Preparation of a MVL-Ca-Alg/CS MEMs system with add-on effect for type 2 diabetes treatment

Add-on drugs, often called as synergistic therapy, for diabetes have been comparatively more promising as they can reduce the systemic adverse effects resulted during respective monotherapy [metformin (MET)/insulin (INS)]. Herewith, we formulated a multivesicular liposome microparticles-embedded Ca-Alg/chitosan microcapsules (MVL-Ca-Alg/CS MEMs) system by a double-emulsion method using a high voltage electrostatic droplet generator. Physical characterization of the designed formulation was elucidated based on particle size and distribution, drug loading and encapsulation efficiency, drug delivery properties, and pharmacodynamic evaluation. The multivesicular liposomes microparticles (MVLs MPs) and MVL-Ca-Alg/CS MEMs have shown good sphericity and dispersion, and the average diameters were 37 and 491?µm, respectively. The confocal laser scanning microscopic observations demonstrated that fluorescein isothiocyanate-conjugated INS is uniformly dispersed in MVLs MPs, predominantly within the lumen of the polycystic liposome. This multicomponent system possessing INS in the inner space and MET at the outer space resulted in orderly and sustained drug release patterns. Furthermore, the obtained in vivo experimental data have shown that the designed MEMs system resulted in significantly higher hypoglycemic effect compared to pure INS, demonstrating that our multicomponent design has an enormous potential for treating diabetes.     

A feedback glucose control strategy for type II diabetes mellitus based on fuzzy logic

Most patients with severe Type II diabetes mellitus, characterised by both insulin resistance and β‐cell failure, eventually require insulin therapy. According to the nonlinear dynamics of homeostasis of blood glucose, proportional‐integral (PI) controller, modified by penalising the feedback error using a fuzzy inference system has been developed to maintain normoglycaemia in a simulated patient using a closed‐loop insulin infusion pump. The simulation employs a compartment model proposed by Vahidi et al. [Vahidi et al., Biochem. Eng. J. 2011, 55(1), 7–16]. The results demonstrate that the fuzzy‐based PI controller is superior to a conventional PI controller for the regulation of blood glucose by insulin infusion for Type II diabetic patients. © 2012 Canadian Society for Chemical Engineering     

Current Knowledge on the Pathophysiology of Lean/Normal-Weight Type 2 Diabetes

Since early times, being overweight and obesity have been associated with impaired glucose metabolism and type 2 diabetes (T2D). Similarly, a less frequent adult-onset diabetes in low body mass index (BMI) people has been known for many decades. This form is mainly found in developing countries, whereby the largest increase in diabetes incidence is expected in coming years. The number of non-obese patients with T2D is also on the rise among non-white ethnic minorities living in high-income Western countries due to growing migratory flows. A great deal of energy has been spent on understanding the mechanisms that bind obesity to T2D. Conversely, the pathophysiologic features and factors driving the risk of T2D development in non-obese people are still much debated. To reduce the global burden of diabetes, we need to understand why not all obese people develop T2D and not all those with T2D are obese. Moreover, through both an effective prevention and the implementation of an individualized clinical management in all people with diabetes, it is hoped that this will help to reduce this global burden. The purpose of this review is to take stock of current knowledge about the pathophysiology of diabetes not associated to obesity and to highlight which aspects are worthy of future studies.     

Serum Level of MMP-3 and MMP-9 in Patients with Diabetes Mellitus Type 2 Infected with Epstein-Barr Virus

Diabetes mellitus type 2 (DM2) has recently become one of the most important health problems in the world. Patients with DM2 with long-term glycaemia are more likely to become infected than the healthy population. Matrix metalloproteinases (MMPs) play a key role in tissue remodeling during various physiological processes. However, it has been reported that certain MMPs are overexpressed during the development of various human diseases. In this study, we analyzed the levels of MMP-3 and MMP-9 in the serum of DM2 patients with and without Epstein-Barr virus (EBV) infection. The study included 115 patients with DM2 hospitalized in the Internal Ward of the Masovian Specialist Hospital in Radom, Poland, who were divided into two groups: EBV-positive and EBV-negative. The levels of MMP-3 and MMP-9 were tested in the serum of patients using the ELISA method, while the presence of EBV in saliva was tested by polymerase chain reaction (PCR). The presented studies showed a significant difference in the concentration of both MMPs in diabetic patients additionally infected with EBV compared to the group of non-infected individuals. It seems that MMPs may be useful biomarkers in the diagnosis, prognosis, and monitoring of diabetes associated with EBV infection.     

