Juhong Yang

Effects of 24-week treatment with acarbose on glucagon-like peptide 1 in newly diagnosed type 2 diabetic patients: a preliminary report.

BackgroundTreatment with the alpha-glucosidase inhibitor (AGI) acarbose is associated with a significant reduction the risk of cardiovascular events. However, the underlying mechanisms of this effect are unclear. AGIs were recently suggested to participate in stimulating glucagon-like peptide 1 (GLP-1) secretion. We therefore examined the effects of a 24-week treatment of acarbose on endogenous GLP-1, nitric oxide (NO) levels, nitric oxide synthase (NOS) activity, and carotid intima-media thickness (CIMT) in newly diagnosed patients with type 2 diabetes (T2D).MethodsBlood was drawn from 24 subjects (14 male, 10 female, age: 50.7 ± 7.36 years, BMI: 26.64 ± 3.38 kg/m2, GHbA1c: 7.00 ± 0.74%) with drug-naïve T2D at 0 and 120 min following a standard mixed meal for the measurements of active GLP-1, NO and NOS. The CIMT was measured prior to and following 24 weeks of acarbose monotherapy (mean dose: 268 mg daily).ResultsFollowing 24 weeks of acarbose treatment, both fasting and postprandial plasma GLP-1 levels were increased. In patients with increased postprandial GLP-1 levels, serum NO levels and NOS activities were also significantly increased and were positively related to GLP-1 levels. Although the CIMT was not significantly altered following treatment with acarbose, a decreased CIMT was negatively correlated with increased GLP-1 levels.ConclusionsTwenty-four weeks of acarbose monotherapy in newly diagnosed patients with T2D is associated with significantly increased levels of both fasting and postprandial GLP-1 as well as significantly increased NO levels and NOS activity for those patients in whom postprandial GLP-1 levels were increased. Therefore, the benefits of acarbose on cardiovascular risk may be related to its stimulation of GLP-1 secretion.

Alteration of the intestinal barrier and GLP2 secretion in Berberine-treated type 2 diabetic rats

For centuries, Berberine has been used in the treatment of enteritis in China, and it is also known to have anti-hyperglycemic effects in type 2 diabetic patients. However, as Berberine is insoluble and rarely absorbed in gastrointestinal tract, the mechanism by which it works is unclear. We hypothesized that it may act locally by ameliorating intestinal barrier abnormalities and endotoxemia. A high-fat diet combined with low-dose streptozotocin was used to induce type 2 diabetes in male Sprague Dawley rats. Berberine (100 mg/kg) was administered by lavage to diabetic rats for 2 weeks and saline was given to controls. Hyperinsulinemia and insulin resistance improved in the Berberine group, although there was no significant decrease in blood glucose. Berberine treatment also led to a notable restoration of intestinal villi/mucosa structure and less infiltration of inflammatory cells, along with a decrease in plasma lipopolysaccharide (LPS) level. Tight junction protein zonula occludens 1 (ZO1) was also decreased in diabetic rats but was restored by Berberine treatment. Glutamine-induced glucagon-like peptide 2 (GLP2) secretion from ileal tissue decreased dramatically in the diabetic group but was restored by Berberine treatment. Fasting insulin, insulin resistance index, plasma LPS level, and ZO1 expression were significantly correlated with GLP2 level. In type 2 diabetic rats, Berberine treatment not only augments GLP2 secretion and improves diabetes but is also effective in repairing the damaged intestinal mucosa, restoring intestinal permeability, and improving endotoxemia. Whether these effects are mechanistically related will require further studies, but they certainly support the hypothesis that Berberine acts via modulation of intestinal function.

Liraglutide reduces the body weight and waist circumference in Chinese overweight and obese type 2 diabetic patients.

