Heart failure among people with Type 2 diabetes mellitus: real-world data of 289 954 people from a diabetes database.

AIM: Comparing people with Type 2 diabetes mellitus with and without heart failure in terms of metabolic control, therapeutic regimen and comorbidities. METHODS: The Prospective Diabetes Registry (DPV) is a longitudinal documentation system for demographics, medical care and outcome in people with diabetes mellitus. It consists of follow-up data from people with diabetes mellitus who have agreed to be recorded in the registry. Clinical data are submitted by general practitioners, specialists and clinics throughout Germany and Austria. Some 289 954 people with Type 2 diabetes mellitus (years 2000 to 2015) were analysed using demographic statistics and adjustment for confounders based on linear and logistic regression analysis. RESULTS: People with Type 2 diabetes mellitus (ICD code: E11) and heart failure (ICD code: I50) (N = 14 723) were older, more often women and presented with longer diabetes duration compared with those without heart failure. After adjustment for age, gender and diabetes duration, people with heart failure showed lower HbA1c , higher BMI and more intense insulin therapy. Analysis revealed that people with heart failure were more often treated with insulin, and more frequently received anti-hypertensives and lipid-lowering medication. They presented with lower systolic and diastolic BP. People with heart failure more frequently showed a history of comorbidities. CONCLUSION: Heart failure is common in diabetes mellitus, but the prevalence in the DPV is lower frequent than expected. The reason for improved metabolic control in heart failure may be intensified therapy with insulin, lipid-lowering medication and anti-hypertensives in this cohort.

Beneficial Metabolic Effects of Duodenal Jejunal Bypass Liner for the Treatment of Adipose Patients with Type 2 Diabetes Mellitus: Analysis of Responders and Non-Responders.

Implantation of a duodenal-jejunal endoluminal bypass liner (DJBL) has shown to induce weight loss and to improve metabolic parameters. DJBL is a reversible endoduodenal sleeve mimicking duodenal bypass while lacking risks and limitations of bariatric surgery.Effects on metabolic control, body mass parameters, appetite regulation, glucose tolerance, organ health, and lipid profile were determined in 16 morbidly overweight patients with type 2 diabetes mellitus. In addition, relevant hormones (leptin, ghrelin, gastric inhibitory peptide, glucagon-like peptide, and insulin) were measured by enzyme-linked immunosorbent assay (ELISA) and chemiluminescent microparticle immunoassay (CMIA) at 0, 1, 32, and 52 weeks post-implant following a mixed meal tolerance test. Lipoprotein subclasses were analysed by proton nuclear magnetic resonance (1H NMR) spectrometry. DJBL provoked weight loss, a decrease in fat mass, and an improvement in insulin resistance and hepatic function in most but not all of the patients, but in the long term did not increase gut hormone fasting levels pointing to a combined effect of more than gut parameters alone. Lipidome analysis was done in 10 patients, allowing classification to responders and non-responders by reduction of sLDL-p subfraction; and to further analyse the atherogenic profile. Responders showed an overall more pronounced effect regarding improvement of HbA1c, BMI, and HOMA index.Implantation of a DJBL in obese type 2 diabetes patients does not per se lead to an improvement of the metabolic situation. Further analyses including larger cohorts have to be performed to identify responding patients, to better treat non-responders and to analyse the key effectors.

[Diabetes, prediabetes and cardiovascular risk]. / Diabetes, Prädiabetes und kardiovaskuläres Risiko.

Cardiovascular diseases continue to be the mainstay in morbidity and mortality in modern society with diabetes mellitus being a known risk factor for coronary artery disease, heart failure and vascular events. Most patients present with a combination of hypertension, dyslipoproteinaemia and (pre)diabetic metabolism potentiating the risk. From the perspective of organ damage two of three patients with coronary artery disease present with impaired glucose metabolism. In case of myocardial infarction 25-28% of patients do not present with impaired glucose metabolism. Women are more often affected than men and exhibit a more severe outcome, if diagnoses of vascular events and diabetes occur in parallel. Atrial fibrillation and heart failure are significantly associated with diabetes and significantly confer to the overall prognosis. Epidemiologically, the risk for vascular events is closely associated with the glucose burden of the affected patient.

