Cerebral oxygenation changes in response to post-hemodialysis standing.

Few reports have examined the association between changes in cerebral oxygenation and clinical factors, including blood pressure (BP), upon standing after hemodialysis (HD). This study aimed to clarify the factors affecting the changes in cerebral regional oxygen saturation (rSO2) upon standing after HD and monitor the differences in cerebral rSO2 changes that occur upon standing after HD in patients with and without diabetes mellitus (DM). Changes in mean BP and cerebral rSO2 were tracked in 43 HD patients during 120 s of standing after HD using an INVOS 5100c oxygen saturation monitor. The post-HD cerebral rSO2 at rest was 55.8 ± 10.2%, while that at 120 s of standing decreased to 51.9 ± 9.6%; therefore, the percentage change in cerebral rSO2 at 120 s of standing was - 6.8 ± 6.4%, which was significantly lower than before HD (p < 0.001). This change was significantly correlated with the presence of DM, HD duration, mean BP at 120 s of standing, and percentage change in mean BP at 120 s of standing. A multivariable linear regression analysis showed that percentage change in cerebral rSO2 at 120 s of standing was independently associated with the percentage change in mean BP at 120 s of standing (standardized coefficient: 0.432; p = 0.004). Furthermore, there were significant decreases in percentage changes in cerebral rSO2 throughout the standing period in HD patients with versus without DM. Therefore, cerebral oxygenation deterioration upon standing after HD should receive attention, particularly in HD patients with DM.

Daily variability in serum levels of calciprotein particles and their association with mineral metabolism parameters: A cross-sectional pilot study.

AIM: Calciprotein particles (CPPs), colloidal protein-mineral nanoparticles composed of solid-phase calcium phosphate and serum protein fetuin-A found in blood, are emerging as a novel component of chronic kidney disease-mineral and bone disorder (CKD-MBD). The relationship of CPPs with factors known to underlie the CKD-MBD pathophysiology is not well known.The aim of this study is to examine daily variations in CPPs as well as their association with mineral metabolism parameters in normal individuals and early-stage CKD patients. METHODS: Twenty subjects (10 healthy adults, 10 diabetic patients) were enrolled. Serum CPP Fetuin-A was measured and analyzed in relation to clinical parameters. RESULTS: Estimated glomerular filtration rates (eGFR) were 103 ± 11 and 75 ± 24 mL/min per 1.73 m2 in healthy adults and diabetic patients, respectively. Serum CPP Fetuin-A (g/L) were elevated at postprandial 2 h in diabetic patients. Furthermore, serum CPP Fetuin-A were inversely correlated with eGFR and serum 1,25-dihydroxyvitamin D3 and magnesium levels and were positively correlated with serum fibroblast growth factor-23. CONCLUSIONS: These findings indicated that serum CPP Fetuin-A were affected by food intake and may contribute to the pathophysiology of mineral metabolism in subjects with normal and moderately impaired renal function.

High-density lipoprotein and apolipoprotein A-I inhibit palmitate-induced translocation of toll-like receptor 4 into lipid rafts and inflammatory cytokines in 3T3-L1 adipocytes.

Saturated fatty acids (SFAs) activate toll-like receptor 4 (TLR4) signal transduction in macrophages and are involved in the chronic inflammation accompanying obesity. High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) produce anti-inflammatory effects via reverse cholesterol transport. However, the underlying mechanisms by which HDL and apoA-I inhibit inflammatory responses in adipocytes remain to be determined. Here we examined whether palmitate increases the translocation of TLR4 into lipid rafts and whether HDL and apoA-I inhibit inflammation in adipocytes. Palmitate exposure (250 µM, 24 h) increased interleukin-6 and tumor necrosis factor-α gene expressions and translocation of TLR4 into lipid rafts in 3T3-L1 adipocytes. Pretreatment with HDL and apoA-I (50 µg/mL, 6 h) suppressed palmitate-induced inflammatory cytokine expression and TLR4 translocation into lipid rafts. Moreover, HDL and apoA-I inhibited palmitate-induced phosphorylation of nuclear factor-kappa B. HDL showed an anti-inflammatory effect via ATP-binding cassette transporter G1 and scavenger receptor class B, member 1, whereas apoA-I showed an effect via ATP-binding cassette transporter A1. These results demonstrated that HDL and apoA-I reduced palmitate-potentiated TLR4 trafficking into lipid rafts and its related inflammation in adipocytes via these specific transporters.

