Distinct effects of rosuvastatin and rosuvastatin/ezetimibe on senescence markers of CD8+ T cells in patients with type 2 diabetes mellitus: a randomized controlled trial.

Objectives: Chronic low-grade inflammation is widely recognized as a pathophysiological defect contributing to ß-cell failure in type 2 diabetes mellitus (T2DM). Statin therapy is known to ameliorate CD8+ T cell senescence, a mediator of chronic inflammation. However, the additional immunomodulatory roles of ezetimibe are not fully understood. Therefore, we investigated the effect of statin or statin/ezetimibe combination treatment on T cell senescence markers. Methods: In this two-group parallel and randomized controlled trial, we enrolled 149 patients with T2DM whose low-density lipoprotein cholesterol (LDL-C) was 100 mg/dL or higher. Patients were randomly assigned to either the rosuvastatin group (N=74) or the rosuvastatin/ezetimibe group (N=75). The immunophenotype of peripheral blood mononuclear cells and metabolic profiles were analyzed using samples from baseline and post-12 weeks of medication. Results: The fractions of CD8+CD57+ (senescent CD8+ T cells) and CD4+FoxP3+ (Treg) significantly decreased after intervention in the rosuvastatin/ezetimibe group (-4.5 ± 14.1% and -1.2 ± 2.3%, respectively), while these fractions showed minimal change in the rosuvastatin group (2.8 ± 9.4% and 1.4 ± 1.5%, respectively). The degree of LDL-C reduction was correlated with an improvement in HbA1c (R=0.193, p=0.021). Changes in the CD8+CD57+ fraction positively correlated with patient age (R=0.538, p=0.026). Notably, the fraction change in senescent CD8+ T cells showed no significant relationship with changes in either HbA1c (p=0.314) or LDL-C (p=0.592). Finally, the ratio of naïve to memory CD8+ T cells increased in the rosuvastatin/ezetimibe group (p=0.011), but not in the rosuvastatin group (p=0.339). Conclusions: We observed a reduction in senescent CD8+ T cells and an increase in the ratio of naive to memory CD8+ T cells with rosuvastatin/ezetimibe treatment. Our results demonstrate the immunomodulatory roles of ezetimibe in combination with statins, independent of improvements in lipid or HbA1c levels.

Differences in patient-reported and clinical characteristics by age group in adults with type 2 diabetes.

BACKGROUND: The global burden of type 2 diabetes (T2D) is growing, and the age of onset is widening, resulting in increasing numbers of young adults and elderly patients with T2D. Age-specific diabetes care needs have yet to be fully explored. AIMS: This study examined (1) differences in patient-reported and clinical characteristics by age group and (2) the effect of age on two proxy measures assessing psychological health and self-care adherence after adjusting for potential mediators. METHODS: A cross-sectional, correlational design was used. Adults with type 2 diabetes (T2D) were recruited from a university hospital in Korea between 2019 and 2020. Participants were divided into four groups based on years of age (40s and younger group [n = 27]; 50s group [n = 47]; 60s group [n = 54]; and 70s and older group [n = 48]) to compare patient-reported and clinical characteristics. Chi-square tests, ANOVA, Kruskal-Wallis tests, and logistic regression analysis were performed to assess group differences and effect of age on psychological health and self-care adherence. RESULTS: Of 178 participants, two-thirds were men (n = 114; 64.41%). The mean ages in the 40s and younger, 50s, 60s, and 70s and older groups were 39.4, 54.7, 63.9, and 76.0 years, respectively. There were significant differences in patient-reported and clinical characteristics by age group. The youngest group reported the poorest psychological health and self-care behaviors. Although the oldest group showed the poorest physical functioning, this group also showed the highest self-care adherence and the best psychological health. Regarding clinical characteristics, traditional diabetes-related blood test results showed no significant group differences. LINKING EVIDENCE TO ACTION: Age-specific diabetes care needs were identified in adults with T2D. Interventions to improve psychological health and priming effects of behavioral adherence need to be developed. Furthermore, meticulous investigation to detect potential complications early is essential in adults with T2D.

