Role of adiponectin in the relationship between visceral adiposity and fibroblast growth factor 23 in non-diabetic men with normal kidney function.

Fibroblast growth factor 23 (FGF23) is a key regulator of phosphate metabolism. Circulating FGF23 levels are associated with obesity, metabolic syndrome, and cardiovascular disease in the general population, but the underlying mechanism remains unclear. Therefore, we aimed to determine the associations between serum FGF23 levels and visceral adiposity as well as serum adiponectin levels in 189 adults without diabetes and with normal kidney function who were selected from the MedCity21 health examination registry. The exclusion criteria included diabetes mellitus or impaired kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). Levels of serum FGF23 and total adiponectin, and visceral fat area (VFA) on computed tomography images were measured. Serum FGF23 levels were higher and VFA was greater, whereas serum adiponectin levels were lower in men than in women. Serum FGF23 levels positively correlated with VFA in men; they remained marginally significant after adjusting for age, eGFR, and serum levels of calcium, phosphate, intact parathyroid hormone, and 1,25-dihydroxyvitamin D. Importantly, when serum adiponectin levels were included as a covariate, serum adiponectin levels comprised an independent determinant of serum FGF23 levels in men, whereas VFA did not. In conclusion, lower serum adiponectin, rather than a greater VFA, was associated with higher serum FGF23 levels in non-diabetic men with normal kidney function. These findings suggest that adiponectin plays a role in the relationship between visceral adiposity and FGF23 in men.

Comparison of CYP Induction by Coleus forskohlii Extract and Recovery in the Small Intestine and Liver of Mice.

We examined CYP induction and recovery at various doses of Coleus forskohlii extract (CFE) to assess potential drug interactions by a mechanism involving intestinal CYP. Mice were administered diets with various doses of CFE up to 0.5% (equivalent to 700-800 mg/kg body weight) for 2 weeks, then CFE was withdrawn for 3 d. Changes in CYP activities and mRNA expression in the small intestine and liver were then evaluated. CFE induced CYP in the small intestine at a higher dose compared to the liver; CYP3A was induced at 0.5% and 0.005% CFE in the small intestine and liver, respectively. There was no sex difference in CFE dose for CYP induction. CYP induction quickly reverted after withdrawal of CFE, especially for CYP3A, in the small intestine; whereas, a gradual recovery was observed in the liver. In conclusion, CFE induced CYP in the small intestine and liver; however, a higher dose of CFE was needed for the small intestine. Moreover, the induction was soon recovered, suggesting actual interactions of CFE with prescription drugs are unlikely to occur through CYP in the small intestine.

Plasma omentin levels are inversely associated with atherosclerosis in type 2 diabetes patients with increased plasma adiponectin levels: a cross-sectional study.

BACKGROUND: Omentin and adiponectin are among the anti-inflammatory and anti-atherogenic adipokines that have potentially beneficial effects on cardiovascular disorders. Recent studies indicate a paradoxical relationship between adiponectin and cardiovascular mortality across many clinical settings including type 2 diabetes. In this study, we characterized the clinical features of type 2 diabetes patients with increased adiponectin levels and examined the association between omentin and atherosclerosis in those patients. METHODS: The subjects were 413 patients with type 2 diabetes. Fasting plasma omentin and total adiponectin levels were measured by enzyme-linked immunosorbent assay. The intima-media thickness (IMT) of the common carotid artery was measured by ultrasonography. The subjects were stratified according to the median value of plasma adiponectin. RESULTS: In high-adiponectin group, omentin levels were higher, while IMT tended to be greater than those in low-adiponectin group. The high-adiponectin group also exhibited older age, higher systolic blood pressure, lower kidney function, body mass index, and insulin resistance index compared to the low-adiponectin group. Multivariate analysis revealed that omentin levels were independently and negatively associated with IMT in high-adiponectin group, but not in low-adiponectin group, after adjusting for adiponectin levels and traditional cardiovascular risk factors. On the other hand, adiponectin levels were not significantly associated with IMT in either group. CONCLUSIONS: Plasma omentin levels are inversely associated with IMT in type 2 diabetes patients with increased adiponectin levels and multiple cardiovascular risk factors. This study suggests a protective role of omentin against atherosclerosis in type 2 diabetes patients, which is potentially influenced by adiponectin level and cardiovascular risk status.

