Significant abnormal glycemic variability increased the risk for arrhythmias in elderly type 2 diabetic patients.

BACKGROUND: Little is known about whether the influence of glycemic variability on arrhythmia is related to age in type 2 diabetes mellitus (T2DM). Therefore, we aimed to compare the association between glycemic variability and arrhythmia in middle-aged and elderly T2DM patients. METHODS: A total of 107 patients were divided into two groups: elderly diabetes mellitus group (EDM, n = 73) and middle-aged diabetes mellitus group (MDM, n = 34). The main clinical data, continuous glucose monitoring (CGM) and dynamic ECG reports were collected. The parameters including standard deviation of blood glucose (SDBG), largest amplitude of glycemic excursions (LAGE), mean amplitude of glycemic excursions (MAGE), absolute means of daily differences (MODD), time in range (TIR), time below range (TBR), time above range (TAR), coefficient of variation (CV) were tested for glycemic variability evaluation. RESULTS: In terms of blood glucose fluctuations, MAGE (5.77 ± 2.16 mmol/L vs 4.63 ± 1.89 mmol/L, P = 0.026), SDBG (2.39 ± 1.00 mmol/L vs 2.00 ± 0.82 mmol/L, P = 0.048), LAGE (9.53 ± 3.37 mmol/L vs 7.84 ± 2.64 mmol/L, P = 0.011) was significantly higher in EDM group than those of MDM group. The incidences of atrial premature beat, couplets of atrial premature beat, atrial tachycardia and ventricular premature beat were significantly higher in EDM group compared with the MDM group (all P < 0.05). Among patients with hypoglycemia events, the incidences of atrial premature beat, couplets of atrial premature beat, atrial tachycardia and ventricular premature beat (all P < 0.05) were significantly higher in the EDM group than those in the MDM group. In EDM group, TIR was negatively correlated with atrial tachycardia in the MAGE1 layer and with atrial tachycardia and ventricular premature beat in the MAGE2 layer, TBR was significantly positively correlated with atrial tachycardia in the MAGE2 layer (all P < 0.05). In MDM group, TAR was positively correlated with ventricular premature beat and atrial tachycardia in the MAGE2 layer (all P < 0.05). CONCLUSIONS: The study demonstrated the elderly patients had greater glycemic variability and were more prone to arrhythmias. Therefore, active control of blood glucose fluctuation in elderly patients will help to reduce the risk of severe arrhythmia.

Patients with true mixed growth hormone and prolactin-secreting pituitary adenoma: a case series of 12 patients.

Objective: Mixed growth hormone (GH) and prolactin (PRL) secreting adenomas are the most common type of plurihormonal pituitary adenomas. We assessed the clinical presentations and impacts of transsphenoidal surgery (TS) on patients with mixed GH and PRL adenomas including surgical outcomes, complications, and prognosis.Method and patients: Twelve patients (7 males, 5 females) were operated in the neurosurgery department of Qilu hospital affiliated to Shandong University, Shandong, China. We analyzed hormone levels of preoperation, postoperation (within 24 h) and at 12-month follow-up and correlated levels with tumor volumes.Results: The remission rate was 66.7% (8/12), the recurrence rate was 16.7% (2/12), the cause-specific mortality was 0 and the overall mortality rate was 16.7% (2/12) due to stroke and myocardial infarction respectively. A significant drop was seen in GH, PRL, and Insulin-like-growth-factor-1 (IGF-1) levels between preoperation and postoperation with mean values from 52.6 to 9.9 ng/ml (p = 0.0015), from 321.6 to 190.9 ng/ml (p = 0.0026) and from 815.7 to 230.6 ng/ml (p = 0.0004), respectively. This drop was more significant between preoperation and follow-up with mean values from 52.6 to 3.0 ng/ml (p = 0.002), from 321.6 to 61.6 ng/ml (p < 0.0001), and from 815.7 to 195.0 ng/ml (p = 0.0001), respectively. However, there was no significant correlation between tumor volume and all of the hormone levels.Conclusions: Most mixed GH and PRL adenomas are aggressive with a high risk of recurrence and mortality.