Comparative Efficacy of Rosuvastatin Monotherapy and Rosuvastatin/Ezetimibe Combination Therapy on Insulin Sensitivity and Vascular Inflammatory Response in Patients with Type 2 Diabetes Mellitus.

BACKGRUOUND: Type 2 diabetes mellitus (T2DM) induces endothelial dysfunction and inflammation, which are the main factors for atherosclerosis and cardiovascular disease. The present study aimed to compare the effects of rosuvastatin monotherapy and rosuvastatin/ezetimibe combination therapy on lipid profile, insulin sensitivity, and vascular inflammatory response in patients with T2DM. METHODS: A total of 101 patients with T2DM and dyslipidemia were randomized to either rosuvastatin monotherapy (5 mg/day, n=47) or rosuvastatin/ezetimibe combination therapy (5 mg/10 mg/day, n=45) and treated for 12 weeks. Serum lipids, glucose, insulin, soluble intercellular adhesion molecule-1 (sICAM-1), and peroxiredoxin 4 (PRDX4) levels were determined before and after 12 weeks of treatment. RESULTS: The reduction in low density lipoprotein cholesterol (LDL-C) by more than 50% from baseline after treatment was more in the combination therapy group. The serum sICAM-1 levels increased significantly in both groups, but there was no difference between the two groups. The significant changes in homeostasis model assessment of insulin resistance (HOMA-IR) and PRDX4 were confirmed only in the subgroup in which LDL-C was reduced by 50% or more in the combination therapy group. However, after adjusting for diabetes mellitus duration and hypertension, the changes in HOMA-IR and PRDX4 were not significant between the two groups. CONCLUSION: Although rosuvastatin/ezetimibe combination therapy had a greater LDL-C reduction effect than rosuvastatin monotherapy, it had no additional effects on insulin sensitivity and vascular inflammatory response. Further studies are needed on the effect of long-term treatment with ezetimibe on insulin sensitivity and vascular inflammatory response.

Comparisons of Psycho-Behavioral Factors, Body Composition, and Clinical Outcomes in Adults With Type 2 Diabetes by Perceived Hypoglycemia.

PURPOSE: The purpose of the study was to examine the associations between perceived hypoglycemia and psycho-behavioral and clinical factors in persons with type 2 diabetes (T2D). METHODS: Adults with T2D were recruited from outpatient clinics in a university hospital in Korea. Sociodemographics, psycho-behavioral and clinical factors, and body composition were assessed. The participants were divided into 2 groups reporting perceived hypoglycemia or not in the previous month based on an item of the Control Problem Scale. Group differences were compared at α = .05 using SPSS (version 26.0). RESULTS: Of 177 participants, approximately one-third (n = 67) perceived hypoglycemia. The hypoglycemia group reported poor health-related quality of life, frequent blood monitoring and foot care, and sleep difficulties. However, no differences between groups were identified for diet, exercise, or glycosylated hemoglobin. The hypoglycemia group had a lower body mass index and a trend toward a lower skeletal muscle mass and fat free mass. CONCLUSIONS: Perceived hypoglycemia was associated with psycho-behavioral factors and body composition. Importantly, some persons on oral antidiabetic medications that do not cause hypoglycemia still perceived hypoglycemia. Further investigation is warranted to examine the efficacy of strategies to minimize hypoglycemia and inappropriate fear of hypoglycemia. In addition, clinicians should be aware of the potential risk of hypoglycemia in persons with lower muscle mass.

Thyroid segmentation using perithyroidal halo layer on 99mTc-pertechnetate thyroid SPECT/CT: An easy and reliable method for accurate quantification of thyroid activity.

