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Hintergrund und Fragestellung: Durch gesunde Ernahrung und Bewegung kann bei Typ-2-Diabetes die Stoffwechseleinstellung verbessert werden. Ohne externe Hilfe sind Lebensstilanderungen fur Betroffene meist schwer umzusetzen, da fur nachhaltigen Erfolg eine Anderung der inneren Einstellung notwendig ist. Daher wurde das computerbasierte medizinisch-mentale Motivationstraining Da Vinci zur Anderung von mentalen Einstellungen und Uberzeugungen entwickelt. Patienten und Methodik: Typ-2-Diabetes-Patienten wurden in 4 Trainingseinheiten in 10 Zentren von Mentaltrainern betreut. Mittels eines interaktiven Computerprogramms wurden Motivationshemmnisse identifiziert und uberwunden. Glukometabolische Parameter wurden zu Beginn, nach 3 Monaten Training sowie 3 und 6 Monate nach Trainingsende erfasst. Ergebnisse: Alle Teilnehmer (n = 61) entwickelten eine positive Einstellung zu ihren Handlungsmoglichkeiten und anderten eigenstandig ihren Lebensstil. Nach 3 Monaten Training kam es zu einer mittleren Reduktion von Gewicht (-4,6 kg; p Folgerung: Im Rahmen des medizinisch-mentalen Motivationstrainings, das keine diabetologischen Schulungsinhalte, sondern nur eine Anderung mentaler Einstellungen und Uberzeugungen vermittelt, gelang es den Teilnehmern, ihr vaskulares Risikoprofil signifikant zu verbessern. Dies weist auf eine nachhaltige Lebensstilanderung hin, da die erzielten Erfolge auch langerfristig aufrechterhalten werden konnen.

The ROSSO study is a retrospective, longitudinal cohort study performed to obtain epidemiological data on self-monitoring of blood glucose (SMBG) in patients with type 2 diabetes and to investigate the impact of SMBG on disease-related morbidity and mortality. 3,268 patients from 192 doctor's practices in Germany were included and their data from diabetes diagnosis (between 1995 and end of 1999) till drop-out (120 died, 17 drop-outs) or end of 2003 were collected from the medical records. The mean observational time was 6.5 years; total patient years of follow-up were 21.266 years. Based on these population data, questions about the motivation of patients with type 2 diabetes to start with SMBG, the changes in diabetes therapy and blood glucose associated with SMBG and the relationship of SMBG with non-fatal or fatal events during follow-up were evaluated. Use of SMBG is significantly associated with personal and baseline conditions. Patients using SMBG are more frequently treated by an internist, more often male, have more frequently a private health insurance, exhibit less frequently arterial hypertension, are younger, have lower systolic blood pressure and higher values of fasting blood glucose (FBG), HbA1c and triglycerides at diagnosis. The start of SMBG is preceded by a steady increase in blood glucose levels. It is accompanied by an intensification of diabetes therapy and followed by a significant reduction of blood glucose in the year after start of SMBG. 67% of the patients treated with diet only before SMBG began with antidiabetic medication concomitantly with SMBG (48% with oral antidiabetic agents (OAD), 9% with insulin and 10% with OAD and insulin) and 30% of the patients treated with OAD started on additional insulin treatment in parallel with SMBG. Switching from no antidiabetic medication to OAD reduced the mean FBG levels significantly from 9.31 to 8.70 mmol/l, from no medication to insulin from 10.05 to 6.93 mmol/l and from no medication to OAD and insulin from 10.85 to 8.92 mmol/l. Similar reductions of mean FBG levels were observed for switching from OAD to insulin therapy. Patients who stayed on OAD therapy also showed a significant reduction of FBG concentrations after the start of SMBG. The hazard for non-fatal events (particularly myocardial infarction and stroke) or overall mortality was significantly reduced for patients who performed SMBG during follow-up (p

This study was done to determine the effects of the angioprotective agent dobesilate on expression and activity on the constitutive nitric oxide synthase (ecNOS) in resident endothelial cells, as well as of the inducible nitric oxide synthase (iNOS) in cytokine-activated endothelial cells, by recording, in culture supernatants, the concentrations of citrulline as a reaction product of both enzymes. In capillary, microvascular, and macrovascular endothelial cells, Mg dobesilate incubation (0.25-1 mM) for 24 hours led to a highly significant concentration-correlating increase in ecNOS activities. These increases were not due to iNOS expression, and with cytokine-activated endothelial cell cultures that do express iNOS only moderate effects with little or no concentration dependency were seen. Addition of the NOS inhibitor NG-monomethyl-L-arginine (NMA) significantly suppresses citrulline formation in all cultures as evidence for the enzyme specificity.