Proteomics-based screening of the target proteins associated with antidepressant-like effect and mechanism of Saikosaponin A.

Depression is a commonly occurring neuropsychiatric disease with an increasing incidence rate. Saikosaponin A (SA), a major bioactive component extracted from Radix Bupleuri, possesses anti-malignant cell proliferation, anti-inflammation, anti-oxidation and liver protective effects. However, few studies have investigated SA's antidepressant effects and pharmacological mechanisms of action. Our study aimed to explore the anti-depression effect of SA and screen the target proteins regulated by SA in a rat model of chronic unpredictable mild stress (CUMS)-induced depression. Results showed that 8-week CUMS combined with separation could successfully produce depressive-like behaviours and cause a decrease of dopamine (DA) in rat hippocampus, and 4-week administration of SA could relieve CUMS rats' depressive symptoms and up-regulated DA content. There were 15 kinds of significant differentially expressed proteins that were detected not only between the control and CUMS groups, but also between the CUMS and SA treatment groups. Proline-rich transmembrane protein 2 (PRRT2) was down-regulated by CUMS while up-regulated by SA. These findings reveal that SA may exert antidepressant effects by up-regulating the expression level of PRRT2 and increasing DA content in hippocampus. The identification of these 15 differentially expressed proteins, including PRRT2, provides further insight into the treatment mechanism of SA for depression.

Low-dose phloretin alleviates diabetic atherosclerosis through endothelial KLF2 restoration.

We investigated whether low-dose phloretin served as daily dietary supplements could ameliorate diabetic atherosclerosis and the role of kruppel-like factor 2 (KLF2). HUVECs cultured in high glucose medium were treated with different concentrations of phloretin and KLF2 mRNA, and protein level was detected. Diabetes was induced using streptozotocin in Apoe-/- mice after which they were fed a high-cholesterol diet for 8 weeks. Diabetic mice injected with KLF2 shRNA-lentivirus or control virus were treated with 20 mg/kg phloretin. Glucose, lipid profile, aortic atheroma, and endothelial nitric oxide synthase (eNOS) expression were detected. Phloretin retained endothelial function by KLF2-eNOS activation under hyperglycemia. Low-dose phloretin helped with lipid metabolism, and blocked the acceleration of atherosclerosis in STZ-induced diabetic mice since the early stage, which was diminished by KLF2 knockdown. Low-dose phloretin exhibited athero-protective effect in diabetic Apoe-/- mice dependent on KLF2 activation. This finding makes phloretin for diabetic atherosclerosis.

Adefovir dipivoxil induced hypophosphatemic osteomalacia in chronic hepatitis B: a comparative study of Chinese and foreign case series.

BACKGROUND: Adefovir dipivoxil (ADV)-induced renal tubular dysfunction and hypophosphatemic osteomalacia (HO) have been given great consideration in the past few years. However, no standard guidance is available due to a lack of powerful evidence from appropriate long-term prospective case-control studies and variations in the definition of renal adverse events. The aim of this study is to clarify clinical features of ADV-related HO in Chinese chronic hepatitis B patients with long-term ADV treatment in Chinese and non-Chinese comparative case series. METHODS: Retrieval of case reports was based on Pubmed, CNKI, Wan Fang and VIP databases using the key words adefovir dipivoxil, hypophosphatemia, osteomalacia and Fanconi syndrome. We divided patients into Chinese (C group) and Foreign (F group) groups according to their nationality. Comparisons involving demographics, clinical manifestations, tests, treatment and prognosis were conducted between the two groups. RESULTS: Of the patients screened, 120 Chinese patients were identified in the C group, and 32 non-Chinese patients were identified in the F group. The average age of the C group was younger than that of the F group (51.89 years ±10.96 years versus 56.47 years ±11.36 years, t = - 2.084, P = 0.039). No significant difference was found in gender (male to female, 3.29:1 versus 3:1, χ 2 = 0.039, P = 0.844). Although there was no significant difference in the duration of ADV therapy before ostalgia onset, the C group tended to develop adverse events earlier, by 2-3 years, while the F group developed adverse events at 4-5 years (Z = - 1.517, P = 0.129). Prognosis was good after adjustment of the ADV dose and supplemental administration of phosphate and calcitriol. Time to resolution of tubular dysfunction was commenced at the first month, and Chinese patients were more prone to recover in the first 3 months than non-Chinese patients (91.3% of patients in the C group versus 56.3% in the F group, Z = - 3.013, P = 0.003). CONCLUSIONS: Sufficient attention is required for middle-aged males before and during exposure to long-term ADV therapy, regardless of nationality. The clinical picture, laboratory and radiograph alterations are important clues for those patients and are usually characterized by polyarthralgia, renal tubular dysfunction and mineralization defects. Implementation of an early renal tubular injury index is recommended for patients with higher risk, which would prevent further renal injury.

