Role of Reactive Oxygen Species in the Progression of Type 2 Diabetes and Atherosclerosis

Type 2 diabetes is the most prevalent and serious metabolic disease all over the world, and its hallmarks are pancreatic β-cell dysfunction and insulin resistance. Under diabetic conditions, chronic hyperglycemia and subsequent augmentation of reactive oxygen species (ROS) deteriorate β-cell function and increase insulin resistance which leads to the aggravation of type 2 diabetes. In addition, chronic hyperglycemia and ROS are also involved in the development of atherosclerosis which is often observed under diabetic conditions. Taken together, it is likely that ROS play an important role in the development of type 2 diabetes and atherosclerosis

Genetic engineering of Agrobacterium tumefaciens to target chloroplasts and identification of a novel nuclear localization signal of VirD2 protein

Agrobacterium tumefaciens has been adopted to become a greatest tool for plant genetic engineering. Since Agrobacteria predominantly integrate single copy of the transgene into the nuclear genome, the transgene expression is relatively low. In contrast, transgene expression from chloroplasts allows high expression. Therefore, my first objective was to develop a new method of chloroplast transformation by modifying Agrobacterium genetics. I attempted to transform tobacco chloroplasts by Agrobacterium carrying the VirD2 protein with inactivated nuclear localization signals (NLSs) fused to a chloroplast transit peptide. However, the transformation of tobacco chloroplasts was unsuccessful. It suggested that the transit peptide was overridden by a novel cryptic NLS of VirD2. My second objective was to determine a novel NLS in VirD2. I discovered the novel NLS in VirD2 by subcellular localization analyses of fusion proteins (fragment of VirD2-green fluorescent protein) in plant cells. My discovery contributed to characterization of VirD2.Alberta Innovates Technology Future

Effects of Gram-negative Rod Blood Stream Infection on Acute GVHD in Allogeneic Hematopoietic Stem Cell Transplantation: A Single-institute Analysis

A bloodstream infection (BSI) is the most common serious infectious complication of hematopoietic stem cell transplantation (HSCT). BSI promotes an inflammatory state, which exacerbates acute graft-versus-host disease (GVHD). We investigated whether a Gram-negative rod bloodstream infection (GNR-BSI), which develops early after allo-HSCT, affected the onset or exacerbated acute GVHD in 465 patients who underwent allo-HSCT from 1995 through 2015 at a single institution. Eighty-eight patients (19%) developed BSI during the study period. Among the cultures, 50 (57%) were Gram-positive cocci (GPC) and 31 (35%) were GNR. Of the 465 patients, 187 (40%) developed acute GVHD of grade II or higher within the first 100 days post-allogeneic HSCT: 124 (27%) had acute GVHD grade II, 47 (10%) had grade III, and 16 (3%) had grade IV. Multivariate analysis revealed that GNR-BSI was a significant risk factor for grade II-IV acute GVHD (grade II-IV: hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.03-2.97; grade III-IV: HR 2.37, 95% CI 1.03-5.43). These results suggest that GNR-BSI may predict the onset and exacerbation of acute GVHD

Dynapenia and sarcopenia diabetes

Aims/Introduction: The present study aimed to clarify the prevalence and clinical characteristics of sarcopenia and dynapenia, which are muscle weakness with and without low muscle mass, respectively, in Japanese patients with type 1 diabetes mellitus and type 2 diabetes mellitus. Materials and Methods: This cross-sectional study enrolled 1,328 participants with type 1 diabetes (n = 177), type 2 diabetes (n = 645) and without diabetes (n = 506). Sarcopenia was defined as a low grip strength and slow gait speed with low skeletal muscle mass index, whereas dynapenia was defined as low strengths of grip and knee extension with a normal skeletal muscle mass index. Participants without sarcopenia and dynapenia were defined as robust. Results: Among participants aged ≥65 years, sarcopenia and dynapenia were observed in 12.2% and 0.5% of individuals without diabetes, 42.9% and 11.4% of type 1 diabetes patients, and 20.9% and 13.9% of type 2 diabetes patients. In both type 1 diabetes and type 2 diabetes patients, sarcopenic patients were significantly older and thinner, and showed a significantly higher rate of diabetic neuropathy than robust patients. In patients with type 1 diabetes and type 2 diabetes, dynapenic patients were older, and showed a higher rate of diabetic neuropathy and lower estimated glomerular filtration rate than robust patients. Patients complicated with sarcopenia and dynapenia showed a significantly lower physical quality of life and higher rate of incidental falls than robust patients. Conclusions: Sarcopenia and dynapenia were more frequent in patients with type 1 diabetes and type 2 diabetes than in individuals without diabetes, which might contribute to their impaired quality of life and incidental falls