OBJECTIVE: In previous fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) studies, tumor segmentation using peritumoral halo layer (PHL; SegPHL) was shown to be reliable and accurate segmentation method in various malignant tumors. We found that the halo layer also was observed on the 99mTc-pertechnetate (99mTcO4) thyroid single photon emission computed tomography (SPECT)/CT. In the present study, we attempted to apply thyroid segmentation using the perithyroidal halo layer (PTHL; SegPTHL) on 99mTcO4 thyroid SPECT/CT and compared SegPTHL with CT-based thyroid segmentation (SegCT). SUBJECTS AND METHODS: A total of 33 patients (19 females, 14 males; mean age, 46.91±15.7 years old) were enrolled in this study. For SegCT, three-dimensional volume of interest (VOI) of the thyroid was generated via multiple 2-dimensional regions of interest (ROI) along the thyroid margin on transaxial CT images that were manually drawn slice by slice. The PTHL was easily identified by an abrupt increase in layer thickness with minimal or mild distortion of the main thyroid contour, and the thyroid margin for SegPTHL was determined at the innermost portion of PTHL. An automated VOI generation for SegPTHL was performed using the Q. Volumetrix software. The correlation and reliability tests were performed between the quantification parameters of SegPTHL and SegCT. RESULTS: The PTHL threshold adjusted according to maximal SUV of thyroid were similar to the results of previous SegPHLstudies of 18F-FDG PET/CT. A good correlation was observed between the thyroid volumes of SegCT and SegPTHL (r=0.725; P<0.0001), although the thyroid volume of SegPTHL was slightly larger than that of SegCT (P=0.0017). The % thyroid uptake (TcTU), total lesion activity (TLA), and mean standardized uptake value (SUVmean) of SegPTHL correlated well with those of SegCT (r=0.9877, 0.9883, 0.9875, respectively; P<0.0001). No significant error was observed between the parameters (i.e., TcTU, TLA, and SUVmean) of SegPTHL and SegCT. CONCLUSION: Thyroid segmentation PTHL may be a useful method for reliable quantification of thyroid uptake, because the SPECT/CT parameters of SegPTHL were strongly correlated with those of SegCT, as well as the process of SegPTHL is easier and faster than that of SegCT.

Age-Dependent Clinicopathological Characteristics of Patients with T1b Papillary Thyroid Carcinoma: Implications for the Possibility of Active Surveillance.

BACKGROUND: Active surveillance (AS) of low-risk T1a papillary thyroid carcinoma (PTC) is generally accepted as an alternative to immediate surgery. The cut-off in the size criterion for AS has recently been extended in select individuals, especially older patients. We evaluated the clinicopathological differences of T1b PTC according to age to investigate the possibility of AS in older patients. PATIENTS AND METHODS: From a cohort study of 1269 patients undergoing lobectomy for PTC, 1223 PTC patients with T1 stage disease (tumor ≤ 2 cm) were enrolled. The clinicopathological characteristics between T1a and T1b patients according to age were analyzed. RESULTS: Among the 1223 T1 cases, 918 (75.1%) were T1a (≤ 1 cm) and 305 (34.9%) T1b (> 1 and ≤ 2 cm). T1b PTC was associated with male sex, minimal extrathyroidal extension, lymphovascular invasion, occult central lymph node (LN) metastasis, and a higher number of metastatic LNs than T1a. However, in patients over 55 years of age, the clinicopathological features of the patients with T1a and T1b PTC were not significantly different except for minimal extrathyroidal extension, although many clinicopathological differences were observed in patients under 55 years of age. CONCLUSION: The clinicopathological features of patients with T1b PTC over 55 years of age are similar to those with T1a PTC and less aggressive than those with T1b PTC under 55 years of age. These findings suggest that AS may be possible in patients with T1b PTC over 55 years of age without high-risk features on preoperative examinations.