Effects of n-3 polyunsaturated fatty acids (PUFAs) on circulating adiponectin and leptin in subjects with type 2 diabetes mellitus.

Recent evidence suggests that omega-3 polyunsaturated fatty acids [n-3 PUFAs: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], improve insulin sensitivity in humans. In a double-blind, placebo-controlled, randomized, crossover study, we investigated the effects of EPA/DHA on paraoxonase-1 activity as well as fasting and postprandial levels of circulating adiponectin and leptin in 34 subjects with type 2 diabetes mellitus who received daily for 6 weeks either 2 g purified EPA/DHA or olive oil (placebo), separated by a 6 weeks washout. At the end of each treatment, measurements were performed in fasting state and 2, 4, and 6 h following a standardized high-fat meal (600 kcal). No significant differences in fasting and postprandial circulating adiponectin, leptin, and paraoxonase-1 activity were seen between n-3 PUFAs and placebo. Our data do not support an insulin sensitizing effect of n-3 PUFAs by means of influencing circulating adipocytokines in this population. Clinical Trial Register Number: NCT00328536.

Methylglyoxal impairs GLUT4 trafficking and leads to increased glucose uptake in L6 myoblasts.

Methylglyoxal (MG) is a highly reactive dicarbonyl compound derived mainly from glucose degradation pathways, but also from protein and fatty acid metabolism. MG modifies structure and function of different biomolecules and thus plays an important role in the pathogenesis of diabetic complications. Hyperglycemia-associated accumulation of MG might be associated with generation of oxidative stress and subsequently insulin resistance. Therefore, the effects of MG on insulin signaling and on translocation of glucose transporter 4 (GLUT4) were investigated in the rat skeletal muscle cell line L6-GLUT4myc stably expressing myc-tagged GLUT4. Twenty four-hour MG treatment resulted in elevated GLUT4 presentation on the surface of L6 myoblasts and in an increased uptake of glucose even without insulin stimulation. Exogenously added MG neither effected IRS-1 expression nor IRS-1 phosphorylation. A decreased expression of Akt1 but not Akt2 and concomitantly increased apoptosis were detected following MG treatment. To exclude that oxidative stress caused by MG treatment leads to increased GLUT4 translocation, effects of pretreatment with 2 antioxidants were investigated. The antioxidant and MG scavenger NAC prevented the MG-induced GLUT4 translocation. In contrast, tiron, a well-known antioxidant that does not exert MG-scavenger function, had no impact on MG-induced GLUT4 translocation supporting the hypothesis of a direct effect of MG on GLUT4 trafficking. In conclusion, prolonged treatment with MG augments GLUT4 level on the surface of L6 myoblasts, at least in part through a higher translocation of GLUT4 from the intracellular compartment as well as a reduction of GLUT4 internalization, resulting in increased glucose uptake.

A randomized, double-blind, crossover, placebo-controlled trial of 6 weeks benfotiamine treatment on postprandial vascular function and variables of autonomic nerve function in Type 2 diabetes.

AIMS: In a pilot study we suggested that benfotiamine, a thiamine prodrug, prevents postprandial endothelial dysfunction in people with Type 2 diabetes mellitus. The aim of this study was to test these effects in a larger population. METHODS: In a double-blind, placebo-controlled, randomized, crossover study, 31 people with Type 2 diabetes received 900 mg/day benfotiamine or a placebo for 6 weeks (with a washout period of 6 weeks between). At the end of each treatment period, macrovascular and microvascular function were assessed, together with variables of autonomic nervous function in a fasting state, as well as 2, 4 and 6 h following a heated, mixed test meal. RESULTS: Participants had an impaired baseline flow-mediated dilatation (2.63 ± 2.49%). Compared with the fasting state, neither variable changed postprandially following the placebo treatment. The 6 weeks' treatment with high doses of benfotiamine did not alter this pattern, either in the fasting state or postprandially. Among a subgroup of patients with the highest flow-mediated dilatation, following placebo treatment there was a significant postprandial flow-mediated dilatation decrease, while this effect was attenuated by benfotiamine pretreatment. CONCLUSIONS: In people with Type 2 diabetes and markedly impaired fasting flow-mediated dilatation, a mixed test meal does not further deteriorate flow-mediated dilatation or variables of microvascular or autonomic nervous function. Because no significant deterioration of postprandial flow-mediated dilatation, microvascular or autonomic nervous function tests occurred after placebo treatment, a prevention of the postprandial deterioration of these variables with benfotiamine was not feasible.

