The global epidemic of diabetes is of significant concern. Diabetes associated vascular disease signifies the principal cause of morbidity and mortality in diabetic patients. It is also the most rapidly increasing risk factor for cognitive impairment, a silent disease that causes loss of creativity, productivity, and quality of life. Small vessel disease in the cerebral vasculature plays a major role in the pathogenesis of cognitive impairment in diabetes. Endothelin system, including endothelin-1 (ET-1) and the receptors (ETA and ETB), is a likely candidate that may be involved in many aspects of the diabetes cerebrovascular disease. In this review, we took a brain-centric approach and discussed the role of the ET system in cerebrovascular and cognitive dysfunction in diabetes., W. Li, Y. Abdul, R. Ward, A. Ergul., and Seznam literatury
Diabetes increases the risk and worsens the progression of cognitive impairment. The hippocampus is an important domain for learning and memory. We previously showed that endothelin-1 (ET-1) reduced diabetes-induced inflammation in hippocampal neurons, suggesting a neuroprotective effect. Given that neurons and endothelial cells within the neurovascular unit depend on each other for proper function, we investigated the effect of ET-1 on brain-derived neurotrophic factor (BDNF) synthesis, a key neurotrophin and prosurvival factor, in neuronal (HT22 hippocampal neurons) and brain microvascular endothelial (BMEC-5i) cells under normal and diabetes-mimicking (high glucose plus palmitate) conditions. Cells were treated with exogenous ET-1 or ET receptor antagonists including ETB receptor selective antagonist BQ788 (1 μM) or dual-receptor antagonist bosentan (10 μM). Mature (m)BDNF, proBDNF and caspase-3 levels were measured by Western blotting. Diabetic conditions reduced the prosurvival mBDNF/proBDNF ratio in both HT22 and BMEC-5i cells. Addition of exogenous ET-1 had no effect on the BDNF system in HT22 cells in diabetic conditions. Both HT22 and BMEC-5i cells had an increase in the mBDNF/proBDNF ratio when grown in diabetes-simulating conditions in the presence of endothelin receptor inhibition. These data suggest that blockade of ET-1 may provide neuroprotection to hippocampal cells through the modulation of the BDNF system., R. Ward, Y. Abdul, A. Ergul., and Seznam literatury
The inotropic effects of insulin in the rat heart are still incompletely understood. In this study, the effects of insulin on cardiac contraction were studied in right ventricular papillary muscles from both control rats and rats with chronic diabetes (lasting 16 weeks). Diabetes was induced by the application of streptozotocin (STZ) and the development of diabetes was documented by increased levels of blood glucose, by reduction in body weight and by decreased plasma concentrations of insulin. The contraction was significantly smaller in diabetic rats. Insulin (80 IU/l) reduced the contraction force in both control and diabetic groups. The post-rest potentiation of contraction was not influenced by insulin in control rats, but insulin increased it in diabetic rats. The negative inotropic effect of insulin was preserved in the presence of cyclopiazonic acid (3 μmol/l), a blocker of sarcoplasmic reticulum (SR) Ca2+ pump, in both control and diabetic groups. In contrast, the negative inotropic effect of insulin was completely prevented in the presence of nifedipine (3 μmol/l), a blocker of L-type Ca2+ current. We conclude that insulin exerts a significant negative inotropic effect in rat myocardium, both control and diabetic. This effect is probably related to processes of SR Ca2+ release triggering, whereas SR Ca2+ loading is not involved.
Recently, the genetic cause of several syndromic forms of glycemia dysregulation has been described. One of them, MEHMO syndrome, is a rare X-linked syndrome recently linked to the EIF2S3 gene mutations. MEHMO is characterized by Mental retardation, Epilepsy, Hypogonadism/hypogenitalism, Microcephaly, and Obesity. Moreover, patients with MEHMO had also diabetes and endocrine phenotype, but detailed information is missing. We aimed to provide more details on the endocrine phenotype in two previously reported male probands with MEHMO carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. Both probands had a neonatal hypoglycemia, early onset insulindependent diabetes, and hypopituitarism due to dysregulation and gradual decline of peptide hormone secretion. Based on the clinical course in our two probands and also in previously published patients, neonatal hypoglycemia followed by earlyonset diabetes and hypopituitarism may be a consistent part of the MEHMO phenotype., J. Staník, M. Škopková, D. Staníková, K. Brennerová, L. Barák, L. Tichá, J. Hornová, I. Klimeš, D. Gasperiková., and Seznam literatury