Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial.

Importance: The effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatment of type 2 diabetes have not been described. Objective: To assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control. Design, Setting, and Participants: Randomized phase 3 clinical trial conducted at 45 medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020; follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin. Interventions: Patients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved. Main Outcomes and Measures: The primary end point was mean change from baseline in glycated hemoglobin A1c (HbA1c) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA1c levels. Results: Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA1c, 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group. At week 40, mean HbA1c change from baseline was -2.40% with 10-mg tirzepatide and -2.34% with 15-mg tirzepatide vs -0.86% with placebo (10 mg: difference vs placebo, -1.53% [97.5% CI, -1.80% to -1.27%]; 15 mg: difference vs placebo, -1.47% [97.5% CI, -1.75% to -1.20%]; P < .001 for both). Mean HbA1c change from baseline was -2.11% with 5-mg tirzepatide (difference vs placebo, -1.24% [95% CI, -1.48% to -1.01%]; P < .001]). Mean body weight change from baseline was -5.4 kg with 5-mg tirzepatide, -7.5 kg with 10-mg tirzepatide, -8.8 kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, -7.1 kg [95% CI, -8.7 to -5.4]; 10 mg: difference, -9.1 kg [95% CI, -10.7 to -7.5]; 15 mg: difference, -10.5 kg [95% CI, -12.1 to -8.8]; P < .001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA1c less than 7% (85%-90% vs 34%; P < .001 for all). The most common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%-21% vs 10%) and nausea (13%-18% vs 3%). Conclusions and Relevance: Among patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically significant improvements in glycemic control after 40 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04039503.

Efficacy and safety of dapagliflozin over 1 year as add-on to insulin therapy in Japanese patients with type 2 diabetes: the DAISY (Dapagliflozin Added to patients under InSulin therapY) trial.

AIMS: To evaluate the efficacy and safety of dapagliflozin as add-on to insulin in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: Insulin-treated Japanese patients were randomized to 5 mg dapagliflozin or placebo during a 16-week double-blind treatment period. Both groups then received dapagliflozin 5 or 10 mg (the dose was increased at or after week 24 if glycated haemoglobin [HbA1c] at the previous visit was >7.5%) during a 36-week open-label extension period. The exploratory efficacy endpoint was to assess the maintenance efficacy of 5/10 mg dapagliflozin + insulin over 52 weeks of treatment. Safety was assessed in terms of adverse events, laboratory variables and vital signs. RESULTS: The changes in HbA1c from baseline to weeks 16 and 52 were -0.62% and -0.74%, respectively, in the dapagliflozin group, vs -0.08% and -0.83%, respectively, in the placebo-dapagliflozin group. Body weight decreased at both time points in the dapagliflozin group and after switching to open-label dapagliflozin in the placebo-dapagliflozin group. The total insulin dose decreased slightly after starting dapagliflozin. Adverse events occurred in 82.9% and 71.7% of patients in the dapagliflozin and placebo-dapagliflozin groups, respectively. Hypoglycaemia occurred in 35.0% and 41.7% of patients in the dapagliflozin and placebo-dapagliflozin groups, respectively, but the incidence was not increased by use of dapagliflozin in either trial period. Genital/urinary tract infections, renal impairment/failure, volume depletion, fracture and hepatic disorders occurred in ≤5% of patients. CONCLUSION: This trial showed that administration of dapagliflozin as an add-on to insulin therapy was effective, was well tolerated and had insulin-sparing effects in Japanese patients with type 2 diabetes.

Analysis of efficacy and safety of dulaglutide 0.75 mg stratified by sex in patients with type 2 diabetes in 2 randomized, controlled phase 3 studies in Japan.

