Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic beta-cells

The role of the adipocyte-derived factor visfatin in metabolism remains controversial, although some pancreatic ß-cell-specific effects have been reported. This study investigated the effects of visfatin upon insulin secretion, insulin receptor activation and mRNA expression of key diabetes-related genes in clonal mouse pancreatic ß-cells. ß-TC6 cells were cultured in RPMI 1640 and were subsequently treated with recombinant visfatin. One-hour static insulin secretion was measured by ELISA. Phospho-specific ELISA and western blotting were used to detect insulin receptor activation. Real-time SYBR Green PCR array technology was used to measure the expression of 84 diabetes-related genes in both treatment and control cells. Incubation with visfatin caused significant changes in the mRNA expression of several key diabetes-related genes, including marked up-regulation of insulin (9-fold increase), hepatocyte nuclear factor (HNF)1ß (32-fold increase), HNF4a (16-fold increase) and nuclear factor ?B (40-fold increase). Significant down-regulation was seen in angiotensin-converting enzyme (-3.73-fold) and UCP2 (-1.3-fold). Visfatin also caused a significant 46% increase in insulin secretion compared to control (P<0.003) at low glucose, and this increase was blocked by co-incubation with the specific nicotinamide phosphoribosyltransferase inhibitor FK866. Both visfatin and nicotinamide mononucleotide induced activation of both insulin receptor and extracellular signal-regulated kinase (ERK)1/2, with visfatin-induced insulin receptor/ERK1/2 activation being inhibited by FK866. We conclude that visfatin can significantly regulate insulin secretion, insulin receptor phosphorylation and intracellular signalling and the expression of a number of ß-cell function-associated genes in mouse ß-cells.

Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes

Dipeptidyl peptidase IV (DPP IV) is a widely distributed physiological enzyme that can be found solubilized in blood, or membrane-anchored in tissues. DPP IV and related dipeptidase enzymes cleave a wide range of physiological peptides and have been associated with several disease processes including Crohn's disease, chronic liver disease, osteoporosis, multiple sclerosis, eating disorders, rheumatoid arthritis, cancer, and of direct relevance to this review, type 2 diabetes. Here, we place particular emphasis on two peptide substrates of DPP IV with insulin-releasing and antidiabetic actions namely, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The rationale for inhibiting DPP IV activity in type 2 diabetes is that it decreases peptide cleavage and thereby enhances endogenous incretin hormone activity. A multitude of novel DPP IV inhibitor compounds have now been developed and tested. Here we examine the information available on DPP IV and related enzymes, review recent preclinical and clinical data for DPP IV inhibitors, and assess their clinical significance.

Ethnic differences in health related quality of life for patients with type 2 diabetes

Background - The objective of this study was to investigate the association between ethnicity and health related quality of life (HRQoL) in patients with type 2 diabetes. Methods - The EuroQol EQ-5D measure was administered to 1,978 patients with type 2 diabetes in the UK Asian Diabetes Study (UKADS): 1,486 of south Asian origin (Indian, Pakistani, Bangladeshi or other south Asian) and 492 of white European origin. Multivariate regression using ordinary least square (OLS), Tobit, fractional logit and Censored Least Absolutes Deviations estimators was used to estimate the impact of ethnicity on both visual analogue scale (VAS) and utility scores for the EuroQol EQ-5D. Results - Mean EQ-5D VAS and utility scores were lower among south Asians with diabetes compared to the white European population; the unadjusted effect on the mean EQ-5D VAS score was −7.82 (Standard error [SE] = 1.06, p < 0.01) and on the EQ-5D utility score was −0.06 (SE = 0.02, p < 0.01) (OLS estimator). After controlling for socio-demographic and clinical confounders, the adjusted effect on the EQ-5D VAS score was −9.35 (SE = 2.46, p < 0.01) and on the EQ-5D utility score was 0.06 (SE = 0.04), although the latter was not statistically significant. Conclusions - There was a large and statistically significant association between south Asian ethnicity and lower EQ-5D VAS scores. In contrast, there was no significant difference in EQ-5D utility scores between the south Asian and white European sub-groups. Further research is needed to explain the differences in effects on subjective EQ-5D VAS scores and population-weighted EQ-5D utility scores in this context.

