Yi-jing Guo

Diabetes Impairs Hippocampal Function via Advanced Glycation End Product Mediated New Neuron Generation in Animals with Diabetes-Related Depression

The diabetes-induced reduction of neurogenesis in hippocampal dentate and its reversal with antidepressant medications implies a potential mechanism for diabetes-related depression and cognitive decline. In the following article, the role of advanced glycation end products (AGEs) in hippocampal neurogenesis deficits in diabetic animals with depression has been further explained in the light of an in vitro study. Diabetes was induced in animals with the use of streptozotocin (55 mg/kg, i.p.), and the animals then divided into those with and those without depression-like behaviors as analyzed by behavioral tests. The AGE formation inhibitor aminoguanidine (10 mg/kg) was administrated for an additional 4 weeks. Proliferating cells, their survival, and their phenotype fate were monitored with bromodeoxyuridine labeling and confocal laser microscopy. The presence of AGE peptides was determined with the use of a flow injection assay. Animals with diabetes and depressive symptoms displayed a reduction in hippocampal neurogenesis and an elevated serum level of AGE peptides, both of which were reversed by a 4-week regimen of aminoguanidine (10 mg/kg, i.p.), which inhibits AGE formation; in addition, the depressive behaviors were improved. These findings provided in vivo evidence that diabetes impairs hippocampal function via the AGE-mediated generation of new neurons. This likely represents a putative mechanism that is responsible for diabetes-related depression and cognitive decline, and it suggests a potential approach for future research.

Meticillin-resistant Staphylococcus aureus isolated from foot ulcers in diabetic patients in a Chinese care hospital: risk factors for infection and prevalence.

A retrospective case-control study of 118 (male : female, 68 : 50) Chinese type 2 diabetic patients with foot ulcers (Wagners grade 3-5) was conducted to determine the prevalence and risk factors for meticillin-resistant Staphylococcus aureus (MRSA) infection in relation to the original community or hospital parameters. Ulcer specimens were processed for Gram staining, aerobic culture and antimicrobial susceptibility testing. Staphylococcus species were tested for meticillin resistance using oxacillin. S. aureus was the most frequent pathogen (25.6 %) in diabetic patient specimens (160 isolates), and a high proportion of S. aureus isolates were MRSA (63.4 %). A high percentage of S. aureus isolates (65.4 %) satisfied the definition for hospital-associated MRSA (HA-MRSA) infection. The size of ulcers [adjusted odds ratio (OR) 1.61; 95 % confidence interval (CI) 1.22-2.12] and osteomyelitis (adjusted OR 18.51, 95 % CI 2.50-137.21) were independent predictors of MRSA infection. The HA-MRSA group had a significantly different distribution from the community-associated MRSA group with respect to age, history of diabetes and length of hospital stay (all P<0.001). Neuropathy, vascular disease (all P=0.049) and osteomyelitis (P=0.026) were the most common underlying conditions observed in the HA-MRSA group. This study contributes to the establishment of precautions against the emergence of MRSA including MRSA acquired from different sources among the Chinese population with diabetic foot ulcers based on their original or clinical parameters.

Neuronal Apoptosis and Synaptic Density in the Dentate Gyrus of Ischemic Rats’ Response to Chronic Mild Stress and the Effects of Notch Signaling

Our previous research highlighted an inconsistency with Notch1 signaling-related compensatory neurogenesis after chronic mild stress (CMS) in rodents suffering from cerebral ischemia, which continue to display post-stroke depressive symptoms. Here, we hypothesize that CMS aggrandized ischemia-related apoptosis injury and worsened synaptic integrity via gamma secretase-meditated Notch1 signaling. Adult rats were exposed to a CMS paradigm after left middle cerebral artery occlusion (MCAO). Open-field and sucrose consumption testing were employed to assess depression-like behavior. Gene expression of pro-apoptotic Bax, anti-apoptotic Bcl-2, and synaptic density-related synaptophysin were measured by western blotting and real-time PCR on Day 28 after MCAO surgery. CMS induced depressive behaviors in ischemic rats, which was accompanied by an elevation in Bax/bcl-2 ratio, TUNEL staining in neurons and reduced synaptophysin expression in the dentate gyrus. These collective effects were reversed by the gamma-secretase inhibitor DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenyl-glycine t-butyl ester). We found that post-stroke stressors made neurons in the dentate gyrus vulnerable to apoptosis, which supports a putative role for Notch signaling in neural integrity, potentially in newborn cells’ synaptic deficit with regard to preexisting cells. These findings suggest that post-stroke depression therapeutically benefits from blocking gamma secretase mediated Notch signaling, and whether this signaling pathway could be a therapeutic target needs to be further investigated.

