[Microbiome, diabetes and heart: a novel link?] / Mikrobiom, Diabetes und Herz: neue Zusammenhänge?

Patients with type 2 diabetes suffer from a high cardiovascular risk. The underlying pathomechanisms are not fully understood and treatment options are correspondingly limited. The gut microbiome could be a new important player in cardiometabolic diseases. Dysbiosis of the intestinal flora has been associated with insulin resistance, diabetes mellitus and cardiovascular diseases, such as atherosclerosis and heart failure. The negative cardiovascular effects of type 2 diabetes mellitus could therefore partly be mediated by gut microbiota. This review article discusses specific gut microbiome-associated mechanisms, which are modulated in both type 2 diabetes and cardiovascular diseases. It is presented how intestinal bacteria may contribute to systemic low-grade inflammation. Furthermore, it is shown how the intestinal microbiome as a complex metabolic organ is able to influence the cardiometabolic phenotype via production of bioactive metabolites. Further studies will have to demonstrate whether these mechanisms contribute to the high cardiovascular risk in type 2 diabetes.

Glucose-dependent insulinotropic peptide secretion is induced by inflammatory stimuli in an interleukin-1-dependent manner in mice.

Recently, glucagon-like peptide-1 (GLP-1) levels have been found to be increased in response to inflammatory stimuli, leading to insulin secretion and prevention of hyperglycaemia during endotoxemia in mice. In the present study, we assess the relevance of the other incretin hormone, glucose-dependent insulinotropic peptide (GIP), as a regulator of glucose metabolism under inflammatory conditions. We found that lipopolysaccharide (LPS) increased GIP secretion in a time- and dose-dependent manner in C57BL/6J mice. To elucidate the underlying mechanisms, mice were injected with inflammatory cytokines known to be released by LPS. Circulating GIP levels significantly increased in response to interleukin (IL)-1ß but not IL-6 or tumour necrosis factor (TNF)-α administration. Using respective knockout mice we found that LPS-mediated GIP secretion was selectively dependent on IL-1 signalling. To evaluate the functional relevance of inflammatory GIP secretion we pretreated mice with the GIP-receptor antagonist (Pro3)GIP. This blunted LPS-induced TNF-α and IL-6 secretion but did not affect LPS-induced insulin secretion or blood glucose-lowering. In conclusion, GIP provides a novel link between the immune system and the gut, with proinflammatory-immune modulatory function but minor glucose regulatory relevance in the context of acute endotoxemia.

[Cardiovascular effects of incretin-based therapies]. / Kardiovaskuläre Effekte inkretinbasierter Therapien.

Pharmacological modulation of the glucagon-like peptide-1 (GLP-1) system has emerged as a new therapeutic option for treatment of diabetes mellitus. In addition to the glucose lowering potential GLP-1 was found to have a variety of cardioprotective effects. GLP-1 reduced the size of myocardial infarction during acute ischemia by activation of prosurvival pathways including PI3-kinase, Akt und ERK1/2. In addition, GLP-1 prevented atherosclerotic lesion formation in experimental models and improved endothelial function while acting anti-inflammatory. Furthermore GLP-1 was found to improve chronic heart failure by increasing insulin independent cellular glucose transport. Consequently GLP-1 based therapies might reduce cardiovascular events in diabetic patients which is currently evaluated in clinical endpoint studies.

[Progressive dyspnoea in two patients with carcinoid syndrome]. / Progrediente Dyspnoe bei Karzinoidsyndrom.

In patients with carcinoid syndrome, there has always to be considered cardiac impairment. We report about two patients with hepatic and bone metastases of a neuroendocrine tumor of the midgut, who suffered from progressive dyspnea. This was caused in both cases by a right-to-left atrial shunt, in case 1 based on a patent foramen ovale (PFO), in case 2 based on a secundum atrial septal defect. Symptoms were significantly reduced by percutaneous closure of PFO and ASD, respectively. Right-to-left atrial shunt was facilitated by right-sided carcinoid induced endocardial fibrosis with the consequence of severe tricuspid regurgitation, leading to an increase of right atrial pressure.

Increase in adiponectin levels during pioglitazone therapy in relation to glucose control, insulin resistance as well as ghrelin and resistin levels.