Effects of sitagliptin as initial therapy in newly diagnosed elderly type 2 diabetics: A randomized controlled study.

The objective of this study was to investigate the characteristics of blood glycemic excursion, incretins and pancreatic hormone secretion in elderly people with newly diagnosed type 2 diabetes mellitus (T2DM) and to study the effects of sitagliptin on glycemic excursion in these subjects. A total of 129 newly diagnosed T2DM patients were enrolled in the study from March 2012 to August 2013. Clinical data, serum incretin, pancreatic hormone and continuous glucose monitoring data were collected. Among these subjects, elderly patients (NEDM) randomly received metformin combined with sitagliptin phosphate or glimepiride for 24 weeks. The blood glucose, glycosylated hemoglobin A1c (GHbA1c), serum incretins and pancreatic hormone levels were determined. During the oral glucose tolerance test (OGTT), 30 min insulin and C-peptide levels, 120 min insulin levels and ratio of the increases of insulin and blood glucose levels after 30 min of sugar loading (∆Ins30/∆Glu30) were significantly lower in elderly patients than in middle-aged patients (P<0.05). In addition, the glucagon elevation at 30 min was higher and the glucagon-like peptide-1 (GLP-1) at 30 min was lower in the elderly patients (P<0.05). Glucose excursion indices, including the standard deviation of the average blood glucose, intraday mean average glucose excursions (MAGE), and mean of daily differences (MODD), were significantly higher in the elderly patients (P<0.05). During the OGTT, insulin, C-peptide and ∆Ins30/∆Glu30 results at 30 min and GLP-1 levels at 120 min in NEDM subjects were significantly increased (P<0.05) and glucagon levels at 30 min was significantly lower after sitagliptin treatment (P<0.05) compared with glimepiride. Moreover, MAGE and MODD were significantly lower in the sitagliptin group after treatment compared to those in the glimepiride group (P<0.05). No severe hypoglycemia or cardiovascular diseases were observed. Strong blood glucose excursions occur in elderly patients with newly diagnosed T2DM. Sitagliptin phosphate combined with metformin effectively and safely improves glycemic excursion and carbohydrate metabolism in NEDM patients by promoting the first phase of insulin and incretin secretion and inhibiting glucagon secretion of.

Autografting of bone marrow mesenchymal stem cells alleviates streptozotocin­induced diabetes in miniature pigs: real-time tracing with MRI in vivo.

Cellular replacement therapy for diabetes mellitus (DM) has received much attention. In this study, we investigated the effect of transplantation of autologous bone marrow­derived mesenchymal stem cells (ABMSCs) in streptozotocin (STZ)­induced diabetic miniature pigs. Miniature pig BMSCs were cultured, labeled with superparamagnetic iron oxide (SPIO) and transplanted into the pancreas of diabetic miniature pigs through targeted intervention. Blood glucose levels, intravenous and oral glucose tolerance test (OGTT), serum insulin, C­peptide and islets histology were analyzed. These transplanted cells were then identified by magnetic resonance imaging (MRI). The results showed that transplantation of ABMSCs reversed STZ­induced diabetes in miniature pigs. Blood glucose levels, intravenous, OGTT, serum insulin and C­peptide were significantly recovered in the diabetic minipigs with the autologous BMSC (DMAB) transplantation group. In addition, the number of islets was significantly increased in this group compared to the diabetic minipig control (DMC) group with conventional therapy. These data suggested the implantation of autologous BMSCs for type 1 diabetes treatment can partially restore the function of islet ß cells and maintain blood glucose homeostasis. Transplanted autologous BMSCs may improve islet repairing by differentiating for new islets and change pancreatic microcirculation and be identified in a real­time manner using MRI in vivo.

