Effectiveness of insulin degludec/liraglutide versus insulin degludec/insulin aspart in Japanese patients with type 2 diabetes.

Aims: To evaluate and compare the effectiveness of once-daily insulin degludec/liraglutide (IDegLira) to that of once-daily insulin degludec/insulin aspart (IDegAsp) after switching from basal insulin therapy at 6 months by assessing changes in hemoglobin A1c (HbA1c), body weight, and insulin doses in patients with type 2 diabetes (T2D). Materials and methods: A total of 91 patients with T2D with HbA1c levels exceeding 7.0% were included in this study. Adjusted least square mean changes in HbA1c, body weight, and total insulin doses were compared between the IDegLira group and IDegAsp group. Subgroup analyses were performed, stratified by median values of HbA1c (< 8.5 and ≥ 8.5%), obesity (body mass index < 25 and ≥ 25 kg/m2), and basal insulin doses (< 14 and ≥ 14 units) at baseline to assess treatment interaction by subgroup. Results: The IDegLira group showed a greater reduction in HbA1c levels than the IDegAsp group (- 0.17 vs - 0.79%, p = 0.003) with comparable body weight changes. The analyses of adjusted mean changes of total insulin doses showed that the IDegAsp group had a larger increase than the IDegLira group (3.64 vs 1.30 unis, p = 0.016). The effect of IDegLira on HbA1c levels was superior to that of IDegAsp in patients with high HbA1c. There were no inter-group differences in the rate of hypoglycemic episodes. Conclusions: Once-daily IDegLira had greater effects on HbA1c and a lesser increase in insulin doses than IDegAsp when patients are switched from basal insulin therapy. Moreover, the effect on HbA1c was enhanced in patients with high HbA1c levels at baseline.

Acute Cholesterol-Lowering Effect of Exendin-4 in Ldlr-/- and C57BL/6J Mice.

AIMS: We previously reported that glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduced serum low-density lipoprotein cholesterol (LDL-C) levels in patients with type 2 diabetes mellitus receiving statins, which increased LDL receptor (LDLR) expression. Nevertheless, it remains unclear how much LDLR expression contributes to the LDL-C-lowering effect of GLP-1RAs. We examined the effect of a GLP-1RA, namely, exendin-4, on serum LDL-C levels and its mechanism in Ldlr-/- and C57BL/6J mice. METHODS: Ten-week-old Ldlr-/- and C57BL/6J mice received exendin-4 or saline for 5 days, and serum lipid profiles and hepatic lipid levels were examined. Cholesterol metabolism-related gene expression and protein levels in the liver and ileum and the fecal bile acid (BA) composition were also examined. RESULTS: Exendin-4 treatment significantly decreased serum very-low-density lipoprotein cholesterol (VLDL-C) and LDL-C levels and mature hepatic SREBP2 levels and increased hepatic Insig1/2 mRNA expression in both mouse strains. In Ldlr-/- mice, exendin-4 treatment also significantly decreased hepatic cholesterol levels and fecal BA excretion, decreased hepatic Cyp7a1 mRNA expression, and increased small intestinal Fgf15 mRNA expression. In C57BL/6J mice, exendin-4 treatment significantly decreased small intestinal NPC1L1 levels. CONCLUSIONS: Our findings demonstrate that exendin-4 treatment decreased serum VLDL-C and LDL-C levels in a manner that was independent of LDLR. Exendin-4 treatment might decrease serum cholesterol levels by lowering hepatic SREBP2 levels and cholesterol absorption in Ldlr-/- and C57BL/6J mice. Exendin-4 treatment might decrease cholesterol absorption by different mechanisms in Ldlr-/- and C57BL/6J mice.

Association between changes in bodyweight and cardiovascular disease risk factors among obese Japanese patients with type 2 diabetes.