Multispectral retinal image analysis (MRIA) for the assessment of subretinal fibrosis in neovascular age-related macular degeneration (nAMD)

Purpose: To investigate the use of MRIA for quantitative characterisation of subretinal fibrosis secondary to nAMD. Methods: MRIA images of the posterior pole were acquired over 4 months from 20 eyes including those with inactive subretinal fibrosis and those being treated with ranibizumab for nAMD. Changes in morphology of the macula affected by nAMD were modelled and reflectance spectra at the MRIA acquisition wavelengths (507, 525, 552, 585, 596, 611 and 650nm) were computed using Monte Carlo simulation. Quantitative indicators of fibrosis were derived by matching image spectra to the model spectra of known morphological properties. Results: The model spectra were comparable to the image spectra, both normal and pathological. The key morphological changes that the model associated with nAMD were gliosis of the IS-OS junction, decrease in retinal blood and decrease in RPE melanin. However, these changes were not specific to fibrosis and none of the quantitative indicators showed a unique association with the degree of fibrosis. Moderate correlations were found with the clinical assessment, but not with the treatment program. Conclusion: MRIA can distinguish subretinal fibrosis from healthy tissue. The methods used show high sensitivity but low specificity, being unable to distinguish scarring from other abnormalities like atrophy. Quantification of scarring was not achieved with the wavelengths used due to the complex structural changes to retinal tissues in the process of nAMD. Further studies, incorporating other wavelengths, will establish whether MRIA has a role in the assessment of subretinal fibrosis in the context of retinal and choroidal pathology

Assessment of Health-Related Quality of Life using the EQ-5D-3L in Individuals with Type 2 Diabetes Mellitus

The daily experience with type 2 diabetes mellitus (T2DM) has significant adverse effects on health-related quality of life (HRQoL). HRQoL assessment is essential for measuring the impact of the disease on the patient and selecting individualized strategies. Generic measures for assessing HRQoL are very useful because, unlike specific measurement instruments, they allow for the comparison with other instruments. The EQ-5D-3L is a generic measure and it describes HRQoL in five dimensions; mobility, self-care, usual activities, pain/discomfort and anxiety/depression, with three levels each. In Portugal, studies using the EQ-5D-3L as a generic measure to assess HRQoL in diabetic patients are scarce. Objective: To assess HRQoL in individuals with T2DM using the Portuguese version of the EQ-5D-3L. Methodology: An accidental sample of patients with T2DM (n=437) was selected at Family Health Units and healthcare centers in Coimbra, Portugal, between January 2013 and January 2014. The EQ-5D-3L was applied in interviews. The EQ-5D-3L score was calculated based on the answers to the five dimensions and the value system for the Portuguese population. Results: In this sample, 100% of the participants answered the EQ-5D-3L. The HRQoL score was 0.6772 in the EQ-5D-3L and 64.85 in the EQ-VAS. The most frequent answers to the five dimensions were no problems or some problems. The mean score of the EQ-5D-3L was significantly associated with age, male gender, high level of education, having an occupation, practicing physical activity, being single and having been diagnosed with T2DM for less time. The Cronbach alpha's value was 0.674, confirming an acceptable internal consistency. Conclusion: HRQoL levels in individuals with T2DM are lower than the national average and vary depending on sociodemographic and clinical characteristics. The EQ-5D-3L is a reliable instrument that can be used to assess the quality of life of diabetic patients and contribute to assess the patients' overall health status, adding data from the subjective dimension of self-care management.

Oxidative Stress And Susceptibility To Mitochondrial Permeability Transition Precedes The Onset Of Diabetes In Autoimmune Non-obese Diabetic Mice.

Beta cell destruction in type 1 diabetes (TID) is associated with cellular oxidative stress and mitochondrial pathway of cell death. The aim of this study was to determine whether oxidative stress and mitochondrial dysfunction are present in T1D model (non-obese diabetic mouse, NOD) and if they are related to the stages of disease development. NOD mice were studied at three stages: non-diabetic, pre-diabetic, and diabetic and compared with age-matched Balb/c mice. Mitochondria respiration rates measured at phosphorylating and resting states in liver and soleus biopsies and in isolated liver mitochondria were similar in NOD and Balb/c mice at the three disease stages. However, NOD liver mitochondria were more susceptible to calcium-induced mitochondrial permeability transition as determined by cyclosporine-A-sensitive swelling and by decreased calcium retention capacity in all three stages of diabetes development. Mitochondria H2O2 production rate was higher in non-diabetic, but unaltered in pre-diabetic and diabetic NOD mice. The global cell reactive oxygen species (ROS), but not specific mitochondria ROS production, was significantly increased in NOD lymphomononuclear and stem cells in all disease stages. In addition, marked elevated rates of 2',7'-dichlorodihydrofluorescein (H2DCF) oxidation were observed in pancreatic islets from non-diabetic NOD mice. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) and lipidomic approach, we identified oxidized lipid markers in NOD liver mitochondria for each disease stage, most of them being derivatives of diacylglycerols and phospholipids. These results suggest that the cellular oxidative stress precedes the establishment of diabetes and may be the cause of mitochondrial dysfunction that is involved in beta cell death.