Glitazones increase the secretion of the adipocyte-derived hormone adiponectin. Furthermore, the gastric signal peptide ghrelin is known to suppress adiponectin expression in adipocyte cell culture models. It is not known whether the increase in adiponectin during glitazone therapy is due to a suppression of ghrelin levels, a decrease of resistin concentrations or an amelioration of glucose control. In 10 patients (age 71+/-9 yr, body mass index 29.9+/-3.6 kg/m(2), HbA1c 6.9+/-0.5%) with Type 2 diabetes, who had already been treated with sulfonylureas, we additionally initiated a pioglitazone therapy (30 mg/day) for 12 weeks. To investigate the pioglitazone effect independently of blood glucose, glycosylated hemoglobin (HbA1c) was kept unchanged by reducing the daily dose of sulfonylurea if necessary. Ghrelin concentration [radioimmunoassay (RIA), Phoenix Pharmaceuticals, Mountain View, CA, USA], adiponectin levels [enzyme-linked immunosorbent assay (ELISA), Biovendor, Heidelberg, Germany] as well as resistin concentrations (ELISA, Linco Research, St. Charles, MO, USA) were measured before and after pioglitazone. Glucose control remained unchanged within the 12-week pioglitazone therapy (HbA1c 6.9+/-0.5% before vs 6.8+/-0.6% after pioglitazone) while body weight increased from 86.6+/-9.2 to 88.0+/-9.4 kg (p<0.05), and insulin concentration decreased from 19.6+/-5.7 to 10.1+/-1.6 microU/ml (p<0.05). Adiponectin concentration increased in all patients from 7.70+/-2.47 to 23.33+/-8.28 microg/ml (p<0.01), while resistin concentrations tended to decrease (by 15%; p=0.059). However, ghrelin remained unchanged during therapy. No correlations were observed either between ghrelin, resistin, insulin and adiponectin, or between body weight and hormone plasma levels. The increase in adiponectin levels during pioglitazone therapy seems to be at least partly independent of blood glucose and insulin concentration as well as of ghrelin levels, and it was not associated with a decrease in resistin concentrations.

Effect of atorvastatin on lipid parameters, LDL subtype distribution, hemorrheological parameters and adhesion molecule concentrations in patients with hypertriglyceridemia.

BACKGROUND AND AIM: Hypertriglyceridemia is a risk factor for atherosclerosis that is typically associated with high concentrations of adhesion molecules, impaired hemorrheology and an unfavourable low-density lipoprotein (LDL) subtype distribution. We hypothesised that some of these risk markers might be beneficially influenced by lipid-lowering therapy with atorvastatin in hypertriglyceridemic patients. METHODS AND RESULTS: Nineteen patents with primary hypertriglyceridemia were given 10 mg of atorvastatin per day for four weeks. Their cholesterol, triglyceride, LDL and high-density lipoprotein cholesterol (HDL-C) levels, LDL subtype profile, hemorrheological parameters and E-selectin, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 concentrations were measured before and at the end of atorvastatin therapy. The levels of total and LDL cholesterol respectively decreased by 25% and 24% (both p < 0.001). Furthermore, cholesterol was reduced by 8-29% in all seven LDL subfractions (density range: 1.020-1.066 g/mL) (p < 0.05). The reduction in triglyceride concentrations was of marginal significance (9%, p = 0.1), but its degree positively correlated with the reduction of small-dense LDL (r = 0.5, p < 0.025). Plasma viscosity and blood viscosity at low shear rates were respectively reduced by 2% and 16% (both p < 0.05). The effect of the treatment on the concentrations of HDL-C, fibrinogen and adhesion molecules was not significant. CONCLUSIONS: Atorvastatin (10 mg/day) not only reduced the plasma concentrations of atherogenic lipoproteins but also improved the LDL-subtype profile and reduced plasma and blood viscosity in patients with hypertriglyceridemia; however, it failed to significantly lower triglyceride concentrations.

High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers.

Pathophysiological parameters such as vascular density and tissue oxygen pressure can influence tumor malignancy and patient survival. Observations from our group showed that metastatic spread of carcinomas of the uterine cervix and of head and neck cancers was closely correlated with the lactate concentration in the primary lesion. Because these results were obtained in a low number of patients, the present investigation was performed to verify such a correlation in a larger population. Cryobiopsies were taken at first diagnosis of cervical cancer from 34 patients. Tissue concentrations of ATP, glucose, and lactate in viable tumor regions of these biopsies were measured microscopically using the technique of imaging bioluminescence. There was no correlation between stage or grade and any of the metabolic parameters measured. ATP and glucose concentrations were not significantly different in metastatic and nonmetastatic primary tumors (P>0.05). However, lactate concentrations were significantly higher (P = 0.001) in tumors with metastatic spread (mean +/- SD, 10.0+/-2.9 micromol/g; n = 20) compared with malignancies in patients without metastases (6.3+/-2.8 micromol/g; n = 14). The majority of patients who suffered a recurrence of the disease (17 of a total of 22 patients) or died (15 of 20) within the observation period of up to 8 years belonged to the metastatic, i.e., high lactate group. A Kaplan-Meier analysis of the data showed that the overall and disease-free survival probabilities of patients having low tumor lactate values were significantly higher compared with patients with high tumor lactate concentrations (P = 0.015 and 0.014, respectively). We conclude that tumor lactate content may be used as a prognostic parameter in the clinic. Furthermore, these findings are in accordance with data from the literature showing that the presence of hypoxia in cervical tumors is associated with a poorer patient survival.