Altered Serum n-6 Polyunsaturated Fatty Acid Profile and Risks of Mortality and Cardiovascular Events in a Cohort of Hemodialysis Patients.

OBJECTIVE: Alterations in the balance between serum n-3 and n-6 polyunsaturated fatty acids (PUFAs) is predictive of cardiovascular events among hemodialysis patients, although little is known about the serum ratio of n-6 arachidonic acid (AA) to n-6 dihomo-γ-linoleic acid (DGLA) in renal failure. We hypothesized that AA/DGLA ratio is altered in hemodialysis patients resulting in poor clinical outcomes. METHODS: This was a single center cohort study in an urban area in Japan with cross-sectional analyses. Subjects were 517 hemodialysis patients and 122 control subjects. The main exposure was serum AA/DGLA ratio, and the main outcome measures were all-cause mortality and cardiovascular events during 5 years. RESULTS: The hemodialysis patients showed a higher median (interquartile range) AA/DGLA ratio than the control subjects (6.46 [5.22-7.81] versus 4.56 [3.74-6.34], P < .001). In a Cox proportional hazard model adjusted for age, sex, dialysis duration, diabetic nephropathy, prior cardiovascular disease, and the ratio of serum n-3 polyunsaturated fatty acids (eicosapentaenoic acid plus docosahexaenoic acid) to AA, the higher quartiles of AA/DGLA ratio were associated with higher risk for all-cause mortality with hazard ratios (95% confidence interval) of 1.50 (0.84-2.76) for quartile 2, 2.10 (1.18-3.86) for quartile 3, and 2.02 (1.10-3.78) for quartile 4 compared with quartile 1. AA/DGLA ratio showed a similar association with the risk of cardiovascular events. CONCLUSIONS: AA/DGLA ratio was elevated in patients with end-stage renal disease requiring hemodialysis, and a high AA/DGLA ratio was an independent predictor of poor clinical outcomes in this population.

Lipopolysaccharide-binding protein is associated with arterial stiffness in patients with type 2 diabetes: a cross-sectional study.

BACKGROUND: Lipopolysaccharide (LPS)-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by LPS. Recent evidence indicates the association of circulating LBP levels with obesity, diabetes, and cardiovascular diseases. In this study, we aimed to investigate the relationship between serum LBP levels and arterial stiffness in patients with type 2 diabetes. METHODS: A total of 196 patients with type 2 diabetes, including 101 men and 95 women, were enrolled in this cross-sectional study. Fasting serum LBP levels were determined by enzyme-linked immunosorbent assay. Arterial stiffness was assessed by measuring the aortic pulse wave velocity (PWV). RESULTS: The mean values of serum LBP and aortic PWV were 18.2 µg/mL and 1194 cm/s, respectively. Serum LBP levels were positively correlated with body mass index, triglycerides, high-sensitivity C-reactive protein, and insulin resistance index and were negatively correlated with high-density lipoprotein cholesterol. They were, however, not significantly correlated with aortic PWV in univariate analyses. Multivariate analysis revealed that serum LBP levels were independently and positively associated with aortic PWV (ß = 0.135, p = 0.026) after adjusting for age, sex, body mass index, albumin, high-sensitivity C-reactive protein, and other cardiovascular risk factors. Further analyses revealed that the impact of serum LBP levels on aortic PWV was modified by sex, and the association between serum LBP levels and aortic PWV was found to be significant only in men. CONCLUSIONS: Serum LBP levels are associated with arterial stiffness, independent of obesity and traditional cardiovascular risk factors, especially in men with type 2 diabetes. This study indicates a potential role of the LPS/LBP-induced innate immunity in the development and progression of arterial stiffness in type 2 diabetes.

Relationship Between Oral Perception and Habitual Chewing Side for Bare Bone Graft With Dental Implants After Mandibular Reconstruction.