Beliefs Related To Adherence To Oral Antidiabetic Treatment According To The Theory Of Planned Behavior.

to identify salient behavioral, normative, control and self-efficacy beliefs related to the behavior of adherence to oral antidiabetic agents, using the Theory of Planned Behavior. cross-sectional, exploratory study with 17 diabetic patients in chronic use of oral antidiabetic medication and in outpatient follow-up. Individual interviews were recorded, transcribed and content-analyzed using pre-established categories. behavioral beliefs concerning advantages and disadvantages of adhering to medication emerged, such as the possibility of avoiding complications from diabetes, preventing or delaying the use of insulin, and a perception of side effects. The children of patients and physicians are seen as important social references who influence medication adherence. The factors that facilitate adherence include access to free-of-cost medication and taking medications associated with temporal markers. On the other hand, a complex therapeutic regimen was considered a factor that hinders adherence. Understanding how to use medication and forgetfulness impact the perception of patients regarding their ability to adhere to oral antidiabetic agents. medication adherence is a complex behavior permeated by behavioral, normative, control and self-efficacy beliefs that should be taken into account when assessing determinants of behavior.

Effect Of Roux-en-y Gastric Bypass On Nonalcoholic Fatty Liver Disease Evaluated Through Nafld Fibrosis Score: A Prospective Study.

Nonalcoholic fatty liver disease (NAFLD) is common among subjects who undergo bariatric surgery and its postsurgical improvement has been reported. This study aimed to determine the evolution of liver disease evaluated through NAFLD fibrosis score 12 months after surgery. It is a prospective cohort study which evaluated patients immediately before and 12 months following Roux-en-Y gastric bypass (RYGB). Mean score decreased from 1.142 to 0.066; surgery led to a resolution rate of advanced fibrosis of 55 %. Resolution was statistically associated with female gender, percentage of excess weight loss, postsurgical body mass index, postsurgical platelet count, and diabetes resolution. As previously reported by studies in which postsurgical biopsies were performed, RYGB leads to a great resolution rate of liver fibrosis. Since postsurgical biopsy is not widely available and has a significant risk, calculation of NAFLD fibrosis score is a simple tool to evaluate this evolution through a noninvasive approach.

Reduced Lrp6 Expression And Increase In The Interaction Of Gsk3β With P53 Contribute To Podocyte Apoptosis In Diabetes Mellitus And Are Prevented By Green Tea.

In diabetes mellitus (DM), podocyte apoptosis leads to albuminuria and nephropathy progression. Low-density lipoprotein receptor-related protein 6 (LRP6) is WNT pathway receptor that is involved in podocyte death, adhesion and motility. Glycogen synthase kinase 3 (GSK3) interaction with p53 (GSK3-p53) promotes apoptosis in carcinoma cells. It is unknown if GSK3-p53 contributes to podocyte apoptosis in DM. In experimental DM, green tea (GT) reduces albuminuria by an unknown mechanism. In the present study, we assessed the role of the GSK3β-p53 in podocyte apoptosis and the effects of GT on these abnormalities. In diabetic spontaneously hypertensive rats (SHRs), GT prevents podocyte's p-LRP6 expression reduction, increased GSK3β-p53 and high p53 levels. In diabetic SHR rats, GT reduces podocyte apoptosis, foot process effacement and albuminuria. In immortalized mouse podocytes (iMPs), high glucose (HG), silencing RNA (siRNA) or blocking LRP6 (DKK-1) reduced p-LRP6 expression, leading to high GSK3β-p53, p53 expression, apoptosis and increased albumin influx. GSK3β blockade by BIO reduced GSK3β-p53 and podocyte apoptosis. In iMPs under HG, GT reduced apoptosis and the albumin influx by blocking GSK3β-p53 following the rise in p-LRP6 expression. These effects of GT were prevented by LRP6 siRNA or DKK-1. In conclusion, in DM, WNT inhibition, via LRP6, increases GSK3β-p53 and podocyte apoptosis. Maneuvers that inactivate GSK3β-p53, such as GT, may be renoprotective in DM.