Aim:To investigate the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor activator, on body weight and waist circumference in Chinese overweight and obese type 2 diabetic patients.Methods:A total of 328 Chinese overweight and obese type 2 diabetic patients were included in this multi-center, open-labeled and self-controlled clinical study. The patients were subcutaneously injected with liraglutide once daily for 24 weeks as add-on therapy to their previous hypoglycemic treatments. Statistical analyses were performed using SPSS software package version 11.5 for Windows.Results:Liraglutide treatment caused significant reduction of the mean body weight (from 86.61±14.09 to 79.10±13.55 kg) and waist circumference (from 101.81±13.96 to 94.29±14.17 cm), resulting in body weight lose of 5%–10% in 43.67% patients, and body weight loss above 10% in 34.06% patients, who had significant lower plasma creatinine levels. Baseline waist circumference, BMI and HOMA-IR were independently correlated with the body weight loss. Furthermore, liraglutide treatment significantly decreased HbA1c levels (from 8.66%±2.17% to 6.92%±0.95%) with HbA1c<7.0% in 35.37% patients, who had a significantly lower baseline level of HbA1c, but higher baseline levels of C peptide and glucagon. Moreover, liraglutide treatment resulted in greater body weight loss in patients with a long duration of diabetes, and better glycemic control in patients with a short duration of diabetes.Conclusion:Liraglutide significantly reduces body weight and waist circumference in Chinese overweight and obese type 2 diabetic patients. Patients with apparent visceral obesity, insulin resistance and a long duration of diabetes may have greater body weight loss; whereas patients with high insulin-secreting ability, hyperglucagonemia, and short-duration diabetes may obtain better glycemic control with liraglutide.

Renal tubular damage may contribute more to acute hyperglycemia induced kidney injury in non-diabetic conscious rats.

AIMS Growing evidences suggest that acute hyperglycemia is strongly related to kidney injury. Our study aimed to investigate the effects of acute hyperglycemia on kidney glomerular and tubular impairment in non-diabetic conscious rats. METHODS Non-diabetic conscious rats were randomly subjected to 6h of saline (control group) or high glucose (acute hyperglycemia group) infusion. Blood glucose was maintained at 16.0-18.0 mmol/L in acute hyperglycemia group. Renal structure and function alterations, systemic/renal inflammation and oxidative stress markers were assessed, and apoptosis markers of renal inherent cells were evaluated. RESULTS Acute hyperglycemia caused significant injury to structure of glomerular filtration barrier, tubular epithelial cells and peritubular vascular endothelial cells. It increased urinary microalbumin (68.01 ± 27.09 μg/24h vs 33.81 ± 13.81 μg/24h , P=0.014), β2-microglobulin, Cystatin C, urinary and serous neutrophil gelatinase-associated lipocalin levels (P < 0.05). Acute hyperglycemia decreased megalin and cubilin expression, activated systemic and renal oxidative stress as well as inflammation and promoted renal inherent cell apoptosis. CONCLUSIONS Acute hyperglycemia causes significant injury to kidney function and structure. Compared with damages of glomerular filtration barrier, renal tubular injury may contribute more to acute hyperglycemia induced proteinuria. Activation of inflammation especially renal inflammation, oxidative stress and enhanced apoptosis may be the underlying mechanisms.

Clinical Characteristics and Predictive Factors of Subclinical Diabetic Nephropathy

BACKGROUND To investigate the clinical characteristics and predictive factors of subclinical diabetic nephropathy in type 2 diabetes patients. METHODS A total of 298 type 2 diabetes patients were divided into 3 groups based on 24-h urinary microalbumin and estimated glomerular filtration rate: patients with normal albuminuria and glomerular filtration rate (NC), patients with normoalbuminuria and glomerular hyperfiltration (SDN) and patients with microalbuminuria (EDN). The renal size, tubular injury markers and ambulatory blood pressure were analyzed. RESULTS Renal size increased in the SDN and EDN groups compared to the NC group (P<0.05), while renal length in the SDN group was greater than the EDN group (P<0.05). Patients in the SDN and EDN groups had higher level of urine retinol binding protein and N-acetyl-β-D-glucosaminidase and most of them developed proximal tubular dysfunction. The SDN group had higher 24-h mean and nocturnal diastolic blood pressure than the NC group (P<0.05), while the EDN group had higher systolic blood pressure and pulse pressure than the SDN group (P<0.01). More patients developed abnormal blood pressure rhythm in the SDN and EDN groups. The likelihood of a decrease in nocturnal systolic blood pressure was lower as the microalbuminuria increased. Increased renal size, more abnormal tubular injury markers and higher 24-h mean and nocturnal blood pressure were all risk factors of subclinical diabetic nephropathy. CONCLUSION Patients with subclinical diabetic nephropathy had increased renal size, abnormal tubular injury markers, high blood pressure and abnormal circadian rhythm.

