A genome-wide association study identifies a locus associated with knee extension strength in older Japanese individuals.

Sarcopenia is a common skeletal muscle disease in older people. Lower limb muscle strength is a good predictive value for sarcopenia; however, little is known about its genetic components. Here, we conducted a genome-wide association study (GWAS) for knee extension strength in a total of 3452 Japanese aged 60 years or older from two independent cohorts. We identified a significant locus, rs10749438 which is an intronic variant in TACC2 (transforming acidic coiled-coil-containing 2) (P = 4.2 × 10-8). TACC2, encoding a cytoskeleton-related protein, is highly expressed in skeletal muscle, and is reported as a target of myotonic dystrophy 1-associated splicing alterations. These suggest that changes in TACC2 expression are associated with variations in muscle strength in older people. The association was consistently observed in young and middle-aged subjects. Our findings would shed light on genetic components of lower limb muscle strength and indicate TACC2 as a potential therapeutic target for sarcopenia.

Internet of things-based approach for glycemic control in people with type 2 diabetes: A randomized controlled trial.

AIMS: The utilization of long-term effect of internet of things (IoT) on glycemic control is controversial. This trial aimed to examine the effect of an IoT-based approach for type 2 diabetes. MATERIALS AND METHODS: This randomized controlled trial enrolled 1,159 adults aged 20-74 years with type 2 diabetes with a HbA1c of 6.0-8.9% (42-74 mmol/mol), who were using a smartphone on a daily basis were randomly assigned to either the IoT-based approach group (ITG) or the control group (CTG). The ITG were supervised to utilize an IoT automated system that demonstrates a summary of lifelogging data (weight, blood pressure, and physical activities) and provides feedback messages that promote behavioral changes in both diet and exercise. The primary end point was a HbA1c change over 52 weeks. RESULTS: Among the patients, 581 were assigned to the ITG and 578 were in the CTG. The changes in HbA1c from baseline to the final measurement at 52 weeks [mean (standard deviation)] were -0.000 (0.6225)% in ITG and - 0.006 (0.6449)% in CTG, respectively (P = 0.8766). In the per protocol set, including ITG using the IoT system almost daily and CTG, excluding those using the application almost daily, the difference in HbA1c from baseline to 52 weeks were -0.098 (0.579)% and 0.027 (0.571)%, respectively (P = 0.0201). We observed no significant difference in the adverse event profile between the groups. CONCLUSIONS: The IoT-based approach did not reduce HbA1c in patients with type 2 diabetes. IoT-based intervention using data on the daily glycemic control and HbA1c level may be required to improve glycemic control.

Effects of empagliflozin in patients with chronic kidney disease from Japan: exploratory analyses from EMPA-KIDNEY.

BACKGROUND: EMPA-KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. METHODS: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20 < 45; or ≥ 45 < 90 ml/min/1.73m2 with a urinary albumin-to-creatinine ratio (uACR) of ≥ 200 mg/g. The primary outcome was a composite of kidney disease progression (end-stage kidney disease, a sustained eGFR decline to < 10 ml/min/1.73m2 or ≥ 40% from randomization, or renal death) or cardiovascular death. In post-hoc analyses, we explored the effects of empagliflozin in participants from Japan vs. non-Japan regions, including additional models assessing whether differences in treatment effects between these regions could result from differences in baseline characteristics. RESULTS: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64-0.82; P < 0.0001). Among the participants from non-Japan regions, there were 399 vs. 494 primary outcomes (0.75, 0.66-0.86), and 33 vs. 64 (0.49, 0.32-0.75; heterogeneity p = 0.06) in Japan. Results were similar when models explicitly considered treatment interactions with diabetes status, categories of eGFR/uACR, and recruitment in Japan (heterogeneity p = 0.08). Safety outcomes were broadly comparable between the two groups, and by Japanese status. CONCLUSIONS: Empagliflozin safely reduced the risk of "kidney disease progression or cardiovascular death" in patients with CKD, with consistent effects in participants from Japan.

Corrigendum: Playing basketball and volleyball during adolescence is associated with higher bone mineral density in old age: the Bunkyo Health Study.

[This corrects the article DOI: 10.3389/fphys.2023.1227639.].

Protein acylations induced by a ketogenic diet demonstrate diverse patterns depending on organs and differ between histones and global proteins.