Increased Pro-Inflammatory T Cells, Senescent T Cells, and Immune-Check Point Molecules in the Placentas of Patients With Gestational Diabetes Mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy. To define the altered pathway in GDM placenta, we investigated the transcriptomic profiles from human placenta between GDM and controls. METHODS: Clinical parameters and postpartum complications were reviewed in all participants. Differentially expressed canonical pathways were analyzed between the GDM and control groups based on transcriptomic analysis. CD4+ T, CD8+ T, and senescent T cell subsets were determined by flow cytometry based on staining for specific intracellular cytokines. RESULTS: Gene ontology analysis revealed that the placenta of GDM revealed upregulation of diverse mitochondria or DNA replication related pathways and downregulation of T-cell immunity related pathways. The maternal placenta of the GDM group had a higher proportion of CD4+ T and CD8+ T cells than the control group. Interestingly, senescent CD4+ T cells tended to increase and CD8+ T cells were significantly increased in GDM compared to controls, along with increased programmed cell death-1 (CD274+) expression. Programmed death-ligand 1 expression in syncytotrophoblasts was also significantly increased in patients with GDM. CONCLUSION: This study demonstrated increased proinflammatory T cells, senescent T cells and immune-check point molecules in GDM placentas, suggesting that changes in senescent T cells and immune-escape signaling might be related to the pathophysiology of GDM.

Serum CD14 concentration is associated with obesity and insulin resistance in non-diabetic individuals.

OBJECTIVE: CD14 is a lipopolysaccharide-binding protein that serves as a marker of monocytes. The role of circulating CD14 in patients with obesity without diabetes remains unknown. Here, we characterized the relationships between serum CD14 concentration and metabolic parameters related to diabetes and obesity. METHODS: We performed an observational, prospective case-control study. Eighty participants were evaluated: 26 drug-naïve patients with type 2 diabetes mellitus and 54 healthy individuals. We compared the circulating CD14 concentration and metabolic parameters of the participants with and without diabetes. RESULTS: The circulating CD14 concentration did not significantly differ between the two groups, but was lower in participants with obesity than in lean controls. No significant associations existed between CD14 concentration and metabolic parameters in the participants with diabetes, but in those without diabetes, the circulating CD14 concentration significantly negatively correlated with body mass index; waist circumference; the concentrations of fasting insulin, 2-hour post-load glucose, 2-h post-load insulin, and low-density lipoprotein-cholesterol; homeostasis model of assessment (HOMA) of insulin resistance; and HOMA beta-cell function. CONCLUSIONS: This is the first study to show associations of serum CD14 concentration with metabolic parameters in non-diabetic individuals. Circulating CD14 may represent a useful biomarker of metabolic dysfunction in non-diabetic individuals.

Effect of cholesterol-lowering agents on soluble epidermal growth factor receptor level in type 2 diabetes and hypercholesterolemia.