Lower 1,5-anhydroglucitol is associated with adverse clinical events after percutaneous coronary intervention.

Diabetes mellitus and impaired glucose tolerance are well-known risk factors for coronary artery disease (CAD) and adverse clinical events after percutaneous coronary intervention (PCI). Postprandial hyperglycemia is an important risk factor for CAD and serum 1,5-anhydroglucitol (1,5-AG) reflects postprandial hyperglycemia more robustly than hemoglobin (Hb)A1c. We aimed to clarify the relationship between serum 1,5-AG level and adverse clinical events after PCI. We enrolled 141 patients after PCI with follow-up coronary angiography. We evaluated associations between glycemic biomarkers including HbA1c and 1,5-AG and cardiovascular events during follow-up. Median serum 1,5-AG level was significantly lower in patients with any coronary revascularization and target lesion revascularization (TLR) [13.4 µg/ml (first quartile, third quartile 9.80, 18.3) vs. 18.7 (12.8, 24.2), p = 0.005; 13.4 µg/ml (10.2, 16.4) vs. 18.7 (12.9, 24.2), p = 0.001, respectively]. Multivariate logistic analysis showed lower 1,5-AG was independently associated with any coronary revascularization and TLR (odds ratio 0.93, 95 % confidence interval 0.86-0.99, p = 0.04; 0.90, 0.81-0.99, p = 0.044, respectively), whereas higher HbA1c was not. Postprandial hyperglycemia and lower 1,5-AG are important risk factors for adverse clinical events after PCI.

Glucose and GTP-binding protein-coupled receptor cooperatively regulate transient receptor potential-channels to stimulate insulin secretion [Review].

In pancreatic ß-cells, glucose-induced closure of the ATP-sensitive K+ (KATP) channel is an initial process triggering glucose-stimulated insulin secretion (GSIS). This KATP-channel dependent pathway has been believed to be a central mechanism for GSIS. However, since the resting membrane potential of cells is determined by the balance of the net result of current amplitudes in outward and inward directions, it must be taken into consideration that not only KATP channel inhibition but also inward current via the basal opening of non-selective cation channels (NSCCs) plays a crucial role in membrane potential regulation. The basal activity of NSCCs is essential to effectively evoke depolarization in concert with KATP channel closure that is dependent on glucose metabolism. The present study summarizes recent findings regarding the roles of NSCCs in GSIS and GTP-binding protein coupled receptor-(GPCR) operated potentiation of GSIS.

Serotonin regulates glucose-stimulated insulin secretion from pancreatic ß cells during pregnancy.

In preparation for the metabolic demands of pregnancy, ß cells in the maternal pancreatic islets increase both in number and in glucose-stimulated insulin secretion (GSIS) per cell. Mechanisms have been proposed for the increased ß cell mass, but not for the increased GSIS. Because serotonin production increases dramatically during pregnancy, we tested whether flux through the ionotropic 5-HT3 receptor (Htr3) affects GSIS during pregnancy. Pregnant Htr3a(-/-) mice exhibited impaired glucose tolerance despite normally increased ß cell mass, and their islets lacked the increase in GSIS seen in islets from pregnant wild-type mice. Electrophysiological studies showed that activation of Htr3 decreased the resting membrane potential in ß cells, which increased Ca(2+) uptake and insulin exocytosis in response to glucose. Thus, our data indicate that serotonin, acting in a paracrine/autocrine manner through Htr3, lowers the ß cell threshold for glucose and plays an essential role in the increased GSIS of pregnancy.

