site suggesting an enhanced autodegradation and a loss-of-function at the autocleavage site.
Journal of Medical Genetics 06/2008; 45(8):507-12. · 5.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hepatitis C virus (HCV) infection is characterized by remarkable levels of oxidative stress induced by virus interactions with hepatic mitochondria.
To examine hepatic mitochondrial function in HCV-infected patients assessed by a non-invasive (13)C-methionine breath test (MeBT) and to explore longitudinal effects of antiviral treatment.
Twenty-one patients with chronic hepatitis C undergoing antiviral treatment with pegIFNalpha and ribavirin and 20 healthy controls were studied. MeBT was performed at baseline, week 12, end-of-treatment and after 24 weeks of follow-up in all patients with early virological response (n = 15).
Twelve patients achieved sustained virological response (SVR); three patients relapsed for HCV-RNA replication. Cumulative percentage 13C-exhalation (cPDR(1.5h)) was significantly decreased in HCV-infected individuals compared to controls irrespective of genotype and fibrosis stage (P < 0.001). Antiviral treatment induced a further decay in cPDR(1.5h) (P < 0.01). After treatment cessation, 13C-exhalation returned at least to baseline values in all patients. SVR was even associated with a mean cPDR(1.5h) increase of 70% compared to baseline.
Hepatitis C virus infection and antiviral treatment synergistically impair hepatic mitochondrial function, which may return to normal after sustained virus elimination. MeBT may be a valuable diagnostic instrument for monitoring hepatic mitochondrial function in particular in patients with mitochondrial comorbidities.
[show abstract][hide abstract] ABSTRACT: Postprandial hyperglycaemia is often assumed in individuals with high glucose excursions during an oral glucose tolerance test (OGTT), but the relationship between glucose levels during the OGTT and after a mixed meal is yet unclear. We addressed whether (i) glucose concentrations after an oral glucose load are similar to those after a test meal or under daily life conditions and (ii) impaired glucose tolerance (IGT) predicts postprandial hyperglycaemia.
A total of 60 subjects with normal (NGT), IGT or diabetic (DM) glucose tolerance were examined with an OGTT, a mixed meal challenge (3433 kJ) and a self-determined 10-point home glucose profile.
There was a significant correlation between the 120-min OGTT glucose levels and the glycaemic excursions after the test meal and during everyday conditions. However, glucose excursions during the OGTT exceeded those after the test meal and during everyday conditions by approximately 20 and approximately 30% respectively. Likewise, insulin and C-peptide levels rose to higher levels after oral glucose compared with mixed meal ingestion. The mean self-determined diurnal glucose levels were already 10% higher in subjects with IGT compared with NGT subjects (p < 0.0001).
Glucose levels reached after an oral glucose challenge and during real life are correlated to some extent, but the absolute levels of glycaemia greatly differ between both conditions. Therefore, 'postchallenge' glucose levels measured during an OGTT might be used as a predictor of 'postprandial hyperglycaemia', but caution should be taken when both terms are used synonymously. Furthermore, subjects with IGT during an OGTT already exhibit increased postprandial glucose levels under real-life conditions. This suggests that IGT should already be considered an overt disease condition rather than merely a high-risk situation.
Diabetes Obesity and Metabolism 06/2008; 11(3):213-22. · 5.18 Impact Factor
[show abstract][hide abstract] ABSTRACT: Primary hyperparathyroidism (pHPT) related hypercalcaemia is considered to represent a risk factor for the development of pancreatitis. We therefore explored whether mutations in the calcium-sensing receptor gene ( CASR) coding for the calcium-sensing receptor (CaR), an essential regulator of the calcium homeostasis in parathyroid chief cells, exist in a cohort of patients with pHPT and pancreatitis.
Among 826 patients prospectively studied between 1987 and 2002 with pHPT, 38 patients were identified with pancreatitis (4.6%). DNA was available of 25 patients (13 females and 12 males). These individuals were analysed for mutations in the CASR by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing.
None of the 25 patients with pHPT and pancreatitis carried a CASR mutation and only one had a known heterozygous polymorphism R990G.
Pancreatitis in primary hyperparathyroidism is not associated with mutations in the CASR gene, while it remains to be determined why the polymorphisms A986S, R990G and Q1011E were less often present in that subgroup than in the normal population.
[show abstract][hide abstract] ABSTRACT: The suppressors of cytokine signalling (SOCS) are inhibitors of cytokine signalling; methylation of SOCS-3 has been implicated in the tumorigenesis of liver as well as head and neck cancer.
