Cardiac Rehabilitation in German Speaking Countries of Europe-Evidence-Based Guidelines from Germany, Austria and Switzerland LLKardReha-DACH-Part 2.

BACKGROUND: Scientific guidelines have been developed to update and harmonize exercise based cardiac rehabilitation (ebCR) in German speaking countries. Key recommendations for ebCR indications have recently been published in part 1 of this journal. The present part 2 updates the evidence with respect to contents and delivery of ebCR in clinical practice, focusing on exercise training (ET), psychological interventions (PI), patient education (PE). In addition, special patients' groups and new developments, such as telemedical (Tele) or home-based ebCR, are discussed as well. METHODS: Generation of evidence and search of literature have been described in part 1. RESULTS: Well documented evidence confirms the prognostic significance of ET in patients with coronary artery disease. Positive clinical effects of ET are described in patients with congestive heart failure, heart valve surgery or intervention, adults with congenital heart disease, and peripheral arterial disease. Specific recommendations for risk stratification and adequate exercise prescription for continuous-, interval-, and strength training are given in detail. PI when added to ebCR did not show significant positive effects in general. There was a positive trend towards reduction in depressive symptoms for "distress management" and "lifestyle changes". PE is able to increase patients' knowledge and motivation, as well as behavior changes, regarding physical activity, dietary habits, and smoking cessation. The evidence for distinct ebCR programs in special patients' groups is less clear. Studies on Tele-CR predominantly included low-risk patients. Hence, it is questionable, whether clinical results derived from studies in conventional ebCR may be transferred to Tele-CR. CONCLUSIONS: ET is the cornerstone of ebCR. Additional PI should be included, adjusted to the needs of the individual patient. PE is able to promote patients self-management, empowerment, and motivation. Diversity-sensitive structures should be established to interact with the needs of special patient groups and gender issues. Tele-CR should be further investigated as a valuable tool to implement ebCR more widely and effectively.

Evaluation of Aerobic Exercise Intensity in Patients with Coronary Artery Disease and Type 2 Diabetes Mellitus.

(1) Background: Physical activity is recommended in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) to reduce hyperglycemia and cardiovascular risk. Effective aerobic exercise intensity, however, is not well defined. (2) Methods: 60 consecutive patients performed cardiopulmonary exercise testing (CPX) of 30 min duration targeting a respiratory exchange ratio (RER) between 0.85 and 0.95, being strictly aerobic. Plasma glucose (PG) was measured before and after CPX as well as one and two h after exercise. Maximum exercise intensity was evaluated using a standard bicycle exercise test. (3) Results: 50 patients completed the protocol (62 ± 10 years, BMI (body mass index) 30.5 ± 4.9 kg/m2, HbA1c (glycated haemoglobin) 6.9 ± 0.8%, left ventricular ejection fraction 55 ± 8%). Aerobic exercise capacity averaged at 32 ± 21 Watt (range 4-76 Watt) representing 29.8% of the maximum exercise intensity reached. PG before and after CPX was 9.3 ± 2.2 and 7.6 ± 1.7 mmol/L, respectively (p < 0.0001). PG was further decreased significantly at one and two h after exercise to 7.5 ± 1.6 mmol/L and 6.0 ± 1.0 mmol/L, respectively (p < 0.0001 for both as compared to PG before CPX). (4) Conclusions: Aerobic exercise capacity is very low in patients with CAD and T2DM. Exercise at aerobic intensity allowed for significant reduction of plasma glucose. Individual and effective aerobic exercise prescription is possible by CPX.

Effects of aerobic and anaerobic exercise on glucose tolerance in patients with coronary heart disease and type 2 diabetes mellitus.