An essential ketone body, ß-hydroxybutyrate (BOHB), plays various roles in physiological regulations via protein acylations such as lysine acetylation and ß-hydroxybutyrylation. Here, to understand how BOHB systemically regulates acylations from an overarching perspective, we administered a ketogenic diet to mice to increase BOHB concentration and examined acylations. We found that global acetylation and ß-hydroxybutyrylation dramatically increase in various organs except for the brains, where the increase was much smaller than in the other organs. Interestingly, we observe no increase in histone acetylation in the organs where significant global protein acetylation occurs despite a substantial rise in histone ß-hydroxybutyrylation. Finally, we compared the transcriptome data of the mice's liver after the ketogenic diet to the public databases, showing that upregulated genes are enriched in those related to histone ß-hydroxybutyrylation in starvation. Our data indicate that a ketogenic diet induces diverse patterns of acylations depending on organs and protein localizations, suggesting that different mechanisms regulate acylations and that the ketogenic diet is associated with starvation in terms of protein modifications.

Assessing interstitial fluid dynamics in type 2 diabetes mellitus and prediabetes cases through diffusion tensor imaging analysis along the perivascular space.

Background and purpose: Glymphatic system in type 2 diabetes mellitus (T2DM) but not in the prodrome, prediabetes (Pre-DM) was investigated using diffusion tensor image analysis along the perivascular space (DTI-ALPS). Association between glymphatic system and insulin resistance of prominent characteristic in T2DM and Pre-DM between is yet elucidated. Therefore, this study delves into the interstitial fluid dynamics using the DTI-ALPS in both Pre-DM and T2DM and association with insulin resistance. Materials and methods: In our cross-sectional study, we assessed 70 elderly individuals from the Bunkyo Health Study, which included 22 with Pre-DM, 18 with T2DM, and 33 healthy controls with normal glucose metabolism (NGM). We utilized the general linear model (GLM) to evaluate the ALPS index based on DTI-ALPS across these groups, considering variables like sex, age, intracranial volume, years of education, anamnesis of hypertension and hyperlipidemia, and the total Fazekas scale. Furthermore, we have explored the relationship between the ALPS index and insulin resistance, as measured by the homeostasis model assessment of insulin resistance (HOMA-IR) using GLM and the same set of covariates. Results: In the T2DM group, the ALPS index demonstrated a reduction compared with the NGM group [family-wise error (FWE)-corrected p < 0.001; Cohen's d = -1.32]. Similarly, the Pre-DM group had a lower ALPS index than the NGM group (FWE-corrected p < 0.001; Cohen's d = -1.04). However, there was no significant disparity between the T2DM and Pre-DM groups (FWE-corrected p = 1.00; Cohen's d = -0.63). A negative correlation was observed between the ALPS index and HOMA-IR in the combined T2DM and Pre-DM groups (partial correlation coefficient r = -0.35, p < 0.005). Conclusion: The ALPS index significantly decreased in both the pre-DM and T2DM groups and showed a correlated with insulin resistance. This indicated that changes in interstitial fluid dynamics are associated with insulin resistance.

Low Handgrip Strength (Possible Sarcopenia) With Insulin Resistance Is Associated With Type 2 Diabetes Mellitus.

Context: Older adults with sarcopenic obesity are at high risk for type 2 diabetes mellitus (T2DM). However, few East Asians have sarcopenic obesity. Since many East Asians have insulin resistance (IR) without obesity, it is possible that older East Asians with sarcopenia and IR might be at high risk for T2DM. However, this relationship has not been studied. Methods: This cross-sectional study included 1629 older adults aged 65 to 84 years registered in the Bunkyo Health Study. All underwent a 75-g oral glucose tolerance test and handgrip strength measurement. Participants were classified into 4 groups by possible sarcopenia (handgrip strength <28 kg in men and <18 kg in women) and IR status (triglyceride glucose [TyG] index ≥8.79 for men and ≥8.62 for women [third quartile]). Modified Poisson regression was used to estimate relative risk (RR) and 95% CIs for T2DM with adjustment for confounding factors. Results: The mean age was 73.1 ± 5.4 years. T2DM was diagnosed in 212 (13.0%) participants. After adjusting for age, sex, body mass index, use of lipid-lowering medications, hypertension, and cardiovascular disease, possible sarcopenia and IR were associated with T2DM, with their coexistence showing a notably stronger association (control: RR, 1.00 [Reference]; possible sarcopenia: RR, 1.55 [95% CI, 1.04-2.30]; IR: RR, 2.69 [95% CI, 1.99-3.65]; and IR possible sarcopenia: RR, 4.76 [95% CI, 3.34-6.79]). Conclusion: Possible sarcopenia based on low handgrip strength and IR based on the TyG index are independently associated with T2DM in older Japanese individuals. Their coexistence shows a particularly strong association with T2DM.