Triptolide prevents extracellular matrix accumulation in experimental diabetic kidney disease by targeting microRNA-137/Notch1 pathway†

MicroRNAs (miRNAs) are involved in multiple biological functions via suppressing target genes. Triptolide is a monomeric compound isolated from a traditional Chinese herb, which exerts protective roles in many kinds of glomerular diseases. However, our understanding of the triptolide effect on miRNAome is still limited. In this study, we found that triptolide significantly decreased albuminuria and improved glomerulosclerosis in rats with diabetic kidney disease (DKD). And triptolide also inhibited extracellular matrix (ECM) protein accumulation and the notch1 pathway activation under diabetic conditions. MiR‐137 was significantly decreased in the HG (high glucose)‐treated HRMCs and in the kidney tissues of the diabetic rats, but was upregulated by triptolide. In addition, overexpression of miR‐137 exerted similar effects to those of triptolide, while miR‐137 inhibition aggravated ECM protein accumulation. Luciferase reporter assay results demonstrated that miR‐137 directly targets Notch1. Furthermore, the miR‐137‐dependent effects were due to Notch1 suppression that in turn inhibited ECM protein expression, key mediators of glomerulosclerosis. Finally, downregulation of miR‐137 reversed the ECM inhibition role of triptolide in HG cultured HRMCs. Taken together, these findings indicate that triptolide is a potential therapeutic option for DKD and that miR‐137/Notch1 pathway play roles in the anti‐glomerulosclerosis mechanism of triptolide.

Atorvastatin inhibits insulin synthesis by inhibiting the Ras/Raf/ERK/CREB pathway in INS-1 cells.

Backround:Type 2 diabetes has become a global epidemic disease. Atorvastatin has become a cornerstone in the prevention and treatment of atherosclerosis. However, increasing evidence showed that statins can dose-dependently increase the risk of diabetes mellitus. The mechanism is not clear. Objective:The Ras complex pathway (Ras/Raf/extracellular signal-regulated kinase [ERK]/cAMP response element-binding protein [CREB]) is the major pathway that regulates the gene transcription. Except for the inhibition of cholesterol synthesis by inhibiting the 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-COA) reductase, statins can also downregulate the phosphorylation of a series of downstream substrates including the key proteins of the Ras complex pathway, therefore may inhibit the insulin syntheses in pancreatic beta cells. In our study, we investigated the inhibitory effect and the underlying mechanism of atorvastatin on insulin synthesis in rat islets. Methods:Islets were isolated from Wistar rats and cultured in Roswell Park Memorial Institute (RPMI)-1640 medium. The insulin content in the medium was measured by radioimmunoassay before and after the treatment of 50 &mgr;M atorvastatin. Effect of atorvastatin on the expression of insulin message Ribonucleic acid (mRNA) in pancreatic islet beta cells was also detected using quantitative real-time polymerase chain reaction. Western blotting was used to explore the possible role of the Ras complex pathway (Ras/Raf/ERK/CREB) in atorvastatin-inhibited insulin synthesis. The effects of atorvastatin on the binding of nuclear transcription factor p-CREB with CRE in INS-1 cells were examined via chromatin immunoprecipitation assay. Results:Compared with the control group, the insulin level decreased by 27.1% at 24 hours after atorvastatin treatment. Atorvastatin inhibited insulin synthesis by decreasing insulin mRNA expression of pancreatic islet beta cells. The activities of Ras, Raf-1, and p-CREB in the Ras complex pathway were inhibited by 50 &mgr;M atorvastatin in INS-1 cells in vitro. Moreover, 50 &mgr;M atorvastatin reduced the binding of p-CREB with deoxyribonucleic acid (DNA) in INS-1 cells in vitro. Conclusion:Atorvastatin inhibits insulin synthesis in beta cells by inhibiting the activation of the Ras complex pathway.