动态血糖监测系统在2型糖尿病患者中的应用

目的探讨不同治疗方式后血糖波动的特点。方法根据糖化血红蛋白(HbA1c)及病程,将抽样对象分为格列美脲(A)组、胰岛素皮下注射(B)组及胰岛素泵(C)组,3组患者血糖控制至目标值即开始进行72h动态血糖监测,根据监测结果调整治疗及饮食。结果 A组的病程、HbA1c及空腹C肽水平明显高于其他2组,其余各项基线资料3组均具有较好的可比性。各组平均血糖值几乎相等;A组低血糖的发生率最低,接近零;B组低血糖的发生率明显高于C组,回归分析显示,B组血糖的波动与晚餐后2h血糖成线性回归关系。结论根据动态血糖监测及双C治疗方案调整降糖药物及饮食规律,可更高效率、更安全地强化血糖控制。     

新型II型糖尿病治疗药物——二肽基肽酶IV抑制剂研究进展

2型糖尿病是一种常见慢性病,严重威胁人类健康,现有药物已无法有效阻止2型糖尿病患者病情的恶化。二肽基肽酶IV（DPP—IV）抑制剂作为一种治疗2型糖尿病的新型药物引起了越来越多的关注。文章介绍了DPP-IV抑制剂药理学作用机制及研究进展。     

Dietary patterns are associated with type 2 diabetes mellitus among middle-aged adults in Zhejiang Province,China

Background

Although some studies have shown the associations between dietary patterns and the risk T2DM in a general population, the associations in middle-aged Chinese have been rarely studied to date. In this study, we aimed to characterize dietary patterns in Chinese adults aged 45-59y (n?=?1918) and to evaluate the relationship between dietary patterns and the risk of T2DM.

Methods

The study population was a part of the population-based the Nutrition and Health Study conducted in the city of Hangzhou, Zhejiang Province, China. Dietary intake was assessed by using a validated food frequency questionnaire (FFQ). Multivariate logistic regression analyses were used to estimate the associations between dietary patterns and the risk of T2DM, adjusting for potential confounders.

Results

Three major dietary patterns were identified using factor analysis, including the traditional southern Chinese, the Western, and the grains-vegetables patterns. After adjusting for the potential confounders, subjects in the highest quartile of the Western dietary pattern scores had greater odds ratio(OR) for T2DM(OR?=?1.28; 95% confidence interval (CI): 1.103–1.697; P?=?0.02) than did those in the lowest quartile. Compared with those in the lowest quartile, subjects in the highest quartile of the grains-vegetables dietary pattern scores had a lower OR for T2DM (OR?=?0.72; 95% CI:0.596–0.952; P?=?0.04). Moreover, no significant association was found between the traditional southern Chinese dietary pattern and risk of developing T2DM.

Conclusions

Our findings indicated that the Western dietary pattern was associated with an elevated risk, whereas the grains-vegetables dietary pattern was associated with a reduced risk of T2DM. Further researches are needed to confirm these findings.

     

Unravelling Novel Roles of Salivary Exosomes in the Regulation of Human Corneal Stromal Cell Migration and Wound Healing

Salivary exosomes have demonstrated vast therapeutic and diagnostic potential in numerous diseases. This study pioneers previously unexplored roles of SE in the context of corneal wound healing by utilizing primary corneal stromal cells from healthy (HCFs), type I diabetes mellitus (T1DMs), type II DM (T2DMs), and keratoconus (HKCs) subjects. Purified, healthy human SEs carrying tetraspanins CD9+, CD63+, and CD81+ were utilized. Scratch and cell migration assays were performed after 0, 6, 12, 24, and 48 h following SE stimulation (5 and 25 µg/mL). Significantly slower wound closure was observed at 6 and 12 h in HCFs with 5 μg/mL SE and T1DMs with 5 and 25 μg/mL SE. All wounds were closed by 24-hour, post-wounding. HKCs, T1DMs, and T2DMs with 25µg/mL SE exhibited a significant upregulation of cleaved vimentin compared to controls. Thrombospondin 1 was significantly upregulated in HCFs, HKCs, and T2DMs with 25 µg/mL SE. Lastly, HKCs, T1DMs, and T2DMs exhibited a significant downregulation of fibronectin with 25 μg/mL SE. Whether SEs can be utilized to clinical settings in restoring corneal defects is unknown. This is the first-ever study exploring the role of SEs in corneal wound healing. While the sample size was small, results are highly novel and provide a strong foundation for future studies.     