We analyzed the efficacy and safety of once weekly dulaglutide 0.75 mg by sex in 2 randomized, controlled phase 3 studies in Japanese patients with type 2 diabetes (a 52-week monotherapy study [comparator liraglutide 0.9 mg] and a 26-week combination therapy study [comparator insulin glargine]). Females comprised 18% of patients in the monotherapy study and 29% of patients in the combination therapy study. Mean reductions from baseline in glycated hemoglobin (HbA1c) were similar between the sexes for dulaglutide- and liraglutide-treated patients (range -1.17% to -1.49%). Females had numerically greater weight loss or less weight gain than males across all treatment groups. The percentages of patients with reductions in both HbA1c and weight from baseline were also greater for females than for males in all treatment groups. In all treatment groups, the incidences of treatment-emergent adverse events tended to be greater among females than among males. No differences in the incidences of total or nocturnal hypoglycemia were observed between the sexes in any treatment group. Overall, in 2 studies in Japan, across all treatment groups it appeared that HbA1c lowering was unaffected by patient sex, while female patients had greater weight loss or less weight gain and greater incidence of adverse events, including nausea, compared to male patients. Incidences of patients discontinuing dulaglutide early due to adverse event were low (<10%) for both sexes, and no new safety concerns related to dulaglutide were identified for either sex. Therefore, the benefit/risk ratio for dulaglutide remains unchanged, positive for both sexes.

Subgroup analysis of phase 3 studies of dulaglutide in Japanese patients with type 2 diabetes.

The efficacy and tolerability of once weekly dulaglutide 0.75 mg in Japanese patients with type 2 diabetes (T2D) were evaluated by subgroups defined by key demographic characteristics. This post hoc analysis included data from patients who received dulaglutide 0.75 mg for up to 26 weeks in three phase 3 trials (one open-label, randomized; one double-blind and open-label, randomized; one open-label, nonrandomized). Patients were classified into subgroups on the basis of sex (male, female), age (<65, ≥65 years), body weight (<70, ≥70 kg), body mass index (BMI; <25, ≥25 kg/m(2)), duration of diabetes (<7, ≥7 years), HbA1c (≤8.5, >8.5%), use of concomitant sulfonylurea (yes, no), and use of concomitant biguanide (yes, no). Efficacy measures analyzed were changes from baseline in HbA1c and body weight and percentages of patients achieving HbA1c <7.0%. Safety measures analyzed were incidence of hypoglycemia and nausea and change from baseline in seated pulse rate. A total of 855 patients were analyzed. Once weekly dulaglutide 0.75 mg improved blood glucose control as measured by HbA1c regardless of patient characteristics; patients with higher baseline HbA1c values had greater improvements compared to patients with lower baseline values. Weight loss was greater in patients with lower baseline HbA1c and in patients taking concomitant biguanides. Concomitant use of sulfonylureas had the greatest effect on the incidence of hypoglycemia. Treatment of T2D with once weekly dulaglutide 0.75 mg for 26 weeks was associated with significant improvement in glycemic control irrespective of age, sex, duration of diabetes, body weight, BMI, or concomitant medication.

A few positively charged residues slow movement of a polypeptide chain across the endoplasmic reticulum membrane.

Many polypeptide chains are translocated across and integrated into the endoplasmic reticulum membrane through protein-conducting channels. During the process, amino acid sequences of translocating polypeptide chains are scanned by the channels and classified to be retained in the membrane or translocated into the lumen. We established an experimental system with which the kinetic effect of each amino acid residue on the polypeptide chain movement can be analyzed with a time resolution of tens of seconds. Positive charges greatly slow movement; only two lysine residues caused a remarkable slow down, and their effects were additive. The lysine residue was more effective than arginine. In contrast, clusters comprising three residues of each of the other 18 amino acids had little effect on chain movement. We also demonstrated that a four lysine cluster can exert the effect after being fully exposed from the ribosome. We concluded that as few as two to three residues of positively charged amino acids can slow the movement of the nascent polypeptide chain across the endoplasmic reticulum membrane. This effect provides a fundamental basis of the topogenic function of positively charged amino acids.

A single amino acid gates the KcsA channel.

The KcsA channel is a proton-activated potassium channel. We have previously shown that the cytoplasmic domain (CPD) acts as a pH-sensor, and the charged states of certain negatively charged amino acids in the CPD play an important role in regulating the pH-dependent gating. Here, we demonstrate the KcsA channel is constitutively open independent of pH upon mutating E146 to a neutrally charged amino acid. In addition, we found that rearrangement of the CPD following this mutation was not large. Our results indicate that minimal rearrangement of the CPD, particularly around E146, is sufficient for opening of the KcsA channel.

Serum butyrylcholinesterase and the risk of future type 2 diabetes: the Kansai Healthcare Study.

