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ZUSAMMENFASSUNGDie Therapie mit SGLT-2-Inhibitoren bei Patienten mit Diabetes mellitus nimmt aufgrund der positiven Ergebnisse auf kardiovaskuläre Ereignisse zu. Dadurch kommt es auch zu einer Zunahme der unerwünschten Nebenwirkungen. Eine seltene, aber lebensbedrohliche Nebenwirkung ist die atypische oder euglykämische diabetische Ketoazidose. Diese Nebenwirkung wird in allen Präparaten dieser Substanzklasse beschrieben. Statistisch ist es eine seltene Nebenwirkung mit einer Inzidenzrate von 0,1–2,2 %. Typische Symptome sind unter anderem Übelkeit, Bauchschmerzen, Erbrechen, vermehrter Durst und Verwirrtheitszustände. Als auslösende Faktoren werden reduzierte Nahrungsaufnahme, Infektionen, reduzierte Insulindosis und größere chirurgische Eingriffe angesehen. Bei Verdacht auf eine solche atypische diabetische Ketoazidose muss sofort ärztliche Hilfe in Anspruch genommen werden.

Breathlessness or dyspnea is a frequent symptom in patients with diabetes and the first disease which has to be excluded is the coronary heart disease. However, previous epidemiological studies have shown that patients with diabetes mellitus have an increased risk for fibrotic pulmonary diseases, such as the idiopathic pulmonary fibrosis (IPF). Recent studies were able to show that patients with newly diagnosed type 2 diabetes have impaired pulmonary oxygen consumption and over 26 % of patients with long-term type 2 diabetes showed restrictive lung function with fibrotic interstitial lung diseases. Especially patients with type 2 diabetes and nephropathy had an 8-fold higher risk for lung diseases. This is not surprising since the pathomechanisms of pulmonary fibrosis and diabetic complications have much in common: reactive oxygen species induce DNA-damage with consecutive activation of inflammatory cytokines which induce fibrotic remodeling of the tissue. This leads us to the suggestion that patients with diabetes, albuminuria and breathlessness should be examined for interstitial lung disease on regular basis. However, data regarding the natural course of diabetic pneumopathy and therapeutic approaches are still missing. Small intervention studies with IPF-patients could show that sports and physical activity were able to stabilize the disease progression.

Radioiodine refractoriness in differentiated thyroid cancer remains an unsolved therapeutic problem. Response to retinoids might depend on specific genetic markers. In this retrospective analysis, associations between BRAF V600E and clinical outcomes after redifferentiation with retinoic acid (RA) and radioiodine therapy (RIT) were investigated. Thirteen patients with radioiodine-refractory (RAI-R) papillary thyroid cancer (PTC) were treated with 13-cis-RA followed by iodine-131 treatment at the Department of Endocrinology, Heidelberg University Hospital, Heidelberg, Germany. DNA sequencing was performed in formalin-fixed paraffin-embedded tissue. Clinical outcome parameters were tumor size, thyroglobulin, and radioiodine uptake in correlation to mutational status. Differences of each parameter were compared before and after RA/RIT. Initial response showed no difference in patients with BRAF V600E compared to patients with wild type. However, after a median follow-up of 2 and a half years, 2 out of 3 patients with BRAF V600E showed response compared to 5 out of 9 with wild type under consideration of all 3 parameters. In this small cohort, more RAI-R PTC patients with BRAF V600E receiving redifferentiation therapy showed response. Verification in a larger study population analyzing mutational status in patients with RAI-R PTC might be helpful to identify patients where redifferentiation therapy might lead to an improved outcome.

There is growing evidence that reactive metabolites, such as reactive oxygen species and dicarbonyls contribute to diabetic complications. Formation, accumulation, and detoxification of these metabolites are controlled by several enzymes, some of which have genetically determined levels of expression or function. This review not only gives an overview of the different SNPs studied in patients with diabetes mellitus type 1 and type 2, but in addition attempts to bridge the gap between a genetic study and clinical use. Therefore, not only the results of the studies are reviewed, but also their use in identification of subgroups where an increased or decreased risk for a diabetic complication is described, as well as their use in developing novel therapeutic options based on understanding the contribution of an enzyme to a given complication.

Comprehensive diabetes treatment has been shown to reduce quality of life in diabetic patients. However, there is evidence to suggest that group singing can have positive effects on quality of life in various clinical settings. In this randomized controlled pilot study, the effect of singing as a therapy to reduce stress and improve quality of life was investigated in insulin-dependent diabetic patients, undergoing a lifestyle intervention program. Patients from the singing group felt less discontented following treatment. This effect, however, was lost after 3 months. No effect on serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels could be seen when comparing the singing group with the control group, although reduced levels of ACTH and cortisol 3 days after treatment could be found and were still present after 3 months within the group of patients who undertook singing as a therapy. Singing led to an increase in bodyweight, which interestingly had no effect on glucose control or methylglyoxal levels. Therefore, singing during a lifestyle intervention program for insulin-dependent diabetic patients had a short lasting and weak effect on patients' mood without affecting glucose control, but no significant effect on stress related hormones.