AIMS/INTRODUCTION: We aimed to assess the association between bodyweight reduction and cardiovascular disease risk factors, and to identify the minimum bodyweight reduction associated with significant improvement in cardiovascular disease risk factors among obese Japanese patients with type 2 diabetes. MATERIALS AND METHODS: The cohort comprised 1,753 patients with type 2 diabetes and body mass index ≥25 kg/m2 , who visited our clinic between 2013 and 2016. Multivariable linear regression analysis was carried out to assess the relationship between bodyweight changes and glycated hemoglobin A1c, serum lipids and blood pressure. Analyses of covariance were carried out to compare mean changes in cardiovascular disease risk factors across six groups of bodyweight change, <-5%, -5% to <-3%, -3% to <-1%, -1% to <1% (reference), 1% to <3% and ≥3%. RESULTS: Log-transformed bodyweight change had a significantly positive relationship with log-transformed glycated hemoglobin A1c, triglycerides, low-density lipoprotein cholesterol and systolic blood pressure changes, and a negative relationship with high-density lipoprotein cholesterol, after adjusting for sex, age, duration of diabetes, body mass index, use of glucose-lowering, lipid-lowering and antihypertensive agents, and changes in the use of these medications. A mean change in glycated hemoglobin A1c was significantly improved only in the <-5% group compared with the reference. Mean changes in triglycerides were improved in all groups, and significantly in the <-5% group. CONCLUSIONS: Bodyweight change was significantly associated with cardiovascular disease risk factor changes, and >5% bodyweight reduction was associated with improved glycated hemoglobin A1c.

Comparative clinical outcomes of insulin degludec and insulin glargine 300 U/mL after switching from other basal insulins in real-world patients with type 1 and type 2 diabetes.

AIMS/INTRODUCTION: To evaluate and compare the efficacy of insulin degludec (IDeg) and insulin glargine 300 U/mL (Gla300) 6 months after switching from other basal insulins by assessing the changes in glycated hemoglobin (HbA1c), body mass index (BMI), and insulin doses in patients with type 1 and type 2 diabetes in a real-world clinical setting. MATERIALS AND METHODS: A total of 307 patients with type 1 diabetes and 294 patients with type 2 diabetes with HbA1c >7.0% were studied. Adjusted mean changes in HbA1c, BMI, and insulin doses were compared between IDeg (IDeg group) and Gla300 (Gla300 group) switchers. Multivariable logistic regression analyses were carried out to examine whether the IDeg or Gla300 group was associated with HbA1c or insulin dose reduction and BMI gain. RESULTS: HbA1c was significantly decreased in both the IDeg and Gla300 groups. Adjusted mean changes in HbA1c (approximately -0.3% and -0.5% in type 1 diabetes and type 2 diabetes patients, respectively) and BMI were similar between both groups. The mean change in insulin dose was slightly larger for dose reduction in the IDeg group than in the Gla300 group. Multivariable logistic regression models showed that the IDeg group was significantly associated with insulin dose reduction after adjusting for basal insulin type, insulin dose, and number of basal insulin injections at baseline and other confounding factors. CONCLUSIONS: The current study suggested that IDeg and Gla300 have similar effects in reducing HbA1c and gaining BMI after switching from other basal insulins in Japanese patients with type 1 diabetes and type 2 diabetes. IDeg selection was associated with insulin dose reduction.

Endogenous testosterone reduces hepatic lipid accumulation in protein-restricted male rats.

OBJECTIVES: Protein deficiency is known to cause ectopic fat accumulation in the liver. The aim of this study was to analyse the mechanism of suppression of hepatic fat accumulation by testosterone and to clarify the mechanism behind the gender difference in fatty liver formation due to protein deficiency. METHODS: Hepatic fat accumulation due to protein deficiency was evaluated in male and female rats before and after sexual maturation. Then, the effects of testosterone on liver lipid, muscle protein metabolism and energy expenditure in adipose tissue were investigated in castrated or testosterone-injected male rats fed control or protein-restricted diet. RESULTS: Hepatic triglyceride accumulation diminished with sex maturation in male but not in female protein-restricted rats. Protein restriction resulted in a significant increase in hepatic triglyceride content in castrated rats but not in sham-operated rats demonstrating that endogenous testosterone reduces hepatic lipid accumulation in male rats. Protein restriction reduced plasma IGF-I and muscle protein synthesis measured using the SUnSET method. Castration increased the plasma corticosterone level and muscle autophagic activity. Muscle weight was reduced and energy expenditure in adipose tissue was increased only when both factors were combined. CONCLUSIONS: Muscle protein synthesis downregulation owing to protein restriction and activation of autophagy following castration reduced muscle mass thereby releasing surplus energy and promoting steatosis in protein-restricted castrated rats despite increased energy expenditure in adipose tissue. We hypothesize that endogenous testosterone reduces hepatic lipid accumulation in protein-deficient male rats and provide novel findings on the gender-specific differences in hepatic steatosis.