OBJECTIVE: The purpose of this study was to investigate the relationship between habitual chewing side and perception of the oral mucosa following reconstruction with dental implants. STUDY DESIGN: Five patients comprised 2 males and 3 females, with ameloblastoma in 2 patients, odontogenic myxoma in 2 patients, and oral squamous cell carcinoma in 1 patient. They were treated using mandibular reconstruction with bare bone graft after segmental resection of the mandible. Perception (tactile, warm, and cold) was measured at 8 points (chin, lower lip, gingiva, and lateral edge of the tongue, bilaterally). Habitual chewing side was evaluated using a computerized index, the first chewing cycle, and a question on chewing. RESULTS: Perception on resected sides was improved at all measurement points for tactile and cold sensitive evaluation, although sensitivities on the resected side remained below the normal range. In the relationship between habitual chewing side and implanted prostheses in reconstructed bone, the chewing side was the resected side in 2 of the 5 patients. When those 2 patients underwent prosthesis implantation after removal of denture, the chewing side changed from the nonresected side to the resected side. Implant prostheses on resected side were suggested to contribute to masticatory function. Perception in those patients was incomplete but was improved compared with other patients. When prosthesis implantation is performed on the reconstructed side, the resected side may become the habitual chewing side. CONCLUSIONS: Recovery of perception can influence acquisition of the habitual chewing side.

Advantage of insulin glulisine over regular insulin in patients with type 2 diabetes and severe renal insufficiency.

OBJECTIVES: To compare the efficacy and safety of insulin glulisine over regular insulin in patients with type 2 diabetes and severe renal insufficiency. SUBJECTS: Our study included 18 patients with type 2 diabetes and a mean (range) estimated glomerular filtration rate of 13.2 mL/minute/1.73 m(2) (5.8-27.6), which corresponds to stage 4-5 chronic kidney disease. DESIGN: After titration of doses, regular insulin was administered thrice daily on Day 1, along with continuous glucose monitoring for 24 h starting at 7 am. Exactly equal doses of insulin glulisine were administered on Day 2. Area under the curve (AUC) for blood glucose level variation after breakfast (AUC-B 0-4), lunch (AUC-L 0-6), and dinner (AUC-D 0-6) were evaluated. RESULTS: AUC-B 0-4 and AUC-D 0-6 were significantly lower with insulin glulisine than with regular insulin (AUC-B 0-4: 3.3 ± 4.7 vs. 6.2 ± 5.4 × 10(2) mmol/L·minute, respectively, P = .028; AUC-D 0-6: 1.8 ± 7.3 vs. 6.5 ± 6.2 × 10(2) mmol/L·minute, respectively, P = .023). In contrast, AUC-L 0-6 was higher with insulin glulisine than with regular insulin (AUC-L 0-6: 7.6 ± 6.4 vs. 4.2 ± 8.7 × 10(2) mmol/L·minute, respectively, P = .099), suggesting a prolonged hypoglycemic action of regular insulin after lunch. CONCLUSIONS: Insulin glulisine effectively suppressed postprandial hyperglycemia, whereas regular insulin caused a prolonged hypoglycemic action. These findings support the effectiveness and safety of insulin glulisine in patients with type 2 diabetes and severe renal insufficiency.

Leptin is associated with vascular endothelial function in overweight patients with type 2 diabetes.

BACKGROUND: The adipocyte-derived hormone leptin plays a key role in the regulation of appetite and body weight. Recent studies have suggested that leptin is also involved in the pathogenesis of obesity-related atherosclerosis and cardiovascular disease. In this study, we investigated the association of plasma leptin levels with vascular endothelial function in lean and overweight patients with type 2 diabetes. METHODS: One hundred seventy-one type 2 diabetic patients, of which 85 were overweight (body mass index (BMI) ≥ 25 kg/m2), were enrolled in this cross-sectional study. Plasma leptin concentrations were measured by enzyme-linked immunosorbent assay. Flow-mediated dilatation (FMD) of the brachial artery was measured to evaluate vascular endothelial function using ultrasound. RESULTS: No significant difference in FMD was found between the lean and overweight groups (7.0 ± 3.8% and 6.5 ± 3.6%, respectively; p = 0.354). FMD was negatively correlated with age (r = -0.371, p < 0.001) and serum creatinine levels (r = -0.236, p = 0.030), but positively correlated with BMI (r = 0.330, p = 0.002) and plasma leptin levels (r = 0.290, p = 0.007) in the overweight group. FMD was not associated with any parameters in the lean group. Multiple regression analysis including possible atherosclerotic risk factors revealed that the plasma leptin level (ß = 0.427, p = 0.013) was independently associated with FMD in the overweight group (R2 = 0.310, p = 0.025), but not the lean group. CONCLUSION: Plasma leptin levels are associated with vascular endothelial function in overweight patients with type 2 diabetes.