OBJECTIVE: Butyrylcholinesterase is synthesized in the liver. The serum butyrylcholinesterase level has been cross-sectionally reported to be higher in patients with diabetes, hyperlipidaemia, obesity and fatty liver than in those without them. It is not known whether serum butyrylcholinesterase is associated with the risk of future type 2 diabetes. DESIGN: A prospective cohort study. PARTICIPANTS: A total of 8470 Japanese men aged 40-55 years without type 2 diabetes at baseline. MEASUREMENTS: Type 2 diabetes was diagnosed if a fasting plasma glucose (FPG) level was ≥7·0 mmol/l, if a HbA1 c level was ≥6·5% or if participants were taking oral hypoglycaemic medication or insulin. RESULTS: During the 42,227 person-years of follow-up, 868 cases had developed type 2 diabetes. Serum butyrylcholinesterase was significantly positively correlated with body mass index (BMI), FPG, alanine aminotransferase (ALT), γ-glutamyltransferase (GGT) and triglycerides (TG), whereas negatively with high-density lipoprotein (HDL) cholesterol. In Cox proportional hazards models, after adjusting for age, BMI, FPG, alcohol consumption, smoking habit, walk to work, regular leisure-time physical activity and family history of diabetes, the highest quartile (398-806 IU/l) of serum butyrylcholinesterase increased the risk of type 2 diabetes compared with the lowest quartile (56-311 IU/l) [hazard ratio (HR) 1·41 (95% confidence interval (CI), 1·14-1·74)]. After further adjusting for ALT and GGT, this association remained [HR 1·40 (95% CI, 1·13-1·73)]. Furthermore, this association was significant independent of TG and HDL cholesterol. CONCLUSIONS: Elevated serum butyrylcholinesterase was independently associated with an increased risk of future type 2 diabetes.

Metabolic Abnormalities Following Tirzepatide Monotherapy in Japanese Patients with Type 2 Diabetes: A Phase 3 SURPASS J-mono Post Hoc Analysis.

INTRODUCTION: The presence of metabolic abnormalities in patients with type 2 diabetes (T2D) increases the risk of cardiovascular disease and other comorbidities. This analysis compared the effects of tirzepatide (5, 10, and 15 mg) and dulaglutide 0.75 mg on the prevalence of metabolic abnormalities in Japanese patients with T2D. METHODS: This was a post hoc analysis of SURPASS J-mono, a multicenter, randomized, double-blind, active-controlled, parallel-group, phase 3 trial that compared the efficacy and safety of tirzepatide monotherapy (5, 10, and 15 mg) to dulaglutide 0.75 mg in Japanese patients with T2D. Thresholds for abnormalities were based on the Japanese criteria for metabolic syndrome. Proportions of participants meeting a composite endpoint (visceral fat accumulation measured by waist circumference plus two or more of dyslipidemia, hypertension, or hyperglycemia) or individual component thresholds were calculated at baseline and week 52 for the overall population and for baseline body mass index (BMI) subgroups (< 25, 25 to < 30, and ≥ 30 kg/m2). RESULTS: Of 636 randomized participants, 431 (67.8%) met the composite endpoint at baseline, with similar findings observed across treatment arms. At week 52, the proportion of participants on treatment that met the composite endpoint was 31.7%, 23.0%, and 14.2% in the tirzepatide 5-, 10-, and 15-mg arms, respectively, and 56.5% in the dulaglutide arm (p < 0.001). A higher proportion met the composite endpoint at baseline in the BMI 25 to < 30 and ≥ 30 kg/m2 subgroups (73.2-79.3%) compared with the < 25 kg/m2 subgroup (45.3%), with reductions observed across all BMI subgroups treated with tirzepatide. The proportion of participants with individual metabolic abnormalities showed similar trends to those observed for the composite endpoint. Tirzepatide was consistently superior to dulaglutide across all assessments. CONCLUSIONS: Tirzepatide reduced the prevalence of multiple metabolic abnormalities, indicating tirzepatide may have metabolic benefit in Japanese patients with T2D. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03861052.

Tail-extension following the termination codon is critical for release of the nascent chain from membrane-bound ribosomes in a reticulocyte lysate cell-free system.