Body Weight Reduction of 5% Improved Blood Pressure and Lipid Profiles in Obese Men and Blood Glucose in Obese Women: A Four-Year Follow-up Observational Study.

Background: Body weight reduction (BWR) of at least 3% in obese Japanese individuals through lifestyle interventions has improved the risk factors for cardiovascular disease (CVD). We aimed to assess the relation between body weight change (BWC) and CVD risk change and to identify lifestyle improvement related to BWR in obese Japanese individuals. Methods: Subjects were 2579 health checkup examinees without medicated diabetes, hypertension or dyslipidemia, and a body mass index ≥25 kg/m2 who completed lifestyle questionnaires in 2008 and 2012. The 4-year changes in fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), lipids, and blood pressure (BP) levels were compared across the five groups based on the 4-year BWC, and presented as <-5%, -5% to -3%, -3% to -1%, -1% to 1%, and ≥1%. Multivariable logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CI) for lifestyle improvement related to BWR. Results: Comparing the groups to the reference group (BWC ranging from -1% to +1%), we observed that FPG and HbA1c levels were lower in women in the <-5% group; BP levels were also lower in the <-5% group; triglyceride levels had improved in the <-3% group, and low-density lipoprotein cholesterol levels in the <-5% group; high-density lipoprotein cholesterol levels had improved in men in the <-5% group. In men, the adjusted OR (95% CI) for BWR related to lifestyle improvement pertaining to "over 30 min exercise" was 2.6 (2.0-3.6). In women, the adjusted ORs for BWR related to "walking or physical activity," "drinking alcohol," and "drinking more than a glass of sake" were 1.7 (1.1-2.7), 1.9 (1.1-3.5), and 1.8 (1.1-3.0), respectively. Conclusions: A 5% BWR improved FPG and HbA1c levels in obese women, and BP and lipid levels in obese men. Improvements in exercise and alcohol consumption habits were associated with BWR in this population.

Serum lipid management in patients with type 1 and type 2 diabetes: a hospital-based cohort study.

INTRODUCTION: Serum lipid management is important for patients with diabetes; however, it has not been examined in our specialized diabetes clinic. AIMS: The aim of the study was to assess the percentage of patients who did not achieve management targets (MT) for low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG), and explore factors related to failure to achieve lipid MT in Japanese patients with type 1 (T1D) and type 2 diabetes (T2D). METHODS: This cross-sectional study included 795 patients (35% men) with T1D and 4018 patients (60% men) with T2D attending our diabetes center. MTs for serum lipids were in accordance with the guidelines of the Japan Atherosclerosis Society. Logistic regression analysis was performed to identify factors related to failure to achieve MTs for serum lipids. RESULTS: The percentages of men/women who did not achieve MT for LDL-C were 34.1/31.8% in T1D and 40.5/52.7% in T2D. The corresponding values for TG were 35.1/14.0% in T1D and 50.1/47.9% in T2D, and for HDL-C were 2.5/0% in T1D and 8.6/2.9% in T2D. Increase in body mass index (BMI) and glycated hemoglobin (HbA1c) were significantly and independently associated with failure to achieve lipid MT in patients with T1D and T2D for both sexes. CONCLUSIONS: The percentages of our patients who did not achieve serum lipid MT were relatively high in T1D and T2D, and higher HbA1c and BMI were associated with failure to achieve serum lipid MTs. More attention should be paid to lipid management in patients with diabetes especially who have higher HbA1c and BMI in our facility.

