scholarly journals Systemic AAV10.COMP-Ang1 rescues renal glomeruli and pancreatic islets in type 2 diabetic mice

2020 ◽  
Vol 8 (1) ◽  
pp. e000882
Author(s):  
Mi Tian ◽  
Lara S Carroll ◽  
Li Tang ◽  
Hironori Uehara ◽  
Christof Westenfelder ◽  
...  

IntroductionDiabetic hyperglycemia causes progressive and generalized damage to the microvasculature. In renal glomeruli, this results in the loss of podocytes with consequent loss of constitutive angiopoietin-1 (Ang1) signaling, which is required for stability of the glomerular endothelium. Repeated tail vein injection of adenovirus expressing COMP-Ang1 (a stable bioengineered form of Ang1) was previously reported to improve diabetic glomerular damage despite the liver and lungs being primary targets of adenoviral infection. We thus hypothesized that localizing delivery of sustained COMP-Ang1 to the kidney could increase its therapeutic efficacy and safety for the treatment of diabetes.Research design and methodsUsing AAVrh10 adeno-associated viral capsid with enhanced kidney tropism, we treated 10-week-old uninephrectomized db/db mice (a model of type 2 diabetes) with a single dose of AAVrh10.COMP-Ang1 delivered via the intracarotid artery, compared with untreated diabetic db/db control and non-diabetic db/m mice.ResultsSurprisingly, both glomerular and pancreatic capillaries expressed COMP-Ang1, compensating for diabetes-induced loss of tissue Ang1. Importantly, treatment with AAVrh10.COMP-Ang1 yielded a significant reduction of glycemia (blood glucose, 241±193 mg/dL vs 576±31 mg/dL; glycosylated hemoglobin, 7.2±1.5% vs 11.3±1.3%) and slowed the progression of albuminuria and glomerulosclerosis in db/db mice by 70% and 61%, respectively, compared with untreated diabetic db/db mice. Furthermore, COMP-Ang1 ameliorated diabetes-induced increases of NF-kBp65, nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase-2 (Nox2), p47phox and productions of myeloperoxidase, the inflammatory markers in both renal and pancreatic tissues, and improved beta-cell density in pancreatic islets.ConclusionsThese results highlight the potential of localized Ang1 therapy for treatment of diabetic visceropathies and provide a mechanistic explanation for reported improvements in glucose control via Ang1/Tie2 signaling in the pancreas.

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 793-803 ◽  
Author(s):  
Joo-Won Lee ◽  
A Hyun Choi ◽  
Mira Ham ◽  
Ji-Won Kim ◽  
Sung Sik Choe ◽  
...  

Increased reactive oxygen species (ROS) induce pancreatic β-cell dysfunction during progressive type 2 diabetes. Glucose-6-phosphate dehydrogenase (G6PD) is a reduced nicotinamide adenine dinucleotide phosphate-producing enzyme that plays a key role in cellular reduction/oxidation regulation. We have investigated whether variations in G6PD contribute to β-cell dysfunction through regulation of ROS accumulation and β-cell gene expression. When the level of G6PD expression in pancreatic islets was examined in several diabetic animal models, such as db/db mice and OLEFT rats, G6PD expression was evidently up-regulated in pancreatic islets in diabetic animals. To investigate the effect of G6PD on β-cell dysfunction, we assessed the levels of cellular ROS, glucose-stimulated insulin secretion and β-cell apoptosis in G6PD-overexpressing pancreatic β-cells. In INS-1 cells, G6PD overexpression augmented ROS accumulation associated with increased expression of prooxidative enzymes, such as inducible nitric oxide synthase and reduced nicotinamide adenine dinucleotide phosphate oxidase. G6PD up-regulation also caused decrease in glucose-stimulated insulin secretion in INS-1 cells and primary pancreatic islets. Moreover, elevated G6PD expression led to β-cell apoptosis, concomitant with the increase in proapoptotic gene expression. On the contrary, suppression of G6PD with small interference RNA attenuated palmitate-induced β-cell apoptosis. Together, these data suggest that up-regulation of G6PD in pancreatic β-cells would induce β-cell dysregulation through ROS accumulation in the development of type 2 diabetes.