In patients with coronary heart disease (CHD) and type 2 diabetes mellitus (T2DM), physical activity is strongly advised as nonpharmacological therapy. In general, a moderate aerobic exercise intensity is recommended. It was also proposed, however, that greater intensities tend to yield even greater benefits in HbA1c. Hence, the most appropriate exercise intensity seems not to be established yet. We compared the effect of moderate (aerobic) and vigorous (anaerobic) activity on postprandial plasma glucose. METHODS: In 10 consecutive patients (63 ± 12 years, BMI 28.3 ± 2.6 kg/m2, fasting plasma glucose 6.1 ± 1.2 mmol/l), 2-hour plasma glucose was ≥11.1 mmol/l in the oral glucose tolerance test at rest (OGTT-0). Cardiopulmonary exercise test (CPX) was performed until a respiratory exchange ratio (RER) ≥1.20, beeing anaerobic (CPX-1), followed by OGTT-1. A steady-state CPX of 30-minute duration was performed targeting an RER between 0.90 and 0.95, being aerobic (CPX-2), followed by OGTT-2. RESULTS: In CPX-1, maximum exercise intensity (maxIntensity) averaged at 99 ± 30 Watt and peak oxygen consumption (VO2peak) reached 15.9 ± 2.8 ml/min/kg. In CPX-2, aerobic intensity averaged at 29 ± 9 Watt, representing 31% of maxIntensity and 61% of VO2peak. After aerobic exercise, 2-hour plasma glucose was significantly reduced to an average of 9.4 ± 2.3 mmol/l (P < 0.05). Anaerobic exercise did not reduce 2-hour plasma glucose as compared to OGTT-0 (12.6 ± 2.2 vs 12.6 ± 3.9 mmol/l). CONCLUSION: Aerobic exercise intensity was very low in our patients with CHD and T2DM. Postprandial plasma glucose was reduced only by aerobic exercise. Larger studies on the optimal exercise intensity are needed in this patient cohort.

Life-threatening endocrine emergencies during pregnancy - management and therapeutic features.

Endocrine emergencies during pregnancy may be life-threatening events for both mother and fetus. Besides pregnancy-associated endocrine disorders, several pre-existing endocrinopathies such as type-1 diabetes and Grave's disease or adrenal failure may acutely deteriorate during pregnancy. Since "classical" signs are often modified by pregnancy, early diagnosis and management may be hampered. In addition, laboratory tests show altered physiologic ranges and pharmacologic options are limited while therapeutic goals are mostly tighter than in the non-pregnant patient. Though subclinical endocrinopathies are more frequent and worth consideration due to their related adverse sequelae, this article focuses on endocrine emergencies complicating pregnancy.

Type 1 diabetes in older adults: Comparing treatments and chronic complications in the United States T1D Exchange and the German/Austrian DPV registries.

AIMS: Compare characteristics, therapies and clinical outcomes in older adults with type 1 diabetes in the United States T1D Exchange (T1DX) and German/Austrian Diabetes Patienten Verlaufsdokumentation (DPV) registries. METHODS: Cross-sectional study of adults ≥60years old with type 1 diabetes seen in 2011-2012 in the T1DX (n=1283) and DPV (n=2014) registries. Wilcoxon rank-sum test was used for continuous variables and chi-square test for categorical variables. Adjusted analyses used generalized linear models. RESULTS: Individuals in both registries were similar in body mass index (mean 27kg/m2), percent with obesity (25%) and gender (48% male). In T1DX there was longer diabetes duration (32.3 vs. 28.8years), greater use of antihypertensive medications (including ACE-I and ARBs; 85% vs. 62%), statins (68% vs. 40%), aspirin (77% vs. 21%), insulin pumps (58% vs. 18%), and less smoking (7% vs. 10%); lower adjusted mean LDL-cholesterol (84 vs. 109mg/dL), and lower adjusted mean systolic and diastolic blood pressures (128 vs. 136 and 68 vs. 74mmHg); fewer myocardial infarctions (6% vs. 9% [99% CI of difference, 1% to 5%]), strokes (2% vs. 8% [3% to 7%]), microvascular complications including microalbuminuria (17% vs. 44% [22% to 32%]) but increased depression (16.1% vs. 8.7%). Adjusted mean HbA1c levels were similar (7.5%, 58mmol/mol). CONCLUSIONS: Differences between the registries included greater use of antihypertensives, statins and insulin pumps, and fewer chronic complications in the T1DX. Further research is needed to better understand the role of intensive therapy in improving outcomes in older adults with type 1 diabetes.