Arcuate Na+,K+-ATPase senses systemic energy states and regulates feeding behavior through glucose-inhibited neurons.

Feeding is regulated by perception in the hypothalamus, particularly the first-order arcuate nucleus (ARC) neurons, of the body's energy state. However, the cellular device for converting energy states to the activity of critical neurons in ARC is less defined. We here show that Na(+),K(+)-ATPase (NKA) in ARC senses energy states to regulate feeding. Fasting-induced systemic ghrelin rise and glucose lowering reduced ATP-hydrolyzing activity of NKA and its substrate ATP level, respectively, preferentially in ARC. Lowering glucose concentration (LG), which mimics fasting, decreased intracellular NAD(P)H and increased Na(+) concentration in single ARC neurons that subsequently exhibited [Ca(2+)]i responses to LG, showing that they were glucose-inhibited (GI) neurons. Third ventricular injection of the NKA inhibitor ouabain induced c-Fos expression in agouti-related protein (AgRP) neurons in ARC and evoked neuropeptide Y (NPY)-dependent feeding. When injected focally into ARC, ouabain stimulated feeding and mRNA expressions for NPY and AgRP. Ouabain increased [Ca(2+)]i in single NPY/AgRP neurons with greater amplitude than in proopiomelanocortin neurons in ARC. Conversely, the specific NKA activator SSA412 suppressed fasting-induced feeding and LG-induced [Ca(2+)]i increases in ARC GI neurons. NPY/AgRP neurons highly expressed NKAα3, whose knockdown impaired feeding behavior. These results demonstrate that fasting, via ghrelin rise and LG, suppresses NKA enzyme/pump activity in ARC and thereby promotes the activation of GI neurons and NPY/AgRP-dependent feeding. This study identifies ARC NKA as a hypothalamic sensor and converter of metabolic states to key neuronal activity and feeding behaviour, providing a new target to treat hyperphagic obesity and diabetes.

Glucagon directly interacts with vagal afferent nodose ganglion neurons to induce Ca(2+) signaling via glucagon receptors.

Glucagon is released from the pancreatic islets postprandially and under hypoglycemic and cold conditions, and regulates glucose metabolism, feeding, energy expenditure and heat production, the functions partly controlled by the brain. Peripheral glucagon could signal to the brain via passing through the blood-brain barrier and/or acting on the vagal afferent. However, the latter remains to be determined. The present study aimed to clarify whether glucagon directly interacts with the nodose ganglion (NG) neurons of vagal afferent nerves in mice. In vivo study showed that intraperitoneal injection of glucagon induced phosphorylation of extracellular signal regulated kinase 1 and 2 (ERK1/2), cellular activation makers, in NG neurons. In fura-2 microfluorometric studies, glucagon increased cytosolic Ca(2+) concentration ([Ca(2+)]i) in single NG neurons. The glucagon-induced [Ca(2+)]i increases were suppressed by a glucagon receptor antagonist, des-His(1)-[Glu(9)]-Glucagon (1-29) amide, and the glucagon receptor mRNA was expressed in NG neurons. The majority of glucagon-responsive NG neurons exhibited [Ca(2+)]i responses to insulin and cholecystokinin-8, the hormones that are secreted postprandially and implicated in satiety. These results demonstrate that glucagon, by interacting with the glucagon receptor, directly activates vagal afferent nerves, possibly being relayed to the signaling to the brain and formation of satiety.

Peripheral oxytocin activates vagal afferent neurons to suppress feeding in normal and leptin-resistant mice: a route for ameliorating hyperphagia and obesity.