Glucagon-like peptide-1 receptor agonists reduced the low-density lipoprotein cholesterol in Japanese patients with type 2 diabetes mellitus treated with statins.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) often have hypercholesterolemia, and their serum low-density lipoprotein cholesterol (LDL-C) levels are not always well-controlled even by statin treatment. The glucose-lowering glucagon-like peptide-1 receptor agonists (GLP-1RAs) are reported to change the lipid profiles in T2DM patients, but their effects have been unclear. OBJECTIVE: We examined whether GLP-1RAs affect serum cholesterol levels in T2DM patients with/without statin treatment. METHODS: We retrospectively assessed the baseline and follow-up (median 119 days) levels of serum lipids, HbA1c, and body mass index (BMI) in 103 and 214 Japanese patients with T2DM in whom GLP-1RAs were initiated (GLP-1RA group) and not initiated (control group), stratified by the use of statins. RESULTS: In the GLP-1RA group, the LDL-C, HbA1c, and BMI significantly decreased; high-density lipoprotein cholesterol and triglycerides did not decrease during follow-up. In the control group, these did not decrease. Among the statin users, the percentage change in LDL-C during follow-up was significantly greater in the GLP-1RA group than that in the control group (-6.5% vs -1.0%, P = .040). In the GLP-1RA group, the percentage reduction in LDL-C was not associated with that in BMI but was associated with that in HbA1c only among the statin users. CONCLUSIONS: Our findings demonstrated that GLP-1RAs reduced the serum LDL-C in Japanese patients with T2DM treated with statins. The percentage reduction in LDL-C by GLP-1RAs was associated with that in HbA1c, but not associated with that in BMI. The combination of GLP-1RAs and statins may be a reasonable therapeutic option in T2DM with dyslipidemia.

Diabetes diagnostic thresholds of the glycated hemoglobin A1c and fasting plasma glucose levels considering the 5-year incidence of retinopathy.

AIMS: As retinopathy is used as a defining threshold of diabetes, we assessed the glycated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) values associated with an increased risk of 5-year incidence of retinopathy. METHODS: We studied HbA1c, FPG, and optic fundus findings of 2605 individuals without previously diagnosed diabetes annually during a 5-year period. Retinopathy was examined using non-mydriatic, 45° digital fundus photography. Baseline levels were stratified as <5.3 [34], 5.3-5.6 [34-38], 5.7-6.0 [39-42], 6.1-6.4 [43-47], and ⩾6.5% [48mmol/mol] for HbA1c and <5.0, 5.0-5.5, 5.6-6.0, 6.1-6.9, and ⩾7.0mmol/L for FPG. Cox proportional hazard models were used to analyze hazard ratios (HRs) associated with HbA1c or FPG for incident retinopathy. RESULTS: During a total of 11845 person-years, we identified 50 (1.9%) cases of incident retinopathy. The adjusted HRs for incident retinopathy associated with a one-standard deviation increase in HbA1c and FPG were 1.2 (95% confidence intervals: 1.1-1.4) and 1.2 (1.1-1.4), respectively. These HRs were significantly higher for a HbA1c level ⩾6.5% (48mmol/mol) (3.4 [1.1-10.2]) or FPG level ⩾7.0mmol/L (3.6 [1.1-11.6]) than for a HbA1c level <5.3% (34mmol/mol) or FPG level <5.0mmol/L. CONCLUSIONS: A HbA1c value of 6.5% (48mmol/mol) and FPG value of 7.0mmol/L might be proper as diabetes diagnostic thresholds that indicate a high risk of future retinopathy.

Associations of HbA1c and fasting plasma glucose with incident diabetes: Implications for pre-diabetes thresholds in a Japanese population.

