iGlarLixi reduces residual hyperglycemia in Japanese patients with type 2 diabetes uncontrolled on basal insulin: A post‐hoc analysis of the LixiLan JP‐L trial

IntroductionTreatments for type 2 diabetes targeting baseline glucose levels but not postprandial glucose can result in normalized fasting blood glucose but suboptimal overall glycemic control (high glycated hemoglobin): residual hyperglycemia. In Japanese patients with type 2 diabetes the predominant pathophysiology is a lower insulin secretory capacity, and residual hyperglycemia is common with basal insulin treatment. Single-injection, fixed-ratio combinations of glucagon-like peptide-1 receptor agonists and basal insulin have been developed. iGlarLixi (insulin glargine 100 units/mL [iGlar]: lixisenatide ratio of 1 unit:1 µg) is for specific use in Japan. Post-hoc analysis of the LixiLan JP-L trial (NCT02752412) compared the effect of iGlarLixi with iGlar on this specific subpopulation with residual hyperglycemia.Materials and MethodsOutcomes at week 26 (based on the last observation carried forward) were assessed in patients in the modified intent-to-treat population with baseline residual hyperglycemia.ResultsOverall, 83 (32.5%) patients in the iGlarLixi group and 79 (30.7%) patients in the iGlar group had baseline residual hyperglycemia. The proportion of patients with residual hyperglycemia at week 26 decreased to 15.7% in the iGlarLixi group, and increased to 36.9% in the iGlar group. Patients in the iGlarLixi group had significantly greater reductions in glycated hemoglobin compared with the iGlar group (−0.72% difference between groups; P < 0.0001).ConclusionsNew data from this post-hoc analysis of the JP-L trial show that treatment with the fixed-ratio combination iGlarLixi reduced the proportion of Japanese patients with residual hyperglycemia from baseline to week 26 and significantly reduced glycated hemoglobin vs similar doses of iGlar alone

Characterization of the novel mutant A78T-HERG from a long QT syndrome type 2 patient: Instability of the mutant protein and stabilization by heat shock factor 1

Background:The human ether-a-go-go-related gene (HERG) encodes the α-subunit of rapidly activating delayed-rectifier potassium channels. Mutations in this gene cause long QT syndrome type 2 (LQT2). In most cases, mutations reduce the stability of the channel protein, which can be restored by heat shock (HS). Methods: We identified the novel mutant A78T-HERG in a patient with LQT2. The purpose of the current study was to characterize this mutant protein and test whether HS and heat shock factors (HSFs) could stabilize the mutant protein. A78T-HERG and wild-type HERG (WT-HERG) were expressed in HEK293 cells and analyzed by immunoblotting, immunoprecipitation, immunofluorescence, and whole-cell patch clamping. Results: When expressed in HEK293 cells, WT-HERG gave rise to immature and mature forms of the protein at 135 and 155 kDa, respectively. A78T-HERG gave rise only to the immature form, which was heavily ubiquitinated. The proteasome inhibitor MG132 increased the expression of immature A78T-HERG and increased both the immature and mature forms of WT-HERG. WT-HERG, but not A78T-HERG, was expressed on the plasma membrane. In whole-cell patch clamping experiments, depolarizing pulses evoked E4031-sensitive HERG channel currents in cells transfected with WT-HERG, but not in cells transfected with A78T-HERG. The A78V mutant, but not A78G mutant, remained in the immature form similarly to A78T. Maturation of the A78T-HERG protein was facilitated by HS, expression of HSF-1, or exposure to geranyl geranyl acetone. Conclusions: A78T-HERG was characterized by protein instability and reduced expression on the plasma membrane. The stability of the mutant was partially restored by HSF-1, indicating that HSF-1 is a target for the treatment for LQT2 caused by the A78T mutation in HERG

当院におけるYUMESUMA e-net(Medical e-Learning システム)の導入と意義

Medical e-Leamingシステム(YUMESUMA e-net:Yokohama City University,MedicalCenter,Medical e-Learning System founded by Sugiyama and Matsuse,e-net)を導入する機会を得たので,オフライン環境下での試行から本番系システムによる実施にいたる概要を報告し,Medical e-Leamingの意義,問題点,今後の方向性などを検討した.その結果,いわゆるe-LeamingシステムどしてのYUMESUMAは,単に学習のIT化という位置づけにおいてのみ有効性が高いのではなく,情報を迅速に伝える手段として,高い確実性を持ちうることが実証された.従って,毎年,多数の専門職が新規に採用され人事異動の頻繁な大学附属病院において,Medical e-Leamingは,情報の周知,安全管埋徹底に極めて有用なシステムと思われた.A medical e-learning system (YUMESUMA e-net) was introduced at our hospital. Here, the processes from its trial in an off-line environment to its application to a real working system are outlined, and the significance, problems, and direction of future development of medical e-learning are evaluated. YUMESUMA as an e-learning system was found to be effective not only as an information technology to assist medical learning but also as a highly reliable tool for rapid transmission of information. Therefore, at a university hospital, where many experts are newly employed every year and personnel changes are frequent, medical e-learning is considered to be a useful system for transmission of information and safety management

Protein Amount, Quality, and Physical Activity

Diet composition determines the risk of obesity, cardiovascular disease, malignant tumors, and type 2 diabetes mellitus [...