Oxytocin (Oxt), a neuropeptide produced in the hypothalamus, is implicated in regulation of feeding. Recent studies have shown that peripheral administration of Oxt suppresses feeding and, when infused subchronically, ameliorates hyperphagic obesity. However, the route through which peripheral Oxt informs the brain is obscure. This study aimed to explore whether vagal afferents mediate the sensing and anorexigenic effect of peripherally injected Oxt in mice. Intraperitoneal Oxt injection suppressed food intake and increased c-Fos expression in nucleus tractus solitarius to which vagal afferents project. The Oxt-induced feeding suppression and c-Fos expression in nucleus tractus solitarius were blunted in mice whose vagal afferent nerves were blocked by subdiaphragmatic vagotomy or capsaicin treatment. Oxt induced membrane depolarization and increases in cytosolic Ca(2+) concentration ([Ca(2+)]i) in single vagal afferent neurons. The Oxt-induced [Ca(2+)]i increases were markedly suppressed by Oxt receptor antagonist. These Oxt-responsive neurons also responded to cholecystokinin-8 and contained cocaine- and amphetamine-regulated transcript. In obese diabetic db/db mice, leptin failed to increase, but Oxt increased [Ca(2+)]i in vagal afferent neurons, and single or subchronic infusion of Oxt decreased food intake and body weight gain. These results demonstrate that peripheral Oxt injection suppresses food intake by activating vagal afferent neurons and thereby ameliorates obesity in leptin-resistant db/db mice. The peripheral Oxt-regulated vagal afferent neuron provides a novel target for treating hyperphagia and obesity.

Dipeptidyl peptidase-4 inhibitors are associated with improved left ventricular diastolic function after acute myocardial infarction in diabetic patients.

Dipeptidyl peptidase-4 (DPP4) is an integral membrane glycoprotein that modulates the pathological state of diabetes mellitus (DM), and DPP4 inhibitors are a new class of anti-type-2 DM drugs. Recent preclinical studies have associated DPP4 inhibition with improved myocardial systolic and diastolic function. Based on preclinical findings, we investigated associations between the administration of DPP4 inhibitors and cardiac function after acute myocardial infarction (AMI) in a clinical setting. We enrolled 34 patients with diabetes who were treated for acute myocardial infarction at our hospital between January 2010 and December 2012. We retrospectively compared changes in cardiac parameters determined by trans-thoracic echocardiography between patients treated with (DPP4-I group; n = 13) or without (non-DPP4-I group; n = 21) a DPP4 inhibitor during follow-up. The values of E/e' and of e'/a' significantly decreased and increased, respectively, in the DPP4-I, compared with the non-DPP4-I group (-2.53 ± 5.53 vs. 2.58 ± 5.68, p = 0.038 and 0.08 ± 0.23 vs. -0.12 ± 0.21, p = 0.036, respectively). We concluded that DPP4 inhibitors could improve E/e' and e'/a' in patients with DM and AMI and thus might be effective for treating left ventricular diastolic failure.

Lower 1,5-anhydroglucitol is associated with denovo coronary artery disease in patients at high cardiovascular risk.

Postprandial hyperglycemia is a risk factor for cardiovascular disease and mortality. Serum 1,5-anhydroglucitol (1,5-AG) level is an useful clinical marker of glucose metabolism which reflects postprandial hyperglycemia more robustly compared to hemoglobin A1c (HbA1c). Relationship between serum 1,5-AG level and cardiovascular disease has been reported; however, comparison between HbA1c and 1,5-AG as markers of cardiovascular disease was not performed. We included 227 consecutive patients who underwent coronary angiography meeting the following inclusion criteria: (1) patients who had no history of coronary artery disease (CAD); (2) patients without acute coronary syndrome; (3) patients without poorly controlled diabetes mellitus; (4) patients without anemia, liver dysfunction, acute, and chronic renal failure and malnutrition; and (5) patients without adhibition of acarbose or Chinese herbal medicine. We measured HbA1c, glycoalbumin, and 1,5-AG. Serum 1,5-AG was significantly lower in patients with CAD (16.6 ± 8.50 vs. 21.1 ± 7.97 µg/ml, P < 0.001). Multivariable logistic regression analysis showed decrease in serum 1,5-AG was independently associated with the presence of denovo CAD (0.93, 95% CI 0.88-0.98, P = 0.006). Serum 1,5-AG was also independently associated with the presence of denovo CAD in patients without diabetes mellitus (0.94, 95% CI 0.88-0.99, P = 0.046). In conclusion, lower serum 1,5-AG was associated with the presence of denovo CAD. Serum 1,5-AG may identify high cardiovascular risk patients for denovo CAD in both diabetic and non-diabetic patients.