Nascent chain release from membrane-bound ribosomes by the termination codon was investigated using a cell-free translation system from rabbit supplemented with rough microsomal membrane vesicles. Chain release was extremely slow when mRNA ended with only the termination codon. Tail extension after the termination codon enhanced the release of the nascent chain. Release reached plateau levels with tail extension of 10 bases. This requirement was observed with all termination codons: TAA, TGA and TAG. Rapid release was also achieved by puromycin even in the absence of the extension. Efficient translation termination cannot be achieved in the presence of only a termination codon on the mRNA. Tail extension might be required for correct positioning of the termination codon in the ribosome and/or efficient recognition by release factors.

Cardiovascular disease prevalence in adults with type 2 diabetes in Japan: results from the Japanese centers in the CAPTURE study.

Introduction: CAPTURE was a cross-sectional, non-interventional study (NCT03786406, NCT03811288) investigating the prevalence and characteristics of cardiovascular disease (CVD) in adults with type 2 diabetes (T2D) across 13 countries worldwide. Here we present the findings for Japan. Materials and methods: Data were collected from adults aged ≥ 20 years (aged ≥ 18 years in countries outside Japan) with T2D who were managed in clinics or hospitals in 2019. Standardized methodology was used for all countries. The prevalence of CVD and its subtypes was estimated, weighted by care setting (clinics versus hospitals). Results: Among participants from Japan (total: 800; clinics: 440; hospitals: 360), mean (standard deviation) age was 65.6 (11.2) years and glycated hemoglobin 7.2% (0.9). Sixty-seven percent of participants were male, 57.8% had diabetes duration > 10 years, 49.8% had body mass index ≥ 25 kg/m2 and 63.1% had hypertension. The weighted prevalences (95% confidence interval [CI]) of CVD and atherosclerotic CVD were 37.3% (34.2;40.3) and 33.5% (30.6;36.4), respectively. The prevalence (95% CI) of the most common subtypes of CVD was: carotid artery disease 20.5% (18.2;22.8), coronary heart disease 11.9% (9.7;14.1) and cerebrovascular disease 10.4% (8.3;12.5). Conclusions: These contemporary data from the CAPTURE study on CVD prevalence in adults with T2D in Japan show that approximately one in three adults with T2D had established CVD, which is comparable to the prevalence in the global study cohort. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-022-00612-y.

Use of diabetes medications in adults with T2D and CVD in Japan: secondary analysis of the CAPTURE study.

Introduction: The CAPTURE study estimated the global prevalence of established cardiovascular disease (CVD) and characterized the usage of glucose-lowering agents (GLAs) in adults with type 2 diabetes (T2D) across 13 countries. The purpose of this secondary analysis of data from the Japanese sites within CAPTURE (NCT03786406, NCT03811288) was to provide data about medication usage stratified by CVD status among Japanese participants with T2D. Materials and methods: Data on GLA usage (including those with proven cardiovascular [CV] benefits) in Japanese participants with T2D managed in clinics or hospitals were collected and stratified by CVD subgroups. Results: There were 800 Japanese participants in the CAPTURE study (n = 502 [no CVD group], n = 298 [CVD group], n = 268 [atherosclerotic CVD subgroup]). Oral antidiabetic agents and insulin were used by 88.5% and 23.4%, respectively, of participants overall. Among participants with established CVD, dipeptidyl peptidase-4 inhibitors (65.1%) were most frequently used, followed by biguanides (50.7%) and insulins (26.2%). The pattern was similar among participants with atherosclerotic CVD. A lower proportion of participants in the CVD group used glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) with proven CV benefits versus the no CVD group (GLP-1 RAs: 7.0% vs. 8.6%; SGLT-2is: 13.4% vs. 19.1%). Conclusion: This analysis of the CAPTURE study provided a comprehensive overview of prescription patterns for the treatment of T2D in Japan. Use of GLAs with proven CV benefit was low, even in participants with established CVD, which was comparable to the findings from the global cohort. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00638-w.

Association of self-stigma with glycated hemoglobin: A single-center, cross-sectional study of adults with type 1 diabetes in Japan.