PPARγ-mediated advanced glycation end products regulation of neural stem cells

Hyperglycemia is accompanied by an accelerated rate of advanced glycation end products (AGEs) formation, which is found to be associated with the pathogenesis of diabetic cognitive deficit, including Alzheimers disease (AD). Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in controlling the proliferation of neural stem cells (NSCs) and their neuronal differentiation. We investigate the hypothesis that PPARgamma could mediate AGEs-related regulation of NSCs, by which AGEs possibly fulfill important roles in diabetic-related cognitive impairment. We found that AGEs down-regulated the proliferation and neurogenic differentiation of NSCs, and protein level of PPARgamma. PPARgamma agonist reversed the proliferation through the aid of AGE-BSA, with the exclusion of the neuronal differentiation of the NSCs which were also downregulated by AGE-BSA. These findings extend our understanding of the central role of PPARgamma in AGEs-related neurogenesis impairment, which probably increased risks of cognitive deficits or AD in diabetic patients.

PPARγ-mediated advanced glycation end products regulate neural stem cell proliferation but not neural differentiation through the BDNF-CREB pathway.

AIMS To investigate the roles of PPARγ in advanced glycation end product (AGE)-mediated characteristics of neural stem cells (NSCs) and the molecular mechanisms of action. METHODS We prepared pLentiLox3.7 lentiviral vectors expressing short hairpin RNA (shRNA) against PPARγ and transduced NSCs. MTT absorbance and cell counts were used to assay cell growth, and cell differentiation was analysed by confocal laser-scanning and western blots for the expression of MAP2/nestin. The protein and gene expression of the BDNF-CREB pathway components were examined by western blotting and real-time PCR. RESULTS Immunoblot analysis indicated that shRNA delivered by lentiviral vectors silenced PPARγ expression in NSCs. The proliferation of NSCs and expression of BDNF pathway components dropped in AGE-BSA culture medium (400 mg/L and 200 mg/L) on Day 3 and Day 7, respectively (all P<0.001). PPARγ-silenced NSCs exhibited a significant increase in cell growth and expression of BDNF pathway components compared with NSCs incubated with AGE-BSA (all P<0.001). Immunocytochemistry and western blotting analysis showed that AGE-BSA (400 mg/L) induced a significant decrease in the expression of MAP2 both in NSCs and PPARγ-silenced NSCs, as standardised by nestin. There was no significant difference between NSCs and PPARγ-silenced NSCs in the presence of AGE-BSA. CONCLUSIONS PPARγ plays roles in the AGE-mediated regulation of NSC proliferation but not neural differentiation through the BDNF-CREB pathway.

The effects of astrocytes on differentiation of neural stem cells are influenced by knock-down of the glutamate transporter, GLT-1

The majority of glutamate released during neurotransmission is uptaken into astrocytes through the glial glutamate transporter GLT-1, by which extracellular glutamate is inactivated. In this study, we determined whether GLT-1 mediated the astrocyte regulation of the cell fate of neural stem/progenitor cells (NSCs) by glutamate reuptake. The astrocytes stimulated neuronal lineage selection but inhibited glial lineage cells. However, all these effects were reversed after siRNA-targeting GLT-1 was delivered into astrocytes by lentiviral vectors. NSC and astrocyte co-culture also increased the synaptophysin protein levels of NSC-derived new neurons through GLT-1. Glutamate was found to be present in the supernatants of the co-culture and astrocytes under different medium conditions, which may be attributed to the slower rate of clearance of the released glutamate. Dysfunctional glutamate reuptake may be the major consequence of GLT-1 functional silence in astrocytes. These results indicated that astrocytes regulated NSCs in reactive astrogliosis, neuronal generation, and synaptic function through GLT-1.

Prevalence and control of dyslipidaemia among diabetic patients with microalbuminuria in a Chinese hospital