Factors affecting the progression of renal dysfunction and the importance of salt restriction in patients with type 2 diabetic kidney disease.

BACKGROUND: Type 2 diabetic kidney disease (DKD) is the most common cause of end-stage renal failure, and the prevention of its progression has been a topic of discussion. METHODS: Sixty type 2 DKD patients were retrospectively evaluated for 1 year. Factors independently affecting the annual Ccr decline were examined by multivariable linear regression analysis. Patients were further divided into 2 groups based on their degree of renal function, and between-group differences at study initiation were evaluated. RESULTS: Ccr values were 21.0 ± 11.8 mL/min/1.73 m(2) at study initiation, and 15.7 ± 10.9 mL/min/1.73 m(2) after 1 year of observation. The multivariable linear regression analysis indicated salt intake (standardized coefficient: -0.34, P = 0.010) and urinary protein excretion (standardized coefficient: -0.33, P = 0.011) to be factors independently affecting the annual Ccr decline. Although decliners (-9.8 ± 4.7 mL/min/1.73 m(2)/year) had a significantly higher salt intake than non-decliners (-1.1 ± 3.8 mL/min/1.73 m(2)/year) at study initiation, this difference disappeared at the end of the study as a result of intensive dietary education. In 21 decliners with an additional year of follow-up, the annual Ccr decline significantly improved from -10.1 ± 5.3 to -5.3 ± 7.4 mL/min/1.73 m(2)/year (P = 0.02). CONCLUSION: Salt intake and urinary protein excretion were associated with annual Ccr decline in type 2 DKD patients. Furthermore, dietary education covering salt intake may have positively affected the change in Ccr.

Circulating betatrophin is elevated in patients with type 1 and type 2 diabetes.

There is evidence that betatrophin, a hormone derived from adipose tissue and liver, affects the proliferation of pancreatic beta cells in mice. The aim of this study was to examine circulating betatrophin concentrations in Japanese healthy controls and patients with type 1 and type 2 diabetes. A total of 76 subjects (12 healthy controls, 34 type 1 diabetes, 30 type 2 diabetes) were enrolled in the study. Circulating betatrophin was measured with an ELISA kit and clinical parameters related to betatrophin were analyzed statistically. Circulating betatrophin (Log transformed) was significantly increased in patients with diabetes compared with healthy subjects (healthy controls, 2.29 ± 0.51; type 1 diabetes, 2.94 ± 0.44; type 2 diabetes, 3.17 ± 0.18; p<0.001, 4.1 to 5.4 times in pg/mL order). Age, HbA1c, fasting plasma glucose and Log triglyceride were strongly associated with Log betatrophin in all subjects (n=76) in correlation analysis. In type 1 diabetes, there was a correlation between Log betatrophin and Log CPR. These results provide the first evidence that circulating betatrophin is significantly elevated in Japanese patients with diabetes. The findings of this pilot study also suggest a possibility of association between the level of betatrophin and the levels of glucose and triglycerides.

A community-based cross-sectional and longitudinal study uncovered asymptomatic proteinuria in Japanese adults with low body weight.