This study was performed to elucidate the role of SOCS-1 and SOCS-3 in Barrett's adenocarcinoma and its precursor lesions.
DNA of specimens from 19 Barrett's adenocarcinomas, 56 Barrett's intraepithelial neoplasias (n = 29 low grade and n = 27 high grade), 30 Barrett's mucosa without neoplasia, 20 samples of normal squamous and gastric epithelium and four cell lines were studied using methylation specific PCR for the SOCS-1 and SOCS-3 promoter following microdissection. The presence of SOCS-3 mRNA transcripts was confirmed by semiquantitative real time PCR, and the SOCS-3 protein was analysed immunohistochemically.
In normal squamous epithelium and normal gastric mucosa, neither SOCS-3 nor SOCS-1 methylation was observed. In Barrett's mucosa without intraepithelial neoplasia, SOCS-3 methylation occurred in 4/30 cases (13%) whereas SOCS-1 was unmethylated. A hypermethylated SOCS-3 promoter was found in 14/19 Barrett's adenocarcinomas (74%) and in 20/29 high and 6/27 low grade intraepithelial neoplasias (69% and 22%, respectively). SOCS-1 promoter hypermethylation occurred in 8/19 adenocarcinomas (42%) and in 6/29 high grade and 1/27 low grade intraepithelial neoplasias (21% and 4%, respectively). Methylation of the SOCS-3 promoter correlated with downregulation of SOCS-3 transcripts and protein expression in these tumours and various cell lines. In the cell lines tested, SOCS-3 and SOCS-1 transcripts increased after treatment with the demethylation compound 5-aza-2-deoxycytidine.
These data indicate that promoter methylation and subsequent transcript downregulation of SOCS-3 transcripts and, to a much lesser extent, SOCS-1 are involved in the multistep carcinogenesis of Barrett's adenocarcinoma.
[show abstract][hide abstract] ABSTRACT: The development of a variety of new substances will considerably expand the therapeutic choices in the treatment of type 2 diabetes. In 2006, the endocannabinoid receptor blocker Rimonabant has been approved for the treatment of type 2 diabetes in Germany. This compound has led to significant reductions of body weight along with improvements of HbA1c levels and lipid profiles, but the lack of health insurance coverage limits its large scale use in germany. In April 2007, the first members of the GLP 1 analogues/incretin mimetics (exenatide, Byetta) and DPP 4 inhbitors (sitagliptin, Januvia) have become available for the treatment of type 2 diabetes in Germany. Both drugs have significantly lowered HbA1c levels in clinical studies. In addition, the incretin mimetics have caused a progressive reduction of body weight, while the DPP 4 inhibitors have been rather weight neutral. Sitagliptin can be administered orally, whereas exenatide has to be injected subcutaneously. Neither the DPP 4 inhibitors, nor the incretin mimetics have led to the development of hypoglycaemia, unless combined with sulfonylureas. Overall, the introduction of these new drug classes will certainly broaden our therapeutic choices in the management of type 2 diabetes. The long-term effects of these drugs on the development of diabetic complications in long-term trials remains to be awaited.
Der Internist 08/2007; 48(7):698, 700-7. · 0.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: The incretin effect describes the augmentation of postprandial insulin secretion by gut hormones. It is not known whether glucagon secretion is also influenced by an incretin effect. A glucagon suppression deficiency has been reported in some patients with type 2 diabetes, but it is unclear whether this abnormality is present prior to diabetes onset. We therefore addressed the questions: (1) Is glucagon secretion different after oral and during intravenous glucose administration? (2) If so, is this related to the secretion of incretin hormones? (3) Is glucagon secretion abnormal in first-degree relatives of patients with type 2 diabetes?
We examined 16 first-degree relatives of patients with type 2 diabetes and ten matched control subjects with an oral glucose load (75 g) and with an 'isoglycaemic' intravenous glucose infusion.
Glucagon levels were significantly suppressed by both oral and intravenous glucose (p < 0.0001), but glucagon suppression was more pronounced during intravenous glucose administration (76 +/- 2%) than after oral glucose administration (48 +/- 4%; p < 0.001). The differences in the glucagon responses to oral and i.v. glucose were correlated with the increments in gastric inhibitory polypeptide (GIP) (r = 0.60, p = 0.001) and glucagon-like peptide (GLP)-1 (r = 0.46, p < 0.05). There were no differences in glucagon levels between first-degree relatives and control subjects.