Subtotal pancreatectomy (90%) in Lewis rats induces chronic islet inflammation and tissue damage in the remaining pancreas 4 months after surgery. Concomitantly, significant enlargement of the islets of Langerhans was observed (90% pancreatectomy: islet/pancreas area: 25.6 +/- 9.6 x 10(-3), beta-cell/pancreas area: 12.4 +/- 4.4 x 10(-3); n = 4; controls without pancreatectomy: islet/pancreas area: 5.5 +/- 1.7 x 10(-3), beta-cell/pancreas area: 4.6 +/- 1.5 x 10(-3); n = 4; p < 0.05, respectively). Islet growth is mainly due to an increase in beta-cell mass. Beta-cell regeneration was not caused by the surgical manipulations or by metabolic stress. The former was ruled out by performing 10% pancreatectomy which did not cause islet enlargement after 4 months (islet/pancreas area: 13.6 +/- 11.3 x 10(-3), beta-cell/pancreas area: 7.1 +/- 2.0 x 10(-3); n = 3). An influence of metabolic stress was excluded by continuous substitution of syngenic islet antigens, which inhibits insulitis. In the absence of islet inflammation, despite persistent metabolic stress, beta-cell regeneration did not occur (islet/pancreas area: 7.0 +/- 5.5 x 10(-3), beta-cell/pancreas area: 5.5 +/- 4.1 x 10(-3); n = 4). Continuous treatment of animals after 90% pancreatectomy by insulin implants (1.5 U/day) avoided insulitis and beta-cell growth (islet/pancreas area: 9.2 +/- 1.1 x 10(-3), beta-cell/pancreas area: 6.8 +/- 1.0 x 10(-3), n = 3): All enlarged islets observed 4 months after 90% pancreatectomy without further treatment were infiltrated. Thus, beta-cell growth appears to be a response to insulitis. The stimulus for beta-cell growth could result from tissue damage caused by infiltrating cells or from cytokines secreted by the infiltrating cells, or both.

Experiments with animal models have proven that intervention protocols avoiding immunosuppressants can effectively prevent immune-mediated diabetes. These new approaches aim at either supporting the defence of islet cells against inflammatory attack or at modulating the type of the immune response to beta cells towards a more benign quality. Another approach is to reduce the exposure to putative diabetogenic dietary factors during infancy. All of the three strategies are presently tried in clinical studies.

A key characteristic of human autoimmune disease is the focus on a few target autoantigens. This phylogenetically conserved antigenic restriction is consistent with the concept that the non adaptive innate immune system is critical to disease development. Indeed, defects of macrophages, dendritic cells or NK T cells have been reported for type I diabetes or its animal models. Products of the innate immune system, such as IL-12, IL-15 and IL-18 have been shown to drive destructive insulitis. Besides the modulatory impact of infections a key environmental factor appears to be the diet. Wheat, soy and cow milk may contain diabetogenic proteins, as judged from animal experiments. These findings indicate a key role of the gut immune system which probably exhibits deficient oral tolerance mechanisms and therefore would mount a proinflammatory response when challenged with putative diabetogenic compounds in the diet. Dietary intervention studies to modulate the natural coursc of type I diabetes are underway.

Obesity and related disorders represent states of systemic low-grade inflammation. Chemokine secretion by adipocytes may initiate leukocyte infiltration in obese adipose tissue and thus mediate an important step in the establishment of chronic immune activation. The chemokine RANTES (regulated upon activation normal T cell expressed and secreted)/CCL5 is a chemoattractant for various leukocyte subsets. This study was designed to examine whether RANTES is expressed and released by human adipocytes and how its expression is regulated. RANTES expression under basal conditions was studied in mature adipocytes. Cells were therefore challenged with lipopolysaccharide (LPS), interferon (IFN)-gamma, interleukin (IL)-4, monocyte chemoattractant protein (MCP)-1 or exposed to low oxygen pressure. RANTES was expressed and secreted constitutively in most samples of mature adipocytes from the omental and the subcutaneous depot. RANTES release was dependent on adipocyte size and also seemed to be higher from cells of obese donors. Hypoxia (4% O (2)) caused an approximately 36% increase of RANTES release. Human adipocytes express the chemokine RANTES and are thus identified as a novel cellular source of this immune mediator. LPS and IFNgamma do not seem to play a significant role for the expression of RANTES in contrast to moderate hypoxia, which points to a distinct role in the innate immune system.