Soluble epidermal growth factor receptor (sEGFR) levels are elevated in patients with type 2 diabetes mellitus (T2DM) and positively correlate with blood glucose and cholesterol levels. However, how cholesterol-lowering treatment in patients with T2DM affects the sEGFR level is unknown. Therefore, we investigated the change of serum sEGFR after cholesterol-lowering treatment in type 2 diabetic patients with hypercholesterolemia. This study is a non-randomized, prospective observational study. A total of 115 patients were treated in either the rosuvastatin monotherapy group (R group, 5 mg/day, n = 59) or the rosuvastatin/ezetimibe combination therapy group (RE group, 5 mg/10 mg/day, n = 56) for 12 weeks. We measured serum levels of lipids and sEGFR using an ELISA kit before and after 12 weeks of treatment in each group. The low-density lipoprotein cholesterol (LDL-C) level was significantly reduced (from 130.27 ± 27.09 to 76.24 ± 26.82 mg/dL; P < .001) after 12 weeks of treatment and more so in the RE group than in the R group (from 131.68 ± 28.72 to 87.13 ± 27.04 mg/dL, P < .001 in the R group; from 128.78 ± 25.58 to 64.75 ± 21.52 mg/dL, P < .001 in the RE group; R vs RE group, P < .001). The sEGFR level was significantly decreased after 12 weeks of treatment (from 50.34 ± 13.31 to 45.75 ± 11.54 ng/mL; P = .007). The RE group only showed a significant reduction in the sEGFR level after treatment (from 50.94 ± 12.10 to 44.80 ± 11.36 ng/mL; P = .007). Moreover, the sEGFR level was significantly reduced only when the LDL-C level was significantly reduced (from 50.46 ± 10.66 to 46.24 ± 11.86 ng/mL; P = .043). The serum sEGFR level was significantly reduced by cholesterol-lowering treatment with rosuvastatin alone or rosuvastatin/ezetimibe. We suggested that sEGFR may play a significant role in insulin resistance (IR) and inflammation, which are central pathophysiological mechanisms. We confirmed the possibility of using sEGFR as a biomarker to predict a good response to lipid-lowering treatment in type 2 diabetes patients with hypercholesterolemia.

Mitoribosome insufficiency in ß cells is associated with type 2 diabetes-like islet failure.

Genetic variations in mitoribosomal subunits and mitochondrial transcription factors are related to type 2 diabetes. However, the role of islet mitoribosomes in the development of type 2 diabetes has not been determined. We investigated the effects of the mitoribosomal gene on ß-cell function and glucose homeostasis. Mitoribosomal gene expression was analyzed in datasets from the NCBI GEO website (GSE25724, GSE76894, and GSE76895) and the European Nucleotide Archive (ERP017126), which contain the transcriptomes of type 2 diabetic and nondiabetic organ donors. We found deregulation of most mitoribosomal genes in islets from individuals with type 2 diabetes, including partial downregulation of CRIF1. The phenotypes of haploinsufficiency in a single mitoribosomal gene were examined using ß-cell-specific Crif1 (Mrpl59) heterozygous-deficient mice. Crif1beta+/- mice had normal glucose tolerance, but their islets showed a loss of first-phase glucose-stimulated insulin secretion. They also showed increased ß-cell mass associated with higher expression of Reg family genes. However, Crif1beta+/- mice showed earlier islet failure in response to high-fat feeding, which was exacerbated by aging. Haploinsufficiency of a single mitoribosomal gene predisposes rodents to glucose intolerance, which resembles the early stages of type 2 diabetes in humans.

Serum MIG6 concentration is increased by cholesterol-lowering treatment in patients with type 2 diabetes mellitus and hypercholesterolemia.

OBJECTIVE: The protein encoded by mitogen-inducible gene 6 (MIG6) plays an essential role in the regulation of cholesterol homeostasis and bile acid synthesis in mice. However, the physiological functions of MIG6 remain poorly understood in humans. Therefore, we aimed to evaluate the relationship between the serum MIG6 concentration and low-density lipoprotein (LDL)-cholesterol in patients undergoing cholesterol-lowering treatment. METHODS: We performed a non-randomized, prospective controlled trial. In total, 63 patients with type 2 diabetes and hypercholesterolemia were treated using either rosuvastatin monotherapy or rosuvastatin/ezetimibe combination therapy for 12 weeks. We then compared their serum lipid and MIG6 concentrations before and after treatment. RESULTS: The serum LDL-cholesterol concentration of the participants significantly decreased and the concentration of MIG6 significantly increased during treatment. In addition, higher pre-treatment serum concentrations of MIG6 were associated with larger reductions in LDL-cholesterol, regardless of the therapeutic agent used. CONCLUSIONS: Serum MIG6 concentration significantly increases alongside the reduction in LDL-cholesterol achieved using cholesterol-lowering therapies in patients with diabetes and hypercholesterolemia. This is the first study to provide evidence that MIG6 may be involved in human cholesterol metabolism.CRIS registration number: KCT0003477. https://cris.nih.go.kr.