Autologous stem cell therapy in the treatment of limb ischaemia induced chronic tissue ulcers of diabetic foot patients.

BACKGROUND AND AIM: Despite improvements in surgical revascularisation, limitations like anatomical factors or atherosclerosis limit the success of revascularisation in diabetic patients with critical limb ischaemia. Stem cells were shown to improve microcirculation in published studies. The aim of this study was to evaluate safety, feasibility and efficacy of transplantation of bone marrow derived cellular products regarding improvement in microcirculation and lowering of amputation rate. METHODS: Bone marrow mononuclear cells (BMCs) in comparison with expanded bone marrow cells enriched in CD90+ cells ('tissue repair cells', TRCs) were used in the treatment of diabetic ulcers to induce revascularisation. Diabetic foot patients with critical limb ischaemia without option for surgical or interventional revascularisation were eligible. Parameters examined were ABI, TcPO(2) , reactive hyperaemia and angiographic imaging before and after therapy. RESULTS: Of 30 patients included in this trial, 24 were randomised to receive either BMCs or TRCs. The high number of drop-outs in the control group (4 of 6) led to exclusion from evaluation. A total of 22 patients entered treatment; one patient in the TRC group and two in the BMC group did not show wound healing during follow up, one patient in each treatment group died before reaching the end of the study; one after having achieved wound healing (BMC group), the other one without having achieved wound healing (TRC group). Thus, 18 patients showed wound healing after 45 weeks. The total number of applicated cells was 3.8 times lower in the TRC group, but TRC patients received significantly higher amounts of CD90+ cells. Improvement in microvascularisation was detected in some, but not all patients by angiography, TcPO(2) improved significantly compared with baseline in both therapy groups. CONCLUSION: The transplantation of BMCs as well as TRCs proved to be safe and feasible. Improvements of microcirculation and complete wound healing were observed in the transplant groups.

Oral glucose tolerance test and HbA1c for diagnosis of diabetes in patients undergoing coronary angiography: [corrected] the Silent Diabetes Study.

AIMS/HYPOTHESIS: The primary aim of this study was to compare the results of HbA(1c) measurements with those of an OGTT for early diagnosis of 'silent diabetes' in patients with coronary artery disease (CAD) undergoing angiography without prediagnosed diabetes. A secondary aim was to investigate the correlation between the extent of CAD and the glycaemic status of the patient. METHODS: Data from 1,015 patients admitted for acute (n = 149) or elective (n = 866) coronary angiography were analysed. Patients with known diabetes were excluded from the study. Using the OGTT results, patients were classified as having normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes. According to the results of the HbA(1c) measurements, patients were classified into three groups: normal (HbA(1c) <5.7% [<39 mmol/mol]), borderline (HbA(1c) 5.7-6.4% [39-47 mmol/mol]) and diabetes (HbA(1c) ≥6.5% [≥48 mmol/mol]). RESULTS: Based on the OGTT, 513 patients (51%) were classified with NGT, 10 (1%) with IFG, 349 (34%) with IGT and 149 (14%) were diagnosed with diabetes. According to HbA(1c) measurements, 588 patients (58%) were classified as normal, 385 (38%) as borderline and 42 (4%) were diagnosed with diabetes. The proportion of patients with IGT and diabetes increased with the extent of CAD (IGT ρ = 0.14, p < 0.001, diabetes ρ = 0.09, p = 0.01). No differences in HbA(1c) were seen among the groups with different extents of CAD (p = 0.652). CONCLUSIONS/INTERPRETATION: An OGTT should be performed routinely for diagnosis of diabetes in patients with CAD undergoing coronary angiography, since HbA(1c) measurement alone appears to miss a substantial proportion of patients with silent diabetes. A limitation of the study is that the OGTT was not performed before the angiography.

Heat shock protein 27 modification is increased in the human diabetic failing heart.