Association of xanthine oxidoreductase inhibitor use with insulin secretory capacity in patients with type 2 diabetes.

AIM/INTRODUCTION: Xanthine oxidoreductase (XOR) inhibitor treatment, which reduces reactive oxygen species (ROS) production and increases adenosine triphosphate (ATP) synthesis, has been reported to improve glycemic control. The possible protective effects of XOR inhibitor treatment on insulin secretory capacity were investigated in patients with type 2 diabetes. MATERIALS AND METHODS: This retrospective cross-sectional study included 428 patients with type 2 diabetes. Insulin secretory capacity was assessed based on fasting serum C-peptide concentration (CPR) and C-peptide index (CPI) in all subjects, while insulin resistance in non-insulin users (n = 312) was determined using the homeostasis model assessment of insulin resistance (HOMA-IR) index. RESULTS: Median values for CPR and CPI in all subjects were 2.4 ng/mL and 1.5, respectively, while that for HOMA-IR in non-insulin users was 3.2. The XOR inhibitor users (n = 72) had significantly (P < 0.001) higher CPR and CPI levels than non-users (n = 356). Multivariable regression analyses showed XOR inhibitor use was positively associated with CPR (ß = 0.153, P = 0.001) and CPI (ß = 0.144, P = 0.001). Similar results were observed in propensity score analyses. In subgroup analyses of patients with a preserved estimated glomerular filtration rate (≥60 mL/min/1.73 m2) and non-insulin users, these associations remained significant. Furthermore, the associations were significant in patients with lower (≤6.0 mg/dL) but not with higher (>6.0 mg/dL) uric acid levels (P for interaction <0.05). On the other hand, XOR inhibitor use showed no significant association with HOMA-IR. CONCLUSIONS: The results of XOR inhibitor treatment, especially a sufficient reduction in serum uric acid level, may provide protective effects on insulin secretory capacity in patients with type 2 diabetes.

Near-Physiological Concentrations of Extracellular Pyruvate Stimulated Glucose Utilization along with Triglyceride Accumulation and Mitochondrial Activity in HepG2 Cells.

Pyruvate, a key intermediate in energy and nutrient metabolism, probably plays important roles in these regulations. In previous reports using cell lines, extracellular pyruvate of supraphysiological concentrations inhibited the glucose uptake by myotubes while being stimulated by adipocytes. As the effect of pyruvate on the glucose utilization is unclear in cultured hepatocytes. We have investigated the effects of extracellular pyruvate on the glucose utilization and the subsequent metabolic changes using the cell line HepG2. In a 24 h culture, pyruvate enhanced the glucose consumption more potently than 1 µM insulin, and this enhancement was detectable at a near-physiological concentrations of ≤1 mM. For metabolic changes following glucose consumption, the conversion ratio of glucose and pyruvate to extracellular lactate was approximately 1.0 without extracellular pyruvate. The addition of pyruvate decreased the conversion ratio to approximately 0.7, indicating that the glycolytic reaction switched from being an anaerobic to a partially aerobic feature. Consistent with this finding, pyruvate increased the accumulation of intracellular triglycerides which are produced through substrate supply from the mitochondria. Furthermore, pyruvate stimulated mitochondria activity as evidenced by increases in ATP content, mitochondrial DNA copy number, enhanced mitochondria-specific functional imaging and oxygen consumption. Interestingly, 1 mM pyruvate increased oxygen consumption immediately after addition. In this study, we found that near-physiological concentrations of extracellular pyruvate exerted various changes in metabolic events, including glucose influx, lactate conversion rations, TG accumulation, and mitochondrial activity in HepG2 cells.

Application to Butterbur Products of a Suggested Daily Intake-Based Safety Evaluation of Individual Herbal Supplements with Cytochrome P450 Expression as a Major Index.

