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.

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 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.

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.

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.

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.

Visceral adiposity is associated with the discrepancy between glycated albumin and HbA1c in type 2 diabetes.

AIM: We investigated the association of visceral adiposity with glycated albumin (GA) as well as GA/hemoglobin A1c (HbA1c) in type 2 diabetes. METHODS: One hundred twenty-three patients (68 males, 55 females) with type 2 diabetes were enrolled in this cross-sectional study. Visceral fat area (VFA) was determined using an abdominal dual bioelectrical impedance analysis (dual BIA) instrument. The relationship of VFA with GA and GA/HbA1c was analyzed. RESULTS: Simple regression analysis showed that BMI was inversely correlated with GA as well as GA/HbA1c, but not with HbA1c, while VFA had a significant correlation with GA and GA/HbA1c. Furthermore, multiple regression analysis revealed VFA as an independent contributor to GA/HbA1c. These results suggest that visceral adiposity is a primary factor associated with GA and HbA1c level discrepancy in patients with type 2 diabetes. CONCLUSIONS: GA is a useful indicator for glycemic control, while visceral obesity should also be taken into consideration in type 2 diabetes cases.

Albuminuria rather than glomerular filtration rate is associated with vascular endothelial function in patients with type 2 diabetes.

AIMS: Albuminuria and reduced glomerular filtration rate (GFR) are manifestations of diabetic kidney disease and are both shown to be associated with cardiovascular outcomes. However, the differential association of albuminuria and reduced GFR with endothelial dysfunction, an early feature of atherosclerotic vascular damage, remains unclear. In this study, we investigated the association between albuminuria or estimated GFR (eGFR) and flow-mediated dilatation (FMD), a marker of endothelial function, in patients with type 2 diabetes. METHODS: This study included 633 patients with type 2 diabetes. The FMD of the brachial artery was measured by ultrasonography. Albuminuria was evaluated by urinary albumin-to-creatinine ratio (ACR). RESULTS: The mean FMD and eGFR, and the median value of ACR were 6.7%, 66.5 mL/min/1.73m2 and 12.5 mg/g creatinine, respectively. Impaired FMD was found in patients with advanced stages of chronic kidney disease based on both GFR and albuminuria categories. Multivariate analysis after adjusting for potential confounders revealed that ACR, but not eGFR, was significantly and inversely associated with FMD. CONCLUSIONS: Albuminuria is associated with FMD, independently of traditional cardiovascular risk factors in patients with type 2 diabetes. This study suggests a close relationship between albuminuria, rather than reduced GFR, and endothelial dysfunction in type 2 diabetes.

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.

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.

Inter-Arm Blood Pressure Difference in Diabetes Mellitus and Its Preferential Association with Peripheral Artery Disease.

AIM: Inter-arm blood pressure difference (IAD) is known to be associated with a composite of cardiovascular disease (CVD) and with CVD risk factors. However, only limited information is available regarding the contribution of diabetes mellitus to IAD and the association of IAD with individual CVDs, such as coronary artery disease (CAD), stroke, and peripheral artery disease (PAD). METHODS: We addressed these issues in this cross-sectional study of 2580 participants who had simultaneous blood pressure measurements in both arms using an automated device. RESULTS: Compared with 1,264 nondiabetic subjects, 1316 patients with diabetes mellitus had a greater IAD (P=0.01) and a higher prevalence of IAD of ≥ 10 mmHg (8.4% vs. 5.4%, P=0.002). However, such difference was not significant after the adjustment for potential confounders. Among CAD, stroke, and PAD, only PAD was significantly associated with IAD in a model adjusted for the CVD risk factors. Age was found to modify the association between IAD and PAD, with the association being more prominent in the younger subgroup. CONCLUSION: Thus, diabetes mellitus itself was not an independent factor associated with IAD. A larger IAD was preferentially associated with the presence of PAD, and this association was modified by age.

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.

