Use of flash glucose-sensing technology in patients with type 2 diabetes treated with liraglutide combined with CSII: a pilot study

Glycemic variability (GV) may be linked to the development of diabetic complications by inducing inflammation, oxidative stress, and endothelial dysfunction. Flash glucose monitoring (FGM) provides a novel method of continuously monitoring interstitial glucose levels for up to 14 days. This study randomly assigned poorly controlled type 2 diabetes mellitus patients treated with metformin and multiple daily injections of insulin (n=60) to either continuous subcutaneous insulin infusion (CSII) treatment or CSII in combination with liraglutide (CSII+Lira) treatment for 14 days during hospitalization. GV was assessed using a FGM system; weight and cardiometabolic biomarkers were also evaluated. The coefficient of variation was significantly reduced in the CSII+Lira group (P<0.001), while no significant change was observed in the CSII group. The changes differed significantly between the two groups in mean amplitude of glycemic excursions (P=0.004), standard deviation (P=0.006), and the percentage of time in the target range (4-10 mmol/L, P=0.005 and >10 mmol/L, P=0.028). The changes in mean of daily differences, interquartile range, and percentage of time in hypoglycemia (<3.3 mmol/L) and hyperglycemia (>13.9 mmol/L) identified by FGM showed no difference. Treatment with liraglutide increased serum adiponectin [33.5 (3.5, 47.7) pg/mL, P=0.003] and heme oxygenase-1 levels [0.4 (-0.0, 1.8) ng/mL, P=0.001] and reduced serum leptin levels [-2.8 (3.9) pg/mL, P<0.001]. Adding the glucagon-like peptide-1 analog liraglutide improved GV, weight, and some cardiometabolic risk markers. The FGM system is, therefore, shown to be a novel and useful method for glucose monitoring.

Use of flash glucose-sensing technology in patients with type 2 diabetes treated with liraglutide combined with CSII: a pilot study.

Glycemic variability (GV) may be linked to the development of diabetic complications by inducing inflammation, oxidative stress, and endothelial dysfunction. Flash glucose monitoring (FGM) provides a novel method of continuously monitoring interstitial glucose levels for up to 14 days. This study randomly assigned poorly controlled type 2 diabetes mellitus patients treated with metformin and multiple daily injections of insulin (n=60) to either continuous subcutaneous insulin infusion (CSII) treatment or CSII in combination with liraglutide (CSII+Lira) treatment for 14 days during hospitalization. GV was assessed using a FGM system; weight and cardiometabolic biomarkers were also evaluated. The coefficient of variation was significantly reduced in the CSII+Lira group (P<0.001), while no significant change was observed in the CSII group. The changes differed significantly between the two groups in mean amplitude of glycemic excursions (P=0.004), standard deviation (P=0.006), and the percentage of time in the target range (4-10 mmol/L, P=0.005 and >10 mmol/L, P=0.028). The changes in mean of daily differences, interquartile range, and percentage of time in hypoglycemia (<3.3 mmol/L) and hyperglycemia (>13.9 mmol/L) identified by FGM showed no difference. Treatment with liraglutide increased serum adiponectin [33.5 (3.5, 47.7) pg/mL, P=0.003] and heme oxygenase-1 levels [0.4 (-0.0, 1.8) ng/mL, P=0.001] and reduced serum leptin levels [-2.8 (3.9) pg/mL, P<0.001]. Adding the glucagon-like peptide-1 analog liraglutide improved GV, weight, and some cardiometabolic risk markers. The FGM system is, therefore, shown to be a novel and useful method for glucose monitoring.

Triptolide enhances the sensitivity of pancreatic cancer PANC-1 cells to gemcitabine by inhibiting TLR4/NF-κB signaling.

BACKGROUND: This study aimed to investigate roles of Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling in triptolide (TPL)-induced sensitivity of pancreatic cancer cells to gemcitabine (GEM). METHODS: In vitro, pancreatic cancer PANC-1 cells were treated with lipopolysaccharide (LPS) to activate TLR4, TLR4-siRNA, GEM alone, or GEM plus TPL. In vivo, nude mice bearing PANC-1 cell xenografts were treated with GEM, TPL, or both. Cell proliferation was detected by MTT assay and Ki-67 staining. Apoptosis was assessed by flow cytometry and TUNEL assay. A double luciferase reporter gene was used to detect NF-κB activity. RESULTS: The sensitivity of PANC-1 cells to GEM was reduced by LPS but enhanced by TLR4-siRNA. TPL inhibited expression of TLR4/NF-κB signaling components, which was reversed by LPS. The TPL+GEM group showed more apoptosis than the LPS+TPL+GEM group. Moreover, the activity of NF-κB and the expression of TLR4, p-p65 Survivin, CyclinD1 and Bcl-2 in the TPL+GEM group were lower than in the LPS+TPL+GEM group, whereas Bax expression was higher. The volume of transplanted tumors in the TPL+GEM group was lower than that in the TPL or GEM group. Phospho-p65, Survivin, CyclinD1 and Bcl-2 expression in transplanted tumors was lower in TPL+GEM group than in either single drug group. The Ki-67 staining score of the TPL+GEM group was lower and tumor cells apoptosis rate was increased when compared with TPL or GEM alone. CONCLUSIONS: TPL enhances the sensitivity of pancreatic cancer PANC-1 cells to GEM by inhibiting TLR4/NF-κB signaling.