The present paper first proposes a method for ensuring the safety of commercial herbal supplements, termed the suggested daily intake-based safety evaluation (SDI-based safety evaluation). This new method was inspired as a backward analog of the acceptable daily intake (ADI) derivation from the no observed adverse effect level (NOAEL), the basis of food additive risk analysis; namely, rats are dosed with individual herbal supplement products at the SDI for human use multiplied by 100 (the usual uncertainty factor value) per body weight for 8 d. The primary endpoint is the sign of adverse effects on liver, especially gene expression of cytochrome P450 (CYP) isoforms. The proposed method was then applied to three butterbur (Petasites hybridus) products without pyrrolizidine alkaloids but lacking clear safety information. Results showed that two oily products markedly enhanced the mRNA expression of CYP2B (>10-fold) and moderately enhanced that of CYP3A1 (<4-fold) with liver enlargement. These products also caused the renal accumulation of alpha 2-microglobulin. One powdery product showed no significant effect on liver and kidney. The large difference in effects of products was due to the difference in chemical composition revealed by liquid chromatography-mass spectroscopy. The oily and the powdery products required attention in terms of safety and effectiveness, respectively. Finally, the results from the SDI-based safety evaluation of butterbur and other herbal supplement products were grouped into four categories and cautionary notes were discussed. The SDI-based safety evaluation of their products by herbal supplement operators would contribute to safe and secure use by consumers.

Serum Fibroblast Growth Factor 23 Levels are Associated with Vascular Smooth Muscle Dysfunction in Type 2 Diabetes.

AIM: Increased level of serum fibroblast growth factor 23 (FGF23) is a hallmark of abnormal phosphate metabolism in patients with chronic kidney disease (CKD) and is recently shown to be associated with the risk of cardiovascular disease even in those without CKD. This study investigated the association between serum FGF23 levels and vascular function in patients with type 2 diabetes. METHODS: This was a cross-sectional study involving 283 Japanese patients with type 2 diabetes. Flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) of the brachial artery were measured via ultrasonography to evaluate vascular endothelial and smooth muscle functions, respectively. Serum intact FGF23 levels were determined via a sandwich enzyme-linked immunosorbent assay. RESULTS: The median values of FMD, NMD, and serum FGF23 were 6.0%, 14.0%, and 27.3 pg/mL, respectively. The serum FGF23 levels were inversely associated with NMD but not with FMD, and the association was independent of atherosclerotic risk factors, estimated glomerular filtration rate (eGFR), and serum phosphate levels. Furthermore, the relationship between serum FGF23 levels and NMD was modified by kidney function, which was pronounced in subjects with normal kidney function (eGFR ≥ 60 mL/min/1.73 m2). CONCLUSION: Serum FGF23 levels are independently and inversely associated with NMD in patients with type 2 diabetes, particularly in those with normal kidney function. Our results indicate that FGF23 is involved in vascular smooth muscle dysfunction and that increased serum levels of FGF23 may serve as a novel biomarker for vascular smooth muscle dysfunction in patients with type 2 diabetes.

New-onset Type 1 Diabetes after COVID-19 mRNA Vaccination.

During the ongoing coronavirus disease 2019 (COVID-19) pandemic, it is critical to ensure the safety of COVID-19 vaccines. We herein report a 51-year-old Japanese woman who developed acute-onset type 1 diabetes with diabetic ketoacidosis six weeks after receiving the first dose of a COVID-19 messenger ribonucleic acid (mRNA) vaccine. Laboratory tests indicated exhaustion of endogenous insulin secretion, a positive result for insulin autoantibody, and latent thyroid autoimmunity. Human leukocyte antigen typing was homozygous for DRB1*09:01-DQB1*03:03 haplotypes. This case suggests that COVID-19 vaccination can induce type 1 diabetes in some individuals with a genetic predisposition.

Factors associated with atrial fibrillation in Japanese patients with type 2 diabetes mellitus: a cross-sectional study.