AIMS/INTRODUCTION: There has been an increase in research on diabetes-related stigma and its association with glycated hemoglobin (HbA1c) over the past years. However, little is known about the association of self-stigma with HbA1c in persons with type 1 diabetes. This study aims to examine the association between self-stigma and HbA1c in Japanese people with type 1 diabetes. MATERIALS AND METHODS: This cross-sectional study was conducted at a clinic in Tokyo. Questionnaires using nine items from the Japanese version of the Self-Stigma Scale was distributed to outpatients with type 1 diabetes, aged ≥18 years. We excluded outpatients with serious mental disorder, those who required urgent medical treatment or received hemodialysis. Adjusted linear regression analyses tested the association between the score of the 9-item Self-Stigma Scale and HbA1c. RESULTS: Questionnaires were distributed to 166 eligible participants. A total of 109 participants were included in the final analysis after excluding participants with incomplete answers and laboratory data. After adjusting for age, sex, employment status, body mass index, duration of diabetes and insulin secretion, there was a significant positive association between self-stigma and HbA1c (ß = 0.05, 95% confidence interval 0.01 to 0.08). CONCLUSIONS: This cross-sectional study showed a significant association between self-stigma and HbA1c in persons with type 1 diabetes. Addressing self-stigma might be as equally essential as measuring HbA1c in evaluating glycemic outcome among individuals with type 1 diabetes.

Association of glucagon-like peptide-1 receptor agonist treatment with gastric residue in an esophagogastroduodenoscopy.

AIMS/INTRODUCTION: Previous studies have reported that the glucagon-like peptide-1 receptor agonist (GLP-1RA) delays gastric emptying, and gastric emptying was assessed by the 13 C breath test or paracetamol absorption technique. However, neither of them is clinically familiar in real-world clinical practice. The purpose of the present study was to investigate the association between GLP-1RA treatment and gastric residue in an esophagogastroduodenoscopy. MATERIALS AND METHODS: This study was a matched pair case-control study. The study population consisted of 1,128 individuals with diabetes who had esophagogastroduodenoscopy at our clinic between July 2020 and June 2022. To account for differences in characteristics, such as age, sex, insulin treatment and glycated hemoglobin, we carried out a one-to-one nearest neighbor propensity score matching analysis between diabetes patients with and without GLP-1RA treatment. After matching, we compared the presence of gastric residue in an esophagogastroduodenoscopy by the McNemar test between patients with and without GLP-1RA treatment. RESULTS: After the propensity score matching, we selected 205 pairs. In the propensity score-matched comparison, the proportion of gastric residue was statistically significantly higher in the GLP-1RA treatment group (0.49% vs 5.4%, P = 0.004). The details of GLP-1RA prescribed for the 11 patients with gastric residue were liraglutide once daily 1.8 mg (n = 2), dulaglutide once weekly 0.75 mg (n = 5), semaglutide once weekly 0.5 mg (n = 2) and semaglutide once weekly 1.0 mg (n = 2). CONCLUSION: GLP-1RA treatment is associated with gastric residue in an esophagogastroduodenoscopy in patients with diabetes.

Quantification of synthetic errors during chemical synthesis of DNA and its suppression by non-canonical nucleosides.

Substitutions, insertions, and deletions derived from synthetic oligonucleotides are the hurdles for the synthesis of long DNA such as genomes. We quantified these synthetic errors by next-generation sequencing and revealed that the quality of the enzymatically amplified final combined product depends on the conditions of the preceding solid phase chemical synthesis, which generates the initial pre-amplified fragments. Among all possible substitutions, the G-to-A substitution was the most prominently observed substitution followed by G-to-T, C-to-T, T-to-C, and A-to-G substitutions. The observed error rate for G-to-A substitution was influenced by capping conditions, suggesting that the capping step played a major role in the generation of G-to-A substitution. Because substitutions observed in long DNA were derived from the generation of non-canonical nucleosides during chemical synthesis, non-canonical nucleosides resistant to side reactions could be used as error-proof nucleosides. As an example of such error-proof nucleosides, we evaluated 7-deaza-2´-deoxyguanosine and 8-aza-7-deaza-2´-deoxyguanosine and showed 50-fold decrease in the error rate of G-to-A substitution when phenoxyacetic anhydride was used as capping reagents. This result is the first example that improves the quality of synthesized sequences by using non-canonical nucleosides as error-proof nucleosides. Our results would contribute to the development of highly accurate template DNA synthesis technologies.

Substitution of telemedicine for clinic visit during the COVID-19 pandemic of 2020: Comparison of telemedicine and clinic visit.