Q-Methodology and Psychological Phenotyping to Design Patient-Centered Diabetes Education for Persons With Type 2 Diabetes on Insulin Therapy.

PURPOSE: The purpose of this study was to identify the psychological phenotypes of persons with type 2 diabetes (T2D) on insulin therapy to better inform personalized diabetes education strategies to improve self-management behaviors. METHODS: Q-methodology, a research approach combining the quantitative rigor of statistical analysis with qualitative data on perception of diabetes self-management by persons with T2D on insulin therapy, was used. The Summary of Diabetes Self-Care Activity measure and A1C in the past 6 months were used to further describe self-management behaviors of each P-sample, Q-sorter. Of 160 statements, 33 Q-sample statements were selected as Q-set. Then, 37 P-samples (24 men; 13 women) were recruited from a university-affiliated diabetes clinic in South Korea. Data obtained from each P-sample with a Q-set and a Q-sorting table, a forced-choice normal distribution table, were analyzed using varimax rotation. RESULTS: Forty-one percent of the variance was explained with 5 factors represented by 27 Q-sorters, explaining variance ranging from 5% to 17% for each factor: Factor A (n = 6): those showing self-management education need but possessing inadequate health literacy; Factor B (n = 4): those valuing lifestyle modification to control diabetes; Factor C (n = 5): those valuing antidiabetic medication to control diabetes; Factor D (n = 6): carpe diem, accepting diabetes as destiny; and Factor E (n = 6): those overestimating their competencies to control diabetes. Ten Q-sorters fell into either confounded or nonsignificant. CONCLUSIONS: Tailoring messages and educational approaches based on patients' psychological phenotypes are necessary to promote optimal self-management behaviors.

Soluble LRIG2 is a potential biomarker for type 2 diabetes mellitus.

BACKGROUND: Early diagnosis and treatment of type 2 diabetes can delay the onset of microvascular and macrovascular complications. Therefore, the identification of a novel biomarker for diagnosing diabetes is necessary. In the present study, the role of serum soluble leucine-rich repeats and immunoglobulin like domains 2 (sLRIG2) was investigated as a diagnostic biomarker of type 2 diabetes. METHODS: A total of 240 subjects with newly diagnosed type 2 diabetes (n=80), prediabetes (n=80), or normal glucose tolerance (NGT; n=80) were included in this study. The fasting serum sLRIG2 level was measured using a quantitative sandwich enzyme immunoassay technique with an enzyme-linked immunosorbent assay (ELISA). Serum sLRIG2 levels were compared among the three groups, and the associations of serum sLRIG2 levels with clinical variables were investigated. RESULTS: Serum sLRIG2 levels were significantly higher in subjects with type 2 diabetes (16.7±8.0 ng/mL) than in subjects without diabetes (NGT group: 12.3±5.3 ng/mL, P<0.001; prediabetes group: 13.2±5.8 ng/mL, P=0.002). Glycosylated hemoglobin (HbA1c: r=0.378, P<0.001) and blood glucose (fasting: r=0.421, P<0.001; 2-hour postprandial: r=0.433, P<0.001) correlated more strongly with sLRIG2 than any other clinical variables. CONCLUSIONS: The serum sLRIG2 levels correlated with glucose parameters; thus, sLRIG2 might be a novel diagnostic biomarker for type 2 diabetes.

Mig-6 is essential for glucose homeostasis and thermogenesis in brown adipose tissue.