Decreased levels of aquaporin-4 in the cerebrospinal fluid of patients with idiopathic intracranial hypertension.

BACKGROUND: Idiopathic intracranial hypertension is characterized by increased intracranial pressure. Its pathogenesis is largely unknown. Aquaporins may play a role in the homeostasis of cerebrospinal fluid. METHODS: We aimed to elucidate the role of aquaporins in idiopathic intracranial hypertension by measuring the level of aquaporin-1 and aquaporin-4 in the cerebrospinal fluid and plasma of 28 patients and 29 controls by enzyme-linked immunosorbent assay. The adipokines leptin and retinol-binding protein 4 were also measured. RESULTS: We found a reduction in aquaporin-4 in the cerebrospinal fluid of patients. Leptin levels were increased in the cerebrospinal fluid and plasma of patients and were correlated with weight, body mass index and body fat. There was no difference between patients and controls in the levels of aquaporin-1 and retinol-binding protein 4. CONCLUSION: Our data suggest that an imbalance of aquaporin-4 in the cerebrospinal fluid of patients with idiopathic intracranial hypertension may contribute to the pathogenesis of this disorder.

Risk of severe hypoglycemia in sulfonylurea-treated patients from diabetes centers in Germany/Austria: How big is the problem? Which patients are at risk?

BACKGROUND: We investigated the rate of severe hypoglycemic events and confounding factors in patients with type 2 diabetes treated with sulfonylurea at specialized diabetes centers, documented in the German/Austrian DPV-Wiss database. METHODS: Data from 29 485 sulfonylurea-treated patients were analyzed (median[IQR] age 70.8[62.2-77.8] years, diabetes duration 8.2[4.3-12.8] years). The primary objective was to estimate the event rate of severe hypoglycemia (requiring external help, causing unconsciousness/coma/convulsion and/or emergency hospitalization). Secondary objectives included exploration of confounding risk factors through group comparison and Poisson regression. RESULTS: Severe hypoglycemic events were reported in 826(2.8%) of all patients during their most recent year of sulfonylurea treatment. Of these, n = 531(1.8%) had coma, n = 501(1.7%) were hospitalized at least once. The adjusted event rate of severe hypoglycemia [95%CI] was 3.9[3.7-4.2] events/100 patient-years (coma: 1.9[1.8-2.1]; hospitalization: 1.6[1.5-1.8]). Adjusted event rates by diabetes treatment were 6.7 (sulfonylurea + insulin), 4.9 (sulfonylurea + insulin + other OAD), 3.1 (sulfonylurea + other OAD) and 3.8 (sulfonylurea only). Patients with ≥1 severe event were older (p < 0.001) and had longer diabetes duration (p = 0.020) than patients without severe events. Participation in educational diabetes-programs and indirect measures of insulin-resistance (increased BMI, plasma-triglycerides) were associated with fewer events (all p < 0.001). Impaired renal function was common (n = 3113 eGFR; ≤30 mL/min) and associated with an increased rate of severe events (≤30 mL/min: 7.7; 30-60 mL/min: 4.8; >60 mL/min: 3.9). CONCLUSIONS: These real-life data showed a rate of severe hypoglycemia of 3.9/100 patient-years in sulfonylurea-treated patients from specialized diabetes centers. Higher risk was associated with known risk factors including lack of diabetes education, older age and decreased eGFR but also with lower BMI and lower triglyceride levels, suggesting that sulfonylurea treatment in those patients should be considered with caution.

HbA1c variability as an independent risk factor for diabetic retinopathy in type 1 diabetes: a German/Austrian multicenter analysis on 35,891 patients.

