Palmitate induces reactive oxygen species production and β-cell dysfunction by activating nicotinamide adenine dinucleotide phosphate oxidase through Src signaling.

[Aims/Introduction]Chronic hyperlipidemia impairs pancreatic β-cell function, referred to as lipotoxicity. We have reported an important role of endogenous reactive oxygen species (ROS) overproduction by activation of Src, a non-receptor tyrosine kinase, in impaired glucose-induced insulin secretion (GIIS) from diabetic rat islets. In the present study, we investigated the role of ROS production by Src signaling in palmitate-induced dysfunction of β-cells. [Materials and Methods]After rat insulinoma INS-1D cells were exposed to 0.6 mmol/L palmitate for 24 h (palmitate exposure); GIIS, ROS production and nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity were examined with or without exposure to10 μmol/L 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), a Src inhibitior, for 30 or 60 min. [Results]Exposure to PP2 recovered impaired GIIS and decreased ROS overproduction as a result of palmitate exposure. Palmitate exposure increased activity of NOX and protein levels of NOX2, a pathological ROS source in β-cells. Palmitate exposure increased the protein level of p47phox, a regulatory protein of NOX2, in membrane fraction compared with control, which was reduced by PP2. Transfection of small interfering ribonucleic acid of p47phox suppressed the augmented p47phox protein level in membrane fraction, decreased augmented ROS production and increased impaired GΙIS by palmitate exposure. In addition, exposure to PP2 ameliorated impaired GIIS and decreased ROS production in isolated islets of KK-Ay mice, an obese diabetic model with hyperlipidemia. [Conclusions]Activation of NOX through Src signaling plays an important role in ROS overproduction and impaired GΙIS caused by chronic exposure to palmitate, suggesting a lipotoxic mechanism of β-cell dysfunction of obese mice

A new equation to estimate basal energy expenditure of patients with diabetes

[Background & aims]Predictive equations for basal energy expenditure (BEE) derived from Caucasians tend to overestimate BEE in non-Caucasians. The aim of this study was to develop a more suitable method to estimate BEE in Japanese patients with diabetes using indices readily measured in clinical practice. [Methods]BEE was measured by indirect calorimetry under a strict basal condition in 68 Japanese patients with type 1 or type 2 diabetes. The best fitting equation was investigated by multiple regression analysis using of age, sex, and anthropometric indices. The resultant new equation was tested in a separate group of 60 Japanese patients with type 1 or type 2 diabetes, and the accuracy compared with existing equations. [Results]The best-fit equation was BEE [kcal/day] = 10 × (body weight)[kg] – 3 × (age)[y] + 125 (if male) + 750. Adjusted coefficient of determination was 81.0%. Root mean squared errors and accurate prediction in the validation set were 103 kcal/day and 78% for the new equation; 184 and 50 for Harris-Benedict; 209 and 38 for Oxford; 205 and 42 for Liu; and 140 and 63 for Ganpule. [Conclusions]This new equation is simpler and estimates BEE more accurately in Japanese patients with diabetes than the presently used equations do

Phase Lag Analyses on Ictal Scalp Electroencephalography May Predict Outcomes of Corpus Callosotomy for Epileptic Spasms

Objective: We aimed to clarify the patterns of ictal power and phase lag among bilateral hemispheres on scalp electroencephalography (EEG) recorded pre-operatively during epileptic spasms (ESs) and the correlation with the outcomes following corpus callosotomy.Methods: We enrolled 17 patients who underwent corpus callosotomy for ESs before 20 years of age. After corpus callosotomy, seven patients did not experience further ESs (favorable outcome group), and the remaining 10 patients had ongoing ESs (unfavorable outcome group). We used pre-operative scalp EEG data from monopolar montages using the average reference. The relative power spectrum (PS), ictal power laterality (IPL) among the hemispheres, and phase lag, calculated by the cross-power spectrum (CPS) among symmetrical electrodes (i.e., F3 and F4), were analyzed in the EEG data of ESs from 143 pre-operative scalp video-EEG records. Analyses were conducted separately in each frequency band from the delta, theta, alpha, beta, and gamma range. We compared the means of those data in each patient between favorable and unfavorable outcome groups.Results: Among all frequency bands, no significant differences were seen in the individual mean relative PSs in the favorable and unfavorable outcome group. Although the mean IPLs in each patient tended to be high in the unfavorable outcome group, no significant differences were found. The mean CPSs in the delta, theta, and gamma frequency bands were significantly higher in the unfavorable than in the favorable outcome group. Using the Youden index, the optimal cutoff points of those mean CPS values for unfavorable outcomes were 64.00 in the delta band (sensitivity: 100%, specificity: 80%), 74.20 in the theta band (100, 80%), and 82.05 in the gamma band (100, 80%). Subanalyses indicated that those CPS differences originated from pairs of symmetrical electrodes in the bilateral frontal and temporal areas.Significance: Ictal power and laterality of the ictal power in each frequency band were not associated with the outcomes of CC; however, the phase lags seen in the delta, theta, and gamma frequency bands were larger in the unfavorable than in the favorable outcome group. The phase lags may predict outcomes of CC for ESs on pre-surgical scalp-ictal EEGs