Chronic conditions like diabetes mellitus (DM) leading to altered metabolism might cause cardiac dysfunction. Hyperglycemia plays an important role in the pathogenesis of diabetic complications including accumulation of methylglyoxal (MG), a highly reactive alpha-dicarbonyl metabolite of glucose degradation pathways and increased generation of advanced glycation endproducts (AGEs). The aim of this investigation was to study the extent of the MG-modification argpyrimidine in human diabetic heart and in rat cardiomyoblasts grown under hyperglycemic conditions. Left ventricular myocardial samples from explanted hearts of patients with cardiomyopathy with (n=8) or without DM (n=8) as well as nonfailing donor organs (n=6), and rat cardiac myoblasts H9c2 treated with glucose were screened for the MG-modification argpyrimidine. The small heat shock protein 27 (Hsp27) revealed to be the major argpyrimidine containing protein in cardiac tissue. Additionally, the modification of arginine leading to argpyrimidine and the phosphorylation of Hsp27 are increased in the myocardium of patients with DM. In H9c2 cells hyperglycemia leads to a decrease of the Hsp27-expression and an increase in argpyrimidine content and phosphorylation of Hsp27, which was accompanied by the induction of oxidative stress and apoptosis. This study shows an association between diabetes and increased argpyrimidine-modification of myocardial Hsp27, a protein which is involved in apoptosis, oxidative stress, and cytoskeleton stabilization.

Sweet heart - contributions of metabolism in the development of heart failure in diabetes mellitus.

With the rapidly increasing prevalence of type 2 diabetes mellitus the risk for cardiovascular events is increasing. Almost 2 of 3 patients who present with symptomatic CHD have abnormal glucose homeostasis. Patients with diabetes mellitus and cardiovascular disease have an unfavourable prognosis. The most important result of diabetes metabolism is the switch from carbohydrates and fatty acids as a source of energy to an excessive use of fatty acids. The adverse influence of diabetes mellitus extends to all components of the cardiovascular system, including microvasculature, the epicardial coronary arteries, the large conduit arteries and the heart, as well as the kidneys. Focus of this review is the myocardial metabolism in heart failure and diabetes mellitus.

Range of therapeutic metformin concentrations in clinical blood samples and comparison to a forensic case with death due to lactic acidosis.

Due to a lack of reference values for blood concentration of metformin in the literature, the forensic evaluation of metformin findings in blood samples is difficult. Interpretations with regard to the assessment of blood concentrations as well as an estimation of the ingested metformin amounts are often vague. Furthermore, post mortem evaluation of death due to lactic acidosis because of metformin is difficult since renal performance or lactate concentrations can not always reliably be determined after death. To describe a concentration range in clinical samples after chronic use of metformin, metformin serum concentrations were determined in serum samples of 95 diabetic patients receiving daily doses of 500mg-3000mg of metformin. The analyses of metformin was carried out using a validated high performance liquid chromatograph coupled to triple quadrupole mass spectrometry (LC-QQQ-MS). On average, metformin concentrations were 1846ng/mL (

Exposure of adhesion molecules on activated platelets in patients with newly diagnosed IDDM is not normalized by near-normoglycemia.

It has been suggested that platelet hyperactivity contributes to the early evolution of diabetic vascular disease per se. This study directly evaluates the level of intravascular platelet activation in newly diagnosed IDDM patients before and after tight metabolic control. Platelet activation was determined by the Duesseldorf-III flow cytometry assay in 21 recent-onset hyperglycemic IDDM patients before insulin, after 3 days of treatment with intravenous insulin, and after 14 and 60 days of intensified conventional insulin therapy. The intravasal platelet activation status was quantified by the percentage of platelets exposing the activation-dependent molecules CD62 (P-selectin), thrombospondin (TSP), and CD63 (GP53) as well as the activated fibrinogen receptor (GPIIB/IIIA). Fifty matched normal subjects served as control subjects. Fourteen patients completed the 60-day study design. After initial recompensation, near-normoglycemic control was achieved after 14 days (fasting blood glucose, 117.0 +/- 19.0 mg/dl), and the HbA1 concentration was 7.6 +/- 1.2% after 60 days. CD62+ (4.0 +/- 4.5%), TSP+ (2.0 +/- 1.8%), CD63+ (11.0 +/- 7.0%), and activated-GPIIB/IIIA+ (7.6 +/- 7.7%) platelet levels were initially 5, 3.3, 5.7, and 2.8 times higher than the mean level of normal. There was no correlation with any of the nearly normalized metabolic parameters. Thus, more activated platelets circulate in newly diagnosed IDDM patients, which supports the assumption of a prethrombotic condition even in disease stages without apparent vascular damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Circulating platelets show increased activation in patients with acute cerebral ischemia.

