Assessment of fetal myocardial performance index in women with pregestational and gestational diabetes mellitus.

AIM: Fetal cardiac left ventricular function in pregnant women with pregestational or gestational diabetes mellitus was investigated by exploring fetal myocardial performance index (MPI) and E wave/A wave peak velocity (E/A) ratio. METHODS: Seventy pregnant women with either pregestational or gestational diabetes mellitus and with no other systemic or pregnancy related disorders were compared with 70 gestational age matched healthy controls by means of fetal left ventricular MPI and E/A ratio. Opening and closing clicks of the mitral and aortic valves were used to define the three time periods: ejection time (ET), isovolumetric contraction time (ICT) and isovolumetric relaxation time (IRT), which were employed in the calculation of MPI (MPI = [ICT + IRT]/ET). Statistical analyses were conducted using receiver operating characteristic analysis and independent two-sample t, Mann-Whitney U and chi-square tests. RESULTS: Fetal left ventricular MPI values were significantly higher in the diabetic group compared with controls (0.56 ± 0.09 vs 0.36 ± 0.04, P < 0.001), whereas E/A ratio was lower (0.66 ± 0.11 vs 0.69 ± 0.09, P = 0.049). The adverse perinatal outcome rate was also higher in the diabetic group. Receiver operating characteristic analysis revealed > 0.39 as the optimal cut-off level for MPI in perinatal adverse outcome prediction (sensitivity: 90.9%, specificity: 47.7%, area under the curve: 0.690, 95% confidence interval: 0.598-0.782, P < 0.001). CONCLUSIONS: We conclude that fetuses of diabetic mothers have significant left ventricular systolic and diastolic dysfunction. MPI may be used in the prediction of adverse perinatal outcome in diabetic pregnancies.

Diabetes mellitus stimulates pancreatic cancer growth and epithelial-mesenchymal transition-mediated metastasis via a p38 MAPK pathway.

Diabetes mellitus (DM) and its accompanying chronic inflammation promote tumor progression. p38 mitogen-activated protein kinase (MAPK) is an essential kinase for inflammation. The effects of p38 MAPK on epithelial-mesenchymal transition (EMT)-mediated diabetic pancreatic cancer metastasis remain unclear. Here, we demonstrate that p38 MAPK phosphorylation was significantly increased in pancreatic cancer cells treated with high glucose and in pancreatic tumors from diabetic animals. A p38 MAPK inhibitor significantly suppressed the proliferation and invasion of pancreatic cancer cells under high-glucose conditions. Moreover, p38 MAPK inhibition not only significantly decreased both the tumor volume monitored by magnetic resonance imaging and EMT-related metastasis but also increased the survival of diabetic mice bearing pancreatic tumors. Furthermore, the inflammation in diabetic animals bearing pancreatic tumors was also significantly lower after therapy. Collectively, our findings reveal that p38 MAPK inhibitors may provide a novel intervention strategy for diabetic pancreatic cancer treatment.

Nrf2 signalling and autophagy are involved in diabetes mellitus-induced defects in the development of mouse placenta.

It is widely accepted that diabetes mellitus impairs placental development, but the mechanism by which the disease operates to impair development remains controversial. In this study, we demonstrated that pregestational diabetes mellitus (PGDM)-induced defects in placental development in mice are mainly characterized by the changes of morphological structure of placenta. The alteration of differentiation-related gene expressions in trophoblast cells rather than cell proliferation/apoptosis is responsible for the phenotypes found in mouse placenta. Meanwhile, excess reactive oxygen species (ROS) production and activated nuclear factor erythroid2-related factor 2 (Nrf2) signalling were observed in the placenta of mice suffering from PGDM. Using BeWo cells, we also demonstrated that excess ROS was produced and Nrf2 signalling molecules were activated in settings characterized by a high concentration of glucose. More interestingly, differentiation-related gene expressions in trophoblast cells were altered when endogenous Nrf2 expression is manipulated by transfecting Nrf2-wt or Nrf2-shRNA. In addition, PGDM interferes with autophagy in both mouse placenta and BeWo cells, implying that autophagy is also involved, directly or indirectly, in PGDM-induced placental phenotypes. Therefore, we revealed that dysfunctional oxidative stress-activated Nrf2 signalling and autophagy are probably responsible for PGDM-induced defects in the placental development of mice. The mechanism was through the interference with differentiation-related gene expression in trophoblast cells.

High prevalence of diabetes mellitus in patients with liver cirrhosis.