Aims: Atrial fibrillation (AF) increases cardiovascular complications and mortality in patients with diabetes. Diabetes is a risk factor for AF; however, risk factors for AF among patients with type 2 diabetes (T2D) remain unknown, especially among Asian people. We clarified the prevalence of AF, regardless of type (i.e., paroxysmal, persistent, or permanent) in Japanese patients with T2D and clarified factors associated with AF. Methods: This cross-sectional study was conducted at Fujiidera Municipal Hospital (Osaka, Japan). Patients with T2D (n = 899: 518 men and 381 women with a mean age ± SD of 69.0 ± 12.1 years) were included. Their electrocardiographs were checked during routine examinations between January 2017 and January 2018. A diagnosis of AF was determined from single time-point standard 12-lead electrocardiographic findings. We analyzed clinical parameters (e.g., age, sex, diabetes duration, glycated hemoglobin, body mass index, estimated glomerular filtration rate, albuminuria or proteinuria, use of biguanide, and presence of hypertension) between patients with and without AF. Results: The prevalence of AF among patients with T2D was 5.9%; it became higher as age increased and tended to be higher in men than in women. The prevalence became higher as albuminuria or proteinuria progressed and as the eGFR decreased. Multiple logistic regression analyses revealed that older age, male sex, and reduced eGFR were independently and significantly associated with the coexistence of AF. However, multiple logistic regression analysis revealed no significant relationships between AF and the presence of albuminuria or proteinuria. Conclusions: Older age, male sex, and reduced eGFR were associated with AF in Japanese patients with T2D. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00563-w.

New-onset fulminant type 1 diabetes after severe acute respiratory syndrome coronavirus 2 vaccination: A case report.

Fulminant type 1 diabetes is characterized by a rapid progression of insulin deficiency triggered by viral infection. Here, we report a case of a 45-year-old Japanese woman with fulminant type 1 diabetes that developed 8 days after receiving messenger ribonucleic acid vaccine against severe acute respiratory syndrome coronavirus 2. She had been healthy and had no symptoms suggestive of viral infection before the vaccination. Laboratory tests showed exhaustion of insulin secretion and negative results for islet autoantibodies. Human leukocyte antigen genotype analysis showed the DRB1*04:05 and DQB1*04:01 alleles. This is the first case report of new-onset fulminant type 1 diabetes after severe acute respiratory syndrome coronavirus 2 vaccination, and suggests that a severe acute respiratory syndrome coronavirus 2 vaccine might trigger the onset of fulminant type 1 diabetes in susceptible individuals. However, a causal relationship remains to be identified, and further studies are required to determine the incidence of such cases.

Influence of zinc deficiency to the mice infected with Babesia microti.

Zinc (Zn) is an essential trace element for DNA synthesis and for cell growth and differentiation. The deficiency induces a wide range of disorders including immunodeficiency. In this study, the influence of Zn deficiency to the mice infected with Babesia microti was examined, and was compared with the influence in the rats infected with B. rodhaini previously reported. Experiments of B. microti infection were conducted using Zn-deficient (ZD; allowed to eat ad libitum on the ZD diet), Zn-adequate (ZA; allowed to eat ad libitum on the ZA diet), and diet-restricted (DR; supplied 2 g/day on the ZA diet) mice. It was suggested that the Zn deficiency exacerbated the infection dynamics of the mice with B. microti by the growth retardation, the reduction of immunity and the decrease in PCV. The results in the mice supported the consequences in the rats previously reported.

Association of Reduced Free T3 to Free T4 Ratio with Lower Serum Creatinine in Japanese Hemodialysis Patients.

PURPOSE: Low T3 syndrome is defined by a fall in free triiodothyronine (FT3) in spite of normal serum thyroid-stimulating hormone (TSH) and often normal free thyroxin (FT4). A low FT3/FT4 ratio, a relevant marker for low T3 syndrome, is known as a risk of mortality in hemodialysis (HD) patients, as well as low muscle mass in the general population. Because of the local activation of T4 to FT3 in muscle tissue, we examined the association of FT3/FT4 ratio with serum creatinine, a marker of muscle mass and strength in HD patients to investigate the significance of muscle tissue in the development of low T3 syndrome in HD patients. METHODS: This was a cross-sectional study derived from our prospective cohort study, named DREAM, of Japanese HD patients. After the exclusion of patients with treated and untreated thyroid dysfunction, 332 patients were analyzed in the study. RESULTS: The serum FT4 and TSH of HD patients (n = 332) were 0.9 ± 0.1 ng/dL. and 2.0 ± 0.9 µIU/mL, which were within the respective normal range, while serum FT3 was 2.2 ± 0.3 pg/mL. As many as 101 out of 332 (30.4%) HD patients exhibited a serum FT3 less than the normal lower limit of 2.2 pg/mL. The serum FT3/FT4 ratio correlated significantly positively with serum creatinine, and inversely with serum log CRP and total cholesterol, while it exhibited a tendency towards positive correlation with serum albumin. Multiple regression analysis, which included serum creatinine, albumin, and log CRP, simultaneously, in addition to sex, age, diabetic kidney disease or not, log HD duration, body mass index, systolic blood pressure, and Kt/V, as independent variables, revealed an independent and significant positive association of serum creatinine, but not serum albumin or CRP, with the serum FT3/FT4 ratio. CONCLUSIONS: The present study demonstrated an independent and positive correlation of serum creatinine with the serum FT3/FT4 ratio in HD patients. The lack of association of the serum FT3/FT4 ratio with serum albumin and CRP suggested the presence of a creatinine-specific mechanism to associate with serum FT3/FT4 ratio. Because of the local activation of T4 to T3 at muscle tissue, a lower muscle mass may be causatively associated with low T3 syndrome.