Continuous subcutaneous insulin infusion combined with liraglutide reduced glycemic variability and oxidative stress in type 2 diabetes mellitus: a study based on the flash glucose monitoring system.

We aimed to explore the use of the flash glucose monitoring (FGM) system in hospitalized newly diagnosed type 2 diabetes mellitus (T2DM) patients and to evaluate a new combination therapy of continuous subcutaneous insulin infusion (CSII) with or without liraglutide. This was an open-label, randomized study that was conducted in 60 newly diagnosed T2DM patients. The patients were randomized to receive either CSII (n = 30) or CSII + liraglutide (n = 30). The FGM system was used to assess the glycemic control and glycemic variability (GV) indices for 2 weeks. Mean blood glucose concentration (MBG), estimated hemoglobin A1c (HbA1c), and measures of GV, including the standard deviation of the mean glucose (SD), coefficient of variation (CV), interquartile range (IQR), mean amplitude of glycemic excursions (MAGE), largest amplitude of glycemic excursions (LAGE), and mean of daily difference (MODD) were compared between the two groups. Two oxidative stress biomarkers, 4-hydroxynonenal (4-HNE) and 8-hydroxydeoxyguanosine (8-OHdG), were measured before and after treatment. The estimated HbA1c and MBG decreased in both groups, especially the CSII + liraglutide group. SD, IQR, LAGE, and MODD were significantly lower in the CSII + liraglutide group than in the CSII group (all p < 0.05); there was no difference in CV or MAGE (p > 0.05). Similarly, the 4-HNE and 8-OHdG levels were significantly lower in the CSII + liraglutide group (p < 0.05). Our findings suggest that CSII with liraglutide was superior to CSII monotherapy in improving glycemic control and glycemic variability and in decreasing oxidative stress markers. Flash glucose monitoring can successfully provide ambulatory glucose profile data in the real world.

Long non-coding RNA ASncmtRNA-2 is upregulated in diabetic kidneys and high glucose-treated mesangial cells.

Diabetic nephropathy (DN) is one of the most frequent complications associated with type I and II diabetes mellitus. Kidneys from patients with DN are characterized by mesangial matrix expansion and increased thickness of the glomerular basement membrane, which are induced by reactive oxygen species (ROS) production. Previous studies have been conducted to investigate this; however, the detailed mechanism of DN progression remains to be elucidated. The present study evaluated the expression of antisense mitochondrial non-coding RNA-2 (ASncmtRNA-2) in an experimental DN model and cultured human mesangial cells. When mice that exhibited genetic type II diabetes developed DN, ASncmtRNA-2 expression was significantly increased (P=0.017) and was positively correlated with pro-fibrotic factor transforming growth factor ß1 (TGFß1) expression and its downstream gene, fibronectin. Inhibition of ROS through administration of the nitric oxide synthase inhibitor, NG-nitro-L-Arginine methylester (L-NAME), significantly reduced (P=0.022) the upregulation of ASncmtRNA-2 in DN. In cultured human renal mesangial cells (HRMCs), ASncmtRNA-2 was upregulated by high glucose stimuli in a time-dependent manner. Glucose-induced upregulation of ASncmtRNA-2 was also reduced by co-incubation of HRMCs with L-NAME. Notably, specific short hairpin RNA against ASncmtRNA-2 significantly downregulated the expression of TGFß1 in HRMCs. The present study suggests that ASncmtRNA-2 is upregulated by ROS and may promote glomerular fibrosis in DN via positively regulating the expression of pro-fibrotic factors. These findings may provide novel potential therapeutic and preventative treatments for DN.

Triptolide induces apoptosis and inhibits the growth and angiogenesis of human pancreatic cancer cells by downregulating COX-2 and VEGF.