BACKGROUND AND OBJECTIVE Worldwide the quality of care of patients with type 2 diabetes has been investigated only by analysing within cross-sectional studies. But the quality of care in relation to statutory or private health plans in not known. It was the aim of this study to ascertain retrospectively, how in the course of time from first diagnosis the quality of medical care of patients with type 2 diabetes differed depending on the type of health insurance of the individual patient. METHODS AND PATIENTS As part of the ROSSO study (a German retrospective epidemiological cohort study), data on all patients diagnosed with type 2 diabetes between 1.1.1995 and 31.12.1999 had been recorded. They had been collected from 192 randomly selected general practitioner or internal medicine specialist practices. RESULTS The data of 3268 patients diagnosed with type 2 diabetes were recorded. The mean observation period was 6.5 years. The mean age of this patients at the time of diagnosis of diabetes was 62.4 +/- 9.6 years, 49 % being male. The portion of patients visiting their chosen practice at least 3 - 4 times in a given year was about 70 - 80 %. Documentation of HbA (1c) or blood pressure as requested in the guideline was presented in 20 - 50 % of patient files with no differences between enrolled in a statutory or private health plans. Even when cholesterol or blood pressure levels were greatly elevated 20 - 50 % of patients had been prescribed no adequate drug treatment. Only 20 % of the patients had been described platelet aggregation inhibitors during the first years after myocardial infarction or stroke. CONCLUSION The quality of care in general practitioner of specialist internal medicine practices failed to meet the guidelines for patients with type 2 diabetes. There were no differences that depended on whether the patients had been enrolled in a statutory or private health plan.

The effect of passive insulin antibody transfer into recipient mice was reevaluated. Mice of inbred strains BALB/c, C57Bl/6 and DBA/2 received 10 injections of hyperimmune guinea pig insulin antiserum within 2 weeks. Ten days later the animals were sacrificed. It was found that up to 40% of animals had developed chronic lymphocytic infiltrations of pancreatic islets (insulitis) without showing diabetic symptoms. It is concluded that repeated damaging of islet tissue by passive insulin antibody transfer may result in chronic, possibly autoimmune insulitis. Our observation supports the concept that partial damage of pancreatic islets by environmental factors may trigger an organ-specific progressive islet cell destruction process mediated by immune cells.

The KORA studies serve as a powerful tool for the genetic analysis of complex diseases like type 2 diabetes or the metabolic syndrome. These studies include more than 2,000 prevalent and incident type 2 diabetes cases. DNA of these patients is available to be used in genetic studies. Up to now the analyses have focussed on genes coding for proteins being involved in the inflammatory response. Interleukin-6 (IL-6) as the key mediator of the acute phase reaction is of interest. Elevated protein concentrations of IL-6 in the blood have been shown to predict type 2 diabetes. We investigated the association of the IL-6 single nucleotide polymorphism (SNP) C-174G with type 2 diabetes in a case-control study of 704 elderly participants of the KORA Survey S4 (1999/2001). When BMI, HDL cholesterol, physical activity, hypertension, hormone replacement therapy and smoking were considered as covariables the SNP C-174G showed a trend for association with type 2 diabetes (- 174G: OR 1.20, 95 % CI 0.90 - 1.59, p = 0.21).

Type 2 diabetes is associated with a systemic low-grade inflammation. First data provided by cross-sectional studies from as early as the 1960s demonstrated elevated systemic levels of glycoproteins and acute-phase reactants and increased leukocyte counts in type 2 diabetes patients. Subsequently, prospective studies showed that elevated concentrations of several acute-phase proteins and cytokines are predictive of later type 2 diabetes. Immune gene variants in man and in animal models were found to affect insulin resistance and diabetes incidence. Antidiabetic treatment by medication, diet or physical activity results in a significant decrease of systemic immune mediator concentrations. Immunological analyses of the KORA Survey S4 (1999/2001) allowed us to show that levels of circulating acute-phase proteins like CRP and of IL-6 are highly correlated and associated not only with overt type 2 diabetes, but already with impaired glucose tolerance (IGT) pointing out a role of these mediators in the pathogenesis of type 2 diabetes. On the contrary, TNFalpha was neither coregulated with CRP nor associated with diabetes status. Our study therefore shows that type 2 diabetes is accompanied by a non-random and differential upregulation of components of the innate immunity and suggests that this inflammatory condition is involved in the aetiology of the disease. Future work will extend the range of analysed immune mediators to chemokines and will also investigate the association of immune markers with indices of obesity to elucidate the relevance of this traditional risk factor for low-grade inflammation.