Despite the glucagonostatic actions of GLP-1, the suppression of glucagon secretion by glucose is diminished after oral glucose ingestion, possibly due to the glucagonotropic actions of GIP and GLP-2. Furthermore, in this group of first-degree relatives, abnormalities in glucagon secretion did not precede the development of other defects, such as impaired insulin secretion.
[show abstract][hide abstract] ABSTRACT: Die Entwicklung einer Vielzahl neuer Substanzen wird das therapeutische Spektrum beim Typ-2-Diabetes in Zukunft deutlich erweitern.
Bereits 2006 wurde der Endocannabinoidrezeptorantagonist Rimonabant für die Therapie übergewichtiger Patienten mit Typ-2-Diabetes
zugelassen. Dieses Präparat führt zum einen zu einer deutlichen Reduktion des Körpergewichts, zum anderen aber auch zu einer
signifikanten Absenkung der HbA1c-Werte sowie einer Verbesserung des Lipidprofils. Allerdings erschwert die fehlende Kostenerstattung
durch die Krankenkassen derzeit einen breiteren Einsatz dieses Präparates. Im April 2007 wurden die jeweils ersten Vertreter
der neuartigen Substanzgruppen der GLP-1-Analoga/Inkretinmimetika (Exenatide, Byetta®) und DPP-4-Hemmer (Sitagliptin, Januvia®)
in Deutschland zugelassen. Beide Substanzen führen in klinischen Studien zu einer deutlichen Absenkung der HbA1c-Werte. Darüber
hinaus führen die Inkretinmimetika zu einer progredienten Gewichtsreduktion, während die DPP-4-Hemmer weitestgehend gewichtsneutral
sind. Die Applikation von Sitagliptin erfolgt oral, während Exenatide subkutan verabreicht wird. Aufgrund der Glukoseanhängigkeit
ihrer Wirkungen führt die alleinige Gabe der DPP-4-Hemmer und Inkretinmimetika nicht zur Auslösung von Hypoglykämien. Insgesamt
stellt die Einführung dieser neuen Substanzgruppen sicherlich eine sinnvolle Erweiterung des therapeutischen Portfolios beim
Typ-2-Diabetes dar. Die Auswirkungen dieser neuen Therapieformen auf die Entwicklung diabetischer Folgekomplikationen in Langzeitstudien
The development of a variety of new substances will considerably expand the therapeutic choices in the treatment of type 2
diabetes. In 2006, the endocannabinoid receptor blocker Rimonabant has been approved for the treatment of type 2 diabetes
in Germany. This compound has led to significant reductions of body weight along with improvements of HbA1c levels and lipid
profiles, but the lack of health insurance coverage limits its large scale use in germany. In April 2007, the first members
of the GLP 1 analogues/incretin mimetics (exenatide, Byetta®) and DPP 4 inhbitors (sitagliptin, Januvia®) have become available
for the treatment of type 2 diabetes in Germany. Both drugs have significantly lowered HbA1c levels in clinical studies. In
addition, the incretin mimetics have caused a progressive reduction of body weight, while the DPP 4 inhibitors have been rather
weight neutral. Sitagliptin can be administered orally, whereas exenatide has to be injected subcutaneously. Neither the DPP
4 inhibitors, nor the incretin mimetics have led to the development of hypoglycaemia, unless combined with sulfonylureas.
Overall, the introduction of these new drug classes will certainly broaden our therapeutic choices in the management of type
2 diabetes. The long-term effects of these drugs on the development of diabetic complications in long-term trials remains
to be awaited.
Der Internist 01/2007; 48(7):698-707. · 0.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: Zusammenfassung Die friedliche Koexistenz mit der luminalen Flora wird im humanen Gastrointestinaltrakt über komplexe Mechanismen vermittelt.
In genetisch prädisponierten Individuen kann es als Folge einer Störung der intestinalen Homöostase zu chronischen Entzündungsreaktionen
kommen, wie sie typischerweise bei der Colitis ulcerosa sowie beim M. Crohn beobachtet werden. Bei diesen Erkrankungen werden
ferner quantitative und qualitative Veränderungen der luminalen Flora beobachtet. Bisherige Studien haben keinen Einzelorganismus
mit pathologischer Relevanz identifiziert, wohl aber kommensale Bakterien mit schädlichem sowie andere mit protektivem Effekt
auf die intestinale Mukosa. Die Manipulation der intestinalen Flora stellt somit eine potenzielle und vielversprechende therapeutische
Option dar. Hier ergeben sich jedoch krankheitsspezifische Unterschiede in der Effektivität einer Therapie mit Antibiotika,
Probiotika oder Präbiotika. Zur Optimierung der bioökologischen Therapie sind eine weitergehende Charakterisierung involvierter
Mechanismen sowie große klinische Studien notwendig.