Although proteinuria is highly prevalent in obese individuals, the association between proteinuria and low body weight is equivocal. In this study we determine whether low body weight is more strongly associated with proteinuria compared with normal weight. The association between body mass index (BMI) and proteinuria was examined in a cross-sectional study of 62,582 asymptomatic individuals aged 20-70 years without known kidney diseases recruited, based on the results of medical checkups in 1999. We also examined the incidence of recurrent or nonrecurrent proteinuria in an 8-year longitudinal analysis of 12,493 individuals without proteinuria at baseline. The prevalence of proteinuria showed a J-shaped relationship with BMI. Multivariate regression analysis showed that BMI of 27.0 kg/m(2) and above or 18.9 kg/m(2) and less was significantly associated with proteinuria relative to BMI 21.0-22.9 kg/m(2), even after adjusting for relevant cardiometabolic risk factors. In the longitudinal study, similar J-shaped relationships between the incident rates of proteinuria and baseline BMI groups were observed at post-baseline checkups. Baseline BMI 27.0 kg/m(2) and above was associated with significantly greater risk for recurrent and nonrecurrent proteinuria, whereas BMI 18.9 kg/m(2) and less was only associated with nonrecurrent proteinuria. Thus, obesity and low body weight may be associated with different types of proteinuria independent of cardiometabolic risk factors.

Inhibition of insulin secretion from rat pancreatic islets by dexmedetomidine and medetomidine, two sedatives frequently used in clinical settings.

The aim of this study was to determine whether dexmedetomidine (DEX) and medetomidine (MED), α2-adrenergic agonists clinically used as sedatives, influence insulin secretion from rat pancreatic islets. Islets were isolated from adult male Wistar rats after collagenase digestion. Static incubation was used to determine effects of DEX or MED on insulin secretion and ionic-channel currents of ß-cells. Results indicate that both drugs dose-dependently inhibit insulin secretion, DEX more potently than MED. The inhibitory effects were attenuated by addition of yohimbine or by pretreatment of rats with pertussis toxin (PTX). 10 nM DEX decreased the current amplitude of voltage-dependent Ca2+ channels, but this did not occur when the N-type Ca2+ channel blocker ω-conotoxin was added. In the presence of tetraethylammonium, a classical voltage-gated K+ channel (Kv channel) blocker, the magnitude of inhibition of insulin secretion by MED was reduced. However, when tolbutamide, a specific blocker of the ATP-sensitive K+ channel (KATP channel), was present, the magnitude of MED inhibition of insulin secretion was not influenced, suggesting that Kv-channel activity alteration, but not that of KATP channels, is involved in MED-associated insulin secretory inhibition. The Kv-channel currents were increased during 1 nM MED exposure at membrane potentials ranging from -30 mV to -10 mV, where action potentials were generated in response to glucose stimulation. These results indicate that DEX and MED inhibit insulin secretion through an α2-adrenoceptor and PTX-sensitive GTP-binding protein pathway that eventually involves Kv channel activation and Ca2+ channel inhibition.

Latent associations of low serum amylase with decreased plasma insulin levels and insulin resistance in asymptomatic middle-aged adults.

BACKGROUND: Low serum amylase is likely to be associated with obesity and metabolic abnormalities, which are often accompanied by impaired insulin action. However, it is unclear whether low serum amylase is associated with impaired insulin action in clinical settings. Therefore, we investigated the associations of low serum amylase with plasma insulin levels, and obesity-related parameters, including leptin. RESEARCH DESIGN AND METHODS: We measured serum amylase, plasma insulin, obesity-related parameters such as leptin, cardiometabolic risk factors, and anthropometric parameters in a cross-sectional study of 54 asymptomatic subjects (mean age 48.6 ± 7.6 years) who were not being treated for diabetes. RESULTS: Body mass index (BMI) and plasma glucose at 120 min after a 75-g oral glucose tolerance test (OGTT) were significantly higher in subjects with low serum amylase (< 60 IU/l, n = 21) than in those with normal-to-high serum amylase (n = 33) (P = 0.04 and P = 0.004, respectively). In univariate correlation analysis, serum amylase was significantly correlated with BMI alone (r = -0.39, P = 0.004). By contrast, multivariate logistic analysis showed that each 1-SD increase in quantitative insulin sensitivity check index, and each 1-SD decrease in plasma insulin OGTT at 0 and 60 min, homeostasis model assessment of insulin resistance (HOMA)-R, and HOMA-ß were significantly associated with low serum amylase, particularly after adjusting for BMI. When subjects were divided into three groups according to HOMA-R, serum amylase levels were significantly lower in subjects with HOMA-R > 2.5 (n = 23) compared with subjects with HOMA-R 1.6-2.5 (n = 10) (61.1 ± 13.6 U/ml versus 76.9 ± 20.5 U/ml, Bonferroni test, P = 0.02), but not compared with subjects with HOMA-R<1.6 (n = 21; 62.7 ± 17.6 U/ml). Similar trends were observed when subjects were divided according to plasma leptin and fasting plasma insulin levels. CONCLUSIONS: These results suggest that after adjusting for BMI, low serum amylase is associated with decreased basal insulin levels and insulin secretion, as well as high insulin resistance. The nature of these associations remains to be elucidated in further studies.