AIMS: This study assessed pre-diabetes (pre-DM) cutoffs for HbA1c and fasting plasma glucose (FPG) that were associated with an increased risk of incident DM. METHODS: We evaluated 2267 non-diabetic Japanese health-check examinees (HbA1c: <6.5% [<48mmol/mol] and FPG: <7.0mmol/L) who were 30-79 years old and were followed-up for 5 years. Incident DM was defined as HbA1c of ≥6.5% (≥48mmol/mol), FPG of ≥7.0mmol/L, or physician-diagnosed DM. RESULTS: During 11047 person-years, we identified 99 incident DM cases (4.3%). The incidence of DM increased with increasing baseline HbA1c or FPG levels, and the change points (95% confidence intervals) were 5.7% (5.6-5.7%; 39mmol/mol [38-39mmol/mol]) for HbA1c and 5.5mmol/L (5.5-5.6mmol/L) for FPG. The adjusted hazard ratios (HRs) for incident DM per one standard deviation-increase in HbA1c and FPG were 5.5 (4.4-6.8) and 4.0 (3.2-4.8), respectively. The adjusted HRs for incident DM were significantly higher at HbA1c of 5.7-6.4% (39-46mmol/mol) or FPG of 5.5-6.9mmol/L, compared to HbA1c of <5.7% (<39mmol/mol) or FPG of <5.5mmol/L. CONCLUSION: The lower cut-offs for pre-DM may be 5.7% (39mmol/mol) for HbA1c and 5.5mmol/L for FPG in this Japanese population.

Association of birthweight with diabetes and insulin sensitivity or secretion in the Japanese general population.

AIMS/INTRODUCTION: Low birthweight (birthweight <2,500 g) has been considered to be a risk factor for diabetes in data from Western countries, and its percentage is increasing in Japan. The aim of the present study was to assess the association between birth weight and diabetes, as well as both insulin resistance and secretion. MATERIALS AND METHODS: The participants were 847 adults who underwent health check-ups. The participants were divided by birthweight into four groups (low birthweight and tertiles 1-3 above it). We assessed the effect of birthweight on diabetes using a logistic regression model. Multivariable liner regression analyses were carried out to examine whether birthweight is independently associated with homeostasis model assessment of insulin resistance and ß-cell function. RESULTS: The prevalence of diabetes tended to increase with decreasing birthweight. The adjusted odds ratio for diabetes with low birthweight was 3.52 (1.04-11.96) as compared with the reference category, tertile 2. Univariable linear regression analyses showed that homeostasis model assessment of insulin resistance was negatively associated with birthweight, and this association remained after adjusting for age, sex, current body mass index and family history of diabetes. There was no significant association between homeostasis model assessment of ß-cell function and birthweight. CONCLUSIONS: Low birthweight was inversely associated with diabetes and insulin resistance in the Japanese general population. Longitudinal data analyses are required to examine the causal relationship between bodyweight and diabetes or insulin resistance in adulthood.

Three-year follow-up of lanthanum carbonate therapy in hemodialysis patients.

For 3 years following the start of lanthanum carbonate therapy, effects on other pharmaceutical treatment with sevelamer hydrochloride (SH), calcium carbonate (CC), and vitamin D, and those on clinical condition were examined. Dialysis patients with hyperphosphatemia (89 cases; average age 55.2 years; dialysis history of 10 years; 50 male and 39 female), who agreed to start lanthanum carbonate (LC) administration, were observed for a mean period of 32.6 ± 6.2 months. Mean daily dosages of CC and SH before starting LC were 2.68 g and 0.73 g; mean daily dosage amounts of LC, CC, and SH at the time of final evaluation were 0.87 g, 2.30 g, and 0.99 g, respectively. After the application of LC, serum phosphate as well as serum calcium controls were significantly improved, and the amounts of active vitamin D agents applied was significantly increased. In conclusion, LC is useful in managing serum phosphorus levels (P levels), and little incidence of hypercalcemia suggests favorable concomitant use with active vitamin D agents in LC therapy.

Healing of experimental apical periodontitis after apicoectomy using different sealing materials on the resected root end.