The Roles of Carbohydrate Response Element Binding Protein in the Relationship between Carbohydrate Intake and Diseases

Carbohydrates are macronutrients that serve as energy sources. Many studies have shown that carbohydrate intake is nonlinearly associated with mortality. Moreover, high-fructose corn syrup (HFCS) consumption is positively associated with obesity, cardiovascular disease, and type 2 diabetes mellitus (T2DM). Accordingly, products with equal amounts of glucose and fructose have the worst effects on caloric intake, body weight gain, and glucose intolerance, suggesting that carbohydrate amount, kind, and form determine mortality. Understanding the role of carbohydrate response element binding protein (ChREBP) in glucose and lipid metabolism will be beneficial for elucidating the harmful effects of high-fructose corn syrup (HFCS), as this glucose-activated transcription factor regulates glycolytic and lipogenic gene expression. Glucose and fructose coordinately supply the metabolites necessary for ChREBP activation and de novo lipogenesis. Chrebp overexpression causes fatty liver and lower plasma glucose levels, and ChREBP deletion prevents obesity and fatty liver. Intestinal ChREBP regulates fructose absorption and catabolism, and adipose-specific Chrebp-knockout mice show insulin resistance. ChREBP also regulates the appetite for sweets by controlling fibroblast growth factor 21, which promotes energy expenditure. Thus, ChREBP partly mimics the effects of carbohydrate, especially HFCS. The relationship between carbohydrate intake and diseases partly resembles those between ChREBP activity and diseases

The Role of Carbohydrate Response Element Binding Protein in Intestinal and Hepatic Fructose Metabolism

Many articles have discussed the relationship between fructose consumption and the incidence of obesity and related diseases. Fructose is absorbed in the intestine and metabolized in the liver to glucose, lactate, glycogen, and, to a lesser extent, lipids. Unabsorbed fructose causes bacterial fermentation, resulting in irritable bowl syndrome. Therefore, understanding the mechanisms underlying intestinal and hepatic fructose metabolism is important for the treatment of metabolic syndrome and fructose malabsorption. Carbohydrate response element binding protein (ChREBP) is a glucose-activated transcription factor that controls approximately 50% of de novo lipogenesis in the liver. ChREBP target genes are involved in glycolysis (Glut2, liver pyruvate kinase), fructolysis (Glut5, ketohexokinase), and lipogenesis (acetyl CoA carboxylase, fatty acid synthase). ChREBP gene deletion protects against high sucrose diet-induced and leptin-deficient obesity, because Chrebp−/− mice cannot consume fructose or sucrose. Moreover, ChREBP contributes to some of the physiological effects of fructose on sweet taste preference and glucose production through regulation of ChREBP target genes, such as fibroblast growth factor-21 and glucose-6-phosphatase catalytic subunits. Thus, ChREBP might play roles in fructose metabolism. Restriction of excess fructose intake will be beneficial for preventing not only metabolic syndrome but also irritable bowl syndrome

Recent Progress on Fructose Metabolism—Chrebp, Fructolysis, and Polyol Pathway

Excess fructose intake is associated with obesity, fatty liver, tooth decay, cancer, and cardiovascular diseases. Even after the ingestion of fructose, fructose concentration in the portal blood is never high; fructose is further metabolized in the liver, and the blood fructose concentration is 1/100th of the glucose concentration. It was previously thought that fructose was metabolized in the liver and not in the small intestine, but it has been reported that metabolism in the small intestine also plays an important role in fructose metabolism. Glut5 knockout mice exhibit poor fructose absorption. In addition, endogenous fructose production via the polyol pathway has also received attention; gene deletion of aldose reductase (Ar), ketohexokinase (Khk), and triokinase (Tkfc) has been found to prevent the development of fructose-induced liver lipidosis. Carbohydrate response element-binding protein (Chrebp) regulates the expression of Glut5, Khk, aldolase b, and Tkfc. We review fructose metabolism with a focus on the roles of the glucose-activating transcription factor Chrebp, fructolysis, and the polyol pathway

Is the Use of Artificial Sweeteners Beneficial for Patients with Diabetes Mellitus? The Advantages and Disadvantages of Artificial Sweeteners

Artificial sweeteners have been developed as substitutes for sugar. Sucralose, acesulfame K (ACE K), aspartame, and saccharin are artificial sweeteners. Previously, artificial sweeteners were thought to be effective in treating obesity and diabetes. Human meta-analyses have reported that artificial sweeteners have no effect on body weight or glycemic control. However, recent studies have shown that artificial sweeteners affect glucose absorption in the intestinal tract as well as insulin and incretin secretion in humans and animals. Moreover, artificial sweeteners alter the composition of the microbiota and worsen the glycemic control owing to changes in the gut microbiota. The early intake of ACE K was also shown to suppress the taste response to sugar. Furthermore, a large cohort study showed that high artificial sweetener intake was associated with all-cause mortality, cardiovascular risk, coronary artery disease risk, cerebrovascular risk, and cancer risk. The role of artificial sweeteners in the treatment of diabetes and obesity should be reconsidered, and the replacement of sugar with artificial sweeteners in patients will require the long-term tracking of not only intake but also changes in blood glucose and weight as well as future guidance based on gut bacteria data. To utilize the beneficial properties of artificial sweeteners in treatment, further studies are needed