Lack of Awareness of Own Hypercholesterolemia or Statin Medication among Adult Statin Users in the United States: Prevalence and Patient Characteristics in a Repeated Cross-Sectional Study.

Knowledge of a patient's medication is important in treating hyperlipidemia; however, little is known about this in practice. We carried out a repeated cross-sectional study to analyze a nationally representative sample of US adult statin users from the National Health and Nutrition Examination Survey, 1999−2018. We used medication bottle checks and self-reported survey data to estimate the percentage of individuals who are unaware of their hypercholesterolemia, type of medication, or how to take their medication. We used logistic regression to examine their characteristics. We included 8798 statin users; however, 17.6% were unaware of their hypercholesterolemia or statin use. Being older, male, non-Hispanic Black, taking a wider range of prescription medications, and previous diabetes or cardiovascular disease diagnosis were associated with lack of awareness. Serum low-density lipoprotein cholesterol level was lower among those lacking awareness (85.5 vs. 100.7 mg/dL; p < 0.001). Many of those unaware of drug type had been given little information about statins; 34.0% had no diagnosis of diabetes or cardiovascular disease, and of these, 27.1% were >75 years old. Roughly one in six lacked awareness, but no association was found with hypercholesterolemia control. Healthcare providers should ascertain a patient's understanding and consider the risks and benefits of statin medication.

A novel mechanism of imeglimin-mediated insulin secretion via the cADPR-TRP channel pathway.

AIMS/INTRODUCTION: Imeglimin is a novel oral hypoglycemic agent that improves blood glucose levels through multiple mechanisms of action including the enhancement of glucose-stimulated insulin secretion (GSIS), however, the details of this mechanism have not been clarified. In the process of GSIS, activation of the transient receptor potential melastatin 2 (TRPM2) channel, a type of non-selective cation channel (NSCCs) in ß-cells, promotes plasma membrane depolarization. The present study aimed to examine whether imeglimin potentiates GSIS via the TRPM2 channel in ß-cells. MATERIALS AND METHODS: Pancreatic islets were isolated by collagenase digestion from male wild-type and TRPM2-knockout (KO) mice. Insulin release and nicotinamide adenine dinucleotide (NAD+ ) production in islets were measured under static incubation. NSCC currents in mouse single ß-cells were measured by patch-clamp experiments. RESULTS: Batch-incubation studies showed that imeglimin enhanced GSIS at stimulatory 16.6 mM glucose, whereas it did not affect basal insulin levels at 2.8 mM glucose. Imeglimin increased the glucose-induced production of NAD+ , a precursor of cADPR, in islets and the insulinotropic effects of imeglimin were attenuated by a cADPR inhibitor 8-Br-cADPR. Furthermore, imeglimin increased NSCC current in ß-cells, and abolished this current in TRPM2-KO mice. Imeglimin did not potentiate GSIS in the TRPM2-KO islets, suggesting that imeglimin's increase of NSCC currents through the TRPM2 channel is causally implicated in its insulin releasing effects. CONCLUSIONS: Imeglimin may activate TRPM2 channels in ß-cells via the production of NAD+ /cADPR, leading to the potentiation of GSIS. Developing approaches to stimulate cADPR-TRPM2 signaling provides a potential therapeutic tool to treat type 2 diabetes.