Daily Treatment of Mice with Type 2 Diabetes with Adropin for Four Weeks Improves Glucolipid Profile,Reduces Hepatic Lipid Content and Restores Elevated Hepatic Enzymes in Serum

Adropin is a peptide hormone encoded by Energy Homeostasis Associated gene. Adropin modulates energy homeostasis and metabolism of lipids and carbohydrates. There is growing evidence demonstrating that adropin enhances insulin sensitivity and lowers hyperlipidemia in obese mice. The aim of this study was to investigate the effects of daily administration of adropin for four weeks in mice with experimentally induced type 2 diabetes (T2D). Adropin improved glucose control without modulating insulin sensitivity. Adropin reduced body weight, size of adipocytes, blood levels of triacylglycerol and cholesterol in T2D mice. T2D mice treated with adropin had lower liver mass, reduced hepatic content of triacylglycerol and cholesterol. Furthermore, adropin attenuated elevated blood levels of hepatic enzymes (ALT, AST, GGT and ALP) in T2D mice. In T2D mice, adropin increased the circulating adiponectin level. Adropin had no effects on circulating insulin and glucagon levels and did not alter pancreatic islets morphology. These results suggest that adropin improves glucose control, lipid metabolism and liver functions in T2D. In conjunction with reduced lipid content in hepatocytes, these results render adropin as an interesting candidate in therapy of T2D.     

Relationship between Proinflammatory and Antioxidant Proteins with the Severity of Cardiovascular Disease in Type 2 Diabetes Mellitus

Type 2 diabetes mellitus patients are at significant risk of cardiovascular disease, however, the pathophysiology of these complications is complex and incompletely known in this population. The aim of this study was to compare the serum proteome of patients with type 2 diabetes mellitus presenting or not presenting cardiovascular disease with non-diabetic subjects to find essential proteins related to these cardiovascular complications. This cross-sectional study compares the serum proteome by a combination of protein depletion with 2D-DIGE (2-dimension Difference Gel Electrophoresis) methodology. The proteins differentially expressed were identified by MALDI TOF/TOF (Matrix-assisted laser desorption/ionization and Time-Of-Flight ion detector) or LC-MS/MS (Liquid Chromatography coupled to Mass-Mass Spectrometry). Type 2 diabetes mellitus patients with cardiovascular disease showed higher expression of plasma retinol binding protein and glutathione peroxidase-3 compared to those without cardiovascular disease and non-diabetic controls. These results show that proteins related to the inflammatory and redox state appear to play an important role in the pathogenesis of the cardiovascular disease in the type 2 diabetes mellitus patients.     

Blocking of SGLT2 to Eliminate NADPH-Induced Oxidative Stress in Lenses of Animals with Fructose-Induced Diabetes Mellitus

Chronic hyperglycemia triggers an abnormal rise in reactive oxygen species (ROS) that leads to blindness in patients with diabetes mellitus (DM) and cataracts. In this study, the effects of dapagliflozin, metformin and resveratrol on ROS production were investigated in lens epithelial cells (LECs) of animals with fructose-induced DM. LECs were isolated from patients without DM, or with DM devoid of diabetic retinopathy. Animals were treated with 10% fructose for 8 weeks to induce DM, which was verified by monitoring blood pressure and serum parameters. For drug treatments, 1.2 mg/day of dapagliflozin was given for 2 weeks, 500 mg/kg/day of metformin was given, and 10 mg/kg/day of resveratrol was given. Dihydroethidium was used to stain endogenous O₂˙⁻ production in vivo of the LECs. Superoxide production was expressed in the cataract of DM, or patients without DM. Sodium–glucose cotransporter 2 (SGLT2), glucose transporter 1 (GLUT1), GLUT5, the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47/p67-phox, NOX4 and RAGE were significantly increased in LECs with DM. In addition, the dapagliflozin treatment reduced GLUT5, p47/p67-phox, NADPH oxidase 4 (NOX4) and receptor for advanced glycation end products (RAGE) expressions. On the contrary, metformin or resveratrol inhibited p47-phox, GLUT5, and SGLT2 expressions, but not nuclear factor erythroid 2–related factor 2 (NRF2). In summary, dapagliflozin, metformin or resveratrol down-regulated p47-phox expression through SGLT2 inactivation and ROS reduction. These important findings imply that SGLT2 can be blocked to ameliorate oxidative stress in the cataracts of DM patients.     