AIMS: The reported prevalence of Type 2 diabetes mellitus in patients with liver cirrhosis is five times higher than in the general population. However, these data were never adjusted for classical risk factors for Type 2 diabetes. We therefore investigated the association between cirrhosis and Type 2 diabetes and adjusted for known risk factors for Type 2 diabetes. METHODS: We reviewed medical files for presence of Type 2 diabetes and potential confounders in 94 patients with cirrhosis (cases) and compared these with a control group of 107 patients with non-ulcer dyspepsia. Multiple logistic regression analysis was used to adjust for potential confounders. RESULTS: The aetiology of our cirrhosis population was alcohol (59%), viral hepatitis (10%), biliary cirrhosis (3%) or cryptogenic (28%). Prevalence of Type 2 diabetes was significantly higher in patients with cirrhosis than in control subjects: 35/94 (37%) vs. 7/107 (7%) (OR 8.5, 95% CI 3.5­20.2, P < 0.001). After adjustment for age, sex, family history of Type 2 diabetes, alcohol use and BMI, cirrhosis remained significantly associated with Type 2 diabetes (OR 13.6, 95% CI 4.3­42.9, P < 0.001). Most cases of Type 2 diabetes were already diagnosed before diagnosis of cirrhosis (21/35, 60%) or were incidentally found together with cirrhosis (5/35, 14%). CONCLUSIONS: Liver cirrhosis had a strong, independent association with Type 2 diabetes. Classical risk factors such as family history and BMI could not explain the high Type 2 diabetes prevalence in cirrhosis. Therefore, a liver-derived factor might aggravate glucose intolerance and cause Type 2 diabetes in cirrhosis. In addition, Type 2 diabetes might also cause cirrhosis through liver steatosis and fibrosis.

Triacylglycerol accumulation is not primarily affected in myotubes established from type 2 diabetic subjects.

In the present study, we investigated triacylglycerol (TAG) accumulation, glucose and fatty acid (FA) uptake, and glycogen synthesis (GS) in human myotubes from healthy, lean, and obese subjects with and without type 2 diabetes (T2D), exposed to increasing palmitate (PA) and oleate (OA) concentrations with/without high glucose and/or high insulin concentrations for 4 days. We showed that these myotubes expressed an increased TAG accumulation (P<0.001) without differences between groups. Chronically high insulin, but not high glucose concentrations, increases TAG accumulation by 25% (P<0.001). Inhibition of oxidative phosphorylation by antimycin A and oligomyin was followed by a reduced lipid oxidation (P<0.05) and increased TAG accumulation (P<0.05), but only in the presence of FAs. Both chronic PA and OA exposure reduced the insulin-mediated PA and OA uptake (fold change) (P<0.001), but could not induce insulin resistance at the level of glucose uptake, whereas high insulin concentrations induced insulin resistance (P<0.001). Chronic, high PA, but not OA, induced insulin resistance at the GS level in control subjects (P<0.05). The TAG content correlated negatively with insulin-stimulated FA uptake (P<0.001), but did not correlate with insulin-stimulated glucose uptake for PA or OA (P>0.05). These results indicate that (1) TAG accumulation is not primarily affected in skeletal muscle tissue of obese and T2D; (2) induced inhibition of oxidative phosphorylation is followed by TAG accumulation; (3) increasing FA and insulin availability, and reduced oxidative phosphorylation, and to a lesser extent glucose, are determinants for differences in intramyocellular TAG accumulation; (4) quantitative TAG content may not be the best marker for insulin resistance. Thus, increased TAG content in skeletal muscle of obese and T2D subjects is adaptive.

Disturbed morphogenesis of cardiac outflow tract and increased rate of aortic arch anomalies in the offspring of diabetic rats.

BACKGROUND: Maternal diabetes (MD) is a risk factor for offspring to develop cardiovascular anomalies; this is of growing clinical concern since the number of women in childbearing age with compromised glucose homeostasis is increasing. Hyperglycemia abrogates cardiovascular development in vitro; however, a link to cardiovascular defects in diabetic offspring remains to be investigated. METHODS: We have studied cardiovascular development in offspring of MD rats by examining serial histological sections of GD 12.0-18.0 offspring. Development of pharyngeal arch artery malformations was analyzed and related to intracardiac anomalies. RESULTS: Pharyngeal arch artery and intracardiac defects were present in 27 of 37 MD GD 13.0-18.0 offspring. Early sixth arch arteries showed abrogated arteriogenesis, whereas fourth arch artery defects developed as a result of abnormal remodeling. Morphometrical analysis showed increased apoptosis in regressing artery segments and reduced apoptosis in persisting artery segments. Double outlet right ventricle with infundibular stenosis (tetralogy of Fallot) was predominantly found in combination with sixth artery defects and pulmonary atresia. As confirmed by morphometric analysis and three-dimensional (3D)-reconstructions, outflow tract defects coincided with endocardial cushion hypoplasia. Cases with teratology of Fallot additionally showed a shorter outflow tract. No relation with apoptosis or disturbed neural crest cell migration was found. CONCLUSIONS: Our data uniquely demonstrate mechanistic differences involved in the development of sixth and fourth artery anomalies. Whereas increased apoptosis induces fourth artery anomalies, pulmonary outflow obstruction abrogates sixth artery differentiation independent of apoptosis. The model presented allows analysis of diabetic conditions on cardiovascular development in vivo, essential for elucidating this teratology.