Background: Accumulating evidence indicates that dyslipidaemia plays an important role in the progression of kidney disease in patients with diabetes. Hyperlipidaemia is a risk factor for microalbuminuria in patients with diabetes. Little information exists on the prevalence and control of dyslipidaemia among diabetic patients with microalbuminuria in China. The aims of this study were to investigate the prevalence and control of dyslipidaemia among diabetic patients with microalbuminuria in a Chinese hospital as well as factors affecting the disease. Methods: A total of 1060 type 2 diabetic inpatients were assigned to the with-microalbuminuria group (n = 635) or the without-microalbuminuria group on the basis of urinary albumin-to-creatinine ratios (UACRs = 30–299 mg/g). Serum levels and the control of lipid profiles were assessed and classified according to the 2011 American Diabetes Association (ADA) guidelines, and low-density lipoprotein–cholesterol (LDL-C) was also assessed and classified according to Chinese intensified control criteria. Multiple regression analyses were performed to examine the factors affecting lipid variables. Results: Among patients with microalbuminuria, a significantly lower prevalence was found (33.1% vs. 58.6%; 35.3% vs. 52.5%, all p < 0.001) at target levels [LDL-C < 2.60 mmol/L or high-density lipoprotein–cholesterol (HDL-C) > 1.0 mmol/L for men and >1.3 mmol/L for women]. According to the intensified LDL-C goal (<2.07 mmol/L), a lower prevalence was found in male patients (15.5% vs. 32.7%, p < 0.001). Fewer patients with microalbuminuria were adherent to the therapy prescribed for dyslipidaemia (28.8% vs. 43.3%, p < 0.001). Even among patients who were on lipid-lowering treatment, the majority of individuals remained uncontrolled for all three lipid fractions [LDL-C, HDL-C and triglyceride (TG)] (82.5% vs. 69.0%, p = 0.003). Lipid and lipoprotein parameters were associated with gender and age. Conclusion: In China, diabetic patients with microalbuminuria displayed typical dyslipidaemias and were not adequately controlled. Intensified LDL-C and overall lipid-lowering clinical goals are potential precautions taken against diabetic nephropathy.

Vulnerability for apoptosis in the hippocampal dentate gyrus of STZ-induced diabetic rats with cognitive impairment

BackgroundHyperglycemia impaired hippocampal network via triggering suicide program of immanent neurons, this is regarded as an etiological factor for diabetic cognition deficits.AimTo investigate the occurrence of apoptosis in the hippocampal dentate gyrus of streptozotocin (STZ)-induced diabetic rats with cognitive impairment and assess the gene and protein expression of the apoptotic proteins bax, bcl-2, and caspase-3.Materials and methodsFour weeks after the verification of STZ-induced diabetes, diabetic rats with and without cognitive decline subgroups were subsequently assigned according to Morris water maze test. The expression levels of apoptotic proteins were measured using real-time RT-PCR and western blotting, respectively. Neuronal apoptosis was detected by TUNEL staining and electron microscopy.ResultsIn the dentate gyrus of the rats with cognitive decline, Bcl-2 exhibited lower gene and protein levels, whereas a higher expression of bax was detected contributing to a significant increase in their mean bax/bcl-2 ratio. However, caspase-3 was not activated. Statistically different numbers of TUNEL-staining cells and features of apoptosis were no found.ConclusionsThe higher bax/bcl ratio probably represents neurons of dentate gyrus vulnerable to apoptosis in the diabetes with cognitive decline. However, the normal caspase-3 level suggests that apoptosis is not active in this illness phase.

PREVALENCE OF SUBCLINICAL HYPOTHYROIDISM IN OLDER PATIENTS WITH DIABETES MELLITUS WITH POORLY CONTROLLED DYSLIPIDEMIA IN CHINA