Milk intake and the risk of type 2 diabetes mellitus, hypertension and prostate cancer

Milk intake is widely recommended for a healthy diet. Recent evidences suggest that milk/dairy products are associated with a lower risk of type 2 diabetes and hypertension. On the other hand, high calcium intake has been associated with a higher risk of prostate cancer. The calcium and vitamin D content in dairy foods could have beneficial effects on glucose metabolism and renin/angiotensin system as well regulates body weight. The association between high dairy/calcium consumption and prostate cancer risk are related to the presence of estrogens and insulin like growth factor (IGF-I) in milk. Based on the current evidence, it is possible that milk/dairy products, when consumed in adequate amounts and mainly with reduced fat content, has a beneficial effect on the prevention of hypertension and diabetes. Its potential role in the pathogenesis of prostate cancer is not well supported and requires additional study.

Limitação de atividades e participação social em pacientes com diabetes

Objetivos: Avaliar a limitação de atividades e a participação social em indivíduos portadores de diabetes melito tipo 2. Métodos: Foram avaliados 79 pacientes, utilizando-se a escala SALSA (Screening of Activity Limitation and Safety Awareness - Triagem de Limitação de Atividade e Consciência de Risco), e a escala de Participação, que abrange oito das nove principais áreas da vida definidas na Classificação Internacional de Funcionalidade, Incapacidade e Saúde (CIF) da OMS. Resultados: A idade média dos participantes foi 61,6 ± 9,8 anos, sendo 55,7 por cento do sexo feminino, 68,4 por cento com companheiro(a), 32,9 por cento com renda até 3 salários mínimos e em 13,9 por cento o diabete influenciou na ocupação. O tempo médio de doença foi 10,3 ± 8,9 anos. Tratamento de 39,3 por cento dos participantes foi com insulina, 70,9 por cento com medicação oral, 51,9 por cento com dieta e 45,6 por cento com exercícios físicos. 48,1 por cento apresentavam alguma complicação da doença. A média de pontos SALSA foi 26,5 ± 11,6 e houve maior pontuação quando o tempo de doença foi superior a 10 anos. Com a evolução do diabetes, pode haver necessidade de insulinoterapia, aparecem as complicações, que podem interferir na ocupação. Estes fatores parecem contribuir para a limitação de atividade. A média de pontos na Escala de Participação foi 9,8±10,9, com maior pontuação quando os entrevistados consideraram sua saúde física alterada no último ano e faziam uso de insulina. Conclusões: A limitação de atividades no diabetes melito tipo 2 se associou ao tempo de doença, com possível contribuição de fatores que ocorrem com sua evolução. Auto-avaliação de saúde física alterada e insulinoterapia se associaram a restrição social

The burden of physical activity on type 2 diabetes public healthcare expenditures among adults: a retrospective study

Background: Determinants of public healthcare expenditures in type 2 diabetics are not well investigated in developing nations and, therefore, it is not clear if higher physical activity decreases healthcare costs. The purpose of this study was to analyze the relationship between physical activity and the expenditures in public healthcare on type 2 diabetes mellitus treatment. Methods: Cross-sectional study carried out in Brazil. A total of 121 type 2 diabetics attended to in two Basic Healthcare Units were evaluated. Public healthcare expenditures in the last year were estimated using a specific standard table. Also evaluated were: socio-demographic variables; chronological age; exogenous insulin use; smoking habits; fasting glucose test; diabetic neuropathy and anthropometric measures. Habitual physical activity was assessed by questionnaire. Results: Age (r = 0.20; p = 0.023), body mass index (r = 0.33; p = 0.001) and waist-to-hip ratio (r = 0.20; p = 0.025) were positively related to expenditures on medication for the treatment of diseases other than diabetes. Insulin use was associated with increased expenditures. Higher physical activity was associated with lower expenditure, provided medication for treatment of diseases other than diabetes (OR = 0.19; p = 0.007) and medical consultations (OR = 0.26; p = 0.029). Conclusions: Type 2 diabetics with higher enrollment in physical activity presented consistently lower healthcare expenditures for the public healthcare system.