2020 ◽  
Vol 8 (1) ◽  
pp. e001007 ◽  
Author(s):  
Rozalina G McCoy ◽  
Kasia J Lipska ◽  
Holly K Van Houten ◽  
Nilay D Shah

IntroductionGlycemic targets and glucose-lowering regimens should be individualized based on multiple factors, including the presence of comorbidities. We examined contemporary patterns of glycemic control and use of medications known to cause hypoglycemia among adults with diabetes across age and multimorbidity.Research design and methodsWe retrospectively examined glycosylated hemoglobin (HbA1c) levels and rates of insulin/sulfonylurea use as a function of age and multimorbidity using administrative claims and laboratory data for adults with type 2 diabetes included in OptumLabs Data Warehouse, 1 January 2014 to 31 December 2016. Comorbidity burden was assessed by counts of any of 16 comorbidities specified by guidelines as warranting relaxation of HbA1c targets, classified as being diabetes concordant (diabetes complications or risk factors), discordant (unrelated to diabetes), or advanced (life limiting).ResultsAmong 194 157 patients with type 2 diabetes included in the study, 45.2% had only concordant comorbidities, 30.6% concordant and discordant, 2.7% only discordant, and 13.0% had ≥1 advanced comorbidity. Mean HbA1c was 7.7% among 18–44 year-olds versus 6.9% among ≥75 year-olds, and was higher among patients with comorbidities: 7.3% with concordant only, 7.1% with discordant only, 7.1% with concordant and discordant, and 7.0% with advanced comorbidities compared with 7.4% among patients without comorbidities. The odds of insulin use decreased with age (OR 0.51 (95% CI 0.48 to 0.54) for age ≥75 vs 18–44 years) but increased with accumulation of concordant (OR 5.50 (95% CI 5.22 to 5.79) for ≥3 vs none), discordant (OR 1.72 (95% CI 1.60 to 1.86) for ≥3 vs none), and advanced (OR 1.45 (95% CI 1.25 to 1.68) for ≥2 vs none) comorbidities. Conversely, sulfonylurea use increased with age (OR 1.36 (95% CI 1.29 to 1.44) for age ≥75 vs 18–44 years) but decreased with accumulation of concordant (OR 0.76 (95% CI 0.73 to 0.79) for ≥3 vs none), discordant (OR 0.70 (95% CI 0.64 to 0.76) for ≥3 vs none), but not advanced (OR 0.86 (95% CI 0.74 to 1.01) for ≥2 vs none) comorbidities.ConclusionsThe proportion of patients achieving low HbA1c levels was highest among older and multimorbid patients. Older patients and patients with higher comorbidity burden were more likely to be treated with insulin to achieve these HbA1c levels despite potential for hypoglycemia and uncertain long-term benefit.


2021 ◽  
Vol 9 (1) ◽  
pp. e001966
Author(s):  
Annie M Dude ◽  
Nevert Badreldin ◽  
Amanda Schieler ◽  
Lynn M Yee

IntroductionTo assess the relationship between periconception glycemic control and congenital anomalies in a contemporary, diverse population of women with pregestational diabetes.Research design and methodsThis is a retrospective cohort study of all pregnant women with pregestational diabetes at a single institution (2003–2017) in the USA. The primary outcome was frequency of major or minor congenital anomalies. Glycemic control was assessed by periconception glycosylated hemoglobin (HbA1c). The association of periconception HbA1c with pregnancy outcomes was assessed using bivariable and multivariable analyses.ResultsOur sample included 351 women, of which 63.8% had type 2 diabetes. Our study cohort is racially and ethnically diverse, with approximately equal numbers of women identifying as white non-Hispanic, black non-Hispanic and Hispanic, with 3.4% identifying as Asian. Of these 351 women, 52 (14.8%) had a fetus with a congenital anomaly, of whom the majority (n=43) had a major anomaly. Over half (51.1%) of all major anomalies were cardiovascular. Compared with the group with the best glycemic control (HbA1c ≤7.4%), which had an anomaly frequency of 10.2%, the frequency of congenital anomalies increased significantly with each category of worsening glycemic control (HbA1c 7.5%–9.4%: 20.6%, adjusted OR (aOR) 2.35, 95% confidence interval (CI) 1.08 to 5.13; HbA1c 9.5% to 11.4%: 25.8%, aOR 2.86, 95% CI 1.08 to 7.59; HbA1c ≥11.5%: 37.5%, aOR 7.66, 95% CI 2.27 to 25.9).ConclusionIn a diverse cohort of women with pregestational diabetes, higher periconception HbA1c, especially HbA1c >9.5, was significantly associated with major congenital fetal anomalies. Our study sample is reflective of the current population of pregnant women with diabetes, including women with type 2 diabetes and from racial and ethnic minorities.