OBJECTIVE: This study aimed to analyze the effect of HbA1c variability on the occurrence of diabetic retinopathy in type 1 diabetes patients. PATIENTS AND METHODS: 35,891 patients with childhood, adolescent or adult onset of type 1 diabetes from a large multicentre survey, the German/Austrian prospective documentation system (DPV), were analysed. Cox proportional hazard models were used to examine whether intra-individual HbA1c variability expressed as variation coefficient is an independent risk factor for the occurrence of diabetic retinopathy. RESULTS: Kaplan-Meier curves stratified by median HbA1c and variation coefficient revealed that retinopathy-free survival probability is lower when both median HbA1c and HbA1c variability are above the 50th percentile. Cox regression models confirmed this finding: After adjustment for age at diabetes onset, gender and median HbA1c, HbA1c variability was independently associated with the occurrence of diabetic retinopathy. Time-covariate interactions used to model non-proportionality indicated an effect decreasing with duration of diabetes for both median HbA1c and HbA1c variability. Predictive accuracy increased significantly when adding HbA1c variability to the Cox regression model. CONCLUSIONS: In patients with type 1 diabetes, HbA1c variability adds to the risk of diabetic retinopathy independently of average metabolic control.

Insulin inhibits caspase-3 activity in human renal tubular epithelial cells via the PI3-kinase/Akt pathway.

Apoptotic mechanisms in proximal renal tubular epithelial cells (PTEC) are crucial in the pathogenesis of acute kidney injury. We investigated whether insulin alters anti-apoptotic signalling in human PTEC. Cells were deprived of insulin for 0, 24 or 48 h and then stimulated with insulin for 0 or 5 min. Apoptosis was induced by camptothecin incubation. Insulin receptor kinase (IR-kinase) activity, phosphorylation of insulin receptor substrate-1 (IRS-1), IRS-1-associated PI3-kinase (p85), Ser(273)-phosphorylation of Akt and caspase-3 activity (C3-activity) were determined. Insulin stimulation increased the activity of IR-kinase, IRS-1 phosphorylation, p85 association with IRS-1 and Ser(273)-phosphorylation of Akt by at least 250%, respectively and decreased the C3-activity by 45% (p < 0.01, respectively). Deprivation of insulin for 24 and 48 h reduced basal and insulin-stimulated IR-kinase activity, IRS-1 phosphorylation, p85 association with IRS-1 and Ser(273)-phosphorylation of Akt by 30-40% and increased C3-activity by 15-20% (p < 0.01, respectively). Incubation with camptothecin increased C3-activity by 250-300% (p < 0.001). Subsequent insulin stimulation reversed the camptothecin induced increase of C3-activity. Our data indicate that apoptosis in PTEC is regulated by the insulin dependent PI3-kinase/Akt pathway. The enhancement of tubular-specific cell survival signals might represent a potential therapeutic tool for the protection of renal function in acute kidney injury.

Calpain inhibition impairs glycogen syntheses in HepG2 hepatoma cells without altering insulin signaling.