AIMS/INTRODUCTION: The purpose of this retrospective observational cohort study was to compare outpatient diabetes care and glycated hemoglobin (HbA1c) level during the coronavirus disease 2019 pandemic in 2020 with 2019, and to compare the glucose-lowering effect of telemedicine and clinic visits during the state of emergency in Japan declared from 7 April to 25 May (inter-period) 2020. MATERIALS AND METHODS: A total of 13 weeks before and after the inter-period were designated as the pre-period and post-period, respectively. The number of study participants who had clinic visits during the pre-period and the post-period were 3,333 in 2020 and 3,608 in 2019. Propensity score matching was carried out to compare the effect of telemedicine and clinic visits on diabetes control in 2020 among diabetes patients with insufficient glucose control (HbA1c ≥7%). The primary outcome was post-period HbA1c. RESULTS: The major difference between 2020 and 2019 was the use of telemedicine in 2020. After adjustment for age, sex, diabetes type, pre-period HbA1c and pre-period body mass index, glycemic control evaluated by HbA1c was significantly worse in the post-period of 2020 than 2019. In the propensity score-matched 618 pairs, the clinic visit group had significantly better post-period HbA1c than the telemedicine group (7.5% vs 7.4%, P = 0.023). CONCLUSIONS: Glycemic control was slightly, but significantly, worse in 2020 than 2019. Although telemedicine significantly improved glycemic control during the coronavirus disease 2019 pandemic in 2020, clinic visits improved HbA1c significantly more. The substitution of telemedicine for clinic visits appears to be a viable option under emergency conditions, but clinic visits might be a better option when possible.

Association of insulin treatment with gastric residue during an esophagogastroduodenoscopy.

The purpose of this study was to investigate the association of glycemic control and diabetes treatment to gastric residue observed during an esophagogastroduodenoscopy. Among 6,592 individuals who had esophagogastroduodenoscopy at our clinic between 2003 and 2019, we retrospectively and longitudinally identified those who had gastric residue during an esophagogastroduodenoscopy. Other data collected were age, sex, diagnosis of diabetes, glycated hemoglobin and diabetes medication. Cox proportional hazards models were used to assess the association of these data with the occurrence of gastric residue. To the best of our knowledge, this is the first retrospective cohort study finding that undergoing insulin treatment is a risk factor for gastric residue independent of age, sex and diabetes or glycated hemoglobin.

Diabetes management by either telemedicine or clinic visit improved glycemic control during the coronavirus disease 2019 pandemic state of emergency in Japan.

The purpose of this retrospective cohort study at a Tokyo diabetes clinic was to evaluate the effect of telemedicine and clinic visit on glycated hemoglobin (HbA1c) during the coronavirus disease 2019 state of emergency. The effect of telemedicine and clinic visit during the emergency period on the post-emergency measured HbA1c was evaluated by multiple regression models and logistic regression models adjusted for age, sex, type of diabetes, pre-emergency HbA1c and body mass index, and body mass index change during the emergency period. Among 2,727 patients who visited the clinic before and after the emergency period, the interval between clinic visits during the emergency period was significantly associated with HbA1c improvement. Telemedicine and clinic visit were independently associated with HbA1c improvement when pre-emergency HbA1c was ≥7%. In conclusion, clinic visit and telemedicine during the coronavirus disease 2019 emergency period were both independently effective in HbA1c improvement in Japanese diabetes patients who had insufficient HbA1c control.

Clinical features and sulfonylurea usage among outpatients with diabetes aged ≥90 years in an urban diabetes clinic in Tokyo.