Low Free Triiodothyronine Level as a Predictor of Cardiovascular Events and All-Cause Mortality in Patients Undergoing Hemodialysis: The DREAM Cohort.

AIM: Low T3 syndrome is characterized by low serum triiodothyronine (T3) levels without elevation of thyroid-stimulating hormone (TSH) in patients without apparent thyroid disease, which is known to be associated with worse clinical outcomes in various populations including those with kidney failure. In this study, we examined whether low free T3 (FT3) levels are independent predictor of cardiovascular disease (CVD) events in patients undergoing hemodialysis. METHODS: This was a prospective cohort study of patients with chronic kidney disease undergoing hemodialysis. From the total of 518 patients, we excluded patients with treated or untreated hyperthyroidism or hypothyroidism and those treated with corticosteroids. RESULTS: We analyzed data from 438 eligible patients. During the 5-year follow-up, 154 new CVD events and 86 all-cause deaths were recorded. Kaplan-Meier analysis showed that lower FT3 levels were associated with higher risks for new cardiovascular events and all-cause death. This inverse association of FT3 and new CVD events remained significant after adjustment for age, sex, duration of hemodialysis, diabetic kidney disease, hypertension, dyslipidemia, and smoking; however, it was no longer significant after further adjustment for prior CVD or N-terminal fragment of probrain natriuretic peptide (NT-proBNP). FT3 did not show an independent association with all-cause mortality. CONCLUSIONS: Our results indicate that low FT3 status is not an independent predictor of new CVD events and that the following factors are closely associated: prior CVD, low FT3 and high NT-proBNP levels at present, and future risk of new CVD events in hemodialysis patients.

Excessive folic acid supplementation in pregnant mice impairs insulin secretion and induces the expression of genes associated with fatty liver in their offspring.

OBJECTIVE: Previous human and animal studies have shown that excessive maternal intake of folic acid (FA) predisposes to impaired glucose tolerance in the offspring. However, the underlying mechanism is unknown. Therefore, we aimed to determine whether excessive supplementation with FA during pregnancy affects the glucose tolerance of mouse offspring. RESEARCH METHODS & PROCEDURES: Pregnant C57BL/6J mice were fed AIN93G diet containing either 2 mg [control group (CN)] or 40 mg [high FA group (HFA)] FA/kg diet throughout their pregnancies. On postnatal days (PD)22 and 50, fasting blood glucose was measured in the offspring of both groups, and an oral glucose tolerance test (OGTT) was performed on PD50. On PD53, tissues were collected, and the tissue masses, area of insulin expression in the pancreas, liver triglyceride content, and gene expression were determined. RESULTS: The blood glucose concentrations at 60 and 120 min of the OGTT were higher in female HFA than CN offspring. The serum fasting and non-fasting insulin concentrations and the area of insulin expression in the pancreas were lower in HFA than CN offspring. The liver triglyceride content was higher in female, and tended to be higher in male (P < 0.05), HFA offspring than CN offspring (P < 0.05). The liver mRNA expression of fat synthesis genes, such as Pparγ2 (male and female) and Cidec (male), was higher in HFA than CN offspring (P < 0.05). CONCLUSION: Excessive maternal supplementation of FA in mice leads to lower insulin synthesis and an impairment in hepatic fat metabolism in the offspring.