Tracing type 1 diabetic Tibet miniature pig's bone marrow mesenchymal stem cells in vitro by magnetic resonance imaging (1).

BACKGROUND: Traditional cell-tracking methods fail to meet the needs of preclinical or clinical research. Thus, the aim of the present study was to establish a new method of double labeling bone marrow mesenchymal stem cells (BMSCs) from type 1 diabetic (T1D) minipigs with super-paramagnetic iron oxide (SPIO) and enhanced green fluorescent protein (eGFP) and tracing them using MRI in vitro. METHODS: Isolated BMSCs from T1D minipigs were labeled with eGFP and different concentrations of SPIO. The effects of lentivirus (LV)-eGFP transfection and SPIO on the viability and growth curves of BMSCs were determined by Trypan blue exclusion, the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay and flow cytometry. Cellular ultrastructure was evaluated by transmission electron microscopy. Magnetic resonance imaging was used to evaluate BMSCs labeled with SPIO-eGFP complexes 6 weeks after labeling. RESULTS: Expression of eGFP in BMSCs peaked 96 h after transfection with LV-eGFP. Prussian blue staining revealed scattered blue granules in the cytoplasm of SPIO-labeled cells. Transmission electron microscopy revealed that the dense granules aggregated mainly in secondary lysosomes. On MRI, T2* -weighted imaging was far more sensitive for SPIO-labeled BMSCs than other image sequences 3 and 6 weeks after the cells had been labeled with SPIO-eGFP. CONCLUSIONS: We have developed a relatively simple and safe method for double labeling of BMSCs from T1D minipigs using SPIO and LV-eGFP and tracing them in vitro by MRI for 6 weeks.

[A study of tracking the superparamagnetic iron oxide and enhanced green fluorescent protein labeled miniature porcine bone marrow stem cells by in vitro MRI].

OBJECTIVES: To track bone marrow stem cells (BMSCs) labeled by enhanced green fluorescent protein (EGFP) and superparamagnetic iron oxide (SPIO)-poly-L-lysine (PLL) compound by MRI in vitro for autotransplantation into pancreas of type 1 diabetes miniature pigs. METHODS: The BMSCs were isolated by density gradient centrifugation and attachment culture from type 1 diabetes minipigs' bone marrow. Expressional intensity of EGFP in BMSCs transfected lentivirus-EGFP with a multiplicity of infection (MOI) of 30:1 reached the highest level after 96 h from transfection, while the positive rate was 43.2%. Different magnetic resonance scanning protocols were carried out on various density BMSCs labeled by different concentration of SPIO in various time-point in vitro. RESULTS: When SPIO concentration was 25 mg/L (count in Fe(3+)), the positive Fe(3+)-labeling rate of BMSCs was 93.1%. Most of SPIO particles in BMSCs' cytoplasm were observed in secondary lysosomes, but they were not detected in important organelle as cell nucleus. Comparing with gelatin the MRI of BMSCs labeled with SPIO in the condition with 1 × 10(4)/ml cells density and 25 mg/L Fe(3+) concentration in vitro, the signal intensity changes (ΔSI) after BMSCs labeled with SPIO 3 weeks and 6 weeks in TSE T(1)WI, TSE T(2)WI and FLASH T(2) WI sequences were 12%, 41%, 63% and 7%, 28%, 46% respectively (P < 0.01 and P < 0.05, respectively). CONCLUSIONS: The data showed that the porcine BMSCs labeled with SPIO and EGFP could be traced successfully in vitro by MRI in the suitable sequences.

Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis.