Calpains are a family of non-lysosomal cytoplasmatic cysteine proteases. Since calpain 10 (CAPN10), a member of the calpain family of proteases, has been found to represent a putative diabetes susceptibility gene, it was argued that calpains may be involved in the development of type 2 diabetes. The functional role of calpains in insulin signaling and/or insulin action is, however, not clear. We investigated the effects of the calpains 1 and 2 inhibitor PD151746 on insulin signaling and insulin action in human hepatoma G2 cells (HepG2). HepG2 cells were incubated without (-PD) or with (+PD) 5.33 micromol/l PD151746 for different times and then stimulated with 100 nmol/l insulin for 0 (t(0)), 5 (t(5)), 15 (t(15)), 30 (t(30)), 45 (t(45)), and 60 (t(60)) min. After solubilization of the cells, insulin receptor kinase activity, tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), IRS-1-associated phosphatidylinositol-3 kinase (PI3-kinase), PI3-kinase activity, Thr(308) phosphorlyation of Akt, amount of protein tyrosine phosphatase-epsilon (PTPepsilon), and glycogen synthase activity were determined. Incubation with PD151746 resulted in a significant reduction of insulin-stimulated glycogen synthesis compared with cells not pre-incubated with the calpain inhibitor (-PD: t(0), 4.90 +/- 1.20%; t(5), 5.90 +/- 1.02%; t(15), 5.29 +/- 0.95%; t(30), 5.60 +/- 1.10%; t(45), 5.52 +/- 0.90%; t(60), 5.67 +/- 0.97%;+PD: t(0), 4.56 +/- 1.10%; t(5), 6.16 +/- 1.05%; t(15), 7.52 +/- 1.09%; t(30), 7.68 +/- 1.10%; t(45), 8.28 +/- 0.89%; t(60), 7.69 +/- 0.98%; P < 0.05). Incubation with PD151746 significantly increased the protein amount of PTPepsilon in the cells after 12 h (-PD: t(1), 0.85 +/- 0.18 RU (Relative unit); t(8), 0.87 +/- 0.18 RU; t(12), 0.9 +/- 0.13 RU; +PD: t(1), 0.92 +/- 0.21 RU; t(8), 1.1 +/- 0.15 RU; t(12), 1.34 +/- 0.16 RU; P < 0.05). Calpain inhibition with PD151746 had no effect on the insulin stimulation of the investigated insulin signaling parameters. These results in HepG2 cells suggest that calpains play a role in the hepatic regulation of insulin-stimulated glycogen synthesis independent of the PI3-kinase/Akt signaling pathway.

[Effects of various HIV protease inhibitors on function of rat insulinoma cells].

OBJECTIVE: To investigate the effects of various HIV protease inhibitors on the function of pancreatic beta-cells. METHODS: Rat insulinoma INS-1 cells were incubated with different concentrations of ritonavir or amprenavir for 48 h and stimulated with 20 mmol/L D-glucose for 30 min. The rate of insulin release was measured in the supernatant by ELISA, normalized to cellular DNA contents. Cells were counted with trypan blue and MTT test were determined to evaluate the effect of protease inhibitors on cell viability. RESULT: Ritonavir treatment significantly decreased baseline insulin release and glucose-stimulated insulin release in a dose-dependent manner (r=-0.861, -0.839, both P<0.01). For 10 micromol/L of ritonavir, the decrease rate of baseline insulin secretion and glucose-stimulated insulin secretion was 46% and 47%, respectively. Amprenavir had no effect on the rate of insulin release. CONCLUSION: Various HIV protease inhibitors present different effect on the insulin release of pancreatic beta-cells.

Simvastatin acutely reduces myocardial reperfusion injury in vivo by activating the phosphatidylinositide 3-kinase/Akt pathway.

Long-term pretreatment with statins reduces myocardial injury after acute ischemia and reperfusion by increasing the expression of endothelial nitric oxide synthase (eNOS). We hypothesized that statins may act rapidly enough to protect the myocardium from ischemia/reperfusion injury when given right at the beginning of the reperfusion period and tried to delineate the role of PI 3-kinase/Akt pathway in early eNOS activation. Activated simvastatin was given intravenously 3 minutes before starting the reperfusion after temporary coronary artery occlusion (CAO) in anaesthetized rats. Simvastatin significantly increased myocardial PI 3-kinase activity, AktSer473, and eNOSSer1177 phosphorylation and reduced infarct size by 42%. Infarct size reduction as well as activation of PI 3-kinase/Akt/eNOS pathway were not observed in rats co-treated with the PI 3-kinase inhibitor wortmannin. Contribution of eNOS was further delineated using the NOS inhibitor L-NAME, which could completely block cardioprotection by the statin. In summary, simvastatin acutely reduces the extent of myocardial necrosis in normocholesterolemic rats in an NO- dependent manner by activating the PI 3-kinase/Akt pathway. This is the first study demonstrating short-term cardioprotective effects of simvastatin in an in vivo model of ischemia/reperfusion.