Author(s):  
Mafooza Rashid ◽  
B. K. Gupta, Vinay Bharat ◽  
Abhishek Gupta ◽  
Zubair Rashid

Background: The aim of the study was to compare the hemoglobin levels among normal controls (patients) and patients of TypeII diabetes with HbA1c levels below 7 % & above 7 %.and secondly to identify the undetected cases of anemia in TypeII diabetes. Materials & Methods - 50 patients of type 2 diabetes mellitus with their glycosylated hemoglobin levels less than 7 %, 50 patients of type 2 diabetes mellitus with their glycosylated hemoglobin levels more than 7 % attending the Medicine outpatient department of Subharti Medical College and Hospital will be the subjects for the study.50 age and sex matched controls will be selected randomly from Subharti Medical College and Hospital. Informed written consent will be taken from all the subjects. The study will be conducted from January 2016 to January. Result - We studied 50 cases with HbA1C>7(poor control),50 cases with HbA1C 5.6 to7 (good control) and 50 controls with HbA1C ≤5.6, we observed in cases with HbA1C>7 (poorly control) ,the mean HbA1C is 9.9±2 and mean Hb is 9.8±1.3 as compared to cases with HbA1C 5.6 to 7(good control) where mean HbA1C is 6±0.4 and Hb is 13±0.5,this clearly indicates that in cases HbA1C is more Hb levels are low and when HbA1C is less Hb levels are higher. Conclusion - In the present study we found negative correlation between HbA1c & Hb levels. As the value of HbA1c increases, as in cases of HbA1c >7(poor diabetic control), we found low Hb levels as compared to the cases with HbA1c <7(5.6-7) (good control).


2020 ◽  
Vol 8 (1) ◽  
pp. e000773
Author(s):  
Carol H Wysham ◽  
Julio Rosenstock ◽  
Marion L Vetter ◽  
Hui Wang ◽  
Elise Hardy ◽  
...  

IntroductionInvestigate the effects of switching from two times per day exenatide to once-weekly exenatide administered by autoinjector (exenatide once-weekly suspension by autoinjector (QWS-AI)) or treatment with exenatide QWS-AI for 1 year.Research design and methodsIn this phase III open-label study, adults with type 2 diabetes were randomized to receive exenatide QWS-AI (2 mg) or exenatide two times per day (5 mcg for 4 weeks, followed by 10 mcg) for 28 weeks. During a subsequent non-randomized 24-week extension, patients who received exenatide two times per day were switched to exenatide QWS-AI and those randomized to exenatide QWS-AI continued this treatment. Efficacy measures included changes from baseline in glycated hemoglobin (A1C), fasting plasma glucose (FPG), and body weight.ResultsIn total, 315 patients (mean baseline A1C of 8.5%) completed the initial 28 weeks of randomized treatment with exenatide QWS-AI (n=197) or exenatide two times per day (n=118) and were included in the 24-week extension (mean A1C of 7.0% and 7.3%, respectively, at week 28). From weeks 28–52, patients who switched from exenatide two times per day to exenatide QWS-AI had additional A1C reductions of approximately 0.5% (mean A1C change from baseline of –1.4% at week 52) and further reductions from baseline in FPG. Patients who continued exenatide QWS-AI treatment for 52 weeks showed clinically relevant A1C reductions (mean A1C change from baseline of –1.3% at week 52). Body-weight reductions achieved through week 28 were sustained at week 52 in both groups. There were no unexpected safety concerns or changes in the safety profile among patients who switched from exenatide two times per day to exenatide QWS-AI or those who continued exenatide QWS-AI treatment for 52 weeks.ConclusionsSwitching from exenatide two times per day to exenatide QWS-AI resulted in further A1C reductions and maintenance of earlier decreases in body weight, while continued therapy with exenatide QWS-AI for 52 weeks maintained A1C and body-weight reductions, without additional safety or tolerability concerns.Trial registration numberNCT01652716.


Angiology ◽  
2021 ◽  
pp. 000331972098459
Author(s):  
Yao-dong Ding ◽  
Yu-qiang Pei ◽  
Rui-Wang ◽  
Jia-xin Yang ◽  
Ying-xin Zhao ◽  
...  