Current guidelines for the treatment of type 2 diabetes focus on pharmacological treatment of glucose and cardio-vascular risk factors. The aim of this prospective randomized controlled intervention study was to examine the effects of a psychosocial intervention on clinical endpoints and risk factors in patients with type 2 diabetes and early diabetic kidney disease.110 patients were randomized to receive an 8-week mindfulness-based stress reduction (MBSR) training (n = 53) compared to standard care (n = 57). The study was carried out open-labelled and randomization was performed computer-generated in a 1:1 ratio. Primary outcome of the study was the change in urinary albumin excretion (albumin-creatinine-ratio, ACR); secondary outcomes were metabolic parameters, intima media thickness (IMT), psychosocial parameters and cardiovascular events.89 patients (42 in control group and 47 in intervention group) were analysed after 3 years of follow-up. After 1 year, the intervention group showed a reduction of ACR from 44 [16/80] to 39 [20/71] mg/g, while controls increased from 47 [16/120] to 59 [19/128] mg/g (p = 0.05). Parallel to the reduction of stress levels after 1 year, the intervention-group additionally showed reduced catecholamine levels (p0.05), improved 24 h-mean arterial (p0.05) and maximum systolic blood pressure (p0.01), as well as a reduction in IMT (p0.01). However, these effects were lost after 2 and 3 years of follow-up.This is the first study to show that a psychosocial intervention improves cardiovascular risk factors in high risk type 2 diabetes patients. Trial-Registration: NCT00263419 http://clinicaltrials.gov/ct2/show/NCT00263419 TRIAL REGISTRATION: clinicaltrials.gov-Identifier: NCT00263419.

The established marker for tubular damage, urinary n-acetyl-beta-d-glucosaminidase is significantly increased in type 1 and 2 diabetes patients and is related to albuminuria and other diabetic complications. In this cross sectional study of type 2 diabetes patients with a history of albuminuria, we studied the relationship between excretion of n-acetyl-beta-d-glucosaminidase in urine and diabetic neuropathy.160 type 2 diabetes patients were screened for diabetic peripheral neuropathy and cardiovascular autonomic neuropathy. N-acetyl-beta-d-glucosaminidase excretion was detected in 24 h urine samples.Urinary excretion of n-acetyl-beta-d-glucosaminidase correlated significantly with -glucose control (fasting glucose r=0.18; p=0.04; HbA1c r=0.20; p=0.02) and urine albumin excretion (r=0.22; p=0.01). Binary regression analyses showed that increased urinary n-acetyl-beta-d-glucosaminidase concentration is an independent predictor for presence of clinical symptoms of peripheral neuropathy (OR 1.8 [95%CI 1.2-2.74] and vibration deficiency [OR 1.7; 95% CI 1.2-2.66]. There was also a significant negative association between urinary n-acetyl-beta-d-glucosaminidase and E/I-Ratio (r=-0.21, p

Introduction: Bariatric surgery results in high remission rates of type 2 diabetes mellitus (T2DM) in obese patients. We have previously shown that Roux-en-Y gastric bypass (RYGB) improves diabetic neuropathy, likely due to a reduction in nitrosative stress. The purpose of this study was to investigate whether RYGB is also able to improve diabetic nephropathy. Methods: Twenty consecutive patients with a body mass index (BMI) between 25 – 35 kg/m2 and a poorly controlled, insulin-dependent T2DM were enrolled. All patients were treated with a standardized RYGB. Changes in serum creatinin levels, urinary albumin excretion and total serum adiponectin were collected. High-molecular weight (HMW) adiponectin as a sensitive marker for nephropathy was measured in serum and urinary samples using ELISAs. Data are presented as mean ± SEM. Results: Over the 24 month follow-up period, serum creatinin levels decreased within 3 months from 0.82 ± 0.05 mg/dl to 0.67 ± 0.03 mg/dl (p < 0.05) and remained at these levels. The urinary albumin/creatinin ratio started decreasing within 3 months and reached significantly lower levels after 6 months (2.38 ± 0.86 mg/mmol to 1.15 ± 0.17 mg/mmol, p < 0.05). Similarly, urinary HMW adiponectin decreased over the 24 month follow-up period (0.185 ± 0.074 ng/ml to 0.074 ± 0.014 ng/ml, p < 0.05). In contrast, total serum adiponectin showed a significant increase over the same period whereas serum HMW adiponectin did not change. Conclusion: RYGB appears to improve microvascular complications of T2DM such as subclinical nephropathy and neuropathy in non-severely obese patients. Further research should investigate by which mechanisms diabetic nephropathy is improved in these patients.

Introduction: Clinical trials have shown that the number of circulating endothelial progenitor cells (EPCs) correlates with cardiovascular risk factors and is an independent predictor of cardiovascular death. We were previously able to show that insulin stimulates the in vitro outgrowth of EPCs. Therefore we studied whether treating type 2 diabetic patients with insulin affects circulating EPCs or vascular function. Study design: 55 patients with type 2 diabetes mellitus on oral antidiabetics were randomized in 3 groups. For the following 4 months patients were treated additionally with insulin glargine (n = 20), NPH insulin (n = 22) or with a combination of oral antidiabetics (n = 13). Data for EPC- mobilization, EPC-differentiation, intima-media thickness (IMT) and HbA1c were documented/performed at the entry visit (visit 1); after 4 weeks (visit 2) and after 4 months (visit 3). Results: HbA1c levels were similarly high in all 3 groups at baseline (p = 0.71). HbA1c was equally decreased after 4 months in all 3 arm groups independently from the form of treatment without showing any statistical significance between the groups (p = 0.61). FACS analysis showed no significant difference between the 3 groups concerning the mobilization of EPCs 4 weeks (p = 0.96) and 4 months (p = 0.55) after treatment. However the number of EPCs as detected by ex-vivo outgrowth was in both insulin groups at visit 3 significantly higher than the oral group (p = 0.013). A statistically significant decrease of IMT from 0.80 mm (± 0.14) at visit 1 to 0.76 mm (± 0.12) at visit 3 could be observed in all patients (p = 0.03). Summary: The study shows that a 4-month treatment with insulin glargine or NPH insulin significantly increases the differentiation of EPCs on patients with type 2 diabetes mellitus, compared to those treated only with oral antidiabetics. Besides it could be shown that all groups achieved a significant decrease of HbA1c as well as a significant reduction of the intima-media thickness.