Berberine (BBR) is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French). It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK) and improvement of insulin sensitivity. However, it is not clear if BBR reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to BBR in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that BBR decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), were decreased in liver by BBR. Hepatic steatosis was also reduced by BBR and expression of fatty acid synthase (FAS) was inhibited in liver. Activities of transcription factors including Forkhead transcription factor O1 (FoxO1), sterol regulatory element-binding protein 1c (SREBP1) and carbohydrate responsive element-binding protein (ChREBP) were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, BBR inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) level. The data suggest that BBR improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that BBR improves glucose metabolism through an insulin-independent pathway.

[A survey of glucose and lipid metabolism and concomitant diseases among inpatients in Guangdong province].

OBJECTIVES: To investigate the epidemiological and clinical characteristics of dyslipidemia as well as its treatment and influence on accompanying diseases in impaired glucose status among inpatients. METHODS: A cross-sectional survey was conducted among the inpatients registered in ten university hospitals of Guangdong, China during the week before the Diabetes Day in 2004. The fasting blood glucose (FBG), lipid profiles, BMI, waist to hip ratio (WHR) and concomitant disorders of the first screen during the hospitalization period were recorded. Those who had FBG level from 5.6 to 6.9 mmol/L and not been previously diagnosed diabetes (PDM) underwent oral glucose tolerance test (OGTT). RESULTS: Of the 8753 inpatients investigated, 1067 cases had complete medical records (CMR case) including PDM cases and previously non-diagnosed diabetes ones with FBG > or = 5.6 mmol/L. Of the previously non-diagnosed diabetes cases with FBG levels from 5.6 to 6.9 mmol/L, 65.8% accepted OGTT. Of the CMR cases, 41.9% had PDM, 21.7% was newly diagnosed diabetes mellitus (NDM), 29.1% had impaired glucose regulation (IGR) and only 7.3% had normal glucose tolerance (NGT). The TG levels in NDM and PDM group were higher than those in IGR and NGT group (P < 0.05, respectively). The HDL-C levels in IGR, NDM and PDM group were lower than those in NGT group (P < 0.05, respectively). Sixty-nine point six percent of the diabetes mellitus (DM) inpatients was accompanied with dyslipidemia and the rate was higher than those in NGT (56.4%) and IGR inpatients (52.5%, P < 0.05, respectively). Only 22.8% of the PDM inpatients underwent treatment of dyslipidaemia and just 3.4% achieved the target suggested by the guideline of ATP-III. BMI was higher and waistline longer in the PDM and NDM inpatients than those in the NGT cases (P < 0.05, respectively). Seventy-two point eight percent of the PDM inpatients was complicated with more than one type of vascular diseases. Nine point seven percent and 0.2% of the NDM inpatients were tormented by diabetic nephropathy and diabetic retinopathy respectively. CONCLUSIONS: More inpatients with accompany DM or IGR had concomitant dyslipidemia than those with NGT, which included hypertriglyceridemia, hypo-high-density lipoproteinemia and metabolic syndrome. Concomitant vascular diseases were more frequently found in PDM inpatients than in the others. Some of the NDM and IGT inpatients were complicated with microvascular diseases.

Inadequate glycaemic control and antidiabetic therapy among inpatients with type 2 diabetes in Guangdong Province of China.

BACKGROUND: Diabetes mellitus has become epidemic in recent years in China. We investigated the prevalence of hyperglycaemia and inadequate glycaemic control among type 2 diabetic inpatients from ten university teaching hospitals in Guangdong Province, China. METHODS: Inadequate glycaemic control in diabetic patients was defined as HbA1c = 6.5%. Therapeutic regimens included no-intervention, lifestyle only, oral antiglycemic agents (OA), insulin plus OA (insulin + OA), or insulin only. Antidiabetic managements included monotherapy, double therapy, triple or quadruple therapy. RESULTS: Among 493 diabetic inpatients with known history, 75% had HbA1c = 6.5%. Inadequate glucose control rates were more frequently seen in patients on insulin + OA regimen (97%) than on OA regimen (71%) (P < 0.001), and more frequent in patients on combination therapy (81% - 96%) than monotherapy (75%) (P < 0.05). Patients on insulin differed significantly from patients on OA by mean HbA1c, glycemic control rate, diabetes duration, microvascular complications, and BMI (P < 0.01). CONCLUSIONS: This study showed that glycaemic control of type 2 diabetic patients deteriorated for patients who received insulin and initiation time of insulin was usually delayed. It is up to clinicians to move from the traditional stepwise therapy to a more active and early combination antidiabetic therapy to provide better glucose control.