Protocol of a Prospective Observational Study on Lifestyle and Quality of Life in Adults with Type 1 Diabetes in Japan.

INTRODUCTION: Recent studies have shown that the quality of life (QOL) of people living with type 1 diabetes (T1D) is poor and must be improved. However, the living situation and QOL of adults living with T1D in Japan have not been fully clarified. This study will examine their lifestyle, QOL, and clinical situation, as well as the relationships between them. METHODS: This is a prospective, 5-year follow-up observational study. Between December 2019 and September 2021, we enrolled adults in Japan who were living with T1D and receiving insulin therapy, and are acquiring longitudinal clinical data and the responses to seven questionnaires regarding lifestyle and QOL. The primary study outcomes are (1) the relationship between Problem Areas in Diabetes (PAID) scores and various factors including demographic data, clinical characteristics, medical history, lifestyle habits, treatment history, biochemical data, and the scores of questionnaires; and (2) the relationship between Beck Depression Inventory (BDI)-II scores and various factors aforementioned. The secondary outcomes are the relationships between various factors aforementioned and each of the following: (1) blood glucose control, (2) blood lipid control, (3) dietary patterns, (4) fear of hypoglycemia, (5) sleep patterns, and (6) physical activity. PLANNED OUTCOME: We registered 352 participants. The median age was 49 (41-63) years, and the median duration of T1D was 13 (8-20) years. All the results will be available in 2026. We expect to clarify the factors associated with decreased QOL, and that this knowledge will contribute to improving QOL in adults in Japan who are living with T1D and receiving insulin therapy. TRIAL REGISTRATION: Clinical Trials.gov identifier, UMIN000044088.

Fat Accumulation and Elevated Free Fatty Acid Are Associated With Age-Related Glucose Intolerance: Bunkyo Health Study.

Context: Older adults have a high prevalence of new-onset diabetes, often attributed to age-related decreases in insulin sensitivity and secretion. It remains unclear whether both insulin sensitivity and secretion continue to deteriorate after age 65. Objective: To investigate the effects of aging on glucose metabolism after age 65 and to identify its determinants. Methods: This cross-sectional study involved 1438 Japanese older adults without diabetes. All participants underwent a 75-g oral glucose tolerance test (OGTT). Body composition and fat distribution were measured with dual-energy X-ray absorptiometry and magnetic resonance imaging. Participants were divided into 4 groups by age (65-69, 70-74, 75-79, and 80-84 years) to compare differences in metabolic parameters. Results: Mean age and body mass index were 73.0 ± 5.4 years and 22.7 ± 3.0 kg/m2. The prevalence of newly diagnosed diabetes increased with age. Fasting glucose, fasting insulin, the area under the curve (AUC)-insulin/AUC-glucose and insulinogenic index were comparable between groups. AUC-glucose and AUC-insulin during OGTT were significantly higher and Matsuda index and disposition index (Matsuda index · AUC-insulin/AUC-glucose) were significantly lower in the age 80-84 group than in the age 65-69 group. Age-related fat accumulation, particularly increased visceral fat area (VFA), and elevated free fatty acid (FFA) levels were observed. Multiple regression revealed strong correlations of both Matsuda index and disposition index with VFA and FFA. Conclusion: Glucose tolerance declined with age in Japanese older adults, possibly due to age-related insulin resistance and ß-cell deterioration associated with fat accumulation and elevated FFA levels.

Third Report of the Japan Diabetes Society (JDS)/Japanese Cancer Association (JCA) Joint Committee on diabetes and cancer: summary of the results of a questionnaire survey of oncologists and diabetologists-secondary publication.

The Japan Diabetes Society (JDS) and the Japan Cancer Association (JCA) launched a joint committee and published their "First Joint Committee Report on Diabetes and Cancer" in 2013, compiling recommendations for physicians and healthcare providers as well as for the general population. In 2016, the "Second Joint Committee Report on Diabetes and Cancer" summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current "Third Joint Committee Report on Diabetes and Cancer", for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology (JSCO) and the Japanese Society of Medical Oncology (JSMO), reports on the results from the questionnaire survey, "Diabetes Management in Patients Receiving Cancer Therapy," which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey demonstrated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients.