SGLT2 Inhibitors as the Most Promising Influencers on the Outcome of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease in the Western world, is a common hepatic manifestation of metabolic syndrome (MetS). A specific cure has not yet been identified, and its treatment is currently based on risk factor therapy. Given that the initial accumulation of triglycerides in the liver parenchyma, in the presence of inflammatory processes, mitochondrial dysfunction, lipotoxicity, glucotoxicity, and oxidative stress, can evolve into non-alcoholic steatohepatitis (NASH). The main goal is to identify the factors contributing to this evolution because, once established, untreated NASH can progress through fibrosis to cirrhosis and, ultimately, be complicated by hepatocellular carcinoma (HCC). Several drugs have been tested in clinical trials for use as specific therapy for NAFLD; most of them are molecules used to cure type 2 diabetes mellitus (T2DM), which is one of the main risk factors for NAFLD. Among the most studied is pioglitazone, either alone or in combination with vitamin E, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors. Actually, the most promising category seems to be sodium-glucose cotransporter (SGLT2) inhibitors. Their action is carried out by inhibiting glucose reabsorption in the proximal renal tubule, leading to its increased excretion in urine and decreased levels in plasma. Experimental studies in animal models have suggested that SGLT2 inhibitors may have beneficial modulatory effects on NAFLD/NASH, and several trials in patients have proven their beneficial effects on liver enzymes, BMI, blood lipids, blood glucose, and insulin resistance in NAFLD patients, thus creating strong expectations for their possible use in preventing the evolution of liver damage in these patients. We will review the main pathogenetic mechanisms, diagnostic modalities, and recent therapies of NAFLD, with particular attention to the use of SGLT2 inhibitors.     

The hypoglycemic effect of the kelp on diabetes mellitus model induced by alloxan in rats

Hypoglycemic effects and the use of kelp in diabetes mellitus (DM) model rats induced by alloxan were investigated. Sixty healthy male rats were used to establish DM models by injecting alloxan intraperitoneally. Kelp powder was added to the general forage for the rats. The levels of fasting blood glucose (FBG) were determined by an automatic blood glucose device. Electrochemiluminescence immunoassay was applied to determine the serum levels of insulin. The serum levels of malondialdehyde (MDA) were measured by thiobarbituric acid assay and nitric oxide (NO) by nitrate reductase assay. The activities of superoxide dismutase (SOD) were determined by xanthinoxidase assay and glutathione peroxidase (GSH-Px) by chemical colorimetry. The shape and structure of islet cells were observed with Hematine-Eosin staining, and the expression of superoxide dismutase (SOD) and inducible nitric oxide synthase (iNOS) in islet cells were detected by immunohistochemical assay. The results showed that the serum levels of insulin after treatment with kelp powder increased significantly compared to those in the DM-model group, while the FBG in the medium-high dose treated groups decreased significantly compared to those in the DM-model group (P < 0.05). The levels of MDA and NO in the kelp powder groups were lower than those in the DM-model group, while the activities of SOD and GSH-Px were higher than those in the DM-model group, of which a significant difference existed between the medium-high dose treated groups and the DM-model group (P < 0.05). The shape and structure of islet cells improved with the up-expressing SOD and down-expressing iNOS in the medium-high dose treated groups compared to those in the DM-model group (P < 0.05). There were no significant differences between the medium and high dose treated groups, all above indexes (P > 0.05). It is suggested that kelp might aid recovery of the the islet cell secreting function and reduce the level of FBG by an antioxidant effect.     