Differentiation of bone marrow-derived mesenchymal stem cells from diabetic patients into insulin-producing cells in vitro.

BACKGROUND: Stem cells, which have the ability to differentiate into insulin-producing cells (IPCs), would provide a potentially unlimited source of islet cells for transplantation and alleviate the major limitations of availability and allogeneic rejection. Therefore, the utilization of stem cells is becoming the most promising therapy for diabetes mellitus (DM). Here, we studied the differentiation capacity of the diabetic patient's bone marrow-derived mesenchymal stem cells (MSCs) and tested the feasibility of using MSCs for beta-cell replacement. METHODS: Bone marrow-derived MSCs were obtained from 10 DM patients (5 type 1 DM and 5 type 2 DM) and induced to IPCs under a three-stage protocol. Representative cell surface antigen expression profiles of MSCs were analysed by flow cytometric analysis. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to detect multiple genes related to pancreatic beta-cell development and function. The identity of the IPCs was illustrated by the analysis of morphology, ditizone staining and immunocytochemistry. Release of insulin by these cells was confirmed by immunoradioassay. RESULTS: Flow cytometric analysis of MSCs at passage 3 showed that these cells expressed high levels of CD29 (98.28%), CD44 (99.56%) and CD106 (98.34%). Typical islet-like cell clusters were observed at the end of the protocol (18 days). Ditizone staining and immunohistochemistry for insulin were both positive. These differentiated cells at stage 2 (10 days) expressed nestin, pancreatic duodenal homeobox-1 (PDX-1), Neurogenin3, Pax4, insulin, glucagon, but at stage 3 (18 days) we observed the high expression of PDX-1, insulin, glucagon. Insulin was secreted by these cells in response to different concentrations of glucose stimulation in a regulated manner (P<0.05). CONCLUSIONS: Bone marrow-derived MSCs from DM patients can differentiate into functional IPCs under certain conditions in vitro. Using diabetic patient's own bone marrow-derived MSCs as a source of autologous IPCs for beta-cell replacement would be feasible.

Depressive symptoms and risk factors in Chinese persons with type 2 diabetes.

BACKGROUND: Our objective was to study depressive symptoms and potential risk factors in Chinese persons with type 2 diabetes. METHODS: Zung self-rating depression scale (ZSDS) was used to scan depressive symptoms. Correlation between depressive symptoms and sociodemographic and medical factors were analyzed by logistic regression. RESULTS: Of 222 patients with type 2 diabetes (115 males, 107 females, age 56.36 +/- 12.67 years, disease duration 7.36 +/- 6.32 years), a total of 51 (23.0%) patients were categorized as having depressive symptoms. Percentage of depressive symptoms in females was higher than in males (29.0% vs. 17.6%, chi(2)=4.2, p <0.05). Percentage of depressive symptoms increased with increase of diabetes duration, HbA(1c), TC, TG, and number of chronic diabetic complications. Univariate logistic regression showed that diabetes duration, number of chronic diabetic complications, HbA(1c), female gender, and TC were significantly correlated with depressive symptoms (p <0.05). Multivariate logistic regression analysis indicated that variables, i.e., diabetes duration, number of chronic diabetic complications, HbA(1C), and female gender were significantly and independently associated with depressive symptoms (p <0.05). CONCLUSIONS: In this Chinese population, depressive symptoms in subjects with type 2 diabetes were frequent. Diabetes duration, number of chronic diabetic complications, HbA(1C), and female gender were independent risk factors for depressive symptoms. Further research on the relationship between diabetes and depressive symptoms in China was necessary.