[show abstract][hide abstract] ABSTRACT: Clostridium difficile ist der hufigste Erreger einer nosokomialen antibiotikaassoziierten Diarrh. Das Spektrum C.-difficile-assoziierter Erkrankungen reicht von einer milden wssrigen Diarrh bis hin zur pseudomembransen Enterokolitis mit fulminantem Verlauf und hoher Mortalitt. Die Pathogenese ist multifaktoriell: Neben der Akquisition des toxinbildenden Erregers sowie Alteration der Darmflora durch eine antibiotische/zytostatische Therapie spielen patientenspezifische Faktoren (hohes Lebensalter, Komorbiditt, eingeschrnkte Immunitt) eine Rolle. Die Diagnostik erfolgt durch Erreger-/Toxinnachweis im Stuhl und das charakteristische endoskopische Bild. Die Beendigung der verursachenden Antibiotikagabe ist die entscheidende therapeutische Sule, eine spezifische Therapie kann primr mit Metronidazol oder Vancomycin erfolgen. Die Rezidivrate ist mit 15–30% sehr hoch. Die Isolierung des Patienten und adquate Hndehygiene sind unabdingbare Manahmen zur Vermeidung der nosokomialen Verbreitung des sporenbildenden Keims.
Clostridium difficile is the chief cause of nosocomial diarrhea related to antibiotic treatment. The clinical picture ranges from mild, acute watery diarrhea to full-blown pseudomembranous enterocolitis. The pathogenesis of the disease is multifactorial and involves the acquisition of the bacteria and an altered composition of the gut flora due to antibiotic or cytotoxic treatment. Host specific risk factors are advanced age, severe comorbidity and immunocompromised states. Diagnosis is based on the detection of the bacteria or its toxins in stool specimens. Termination of the disease causing antibiotic regimen is the first therapeutic goal. Metronidazole or orally administered vancomycin have proven effective in the eradication of C.difficile. Recurrence rates are as high as 30%. To prevent further nosocomial spread of spores, affected patients require isolation, and personnel must adhere to strict hygienic standards including hand scrubbing and disinfection.
[show abstract][hide abstract] ABSTRACT: VEGF is a glycoprotein with various (e.g. angiogenic) activities. So far, research has focused on its angiogenic properties. VEGF receptors are localized on epithelial cells of patients with inflammatory bowel disease (IBD) and also on Caco-2 and IEC-18 cells. Our aim was to evaluate the role of VEGF on intestinal epithelial cell (IEC) migration and proliferation by utilizing an established in vitro model.
IEC-18 and Caco-2 monolayers were wounded with a razor blade as described previously. Cells were incubated in medium w/o rat VEGF(164). After 24 h, migration was assessed by counting cells across the wound edge. Migration was blocked with neutralizing TGF-beta(1) antibodies. IEC proliferation was assessed using the MTT (3-[4, 5-Dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide) test. Semi-quantitative changes of the TGF-beta(1) mRNA expression were evaluated before and after stimulation of the cells with VEGF(164) by RT-PCR. Statistical analysis was performed with ANOVA and the Wilcoxon test.
VEGF(164) significantly induced epithelial cell migration in Caco-2 and IEC-18 cells compared to control. TGF-beta(1) antibodies completely abolished this VEGF-induced cell migration. TGF-beta(1) mRNA significantly increased in IEC-18 and Caco-2 cells after stimulation with VEGF. VEGF significantly inhibited epithelial cell proliferation in IEC-18 and in Caco-2 cells, indicating that the observed effects on cell migration were not due to any proliferate effects.
VEGF effects on epithelial cell migration play an important part in epithelial cell restitution by maintaining mucosal homeostasis after mucosal injury. This effect is mediated by TGF-beta(1). Our results obtain another possible role for increased VEGF levels in the intestinal mucosa of patients with IBD as reported recently by others.
Scandinavian Journal of Gastroenterology 07/2006; 41(6):687-92. · 2.16 Impact Factor