Brown adipose tissue (BAT) is an anti-obese and anti-diabetic tissue that stimulates energy expenditure in the form of adaptive thermogenesis through uncoupling protein 1 (UCP1). Mitogen-inducible gene-6 (Mig-6) is a negative regulator of epidermal growth factor receptor (EGFR) that interacts with many cellular partners and has multiple cellular functions. We have recently reported that Mig-6 is associated with diabetes and metabolic syndrome. However, its function in BAT is unknown. We generated a brown adipocyte-specific Mig-6 knock-in mouse (BKI) to examine the role of Mig-6 in BAT. Mig-6 BKI mice had improved glucose tolerance on a normal chow diet. Mig-6 BKI mice also revealed activated thermogenesis and the size of the BAT lipid droplets was reduced. Additionally, Mig-6 regulated cAMP-PKA signaling-induced UCP1 expression in brown adipocytes. Taken together, these results demonstrate that Mig-6 affects glucose tolerance and thermogenesis in BAT.

Association between IL-1beta and cardiovascular disease risk in patients with newly diagnosed, drug-naïve type 2 diabetes mellitus: a cross-sectional study.

BACKGROUND: To determine whether the pro-inflammatory cytokine interleukin (IL)-1beta, as a marker of the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, can be used to predict cardiovascular disease (CVD) risk in patients with newly diagnosed, drug-naïve type 2 diabetes mellitus (T2DM). METHODS: A total of 110 subjects with no history of diabetes were enrolled and divided into control subjects (non-DM group, n=52) and patients with newly diagnosed, drug-naïve T2DM (DM group, n=58). RESULTS: Serum IL-1beta levels were not different between the two groups. The Framingham CVD risk score (F-score) was positively correlated with the serum IL-1beta level in the DM group. Multivariate regression analyses showed that the F-score was independently associated with the serum IL-1beta level in the DM group. Patients with an intermediate to high CVD risk (F-score ≥10%) also had significantly higher serum IL-1beta levels than did those with a low CVD risk (F-score <5%). Smokers in the DM group had higher IL-1beta levels than did those in the non-DM group, regardless of the F-score. CONCLUSIONS: These results suggest that serum IL-1beta levels might be useful as an independent risk factor predicting CVD risk in patients with newly diagnosed, drug naïve T2DM, particularly those who smoke.

Association between glycemic state and pulmonary function and effect of walking as a protective factor in subjects with diabetes mellitus.

BACKGROUND: Several population-based studies have shown that individuals with type 2 diabetes mellitus (T2DM) have decreased pulmonary function. Moreover, impaired pulmonary function is associated with all-cause mortality in T2DM. We investigated the association between glycemic state and pulmonary function and evaluated the role of walking as protective factor in subjects with diabetes using a nationwide, population-based, cross-sectional survey. METHODS: The study included 17,542 subjects: 2,195 with diabetes, 4,042 with prediabetes, and 11,305 with normal glucose tolerance. Furthermore, 1,770 subjects with available data on walking exercise were divided into three groups according to weekly exercise time: <150, 150-300, and ≥ 300 min/week. RESULTS: The diabetes group had reduced pulmonary function, particularly forced vital capacity (FVC) (P<0.001), and a decrease in pulmonary function was observed in the subjects with prediabetes (P<0.001). The walking exercise analysis revealed that the percentage of predicted FVC (P=0.001) and percentage of predicted forced expiratory volume in 1 s (P=0.021) were highest in the subjects with diabetes who walked ≥300 min/week after adjustment for age, sex, body mass index, and waist circumference (WC) measurements. CONCLUSIONS: Pulmonary function was significantly associated with walking exercise in diabetic patients, and walking ≥300 min/week may have a preventive effect against pulmonary dysfunction in subjects with diabetes.

T-cell senescence contributes to abnormal glucose homeostasis in humans and mice.