Plasma omentin levels are associated with vascular endothelial function in patients with type 2 diabetes at elevated cardiovascular risk.

AIMS: Omentin is an adipokine that has protective effects against cardiovascular damage. Previous studies showed an inverse relationship between omentin and obesity, diabetes, and cardiovascular disease. This study aimed to investigate the association between omentin and vascular endothelial function in patients with type 2 diabetes (T2D). METHODS: The subjects were 425 patients with T2D and 223 non-diabetic controls. Fasting plasma omentin levels were measured by enzyme-linked immunosorbent assay, and the endothelium-dependent, flow-mediated dilatation (FMD) was measured by ultrasonography. RESULTS: Plasma omentin levels were higher, while FMD was lower in participants with T2D than in non-diabetic controls. No significant correlation was found between plasma omentin levels and FMD in either non-diabetic controls or participants with T2D on multivariate analysis. However, stratified analysis in T2D patients revealed that plasma omentin levels were independently and positively associated with FMD in high cardiovascular risk subgroups according to age (≥65 years), estimated glomerular filtration rate (<60 mL/min/1.73 m2), or preexisting cardiovascular diseases but not in low-risk subgroups. CONCLUSIONS: Plasma omentin levels are independently associated with endothelial function in subgroups of patients with T2D at elevated cardiovascular risk. This study suggests a protective role of omentin against endothelial dysfunction, particularly in high-risk patients.

Plasma polyunsaturated fatty acid profile is associated with vascular endothelial function in patients with type 2 diabetes.

Decreased plasma n-3 polyunsaturated fatty acid levels or the n-3/n-6 polyunsaturated fatty acid ratios are associated with a risk of cardiovascular events. In this cross-sectional study, we measured plasma levels of eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid and investigated the association between the plasma polyunsaturated fatty acid profile and vascular endothelial function in 396 patients with type 2 diabetes. Endothelium-dependent, flow-mediated dilatation of the brachial artery was measured using ultrasonography. Multiple regression analyses, including age, sex, body mass index, and other cardiovascular risk factors, revealed that plasma eicosapentaenoic acid levels ( ß = 0.140, p = 0.008) and the eicosapentaenoic acid/arachidonic acid ratio ( ß = 0.127, p = 0.019), but not plasma docosahexaenoic acid levels ( ß = 0.067, p = 0.220) or the docosahexaenoic acid/arachidonic acid ratio ( ß = 0.034, p = 0.559), were independently and positively associated with flow-mediated dilatation. In conclusion, plasma eicosapentaenoic acid levels and the eicosapentaenoic acid/arachidonic acid ratio are independently associated with endothelial function in patients with type 2 diabetes. This study indicates a positive association between eicosapentaenoic acid, rather than docosahexaenoic acid, and endothelial function in type 2 diabetes.

Correlation analysis of monocyte subsets and insulin resistance considering fetuin-A involvement in patients with type 2 diabetes.

BACKGROUND: Fetuin-A is a multifunctional circulating glycoprotein that can induce insulin resistance. Lately, adipose tissue has gained prominence as an effector site of fetuin-A. Although fetuin-A-induced proinflammatory polarization and migration of macrophages plays a crucial role, it remains obscure whether monocyte subsets in circulation could simulate characteristics of macrophages in adipose tissues. This study aims to investigate the correlation between monocyte subsets with fetuin-A and its relevant insulin resistance. RESULTS: We evaluated serum fetuin-A levels in 107 patients with type 2 diabetes (T2D). Using flow cytometry, we classified monocyte subsets into three subtypes: (a) classical, CD14++CD16-; (b) intermediate, CD14++CD16+, the most proinflammatory one; (c) and nonclassical, CD14+CD16++. We assessed the insulin resistance by the homeostasis model assessment for insulin resistance (HOMA-IR) in 68 patients without insulin injections. We observed no correlation between fetuin-A levels and classical (ρ = - 0.005; P = 0.959), intermediate (ρ = 0.022; P = 0.826), and nonclassical monocyte counts (ρ = 0.063; P = 0.516), respectively. In addition, no significant correlation was found between log (HOMA-IR) and classical (ρ = 0.052; P = 0.688), intermediate (ρ = 0.054; P = 0.676), and nonclassical monocyte counts (ρ = 0.012; P = 0.353), respectively. However, serum fetuin-A levels showed positive correlation with log (HOMA-IR) (ρ = 0.340; P = 0.007). Multiple regression analyses revealed a significant relationship between fetuin-A and log (HOMA-IR) (ß = 0.313; P = 0.016), but not with monocyte subsets. CONCLUSIONS: Monocyte subsets in circulation, including proinflammatory intermediate monocytes, were not associated with fetuin-A and insulin resistance.