AIMS/INTRODUCTION: Aging of society is accelerating in many countries. The purpose of this study was to describe the clinical features and sulfonylurea usage among diabetes outpatients aged ≥90 years (nonagenarians). MATERIALS AND METHODS: This study was a retrospective observational study. The study population consisted of 69 nonagenarian diabetes outpatients and 857 diabetes outpatients aged <90 years. Patients were classified into four groups: group 1, <65 years; group 2, 65-74 years; group 3, 75-89 years; and group 4, ≥90 years. The presence of hypoglycemic episodes was defined as having self-reported symptoms, or self-monitored or clinically measured blood glucose level <70 mg/dL. RESULTS: The median glycated hemoglobin (HbA1c) in group 1 and group 4 was 7.0% and 7.2%, respectively (P = 0.506). The proportion of sulfonylurea treatment in group 4 was 45.5%, which is significantly higher compared with the other three groups (20.0-27.8%, P < 0.001). In group 4, there was no difference between patients with or without sulfonylurea in age, sex, body mass index, HbA1c and number of antihyperglycemic agents. Five out of 25 nonagenarian sulfonylurea-treated patients had hypoglycemic episodes within the last 2 years, their HbA1c were all 7.0 ≤ HbA1c < 8.0, and sulfonylurea or insulin was tapered in all cases after confirming hypoglycemia. Tapering dosage was attempted in all 25 sulfonylurea-treated nonagenarian patients, but 15 needed to continue sulfonylurea for glycemic control, and 10 continued sulfonylurea with unknown reasons from their medical records. CONCLUSIONS: Although tapering the dosage of sulfonylurea was attempted in nonagenarian patients, sulfonylurea was widely continued for glycemic control. Reverse clinical inertia may exist in some sulfonylurea-treated nonagenarian patients.

Synergistic association of the copper/zinc ratio under inflammatory conditions with diabetic kidney disease in patients with type 2 diabetes: The Asahi Diabetes Complications Study.

AIMS/INTRODUCTION: We aimed to study the relationships among the copper (Cu)/zinc (Zn) ratio, inflammatory biomarkers, and the prevalence of diabetic kidney disease (DKD) in patients with type 2 diabetes. MATERIALS AND METHODS: A cross-sectional study was performed on 651 patients with type 2 diabetes. DKD was defined as a urinary albumin-to-creatinine ratio of ≥30 mg/g creatinine and/or an estimated glomerular filtration rate using cystatin C of < 60 mL/min/1.73 m2 . Areas under the curves (AUCs), cutoff values, and thresholds for detecting DKD were determined for the Cu/Zn ratio, soluble tumor necrosis factor-α receptor 1 (sTNFαR1), and high-sensitivity C-reactive protein (hsCRP). Patients were categorized by each cutoff value of sTNFαR1 and the Cu/Zn ratio. Odds ratios (ORs) and biological interactions for the prevalence of DKD were determined. RESULTS: DKD was identified in 220 patients. AUC/optimal cutoff values were 0.777/1300 pg/mL for sTNFαR1, 0.603/1.1648 for the Cu/Zn ratio, and 0.582/305 ng/mL for hsCRP. The ORs for DKD were higher, but not significantly, in the sTNFαR1 < 1300 and Cu/Zn ≥ 1.1648 group, significantly higher in the sTNFαR1 ≥ 1300 and Cu/Zn < 1.1648 group (P < 0.0001), and further synergistically elevated in the sTNFαR1 ≥ 1300 and Cu/Zn ≥ 1.1648 group (P < 0.0001) compared with the sTNFαR1 < 1300 and Cu/Zn < 1.1648 group after multivariable adjustment. Levels of sTNFαR1 were significantly higher in the sTNFαR1 ≥ 1300 and Cu/Zn ≥ 1.1648 group than in the sTNFαR1 ≥ 1300 and Cu/Zn < 1.1648 group (P = 0.0006). CONCLUSIONS: Under an inflammatory initiation signal of elevated serum sTNFαR1 levels, an increase in the Cu/Zn ratio may further exacerbate inflammation and is synergistically associated with a high prevalence of DKD in patients with type 2 diabetes.

Role of the KcsA channel cytoplasmic domain in pH-dependent gating.

The KcsA channel is a representative potassium channel that is activated by changes in pH. Previous studies suggested that the region that senses pH is entirely within its transmembrane segments. However, we recently revealed that the cytoplasmic domain also has an important role, because its conformation was observed to change dramatically in response to pH changes. Here, to investigate the effects of the cytoplasmic domain on pH-dependent gating, we made a chimera mutant channel consisting of the cytoplasmic domain of the KcsA channel and the transmembrane region of the MthK channel. The chimera showed a pH dependency similar to that of KcsA, indicating that the cytoplasmic domain can act as a pH sensor. To identify how this region detects pH, we substituted certain cytoplasmic domain amino acids that are normally negatively charged at pH 7 for neutral ones in the KcsA channels. These mutants opened independently of pH, suggesting that electrostatic charges have a major role in the cytoplasmic domain's ability to sense and respond to pH.