Investigation of the effect of canagliflozin on the disposition index, a marker of pancreatic beta cell function, in patients with type 2 diabetes

This article is published in Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 18 November 2020, Volume 2020:13, Pages 4457-4468

Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice

Aims/hypothesis Pancreatic polypeptide (PP) cells, which secrete PP (encoded by the Ppy gene), are a minor population of pancreatic endocrine cells. Although it has been reported that the loss of beta cell identity might be associated with beta-to-PP cell-fate conversion, at present, little is known regarding the characteristics of Ppy-lineage cells. Methods We used Ppy-Cre driver mice and a PP-specific monoclonal antibody to investigate the association between Ppy-lineage cells and beta cells. The molecular profiles of endocrine cells were investigated by single-cell transcriptome analysis and the glucose responsiveness of beta cells was assessed by Ca2+ imaging. Diabetic conditions were experimentally induced in mice by either streptozotocin or diphtheria toxin. Results Ppy-lineage cells were found to contribute to the four major types of endocrine cells, including beta cells. Ppy-lineage beta cells are a minor subpopulation, accounting for 12–15% of total beta cells, and are mostly (81.2%) localised at the islet periphery. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorised into two groups (i.e. Ppy-lineage and non-Ppy-lineage beta cells). These subpopulations of beta cells demonstrated distinct characteristics regarding their functionality and gene expression profiles. Ppy-lineage beta cells had a reduced glucose-stimulated Ca2+ signalling response and were increased in number in experimental diabetes models. Conclusions/interpretation Our results indicate that an unexpected degree of beta cell heterogeneity is defined by Ppy gene activation, providing valuable insight into the homeostatic regulation of pancreatic islets and future therapeutic strategies against diabetes

Muscle mass, quality, and strength; physical function and activity; and metabolic status in cachectic patients with head and neck cancer

Background & aims: Cancer cachexia is commonly associated with poor prognosis in patients with head and neck cancer (HNC). However, its pathophysiology and treatment are not well established. The current study aimed to assess the muscle mass/quality/strength, physical function and activity, resting energy expenditure (REE), and respiratory quotient (RQ) in cachectic patients with HNC. Methods: This prospective cross-sectional study analyzed 64 patients with HNC. Body composition was measured via direct segmental multifrequency bioelectrical impedance analysis, and muscle quality was assessed using echo intensity on ultrasonography images. Muscle strength was investigated utilizing handgrip strength and isometric knee extension force (IKEF). Physical function was evaluated using the 10-mwalking speed test and the five times sit-to-stand (5-STS) test. Physical activity was examined using a wearable triaxial accelerometer. REE and RQ were measured via indirect calorimetry. These parameters were compared between the cachectic and noncachectic groups. Results: In total, 23 (36%) patients were diagnosed with cachexia. The cachectic group had a significantly lower muscle mass than the noncachectic group. Nevertheless, there was no significant difference in terms of fat between the two groups. The cachectic group had a higher quadriceps echo intensity and a lower handgrip strength and IKEF than the noncachectic group. Moreover, they had a significantly slower normal and maximum walking speed and 5 STS speed. The number of steps, total activity time, and time of activity (<3 Mets) did not significantly differ between the two groups. The cachectic group had a shorter time of activity (≥3 Mets) than the noncachectic group. Furthermore, the cachectic group had a significantly higher REE/body weight and REE/fat free mass and a significantly lower RQ than the noncachectic group. Conclusions: The cachectic group had a lower muscle mass/quality/strength and physical function and activity and a higher REE than the noncachectic group. Thus, REE and physical activity should be evaluated to determine energy requirements. The RQ was lower in the cachectic group than that in the noncachectic group, indicating changes in energy substrate. Further studies must be conducted to examine effective nutritional and exercise interventions for patients with cancer cachexia