D-二聚体测定在2型糖尿病血管病变中的临床分析

目的分析血浆D-二聚体与2型糖尿病血管病变的关系。方法将48例糖尿病组分为无并发症22例,有血管病变26例,并与对照组51例进行比较,采用免疫比浊法测定各组血浆D-二聚体水平。结果结果与对照组比较有血管病变组和无血管病变组,2组糖尿病病人的D-二聚体均明显生高,(P<0.01),有血管病变组较无血管病变组升高明显,2组之间有显著差异(P<0.05)。结论血浆D-二聚体的检测可能对预示糖尿病患者血管并发症的危险性有一定的临床意义。     

Advanced Glycation End Product Inhibitor Pyridoxamine Attenuates IVD Degeneration in Type 2 Diabetic Rats

Type 2 diabetes mellitus (T2DM) is associated with advanced glycation end product (AGE) enrichment and considered a risk factor for intervertebral disc (IVD) degeneration. We hypothesized that systemic AGE inhibition, achieved using pyridoxamine (PM), attenuates IVD degeneration in T2DM rats. To induce IVD degeneration, lumbar disc injury or sham surgery was performed on Zucker Diabetic Sprague Dawley (ZDSD) or control Sprague Dawley (SD) rats. Post-surgery, IVD-injured ZDSD rats received daily PM dissolved in drinking water or water only. The resulting groups were SD uninjured, SD injured, ZDSD uninjured, ZDSD injured, and ZDSD injured + PM. Levels of blood glycation and disc degeneration were investigated. At week 8 post-surgery, glycated serum protein (GSP) levels were increased in ZDSDs compared to SDs. PM treatment attenuated this increase. Micro-MRI analysis demonstrated IVD dehydration in injured versus uninjured SDs and ZDSDs. In the ZDSD injured + PM group, IVD dehydration was diminished compared to ZDSD injured. AGE levels were decreased and aggrecan levels increased in ZDSD injured + PM versus ZDSD injured rats. Histological and immunohistochemical analyses further supported the beneficial effect of PM. In summary, PM attenuated GSP levels and IVD degeneration processes in ZDSD rats, demonstrating its potential to attenuate IVD degeneration in addition to managing glycemia in T2DM.     

Effect of a low-fat diet enriched with oleic acid on postprandial lipemia in patients with type 2 diabetes mellitus

The aim of the present study was to compare the effects of a low-fat diet enriched with oleic acid to those of a low-fat diet enriched with linoleic acid on fasting lipids, postprandial lipemia, and oxidative susceptibility of low-density lipoprotein (LDL) in patients with type 2 diabetes mellitus (DM). In a 3-wk randomized crossover study, eight patients with type 2 DM were given an experimental low-fat diet enriched with either oleic acid or linoleic acid. The oleic-acid-enriched diet contained 5, 15, and 5% energy from saturated, monounsaturated, and polyunsaturated fatty acids, and the linoleic-acid-enriched diet contained 5, 5, and 15% energy from saturated, monounsaturated, and polyunsaturated fatty acids, respectively. In addition to evaluating the fasting lipids and oxidative susceptibility of LDL, we evaluated postprandial lipemia using an oral fat load at the end of each 3-wk dietary phase. There were no significant differences in fasting lipid profile or lag time of LDL oxidation between the two experimental dietary phases. The average and maximal increments of remnant-like particle (RLP) cholesterol levels during oral fat load were significantly higher after the oleic-acid-enriched dietary phase than after the linoleic-acid-enriched dietary phase. The area under the curve of RLP cholesterol was also significantly larger after the oleicacid-enriched dietary phase than after the linoleic-acid-enriched dietary phase. These results suggest that the oleic-acidenriched diet was associated with increased formation of postprandial chylomicron remnants compared with the linoleicacid-enriched diet.     

Ranolazine Attenuates Brain Inflammation in a Rat Model of Type 2 Diabetes

Recent studies suggest a pathogenetic association between metabolic disturbances, including type 2 diabetes (T2DM), and cognitive decline and indicate that T2DM may represent a risk factor for Alzheimer’s disease (AD). There are a number of experimental studies presenting evidence that ranolazine, an antianginal drug, acts as a neuroprotective drug. The aim of the present study was to evaluate the effects of ranolazine on hippocampal neurodegeneration and astrocytes activation in a T2DM rat model. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ) injection. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine and NCD + Metformin. The presence of neurodegeneration was evaluated in the hippocampal cornus ammonis 1 (CA1) region by cresyl violet staining histological methods, while astrocyte activation was assessed by western blot analysis. Staining with cresyl violet highlighted a decrease in neuronal density and cell volume in the hippocampal CA1 area in diabetic HFD/STZ + Vehicle rats, while ranolazine and metformin both improved T2DM-induced neuronal loss and neuronal damage. Moreover, there was an increased expression of GFAP in the HFD/STZ + Vehicle group compared to the treated diabetic groups. In conclusion, in the present study, we obtained additional evidence supporting the potential use of ranolazine to counteract T2DM-associated cognitive decline.