Role of Reactive Oxygen Species in Glucose Metabolism Disorder in Diabetic Pancreatic β-Cells

The dysfunction of pancreatic β-cells plays a central role in the onset and progression of type 2 diabetes mellitus (T2DM). Insulin secretory defects in β-cells are characterized by a selective impairment of glucose stimulation, and a reduction in glucose-induced ATP production, which is essential for insulin secretion. High glucose metabolism for insulin secretion generates reactive oxygen species (ROS) in mitochondria. In addition, the expression of antioxidant enzymes is very low in β-cells. Therefore, β-cells are easily exposed to oxidative stress. In islet studies using a nonobese T2DM animal model that exhibits selective impairment of glucose-induced insulin secretion (GSIS), quenching ROS generated by glucose stimulation and accumulated under glucose toxicity can improve impaired GSIS. Acute ROS generation and toxicity cause glucose metabolism disorders through different molecular mechanisms. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, is a master regulator of antioxidant defense and a potential therapeutic target in oxidative stress-related diseases, suggesting the possible involvement of Nrf2 in β-cell dysfunction caused by ROS. In this review, we describe the mechanisms of insulin secretory defects induced by oxidative stress in diabetic β-cells

Carbohydrate intake is associated with time spent in the euglycemic range in patients with type 1 diabetes.

[Aims/Introduction]Greater glycemic variability and lack of predictability are important issues for patients with type 1 diabetes. Dietary factors are one of the contributors to this variability, but how closely diet is linked to glycemic fluctuation on a daily basis has not been investigated. We examined the association between carbohydrate intake and glycemic excursion in outpatients. [Materials and Methods]A total of 33 patients with type 1 diabetes were included in the analyses (age 44.5 ± 14.7 years, diabetes duration 15.1 ± 8.3 years, 64% female, 30% using insulin pump, glycated hemoglobin 8.1 ± 1.3%). Time spent in euglycemia (70–180 mg/dL), hyperglycemia (>180 mg/dL) and hypoglycemia (<70 mg/dL) of consecutive 48-h periods of continuous glucose monitoring data were collected together with simultaneous records of dietary intake, insulin dose and physical activity. Correlation analyses and multiple regression analyses were used to evaluate the contribution of carbohydrate intake to time spent in the target glycemic range. [Results]In multiple regression analyses, carbohydrate intake (β = 0.53, P = 0.001), basal insulin dose per kg per day (β = −0.31, P = 0.034) and diabetes duration (β = 0.30, P = 0.042) were independent predictors of time spent in euglycemia. Carbohydrate intake (β = −0.51, P = 0.001) and insulin pump use (β = −0.34, P = 0.024) were independent predictors of time spent in hyperglycemia. Insulin pump use (β = 0.52, P < 0.001) and bolus insulin dose per kg per day (β = 0.46, P = 0.001) were independent predictors of time spent in hypoglycemia. [Conclusions]Carbohydrate intake is associated with time spent in euglycemia in patients with type 1 diabetes

Fasting plasma mannose levels are associated with insulin sensitivity independent of BMI in Japanese individuals with diabetes

Abstract Background Recently, an integrated network analysis has revealed dysregulation in the metabolism of mannose, a glucose epimer, in severely obese individuals without diabetes. In addition, fasting plasma mannose levels (M0) are associated with insulin resistance independent of BMI. Since the association between mannose and insulin sensitivity (IS) in those with impaired glucose tolerance remains unknown, we aimed to investigate this association in individuals without severe obesity but with varying degrees of glucose tolerance. Methods Based on 75 g OGTT data in Japanese individuals without diabetic medication, individuals were classified as having normal glucose tolerance (NGT), impaired glucose metabolism (IGM), or diabetes (DM). In each group, 25 individuals were consecutively recruited [total 75 individuals, age: 65 ± 11 (mean ± SD); BMI: 24.9 ± 3.8 kg/m2]. QUICKI and Matsuda index (MI) were calculated as IS indices. M0 was assayed using HPLC. Normally-distributed loge-transformed (ln-) values were used for MI and leptin. Results In the simple regression analysis, ln-MI was negatively correlated with BMI (NGT: r = − 0.639, IGM: r = − 0.466, DM: r = − 0.613) and ln-leptin (NGT: r = − 0.480, IGT: r = − 0.447, DM: r = − 0.593) in all 3 groups. Ln-MI was not significantly correlated with M0 in NGT (r = 0.241, P = 0.245) and IGT (r = − 0.296, P = 0.152) groups, it was moderately and negatively correlated in the DM group (r = − 0.626, P < 0.001). Similar results were obtained, when QUICKI was used instead of MI as an index of IS. In multiple regression analysis in the DM group, QUICKI (Q) and ln-MI (M) were independently predicted by BMI (Q: β = − 0.413; M: β = − 0.400) and M0 (Q: β = − 0.413, M: β = − 0.426), accounting for 51.2% (P = 0.0004) and 51.2% (P = 0.0004) of the variability, respectively, which was larger than the prediction for BMI alone (Q: 38.4%, M: 37.6%). Conclusion Fasting plasma mannose was associated with IS independent of BMI in Japanese individuals with DM