We investigated the association between plasma microRNA (miR)-204 and coronary artery calcification (CAC) in patients with type 2 diabetes mellitus (T2DM). We consecutively enrolled 179 individuals with T2DM who underwent coronary computed tomography at Anzhen Hospital from January 2015 to September 2016. The CAC score (CACS) was expressed in Agatston units and >10 Hounsfield units were defined as CAC-positive status. Significant CAC was observed in 98 (54.7%) patients. Plasma miR-204 levels (relative expression) were significantly lower in patients with significant CAC than controls (1.001 ± 0.100 vs 0.634 ± 0.211, P < .001). Plasma miR-204 levels were also negatively correlated with the glycosylated hemoglobin A1c (HbA1c) level (r = −0.702, P < .001), CACS (r = −0.710, P < .001), and the United Kingdom Prospective Diabetes Study (UKPDS) score (r = −0.355, P < .001). After multivariate logistic analyses, plasma miR-204 levels were still significantly and independently associated with the presence of CAC (odds ratio = 0.103, CI = 0.018-0.583, P < .001) after adjustment for conventional risk factors. Receiver operating characteristic curve analysis showed that plasma miR-204 levels can predict the severity and extent of CAC, and the specificity was higher than that of the traditional risk factors UKPDS score and HbA1c. In conclusion, the downregulation of miR-204 was independently associated with CAC in patients with T2DM.


2021 ◽  
Vol 9 (1) ◽  
pp. e002035
Author(s):  
Merel M Ruissen ◽  
Hannah Regeer ◽  
Cyril P Landstra ◽  
Marielle Schroijen ◽  
Ingrid Jazet ◽  
...  

IntroductionLockdown measures have a profound effect on many aspects of daily life relevant for diabetes self-management. We assessed whether lockdown measures, in the context of the COVID-19 pandemic, differentially affect perceived stress, body weight, exercise and related this to glycemic control in people with type 1 and type 2 diabetes.Research design and methodsWe performed a short-term observational cohort study at the Leiden University Medical Center. People with type 1 and type 2 diabetes ≥18 years were eligible to participate. Participants filled out online questionnaires, sent in blood for hemoglobin A1c (HbA1c) analysis and shared data of their flash or continuous glucose sensors. HbA1c during the lockdown was compared with the last known HbA1c before the lockdown.ResultsIn total, 435 people were included (type 1 diabetes n=280, type 2 diabetes n=155). An increase in perceived stress and anxiety, weight gain and less exercise was observed in both groups. There was improvement in glycemic control in the group with the highest HbA1c tertile (type 1 diabetes: −0.39% (−4.3 mmol/mol) (p<0.0001 and type 2 diabetes: −0.62% (−6.8 mmol/mol) (p=0.0036). Perceived stress was associated with difficulty with glycemic control (p<0.0001).ConclusionsAn increase in perceived stress and anxiety, weight gain and less exercise but no deterioration of glycemic control occurs in both people with relatively well-controlled type 1 and type 2 diabetes during short-term lockdown measures. As perceived stress showed to be associated with glycemic control, this provides opportunities for healthcare professionals to put more emphasis on psychological aspects during diabetes care consultations.


2021 ◽  
Vol 9 (1) ◽  
pp. e002057
Author(s):  
Alexander S Atkin ◽  
Abu Saleh Md Moin ◽  
Ahmed Al-Qaissi ◽  
Thozhukat Sathyapalan ◽  
Stephen L Atkin ◽  
...  