Platelet activation plays a central role in acute arterial stenosis as has been shown in coronary heart disease. Likewise it can be assumed to be of importance in the evolution of acute cerebral ischemia (ACI), particularly in patients with large vessel disease. Flow cytometric detection of platelet adhesion molecules as a marker of platelet activation in a group of patients with ACI and different etiologies has not been evaluated. In 72 patients with ACI and 72 controls, the exposure of activation-dependent adhesion molecules was determined using flow cytometry after immunostaining with monoclonal antibodies against CD 62, CD 63 and thrombospondin. The extent of platelet activation differed as a function of the etiology of ACI: platelets from patients with atherosclerosis of brain-supplying arteries expressed significantly more activation markers than did controls, whereas patients with cardioembolic stroke did not. By analyzing platelet adhesion molecules it is possible to describe platelet activation profiles in patients with acute cerebral ischemia. This diagnostic procedure will be useful for monitoring individualized anti-platelet therapy and may enable distinguishing different subgroups of stroke patients.

Adhesion molecules influencing atherosclerosis.

Life limiting diabetes heart problems predominantly result from accelerated thrombogenesis superimposed on a localized arterial vessel stenosis (atherothrombosis). The atherosclerotic process is a slowly progressing vitious cycle of self-amplifying cell-cell interactions. Initially, corpuscular blood elements, predominantly monocytes adhere to locally activated endothelial cells, before they convert into lipid laden macrophages. The proliferative response of media smooth muscle cells to foam cell derived mediators proceeds to the fibrous plaque where underlying subendothelial matrix material activates bypassing platelets. The new concept of adhesion molecules explains how streaming white blood cells can locally adhere to the endothelial cells (selectin mediated), become triggered, stick (integrin mediated) and consecutively transmigrate. P-Selectin rapidly appears in the outer membrane of activated endothelial cells and platelets. It serves as receptor for sialic acid containing oligosaccharides within the monocyte/PMN membrane. These cells adhere to locally activated endothelium (nondenuding injury) and form nidus for the further adherence of activated platelets. Later, when platelets become activated in response to nuding endothelial injury, exposure of P-Selectin leads to the parallel local recruitment of white blood cells. Diabetic patients with clinically overt angiopathy, but also immediately after onset of the metabolic disease, were shown to have increased levels of circulating P-Selectin positive platelets. Therefore, it is suggested that enhanced platelet-leukocyte interaction might be pathogenetic for atherogenesis from the very beginning as it must be considered of importance for reperfusion injury and remodelling in a highly affected myocardium when the catastrophe of myocardial infarction has finally occurred.

Heart disease in diabetes mellitus: a challenge for early diagnosis and intervention.

Most people with diabetes die from thrombotic complications superimposed to degenerative arterial vascular lesions, mostly myocardial infarction. Diabetes is a risk factor per se for such complications, but often clusters with dyslipoproteinemia, hypertension and obesity. In NIDDM (Type-II) patients this is referred to as "metabolic syndrome" and often operates on a genetically programmed susceptibility which accelerates the pathogenesis of coronary artery disease in front of a much wider diabetes specific cardiopathy. From a pathophysiological point of view none of these associated risk factors explains the pathogenetic series of events leading to the precipitation of an occlusive thrombus at sites of complicated coronary plaques. In patients with diabetes the coagulation system is switched towards a prethrombotic state, involving increased plasmatic coagulation, diminished fibrinolysis, decreased endothelial thromboresistance and predominantly platelet hyperreactivity ("diabetic thrombocytopathy"). Some of these factors are associated with an increased coronary risk (e.g. fibrinogen, PAI-1, platelets), but are also directly linked to the pathogenesis of "atherothrombosis". Altered cardiac remodelling together with adhesion and coagulation mechanisms appears suitable to explain decreased functional performance of infarcted organs, decreased success of acute (reduced fibrinolytic response, reperfusion injury) and longterm intervention strategies (PTCA, CABG) in diabetes. Glucose adjustment alone will not adequately neutralize these complex mechanisms. Particularly in diabetes a multidimensional interventional repertoire is required including antihypertensive, antidyslipoproteinemic and antithrombotic drugs, customized according to the individual patients needs as assessed by early diagnostic measures ("early secondary prevention").