Theoretical study on the molecular and electronic properties of some substances used for diabetes mellitus treatment

Diabetes mellitus (DM) is a disease that affects a large number of people, and the number of problems associated with the disease has been increasing in the past few decades. These problems include cardiovascular disorders, blindness and the eventual need to amputate limbs. Therefore, the quality of life for people living with DM is less than it is for healthy people. In several cases, metabolic syndrome (MS), which can be considered a disturbance of the lipid metabolism, is associated with DM. In this work, two drugs used to treat DM, pioglitazone and rosiglitazone, were studied using theoretical methods, and their molecular properties were related to the biological activity of these drugs. From the results, it was possible to correlate the properties of each substance-particularly electronic properties-with the biological interactions that are linked to their pharmacological effects. These results suggest that there are future prospects for designing or developing new drugs based on the correlation between theoretical and experimental properties.

Angiotensin receptor blockade improves the net balance of cardiac Ca(2+) handling-related proteins in sympathetic hyperactivity-induced heart failure

Aims: The clinical benefits of angiotensin II type 1 (AT1) receptor blockers (ARB) in heart failure (HF) include cardiac anti-remodeling and improved ventricular function. However, the cellular mechanisms underlying the benefits of ARB on ventricular function need to be better clarified. In the present manuscript, we evaluated the effects of AT1 receptor blockade on the net balance of Ca(2+) handling proteins in hearts of mice lacking alpha(2A) and alpha(2C) adrenoceptors (alpha(2A)/alpha(2C)ARKO), which develop sympathetic hyperactivity (SH) induced-HF. Main methods: A cohort of male wild-type (WT) and congenic alpha(2A)/alpha(2C)ARKO mice in a C57BL6/J genetic background (5-7 mo of age) was randomly assigned to receive either placebo or ARB (Losartan, 10 mg/kg for 8wks). Ventricular function (VF) was assessed by echocardiography, and cardiac myocyte width and ventricular fibrosis by a computer-assisted morphometric system. Sarcoplasmic reticulum Ca(2+) ATPase (SERCA2), phospholamban (PLN), phospho-Ser(16)-PLN, phospho-Thr(17)-PLN, phosphatase 1 (PP1), Na(+)-Ca(2+) exchanger (NCX), Ca(2+)/calmodulin-dependent protein kinase 11 (CaMKII) and phospho-Thr(286)-CaMKII were analyzed by Western blot. Key findings: alpha(2A)/alpha(2C)ARKO mice displayed ventricular dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis paralleled by decreased SERCA2 and increased phospho-Thr(17)-PLN, CaMKII, phospho-Thr(286)-CaMKII and NCX levels. ARB induced anti-cardiac remodeling effect and improved VF in alpha(2A)/alpha(2C)ARKO associated with increased SERCA2 and phospho-Ser(16)-PLN levels, and SERCA2:NCX ratio. Additionally, ARB decreased phospho-Thr(17)-PLN levels as well as reestablished NCX, CaMKII and phospho-Thr(286)-CaMKII toward WT levels. Significance: Altogether, these data provide new insights on intracellular Ca(2+) regulatory mechanisms underlying improved ventricular function by ARB therapy in HF. (c) 2011 Elsevier Inc. All rights reserved.

Association Among Microalbuminuria and Oxidative Stress Biomarkers in Patients With Type 2 Diabetes

Aim: Hyperglycemia in diabetes mellitus (DM) may be one of the most important factors responsible for the development of oxidative stress, which promotes the main complications in DM patients. Therefore, this study evaluated if the hyperglycemia could be related to oxidative stress biomarkers, lipid profile, and renal function in type 2 diabetes patients without clinic complications. Methods: Plasmatic malondialdehyde (MDA), serum protein carbonyl (PCO), serum creatinine levels, microalbuminuria, glycated hemoglobin, and lipid profile were analyzed in 37 type 2 diabetic patients and 25 subjects with no diabetes. Results: Serum creatinine levels were within the reference values, but microalbuminuria presented increased levels in all the patients compared with controls (P G 0.05) and above of the reference values. The MDA, PCO, low- density lipoprotein, and triglyceride levels showed positive correlation with microalbuminuria levels. Moreover, glycated hemoglobin presented positive correlation with MDA, PCO, and microalbuminuria levels. Conclusions: The hyperglycemia could be responsible for the increase of the microalbuminuria levels and for the oxidation process in lipids and proteins in DM patients. Therefore, we suggested that the microvascular lesion is a direct consequence from hyperglycemia and an indirect one from the increased oxidative stress. Malondialdehyde and protein carbonyl levels could be suggested as additional biochemical evaluation to verify tissue damage in type 2 DM patients.