Third Report of the Japan Diabetes Society/Japanese Cancer Association Joint Committee on Diabetes and Cancer: Summary of the results of a questionnaire survey of oncologists and diabetologists-Secondary publication.

The Japan Diabetes Society and the Japan Cancer Association launched a joint committee and published their "First Joint Committee Report on Diabetes and Cancer" in 2013, compiling recommendations for physicians and health-care providers as well as for the general population. In 2016, the "Second Joint Committee Report on Diabetes and Cancer" summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current "Third Joint Committee Report on Diabetes and Cancer", for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology and the Japanese Society of Medical Oncology, reports on the results from the questionnaire survey, "Diabetes Management in Patients Receiving Cancer Therapy," which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey indicated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients.

Novel time-resolved reporter mouse reveals spatial and transcriptional heterogeneity during alpha cell differentiation.

AIMS/HYPOTHESIS: Glucagon-expressing pancreatic alpha cells have attracted much attention for their plasticity to transdifferentiate into insulin-producing beta cells; however, it remains unclear precisely when, and from where, alpha cells emerge and what regulates alpha cell fate. We therefore explored the spatial and transcriptional heterogeneity of alpha cell differentiation using a novel time-resolved reporter system. METHODS: We established the mouse model, 'Gcg-Timer', in which newly generated alpha cells can be distinguished from more-differentiated cells by their fluorescence. Fluorescence imaging and transcriptome analysis were performed with Gcg-Timer mice during the embryonic and postnatal stages. RESULTS: Fluorescence imaging and flow cytometry demonstrated that green fluorescence-dominant cells were present in Gcg-Timer mice at the embryonic and neonatal stages but not after 1 week of age, suggesting that alpha cell neogenesis occurs during embryogenesis and early neonatal stages under physiological conditions. Transcriptome analysis of Gcg-Timer embryos revealed that the mRNAs related to angiogenesis were enriched in newly generated alpha cells. Histological analysis revealed that some alpha cells arise close to the pancreatic ducts, whereas the others arise away from the ducts and adjacent to the blood vessels. Notably, when the glucagon signal was suppressed by genetic ablation or by chemicals, such as neutralising glucagon antibody, green-dominant cells emerged again in adult mice. CONCLUSIONS/INTERPRETATION: Novel time-resolved analysis with Gcg-Timer reporter mice uncovered spatiotemporal features of alpha cell neogenesis that will enhance our understanding of cellular identity and plasticity within the islets. DATA AVAILABILITY: Raw and processed RNA sequencing data for this study has been deposited in the Gene Expression Omnibus under accession number GSE229090.

Medial meniscus extrusion is invariably observed and consistent with tibial osteophyte width in elderly populations: The Bunkyo Health Study.

We reported that the full-length width of medial tibial osteophytes comprising cartilage and bone parts correlates with medial meniscus extrusion (MME) in early-stage knee osteoarthritis (OA). However, no data exist on the prevalence of MME and its relationship with osteophytes in the elderly population. 1191 elderly individuals (females 57%; 72.9 years old on average) in the Bunkyo Health Study underwent standing plain radiograph and proton density-weighted MRI on knee joints. MRI-detected OA changes were evaluated according to the Whole-Organ Magnetic Resonance Imaging Score. A new method of assessing the cartilage and bone parts of osteophytes was developed using pseudo-coloring images of proton density-weighted fat-suppressed MRI. Most subjects showed Kellgren-Lawrence grade 1 or 2 radiographic medial knee OA (88.1%), MME (98.7%, 3.90 ± 2.01 mm), and medial tibial osteophytes (99.3%, 3.27 ± 1.50 mm). Regarding OA changes, MME was closely associated with the full-length width of medial tibial osteophytes (ß = 1.114; 95% CI 1.069-1.159; p < 0.001) in line with osteophyte width (intraclass correlation coefficient, 0.804; 95% CI 0.783-0.823). Our data revealed that MME and medial tibial osteophytes are observed in the elderly and demonstrate that the degree of MME is consistent with the full-length width of medial tibial osteophytes, suggesting that osteophytes might be implicated in MME.