Macrovascular disease in diabetes: current status.

Clearly, macrovascular complications are the prognosis limiting problem of diabetes patients which consecutively account for the majority of socio-economic burden of the disease. The overall morbidity and mortality development does not indicate improvement hallmarking better or at least adequate care for these patients. Possible explanations address the late detection problem of a clinically silent disease onset as well as unrecognised multiple comorbid conditions all of which end-up with endothelial dysfunction as representation of the so called "functional atherosclerosis" and blood hyperresponsiveness. Here, we describe new experimental aspects of the early atherosclerosis development focussing inflammation as one driving pathogenetic force for the evolution of the complicated lesion type in diabetes. However, emphasis is put on the view that inflammation, atherogenesis and thrombogenesis are severely crosslinked by soluble and cellular adhesion molecules. From a diagnostic point of view genomic detection of risk associated genes opens both the vision of early identification of high risk individuals and the targeting of drug intervention based on conditioned responsiveness. By using available drugs and evidence based risk factor intervention strategies a plea is made for a multimodal therapeutic approach fitted to the individual patient's needs aiming at endpoint reduction. This corresponds to the recent releases of guidelines from nearly all vascular medicine related scientific societies. Diabetes is a vascular disease!

Medical management for adults with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic disorder characterized by morbid obesity resulting from insatiable appetite. Complications like diabetes mellitus or other cardiovascular diseases typically occur during lifetime. Lifestyle advice and education as well as limited caloric intake are the major concepts in assistance of PWS patients. METHODS: A 12.9-month follow-up study, which included 8 formerly genetically diagnosed PWS patients, was conducted. Physical and laboratory examinations were done at the beginning and at the end of the follow-up. Improved medical care and lifestyle advice were given. The participants lived in an assisted living environment with a fixed daily schedule and limited caloric intake. RESULTS: The group of patients consisted of manifest diabetics (n=6) as well as nondiabetics (n=2). Therapeutic concepts were simplified in 2 patients by switching from insulin to oral antidiabetics. The reduction in body weight was moderate, but attributable to a loss of fat mass. A significant reduction in blood cholesterol and triglyceride content was achieved along the observational period as well as a significant reduction of glycosylated hemoglobin (HbA1c) in the group of diabetic PWS patients. Systolic blood pressure improved during the study. CONCLUSION: A combination of an assisted living environment following conservative treatments as well as consistent patient care improved the daily and medical situation of PWS patients. Weight loss and, as a consequence, improvements in terms of metabolic condition and blood pressure were observed. A combination of medical and daily routine management should be established in PWS patients to improve their quality of life.

[Diabetes and heart failure: a practically oriented critical appraisal]. / Diabetes und Herzinsuffizienz: eine praxisorientierte, kritische Bestandsaufnahme.

Patients with type 2 diabetes have an increased risk for developing symptoms of heart failure. These can be accompanied by a reduction of left ventricular ejection fraction (HFREF, systolic heart failure) or by a preserved function (HFPEF, diastolic heart failure). The pathophysiology of both entities is distinct and involves impairment of myocardial metabolism and coronary circulation alike. Although diabetes and heart failure often coincide, the management of these patients particularly with respect to the specific benefits or possible hazards of antidiabetic treatment is vague. Therefore, from a pathophysiological as well as clinical viewpoint, 1) diabetic patients with symptoms of heart failure have to be differentiated regarding systolic as well as diastolic left ventricular function by echocardiography and tissue doppler imaging. 2) Heart failure in diabetic patients needs similar attention due to a prognosis and interactions. 3) Optimized blood glucose lowering in combination with improvement of other cardiovascular risk factors is evident for HFREF and is assumed to be beneficial for HFPEF. 4) Antidiabetic medication has to be specifically adapted for both entities. As prospective, controlled studies are scarce, future interventional studies should specifically focus on clinical outcome in diabetic patients with different entities of heart failure.