Low serum amylase in association with metabolic syndrome and diabetes: A community-based study.

BACKGROUND: Low serum amylase levels may reflect impaired exocrine-endocrine relationship in the pancreas. However, few clinical studies have addressed this issue. Therefore, in this epidemiological study, we investigated whether low serum amylase was associated with the pathogenesis of impaired insulin action: metabolic syndrome (MetS) and diabetes. RESEARCH DESIGN AND METHODS: Serum amylase, cardiometabolic risk factors, MetS (Adult Treatment Panel III criteria), and diabetes were examined in 2,425 asymptomatic subjects aged 30-80 years who underwent medical checkups recently (April 2009-March 2010) and 5 years ago. RESULTS: Clinical variables, except for age and estimated glomerular filtration rate (eGFR), shifted favorably with increasing serum amylase levels. Plasma glucose levels at 1- and 2-hr during OGTT increased significantly with decreasing serum amylase levels. Multiple logistic analyses showed that, compared with highest quartile of serum amylase, lowest quartile was associated with increased risk for MetS and diabetes after adjustment for confounding factors [odds ratio (95% CI), 2.07 (1.39-3.07) and 2.76 (1.49-5.11), respectively]. In subjects who underwent checkups 5 years ago (n = 571), lower amylase at the previous checkup were associated with larger numbers of metabolic abnormalities at the recent checkup. The fluctuation over time in serum amylase levels in subjects with low serum amylase at the previous checkup was slight and was unaffected by kidney dysfunction. CONCLUSIONS: Our results indicate that low serum amylase is associated with increased risk of metabolic abnormalities, MetS and diabetes. These results suggest a pancreatic exocrine-endocrine relationship in certain clinical conditions.

Muscle mass evaluation using psoas muscle mass index by computed tomography imaging in hemodialysis patients.

BACKGROUND AND AIMS: The use of the psoas muscle mass index (PMI) using computed tomography (CT) has become a marker of interest to evaluate whole body muscle mass. However, in hemodialysis (HD) patients, reports about the clinical significance of psoas muscle evaluation are limited. We aimed to clarify the association between PMI and skeletal muscle mass index (SMI) using bioelectrical impedance analysis (BIA), and to investigate factors affecting PMI in HD patients. METHODS: In this prospective observational study, to evaluate muscle mass, SMI was measured using BIA after HD, and PMI was measured by the manual trace method on routinely available CT scans. PMI measurement was assessed twice by two physicians to compute intra-rater and inter-rater reliability. The correlations between PMI and the clinical factors were evaluated using Pearson's correlation coefficient and a linear regression analysis. Variables with a p-value < 0.05 in the simple linear regression analysis were included in the multivariable linear regression analysis to identify the factors that affected PMI of the HD patients. RESULTS: Fifty HD patients were recruited (31 males and 19 females; HD duration, 9.0 ± 8.8 years). The SMI was 6.10 ± 1.20 kg/m2, and the PMI was 4.79 ± 1.61 cm2/m2. Regarding the reliability of PMI measurements, intra-rater reliability [intra-class correlation (ICC) = 0.999] and inter-rater reliability (ICC = 0.998) were high in this study. The mean PMI of male patients was 5.40 ± 1.62 cm2/m2, while that of female patients was significantly lower (3.78 ± 0.98 cm2/m2; p < 0.001). The PMI was significantly and positively correlated with SMI (r = 0.630, p < 0.001), in addition to HD duration, body mass index (BMI), serum phosphate and serum creatinine (Cr). In the multivariate linear regression analysis by two models using SMI or BMI, they were respectively extracted as an independent factor associating with PMI, in addition to serum Cr and the difference of sex. CONCLUSIONS: PMI assessed with CT positively correlated with SMI measured using BIA. PMI might be one of the methods for evaluating the muscle mass in HD patients, when CT scans are taken as part of routine care.