Chronic inflammation is a driving force for the development of metabolic disease including diabetes and obesity. However, the functional characteristics of T-cell senescence in the abnormal glucose homeostasis are not fully understood. We studied the patients visiting a hospital for routine health check-ups, who were divided into two groups: normal controls and people with prediabetes. Gene expression profiling of peripheral blood mononuclear cells from normal controls and patients with type 2 diabetes was undertaken using microarray analysis. We also investigated the immunometabolic characteristics of peripheral and hepatic senescent T cells in the normal subjects and patients with prediabetes. Moreover, murine senescent T cells were tested functionally in the liver of normal or mice with metabolic deterioration caused by diet-induced obesity. Human senescent (CD28-CD57+) CD8+ T cells are increased in the development of diabetes and proinflammatory cytokines and cytotoxic molecules are highly expressed in senescent T cells from patients with prediabetes. Moreover, we demonstrate that patients with prediabetes have higher concentrations of reactive oxygen species (ROS) in their senescent CD8+ T cells via enhancing capacity to use glycolysis. These functional properties of senescent CD8+ T cells contribute to the impairment of hepatic insulin sensitivity in humans. Furthermore, we found an increase of hepatic senescent T cells in mouse models of aging and diet-induced obesity. Adoptive transfer of senescent CD8+ T cells also led to a significant deterioration in systemic abnormal glucose homeostasis, which is improved by ROS scavengers in mice. This study defines a new clinically relevant concept of T-cell senescence-mediated inflammatory responses in the pathophysiology of abnormal glucose homeostasis. We also found that T-cell senescence is associated with systemic inflammation and alters hepatic glucose homeostasis. The rational modulation of T-cell senescence would be a promising avenue for the treatment or prevention of diabetes.

Epidermal growth factor receptor inhibition attenuates non-alcoholic fatty liver disease in diet-induced obese mice.

Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of chronic liver disease. NAFLD begins with excessive lipid accumulation in the liver and progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is closely linked to dysregulated hepatic lipid metabolism. Although recent studies have reported that epidermal growth factor receptor (EGFR) signaling regulates lipid metabolism, the roles of EGFR and EGFR inhibitors as modulators of lipid metabolism are largely unknown. Here, we investigated whether inhibiting EGFR using the EGFR tyrosine kinase inhibitor (TKI) PD153035 improves NAFLD. Our results demonstrate that EGFR was activated in liver tissues from high fat diet (HFD)-induced NAFLD mice. Inhibiting EGFR using PD153035 significantly reduced phosphatidylinositol-3-kinase/protein kinase B signaling and sterol responsive elementary binding protein 1 and 2 expression, which prevented HFD-induced hepatic steatosis and hypercholesterolemia by reducing de novo lipogenesis and cholesterol synthesis and enhancing fatty acid oxidation. Additionally, inhibiting EGFR improved HFD-induced glucose intolerance. In conclusion, these results indicate that EGFR plays an important role in NAFLD and is a potential therapeutic target.

Serum R-Spondin 1 Is a New Surrogate Marker for Obesity and Insulin Resistance.

BACKGROUND: Recent in vivo studies indicated that R-spondin 1 (RSPO1) regulates food intake and increases insulin secretion, but its role in humans remains unknown. This study investigated the association between serum levels of RSPO1 and diverse metabolic parameters in humans. METHODS: The study population consisted of 43 subjects with newly diagnosed diabetes mellitus, and 79 non-diabetic participants. Serum levels of RSPO1 were measured using the enzyme-linked immunosorbent assay. The relationships between circulating RSPO1 and diverse metabolic parameters were analyzed. RESULTS: Circulating RSPO1 levels increased to a greater extent in the obese group than in the lean group. Moreover, serum levels of RSPO1 were higher in the insulin-resistant group than in the insulin-sensitive group. Serum levels of RSPO1 were significantly correlated with a range of metabolic parameters including body mass index, fasting C-peptide, homeostasis model assessment of insulin resistance index, and lipid profile. Moreover, levels were significantly associated with insulin resistance and obesity in non-diabetic subjects. CONCLUSION: This study demonstrated the association between serum levels of RSPO1 and a range of metabolic parameters in humans. Serum levels of RSPO1 are significantly related to obesity and insulin resistance, although the precise mechanisms remain unknown.