Positive association of plasma leptin with sleep quality in obese type 2 diabetes patients.

AIMS/INTRODUCTION: Poor sleep quality is associated with obesity and diabetes. The adipocyte-derived hormone, leptin, was recently shown to underlie the link between abnormal sleep and obesity. We aimed to investigate the association between leptin and sleep quality in type 2 diabetes patients. MATERIALS AND METHODS: In the present cross-sectional study, we studied 182 type 2 diabetes patients, among whom 113 were diagnosed with obesity (body mass index ≥25 kg/m2 ). Fasting plasma leptin levels were measured, and sleep architecture was assessed using single-channel electroencephalography. RESULTS: Using unadjusted analyses, the obese type 2 diabetes patients, but not their non-obese counterparts, showed a positive correlation between plasma leptin levels and a parameter for deep sleep assessed by delta power during the first sleep cycle. Multivariate analysis showed that plasma leptin levels were positively associated with delta power, but not with the total sleep time, after adjusting for potential confounders including age, body mass index and the apnea-hypopnea index, in the obesity group. However, neither delta power nor total sleep time was associated with leptin in the non-obesity group. CONCLUSIONS: Plasma leptin levels are independently associated with sleep quality in obese, but not in non-obese, type 2 diabetes patients. The present study indicates a favorable relationship between leptin and sleep quality in obese type 2 diabetes patients.

Plasma soluble leptin receptor levels are associated with pancreatic ß-cell dysfunction in patients with type 2 diabetes.

AIMS/INTRODUCTION: A soluble form of the leptin receptor (soluble Ob-R) in the circulation regulates leptin's bioactivity, and is inversely associated with body adiposity and circulating leptin levels. However, no study has examined the clinical impact of soluble Ob-R on glucose metabolism in diabetes. The present study aimed to investigate the association of plasma soluble Ob-R levels with insulin resistance and pancreatic ß-cell function in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 289 Japanese patients with type 2 diabetes were included in the present study. Fasting plasma soluble Ob-R levels and plasma leptin levels were measured by enzyme-linked immunosorbent assay. Insulin resistance and pancreatic ß-cell function were estimated by homeostasis model assessment of insulin resistance, homeostasis model assessment of ß-cell function and fasting C-peptide index. RESULTS: The median plasma soluble Ob-R level and plasma leptin level were 3.4 ng/mL and 23.6 ng/mL, respectively. Plasma soluble Ob-R levels were negatively correlated with homeostasis model assessment of insulin resistance, homeostasis model assessment of ß-cell function and the C-peptide index, whereas plasma leptin levels were positively correlated with each index in univariate analyses. Multivariate analyses including plasma soluble Ob-R levels, plasma leptin levels and use of sulfonylureas, along with age, sex, body mass index and other covariates, showed that soluble Ob-R levels were independently and negatively associated with homeostasis model assessment of ß-cell function and the C-peptide index, but not significantly associated with homeostasis model assessment of insulin resistance. CONCLUSIONS: Plasma soluble Ob-R levels are independently associated with pancreatic ß-cell function, but not with insulin resistance, in patients with type 2 diabetes. The present study implicates the role of soluble Ob-R in pancreatic ß-cell dysfunction in type 2 diabetes.