IntroductionGlucose variability is associated with mortality and macrovascular diabetes complications. The mechanisms through which glucose variability mediates tissue damage are not well understood, although cellular oxidative stress is likely involved. As heat shock proteins (HSPs) play a role in the pathogenesis of type 2 diabetes (T2D) complications and are rapidly responsive, we hypothesized that HSP-related proteins (HSPRPs) would differ in diabetes and may respond to glucose normalization.Research design and methodsA prospective, parallel study in T2D (n=23) and controls (n=23) was undertaken. T2D subjects underwent insulin-induced blood glucose normalization from baseline 7.6±0.4 mmol/L (136.8±7.2 mg/dL) to 4.5±0.07 mmol/L (81±1.2 mg/dL) for 1 hour. Control subjects were maintained at 4.9±0.1 mmol/L (88.2±1.8 mg/dL). Slow Off-rate Modified Aptamer-scan plasma protein measurement determined a panel of HSPRPs.ResultsAt baseline, E3-ubiquitin-protein ligase (carboxyl-terminus of Hsc70 interacting protein (CHIP) or HSPABP2) was lower (p=0.03) and ubiquitin-conjugating enzyme E2G2 higher (p=0.003) in T2D versus controls. Following glucose normalization, DnaJ homolog subfamily B member 1 (DNAJB1 or HSP40) was reduced (p=0.02) in T2D, with HSP beta-1 (HSPB1) and HSP-70-1A (HSP70-1A) (p=0.07 and p=0.09, respectively) also approaching significance relative to T2D baseline levels.ConclusionsKey HSPRPs involved in critical protein interactions, CHIP and UBE2G2, were altered in diabetes at baseline. DNAJB1 fell in response to euglycemia, suggesting that HSPs are reacting to basal stress that could be mitigated by tight glucose control with reduction of glucose variability.


Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 404
Author(s):  
Emma Altobelli ◽  
Paolo Matteo Angeletti ◽  
Ciro Marziliano ◽  
Marianna Mastrodomenico ◽  
Anna Rita Giuliani ◽  
...  

Diabetes mellitus is an important issue for public health, and it is growing in the world. In recent years, there has been a growing research interest on efficacy evidence of the curcumin use in the regulation of glycemia and lipidaemia. The molecular structure of curcumins allows to intercept reactive oxygen species (ROI) that are particularly harmful in chronic inflammation and tumorigenesis models. The aim of our study performed a systematic review and meta-analysis to evaluate the effect of curcumin on glycemic and lipid profile in subjects with uncomplicated type 2 diabetes. The papers included in the meta-analysis were sought in the MEDLINE, EMBASE, Scopus, Clinicaltrials.gov, Web of Science, and Cochrane Library databases as of October 2020. The sizes were pooled across studies in order to obtain an overall effect size. A random effects model was used to account for different sources of variation among studies. Cohen’s d, with 95% confidence interval (CI) was used as a measure of the effect size. Heterogeneity was assessed while using Q statistics. The ANOVA-Q test was used to value the differences among groups. Publication bias was analyzed and represented by a funnel plot. Curcumin treatment does not show a statistically significant reduction between treated and untreated patients. On the other hand, glycosylated hemoglobin, homeostasis model assessment (HOMA), and low-density lipoprotein (LDL) showed a statistically significant reduction in subjects that were treated with curcumin, respectively (p = 0.008, p < 0.001, p = 0.021). When considering HBA1c, the meta-regressions only showed statistical significance for gender (p = 0.034). Our meta-analysis seems to confirm the benefits on glucose metabolism, with results that appear to be more solid than those of lipid metabolism. However, further studies are needed in order to test the efficacy and safety of curcumin in uncomplicated type 2 diabetes.


Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2408
Author(s):  
Jesús Martínez-Solís ◽  
Fernando Calzada ◽  
Elizabeth Barbosa ◽  
Miguel Valdés

The antihyperglycemic and antilipidemic effects of the tea infusion extracts of leaves from Annona cherimola Miller (IELAc-0.5, IELAc-1.5, and IELAc-3.0) were evaluated on normoglycemic (NG) and streptozocin-induced diabetic (STID) mice. In the acute test, IELAc-1.5 at 300 mg/kg bodyweight (bw) exhibited antihyperglycemic activity on STID mice since the first hour of treatment. Then, its antidiabetic potential was analyzed in a subchronic evaluation. IELAc-1.5 was able to reduce the blood glucose level, glycated hemoglobin (HbA1c), cholesterol (CHO), and triglycerides (TG); high-density lipoprotein (HDL) showed an increase at the end of treatment. IELAc-1.5 did not modify the urine profile at the end of the evaluation, and neither toxicity nor macroscopic organ damage were observed in acute and subchronic assays. In addition, a major flavonol glycoside present in the tea infusion extracts was identified using high-performance liquid chromatography with diode array detection (HPLC-DAD). The analysis of the tea infusion extracts by HPLC revealed that rutin was the major component. This study supports the use of tea infusions from Annona cherimola for the treatment of diabetes and suggests that rutin could be responsible, at least in part, for their antidiabetic properties.


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