Glucagon secretion is increased in patients with Type 2 diabetic nephropathy

AIMS Currently little is known about the relationship between renal function, albuminuria and glucagon; we analyzed the secretion of glucagon (GLA) and C-peptide in Type 2 diabetic patients with different degrees of nephropathy. METHODS 357 patients with Type 2 diabetes including 119 cases without nephropathy and 238 cases with nephropathy were divided into four groups according to the stages of diabetic nephropathy. Patients with diabetic nephropathy were further classified according to the level of estimated glomerular filtration rate (eGFR). OGTT and insulin, C-peptide, glucagon releasing tests were performed in all patients. Characteristics of glucagon and C-peptide secretion in different groups were compared. Glucagon/glucose ratio (GLA/GLU) and glucagon/insulin ratio (GLA/INS) were used to represent the inhibition of glucose or insulin on glucagon secretion, respectively. RESULTS With the progress of diabetic nephropathy, glucagon level increased significantly; the glucagon peak after glucose load delayed from 60 min to 120 min, whereas C-peptide level decreased significantly. Related factors analysis suggested that glucagon was independently correlated with eGFR. Further analysis showed that glucagon level was higher in group with eGFR<60 ml/min compared with that in group with eGFR≥60 ml/min. In addition, both GLA/INS and GLA/GLU were higher in group with eGFR<60 ml/min compared with those in group with eGFR≥60 ml/min. CONCLUSIONS Patients with Type 2 diabetic nephropathy have worsened islet alpha and beta cell function. Therefore medications based on the regulation of glucagon secretion may improve glycemic control and also be beneficial for delaying the progress of diabetic nephropathy.

Effects of metformin and sitagliptin on glycolipid metabolism in type 2 diabetic rats on different diets

Introduction The aim of the study was to investigate the effects of metformin and sitagliptin on glycolipid metabolism in type 2 diabetes after different diets. Material and methods Seventy Male Sprague Dawley rats were fed with a high fat diet followed by streptozotocin treatment to induce type 2 diabetes. Then all rats were randomly divided into a control group, a metformin group (200 mg/kg), and a sitagliptin group (10 mg/kg). Each group was further divided into 4 groups receiving one load of high carbohydrate diet (45% glucose, 4.5 ml/kg), high fat diet (20% lipid emulsion, 4.5 ml/kg), high protein diet (20% whey protein, 10 ml/kg) or mixed meal, respectively. The caloric densities were all 33 kJ/kg. Postprandial blood glucose (P2BG), triglyceride (TG), glucagon-like peptide-1 (GLP-1), glucagon and insulin levels were measured. Results In the high carbohydrate group, sitagliptin was more efficient in lowering P2BG compared with metformin (p < 0.05). In the high-fat group, metformin was more powerful in lowering TG (p < 0.05) and P2BG (p < 0.05) levels because of its improvement of insulin sensitivity. In the high protein diet group, metformin did not reduce the P2BG level (p > 0.05), although it did reduce the TG level (p < 0.05). In the mixed diet group, metformin was more efficient in lowering P2BG (p < 0.05) but had a similar effect on TG (p > 0.05) compared with sitagliptin. Conclusions In the type 2 diabetic model, metformin and sitagliptin have different effects on glycolipid metabolism after different diets. If it is proved in type 2 diabetic patients, then different medicines may be recommended according to different diets in order to improve glycolipid metabolism.

An Analysis of Cancer Incidence in Tianjin from 2002 to 2011

Objective: To investigate the characteristics and trends of cancer incidence from 2002 to 2011 in the Tianjin area of China. Methods: Based on the Tianjin Public Health Bureau statistics data from 2002 to 2011, the incidences of cancer were analyzed according to sex, age group, cancer site, and geographic region (Tianjin area versus overall China from 2003 to 2007). Results: The crude incidence of cancer in Tianjin was 162.33 per 100,000 (men: 163.22 per 100,000; women: 161.43 per 100,000). Age-standardized incidences according to the Chinese standard population (Age-standardized rate (ASR) China) and the world standard population were 84.05 and 107.67 per 100,000, respectively. From 2002 to 2011, the incidence of cancer increased from year to year. Age-specific incidence reached a peak at 703.60 per 100,000 in the age group of 75–79 years old. Among group between 25 and 54 years old, the cancer incidence rate of the male group was significantly lower than that of the female group ( P<0.05) ; Among people aged over 60, the cancer incidence rate of the male group was significantly higher than that of the female group ( P<0.05) . The most common cancer in Tianjin residents was lung cancer, followed by breast cancer, colorectal cancer, stomach cancer, and liver cancer. The five most common sites for cancer in men were lung, liver, stomach, colorectal, and bladder, while in women were breast, lung, colorectal, stomach, and cervix. Conclusions: From 2002 to 2011, the incidence of cancer has been increasing. In view of the high incidence of lung and breast cancers in Tianjin, early screening focused on high-risk groups should be implemented to improve early diagnosis and treatment for these cancers.