To the Editor: Atherosclerotic complications are the leading cause of death in patients with diabetes mellitus. Poor control of dyslipidemia is often observed in these patients and is considered to be a cardiovascular risk factor. It was recently found that the prevalence of uncontrolled dyslipidemia is high in Chinese patients with diabetes mellitus, particularly in women. Subclinical hypothyroidism (SCH) is a state in which patients have mildly high serum thyroidstimulating hormone (TSH) concentrations with normal serum levels of free thyroxine and triiodothyroxine. Despite conflicting results, SCH is thought to increase the risk for atherosclerosis because of its association with dyslipidemia. Controversy still persists as to whether screening and treatment of SCH is warranted because of a lack of persuasive evidence, and the prevalence of SCH in older patients with diabetes mellitus and poorly controlled dyslipidemia in China is unknown. This cross-sectional study included data collected for 532 Chinese inpatients aged 60 and older with type 2 diabetes mellitus and poorly controlled dyslipidemia. They had no history of previous lipid-lowering therapy. Dyslipidemia was defined as low-density lipoprotein cholesterol (LDL-C) of 2.6 mmol/L (100 mg/dL) or greater, high-density lipoprotein cholesterol (HDL-C) of 1.0 mmol/L (40 mg/ dL) or less in men and 1.3 mmol/L (50 mg/dL) or less in women, triglycerides (TG) of 1.5 mmol/L or greater, or total cholesterol (TC) of 4.5 mmol/L or greater. The prevalence of SCH was calculated for each sex and for the lipoprotein levels mentioned above. Male and female patients with diabetes mellitus and well-controlled dyslipidemia had similar ages, frequency of tobacco consumption, hypertension, diabetes control status, glycosylated hemoglobin, and body mass indexes. In terms of lipoprotein profiles, men and women with poorly controlled dyslipidemia had higher TG, TC, and LDL-C levels and lower HDL-C levels than their counterparts (all Po.001). The apolipoprotein (apo) A1 level was similar between those with well-controlled and poorly controlled dyslipidemia in men and women, although the ratio of apo B to apo A1 was higher in men and women with poorly controlled dyslipidemia. The proportion of patients with SCH was higher in patients with LDL-C of 2.6 mmol/L or greater than in those with LDL-C less than 2.6 mmol/L (P 5.02). Similarly, the prevalence of SCH was significantly higher in men with HDL-C of 1.0 mmol/L or less and in women with HDL-C of 1.3 mmol/L or less (P 5.047). There was no significant difference in the prevalence of SCH according to control of TG and TC (P 5.42, P 5.70; Figure 1). A total of 17.5% of the women with diabetes mellitus and poorly controlled dyslipidemia were diagnosed with SCH, which was significantly higher than in those with well-controlled dyslipidemia (7.1%, P 5.01). No significant difference was observed in male patients (3.8% vs 3.2%, P 5.81). The proportion of female patients with LDL-C of 2.6 mmol/L or greater with SCH was greater than that for female patients with LDL-C less than 2.6 mmol/L (22.7% vs 7.7%, P 5.02), whereas there was no difference in male patients (P 5.15). Furthermore, for male or female patients with uncontrolled dyslipidemia, there was no difference in the prevalence of SCH between patients with HDL-C greater than 1.0 mmol/L for men or greater than 1.3 mmol/ L for women and those with HDL-C of 1.0 mmol/L or less for men (P 5.78) or 1.3 mmol/L or less for women (P 5.63). Similarly, there was no difference in the prevalence of SCH between patients with TG of 1.5 mmol/L or greater and those with TG less than 1.5 mmol/L (P 5.54 for men, P 5.98 for women) or between patients with TC of 4.5 mmol/L or greater and those with TC less than 4.5 mmol/L (P 5.22 for men and P 5.52 for women). The number of subjects was too small to stratify the TSH levels in patients with SCH, particularly men, to study the association between dyslipidemia and the level of TSH. It was appropriate for the data to be analyzed by comparing the lipid status of those with supposed SCH with that of those without SCH. For the female patients with diabetes mellitus and SCH, the prevalence of poorly controlled LDL-C ( 2.6 vs o2.6 mmol/L, 62.9% vs 31.4%), HDL-C ( 1.3 vs 41.3 mmol/L, 60.0% vs 36.3%), or TC ( 4.5 vs o4.5 mmol/L, 51.4% vs 29.4%) was higher than in those without SCH (all Po.05). This finding suggests an association between dyslipidemia and SCH in female patients with diabetes mellitus. These data indicate that SCH is more common in older female patients with diabetes mellitus (aged 60) with poorly controlled dyslipidemia. These findings are also consistent with recent American guidelines, which recommend LDL-C HDL-C TG TC Diabetes mellitus without dyslipidemia

Optimal target range for blood glucose in hyperglycaemic patients in a neurocritical care unit

Background: Hyperglycaemia is common among patients with critical neurological injury, even if they have no history of diabetes. The optimal target range for normalizing their blood glucose is unknown. Methods: Retrospective data were extracted from 890 hyperglycaemic individuals (glucose > 200 mg/dL) admitted to neuroscience critical care unit (NCCU) and these patients were divided into two groups: intensive glucose control group with target glucose of < 140 mg/dL achieved and moderate control with glucose levels 140-180 mg/dL. The groups were also stratified according to the hyperglycaemia type (pre-existing diabetes or stress-related). We defined the primary endpoint as death from any cause during NCCU admission. Results: In NCCU, tighter control of blood glucose at ≤ 140 mg/dL was associated with increased, mortality of individuals with pre-existing diabetes compared with moderate control [29 of 310 patients (9.4%) vs 15 of 304 patients (4.9%), p = 0.034]. Patient age [adjusted odds ratio (OR) = 1.12; 95% confidence interval (CI) = 1.05–1.19; p < 0.001], level of glycated haemoglobin (adjusted OR = 1.24; 95% CI = 1.04–1.48; p = 0.017) and hypoglycaemia (adjusted OR = 10.3; 95% CI = 2.92–36.6; p < 0.001) were positively associated with higher mortality. Death rate was lower among stress-related hyperglycaemic patients with tighter glucose controlled at ≤ 140 mg/dL [6 of 140 patients (4.3%) vs 15 of 136 patients (11.0%), p = 0.035]. Conclusion: A differential association is evident between glucose levels and mortality in diabetes and stress-related hyperglycaemia patients. However, given the observational nature of our work, no clinical recommendations can be given and prospective studies are required to further investigate these findings.