[Impairment of IRS-2 signaling in rat insulinoma INS-1 cells by nelfinavir].

OBJECTIVE: To investigate whether HIV-1 protease inhibitor nelfinavir alters the insulin stimulated phosphorylation of insulin signaling parameters in rat insulinoma INS-1 cells. METHODS: INS-1 cells were incubated with nelfinavir for 48 h and stimulated with 100 nmol/L insulin for 2 min. Immunoprecipitation and Western blot analysis of the insulin stimulated insulin receptor substrate (IRS)-1,-2 and Akt-Thr(308) phosphorylation were performed on cell lysates. Cytotoxic effects of nelfinavir were measured by cell count with trypan blue and MTT reduction test. RESULT: Nelfinavir decreased insulin stimulated phosphorylation of IRS-2 and Akt-Thr(308) in a dose-dependent manner; for 10 micromol/L of nelfinavir, the decrease was 52% and 55%, respectively. CONCLUSION: Treatment with nelfinavir might impair IRS-2-mediated signaling in pancreatic beta cells.

First molecular identification of human Dobrava virus infection in central Europe.

Viral RNA was amplified by reverse transcription-PCR from a patient suffering from hemorrhagic fever with renal syndrome (HFRS) in Germany. The virus strain could be assigned to the Dobrava hantavirus (DOBV). This is the first molecular identification of human infection by DOBV in central Europe and the first proof that a virus strain related to the DOBV-Aa lineage, carried by Apodemus agrarius rodents, is able to cause HFRS.

[The HIV protease inhibitor-induced insulin resistance syndrome]. / Das HIV-Proteasehemmer-induzierte Insulinresistenzsyndrom.

BACKGROUND: HIV protease inhibitors improve the morbidity and mortality of HIV infection, however, this therapy also initiates insulin resistance that is associated with an increasing development of disturbances in glucose and lipid metabolism. Similar to the common insulin resistance syndrome, treated patients also suffer from an increased cardiovascular risk. PATHOGENESIS: Studies based on animal or cell models suggest that HIV protease inhibitors induce short-term effects on GLUT4 glucose transport and longterm effects on insulin signal transduction. CONCLUSION: Therapy with HIV protease inhibitors should include regular monitoring of metabolic alterations and cardiovascular damage. Particularly patients with genetic or traditional risk factors for type 2 diabetes should be monitored frequently.

Recurrent hypoglycaemic episodes in a patient with Type 2 diabetes under fibrate therapy.

The causal relationship between dyslipidaemia and insulin resistance, two central components of the metabolic syndrome, is still poorly understood. We describe a 76-year-old patient with Type 2 diabetes mellitus and pronounced hypertriglyceridaemia. The patient required a total insulin dose of 148 IU/day for decent glycaemic control. The addition of the fibrate gemfibrozil to her medication resulted in a remarkable reduction in triglyceride levels (from 31.7 to 7.1 mmol/l). Consequently, the patient experienced recurrent hypoglycaemic episodes concurrent with a massive reduction in insulin requirements. Eventually, the insulin dosage was reduced by more than 65% to 48 IU/day, and HbA1c levels dropped from 9% to 6.5% over a period of 5 months without alterations in lifestyle, diet, body weight, or any other blood chemical values. Thus, this case report illustrates that treatment of hypertriglyceridaemia can reduce insulin requirements and harbours the risk of hypoglycaemia in patients with insulin-treated Type 2 diabetes mellitus.

HIV-1 protease inhibitor nelfinavir decreases insulin secretion from rat insulinoma INS-1 cells / 中华内分泌代谢杂志

Rat INS-1 cells treated with HIV-1 protease inhibitor Nelfinavir for 48 h showed that both basal and glucose-stimulated insulin secretion decreased, the latter was more marked, suggesting that long-term treatment with Nelfinavir may impair ?-cell function.