Effect of sitagliptin on tissue characteristics of the carotid wall in patients with type 2 diabetes: a post hoc sub-analysis of the sitagliptin preventive study of intima-media thickness evaluation (SPIKE)

BackgroundUltrasonic gray-scale median (GSM) of the carotid wall reflects its composition and low-GSM carotid plaque is considered to be vulnerable. This study aimed to evaluate the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on the longitudinal change in GSM, an index of the tissue characteristics of the carotid wall, in patients with type 2 diabetes mellitus (T2DM).MethodsThis is a post hoc sub-analysis using data obtained from the SPIKE trial, a randomized controlled trial that demonstrated the beneficial effect of sitagliptin on the progression of carotid intima-media thickness in patients with T2DM. A total of 274 T2DM patients with no past history of apparent cardiovascular disease (137 in the sitagliptin treatment group and 137 in the conventional treatment group) were enrolled. The primary outcome was the change from baseline in mean GSM-CCA during the 104-week treatment period.ResultsThe mean GSM-CCA significantly increased in the sitagliptin treatment group (adjusted ΔGSM = 2.40 ± 1.19 [mean ± SE], p = 0.044) but not in the conventional treatment group (adjusted ΔGSM = 1.32 ± 1.19, p = 0.27). However, there was no significant difference in changes in mean GSM-CCA between the treatment groups.ConclusionsA post hoc sub-analysis suggests that the tissue characteristics of the carotid arterial wall were improved in the sitagliptin treatment group during the 104-week treatment period, but not in the conventional treatment group. However, there was no between-group difference in the changes of GSM values between the two treatment groups. Prespecified studies with large sample sizes would be necessary to confirm our findings

Identification of oxidative stress-regulated genes in rat aortic smooth muscle cells by suppression subtractive hybridization

AbstractA suppression subtractive hybridization technique was used to identify reactive oxygen species (ROS)-regulated genes in rat vascular smooth muscle cells. Three genes out of 89 clones, identified as fibronectin, p105 coactivator and ECA39, showed increased expression after treatment with H2O2. The mRNA expressions of these three genes were induced in a time- and dose-dependent manner, independent of protein kinase C activation. Immunohistochemical staining showed that the p105 coactivator expression was markedly induced in the neointima of balloon-injured rat carotid arteries. These results suggest that ROS may play an important role in the development of atherosclerosis by regulating the gene expressions we identified in this study

Osteocalcin and body fat in type 1 diabetes

The objective of the present study was to investigate the correlations between serum under-carboxylated osteocalcin (ucOC) or osteocalcin (OC) concentrations and %body fat, serum adiponectin and free-testosterone concentration, muscle strength and dose of exogenous insulin in patients with type 1 diabetes. We recruited 73 Japanese young adult patients with childhood-onset type 1 diabetes. All participants were receiving insulin replacement therapy. The correlations between logarithmic serum ucOC or OC concentrations and each parameter were examined. Serum ucOC and OC concentrations were inversely correlated with% body fat (r = -0.319, P = 0.007; r = -0.321, P = 0.006, respectively). Furthermore, multiple linear regression analyses were performed to determine whether or not serum ucOC or OC concentrations were factors associated with %body fat. Serum ucOC and OC concentrations remained significant factors even after adjusting for gender, HbA1c, body weight-adjusted total daily dose of insulin and duration of diabetes (β = -0.260, P = 0.027; β = -0.254, P = 0.031, respectively). However, serum ucOC and OC concentrations were not correlated with serum adiponectin or free-testosterone concentrations, muscle strength or dose of exogenous insulin. In conclusion, our study demonstrates the inverse correlation between serum ucOC or OC concentrations and body fat in patients with type 1 diabetes