This study evaluated apical periodontal healing after root-end sealing using 4-META/MMA-TBB resin (SB), and root-end filling using reinforced zinc oxide eugenol cement (EBA) or mineral trioxide aggregate (MTA) when root canal infection persisted. Apical periodontitis was induced in mandibular premolars of beagles by contaminating the root canals with dental plaque. After 1 month, in the SB group, SB was applied to the resected surface following apicoectomy. In the EBA and MTA groups, a root-end cavity was prepared and filled with EBA or MTA. In the control group, the root-end was not filled. Fourteen weeks after surgery, histological and radiographic analyses in a beagle model were performed. The bone defect area in the SB, EBA and MTA groups was significantly smaller than that in the control group. The result indicated that root-end sealing using SB and root-end filling using EBA or MTA are significantly better than control.

Decreased expression of catalase mRNA in thyroid anaplastic carcinoma.

BACKGROUND: A decreased expression of glutathione peroxidase mRNA, an antioxidant enzyme, was previously observed in thyroid anaplastic carcinomas. METHODS: To clarify the expression of antioxidant-related enzymes in thyroid anaplastic carcinomas, the expression levels of catalase, copper and zinc superoxide dismutase and manganese superoxide dismutase mRNA in 85 benign and malignant thyroid tissues were measured by means of real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: Decreased expression levels of catalase and copper and zinc superoxide dismutase mRNAs, but not manganese mRNA, were observed in five anaplastic carcinomas compared with normal thyroid tissues and differentiated tumors. CONCLUSION: These results suggest the possibility that anaplastic carcinoma cells are more likely to suffer damage by oxygen free radicals than normal thyroid cells or differentiated tumor cells.

Quantitative analysis of osteonectin mRNA in thyroid carcinomas.

Our recent study of the gene expression profile in thyroid carcinoma showed an overexpression of osteonectin mRNA, an extracellular matrix protein, in an anaplastic carcinoma. To confirm this, we measured the expression levels of osteonectin mRNA in 84 thyroid normal and tumor tissues, including five anaplastic carcinomas by realtime quantitative reverse-transcription PCR. Increased expression of osteonectin mRNA was observed in anaplastic carcinoma tissue. However, in five anaplastic carcinoma cell lines, no increase was observed in the expression levels of osteonectin mRNA. These findings suggest the possibility that increased expression of osteonectin mRNA in anaplastic carcinoma tissue may be due to its overexpression in stromal cells, but not in anaplastic carcinoma cells.

Quantitative analysis of thymosin beta-10 messenger RNA in thyroid carcinomas.

BACKGROUND: Genes that are differentially expressed in benign and malignant tissues are important for the establishment of molecular-based diagnosis of carcinomas. Our recent study on the gene expression profile of thyroid carcinomas revealed an increased expression of thymosin beta-10 mRNA. METHODS: To confirm this, we measured the expression levels of thymosin beta-10 mRNA in 84 thyroid benign and malignant thyroid tissues, including five anaplastic carcinomas, by means of real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: We found an increased expression of thymosin beta-10 mRNA in thyroid carcinomas, especially in anaplastic carcinomas. Expression levels of thymosin beta-10 mRNA relative to thyroglobulin mRNA in anaplastic carcinomas were greatly increased compared with those in differentiated carcinomas. CONCLUSION: These results suggest the usefulness of the quantitative measurement of thymosin beta-10 mRNA in molecular-based diagnosis of thyroid anaplastic carcinomas, but not of differentiated carcinomas.

Decreased expression of glutathione peroxidase mRNA in thyroid anaplastic carcinoma.

Our recent study using serial analysis of gene expression show the decreased expression of glutathione peroxidase (GPx), an antioxidant enzyme, in an anaplastic carcinoma. To clarify the expression of GPx in various kinds of thyroid tumors, the expression levels of GPx mRNA in 79 benign and malignant thyroid tissues were measured by means of real-time quantitative reverse transcription-polymerase chain reaction. A decreased expression of GPx mRNA was observed in all of five anaplastic carcinomas and some of the papillary carcinomas. A molecular-based therapy which produces O(2) radical may be considered as an alternative choice for the treatment of anaplastic carcinomas.