Triptolide (TPL) inhibits the growth and proliferation of a wide range of human cancer cells, but the underlying mechanism is largely unknown. Here, we report that TPL induces apoptosis and inhibits proliferation of PANC-1 pancreatic cancer cells by downregulating cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF). Cell viability and apoptosis were measured by MTT assay and flow cytometry. Real-time PCR and Western blot were used to examine the expression of COX-2 and VEGF. The Matrigel angiogenesis and Transwell migration were employed to assess tube formation and cell migration. Pancreatic cancer mouse xenografts were established to investigate the in vivo antitumor effects of TPL. TUNEL staining and immunohistochemistry were used to detect the apoptosis rate and protein expression in tumor tissues. TPL inhibited the proliferation of pancreatic cancer cells in a time and concentration-dependent manner and decreased the expression of COX-2 and VEGF in vitro. Furthermore, medium from TPL-treated PANC-1 cells inhibited the proliferation, migration, and tube formation of HUVECs. TPL significantly reduced the growth of pancreatic cancer mouse xenografts, accompanied by an induction of apoptosis, inhibition of angiogenesis, and reduction of COX-2 and VEGF. Our data indicate that suppressing the expression of COX-2 and VEGF may be one of the molecular mechanisms by which TPL induces apoptosis and inhibits the growth and angiogenesis of human pancreatic cancer cells.

Continuous and low-energy 125I seed irradiation changes DNA methyltransferases expression patterns and inhibits pancreatic cancer tumor growth.

BACKGROUND: Iodine 125 (125I) seed irradiation is an effective treatment for unresectable pancreatic cancers. However, the radiobiological mechanisms underlying brachytherapy remain unclear. Therefore, we investigated the influence of continuous and low-energy 125I irradiation on apoptosis, expression of DNA methyltransferases (DNMTs) and cell growth in pancreatic cancers. MATERIALS AND METHODS: For in vitro 125I seed irradiation, SW-1990 cells were divided into three groups: control (0 Gy), 2 Gy, and 4 Gy. To create an animal model of pancreatic cancer, the SW 1990 cells were surgically implanted into the mouse pancreas. At 10 d post-implantation, the 30 mice with pancreatic cancer underwent 125I seed implantation and were separated into three groups: 0 Gy, 2 Gy, and 4 Gy group. At 48 or 72 h after irradiation, apoptosis was detected by flow cytometry; changes in DNMTs mRNA and protein expression were assessed by real-time PCR and western blotting analysis, respectively. At 28 d after 125I seed implantation, in vivo apoptosis was evaluated with TUNEL staining, while DNMTs protein expression was detected with immunohistochemical staining. The tumor volume was measured 0 and 28 d after 125I seed implantation. RESULTS: 125I seed irradiation induced significant apoptosis, especially at 4 Gy. DNMT1 and DNMT3b mRNA and protein expression were substantially higher in the 2 Gy group than in the control group. Conversely, the 4 Gy cell group exhibited significantly decreased DNMT3b mRNA and protein expression relative to the control group. There were substantially more TUNEL positive in the 125I seed implantation treatment group than in the control group, especially at 4 Gy. The 4 Gy seed implantation group showed weaker staining for DNMT1 and DNMT3b protein relative to the control group. Consequently, 125I seed implantation inhibited cancer growth and reduced cancer volume. CONCLUSION: 125I seed implantation kills pancreatic cancer cells, especially at 4 Gy. 125I-induced apoptosis and changes in DNMT1 and DNMT3b expression suggest potential mechanisms underlying effective brachytherapy.

[Effect of the Wnt/LRP5/ß-catenin signaling pathway on the pathogenesis of postmenopausal osteoporosis].

OBJECTIVE: To investigate the role of the Wnt/LRP5/ß-catenin signaling pathway in the pathogenesis of postmenopausal osteoporosis. METHODS: Fifty female Wistar rats aged 6-month-old, were randomly divided into control group (NS, n = 24) and ovariectomized group (NOVX, n = 26), NOVX underwent bilateral ovariectomy. At 0, 4 and 8 weeks, all of rats were measured blood estrogen (E(2)) and bone mineral density (BMD), 4 and 8 weeks, low density lipoprotein receptor-related protein 5 (LRP5), ß-catenin and Runx2 mRNA in bone were measured respectively by reverse transcription (RT)-PCR. RESULTS: In 4 and 8 weeks, compared with NS which had (117 ± 29) and (114 ± 15) pmol/L in E(2) level, (0.098 ± 0.016) and (0.095 ± 0.028) g/cm(2) in BMD, NOVX had significantly decreased to (92 ± 15) and (95 ± 22) pmol/L in E(2) level (P < 0.05), (0.076 ± 0.016) and (0.052 ± 0.013) g/cm(2) in BMD values (P < 0.01). And bone tissue LRP5, ß-catenin and Runx2 mRNA expression was 1.02 ± 0.06, 1.04 ± 0.05, 1.07 ± 0.21 in NS, NOVX was significantly reduced to 0.97 ± 0.04, 0.58 ± 0.05, 0.86 ± 0.03 (P < 0.05). CONCLUSION: Wnt/LRP5/ß-catenin signaling pathway may be important in the pathogenesis of postmenopausal osteoporosis.