Type 1 diabetes is an immune-mediated disease with pancreatic infiltration and subsequent beta cell destruction. In this study pancreatic exocrinopathy in non-obese diabetic mice (NOD) was identified using gene subtraction methods (SSH) and macroarray analysis. Female NOD mice were treated with cyclophosphamide for acceleration and synchronization of the disease process at 70 d of age and analysed 10 d later, before the onset of overt diabetes. Extraction of total RNA of pancreas was followed by subtraction using the SSH technique. Pools of cDNA were generated using total RNA from treated and untreated NOD mice. Subtraction of cDNA pools of cyclophosphamide treated mice from cDNA pools of untreated mice resulted in a cDNA library, from which 480 clones were randomly selected. The clones were hybridized against labelled cDNA-probes generated from cyclophosphamide-treated and control NOD mice. Fifty-three clones (11 %) revealed at least twofold differential gene expression after cyclophosphamide treatment. Three of the downregulated genes (amylase, carboxypeptidase and preprotrypsin) were selected for evaluation of macroarray data by quantitative real-time PCR. Analysis of real-time PCR data confirmed suppression of gene expression with highest fold change for amylase (4.68-fold) followed by carboxypeptidase (2.79-fold) and preprotrypsin (2.14-fold). These results lead to the conclusion that inflammation in this animal model of type 1 diabetes is not restricted to pancreatic islets and that subtraction followed by macroarray analysis is capable of identifying genes responsible associated with disease progression.

Interleukin (IL)-4 is a key cytokine in T-helper type 2 (Th2) immune response. We have constructed a dimeric IL-4 molecule consisting of the murine IL-4 and the murine Fc part of IgG2a. We first tested the biological activity of the chimeric protein by in vitro studies using isolated murine spleen cells. IL-4-Ig was found to downregulate LPS-induced IFN-gamma and TNF-alpha production. The immunomodulatory potential of the fusion protein was also analyzed in non-obese diabetic (NOD) mice, an animal model for human type 1 diabetes. Female NOD mice aged 10 weeks were treated once with cyclophosphamide to accelerate and synchronize the progression of insulitis. Treatment with IL-4-Ig induced strong modulation of the pancreatic cytokine balance. Expression was downregulated for both Th1-specific cytokine IFN-gamma and the Th2-specific cytokine IL-10. IL-12p40 expression was only slightly affected. Interestingly, infiltration increased in the islets of IL-4-Ig-treated animals, and therefore did not correlate with the decreased IFN-gamma expression. Hence, IL-4-Ig did not prevent the progression from peri- to intra-insulitis, but suppressed inflammatory cytokine production. In most experiments, the biological activity of IL-4-Ig and IL-4 was comparable. We conclude that treatment with the chimeric protein IL-4-Ig effectively downregulates Th1 responses but simultaneously augments intra-islet infiltration.

Activation of the nuclear enzyme poly(ADP-ribose)polymerase (PARP) is a critical step in beta-cell death in response to exposure with free radicals or other DNA damaging agents. Nicotinamide, a B vitamin, exerts its beta-cell protective action primarily via its ability to block excessive PARP activity. We show here that the isoquinolinone derivative PD128763, a specific PARP inhibitor, provides protection from cell death in islet cells exposed in vitro to nitric oxide or oxygen radical generating compounds or to the beta-cell toxin streptozotocin, at concentrations 100 times less than required for nicotinamide. Furthermore, while the protective action of nicotinamide is rapidly lost after washing of islet cells, the effects of PD128763 are more long lasting. Both compounds had little capacity to rescue damaged islet cells from subsequent lysis. We conclude that the isoquinolinone derivative PD128763 is superior to nicotinamide in enhancing the resistance of beta-cells towards inflammatory attacks.