Playing basketball and volleyball during adolescence is associated with higher bone mineral density in old age: the Bunkyo Health Study.

Introduction: Exercise is beneficial for increasing areal bone mineral density (aBMD) in adolescence and maintaining it in old age. Moreover, high-impact sports are more effective than low-impact sports in increasing aBMD. This study aimed to determine the types of adolescent sports played in school-based sports clubs associated with aBMD in old age. Methods: In total, 1,596 older adults (681 men and 915 women, age: 65-84 years) living in an urban area of Japan were evaluated for the femoral neck and lumbar spine aBMD using dual-energy X-ray absorptiometry. The association between adolescent sports played in sports clubs and aBMD in old age was analyzed using multiple regression analysis, with femoral neck and lumbar spine aBMD as dependent variables, and sports type and participant characteristics such as age, body weight, and serum 25-hydroxyvitamin D [25(OH)D] level, as independent variables. Results: For the femoral neck, basketball was associated with aBMD in older men (ß = 0.079, p < 0.05) and women (ß = 0.08, p < 0.01), whereas current body weight and 25(OH)D level were associated with aBMD in both sexes. For the lumbar spine, volleyball (ß = 0.08, p < 0.01) and swimming (ß = 0.06, p < 0.05) was significantly associated with lumbar spine aBMD, whereas current body weight, 25(OH)D, and diabetes mellitus were associated with aBMD in older women. Conclusion: Both men and women who played basketball in adolescence had higher femoral neck aBMD in old age. Moreover, women who played volleyball in adolescence had higher lumbar spine aBMD in old age.

Reduced gray matter volume in the default-mode network associated with insulin resistance.

Insulin resistance may lead to structural and functional abnormalities of the human brain. However, the mechanism by which insulin resistance impairs the brain remains elusive. In this study, we used two large neuroimaging databases to investigate the brain regions where insulin resistance was associated with the gray matter volume and to examine the resting-state functional connectivity between these brain regions and each hypothalamic nucleus. Insulin resistance was associated with reduced gray matter volume in the regions of the default-mode and limbic networks in the cerebral cortex in older adults. Resting-state functional connectivity was prominent between these networks and the paraventricular nucleus of the hypothalamus, a hypothalamic interface connecting functionally with the cerebral cortex. Furthermore, we found a significant correlation in these networks between insulin resistance-related gray matter volume reduction and network paraventricular nucleus of the hypothalamus resting-state functional connectivity. These results suggest that insulin resistance-related gray matter volume reduction in the default-mode and limbic networks emerged through metabolic homeostasis mechanisms in the hypothalamus.

Continuous glucose monitoring-derived time in range and CV are associated with altered tissue characteristics of the carotid artery wall in people with type 2 diabetes.

AIMS/HYPOTHESIS: Previous studies have suggested that glucose variability may accelerate atherosclerosis progression in people with type 2 diabetes. Current guidelines recommend assessing glycaemic control using continuous glucose monitoring (CGM), which provides a comprehensive glycaemic profile to supplement HbA1c measurement. However, the association between CGM-derived metrics and atherosclerosis progression is not entirely clear. METHODS: This exploratory study used baseline data and data obtained after 104 weeks from an ongoing prospective, multicentre, observational study. Six hundred study participants with type 2 diabetes and no apparent history of symptomatic cardiovascular disease underwent CGM and ultrasonographic atherosclerosis measurements of the carotid arteries, including the intima-media thickness (IMT) and grey-scale median (GSM), at baseline and 104 weeks. Non-invasive ultrasonic tissue characterisation of the carotid artery wall or plaque using the GSM reflects vascular composition. Multivariate regression models were used to analyse the association between CGM-derived indices, mainly time in range (TIR) and CV, and changes in carotid atherosclerosis index values. RESULTS: Over the 104-week study period, there were modest increases in mean IMT (from 0.759±0.153 to 0.773±0.152 mm, p<0.001) and thickened-lesion GSM (from 43.5±19.5 to 53.9±23.5 units, p<0.001), but no significant changes in common carotid artery maximum-IMT (from 1.109±0.442 to 1.116±0.469 mm, p=0.453) or mean GSM (from 48.7±19.3 to 49.8±20.8 units, p=0.092). In a linear regression model with adjustment for possible atherosclerotic risk factors, including HbA1c, TIR and CV at baseline were significantly associated with the annual change in mean GSM (regression coefficient per 10% increase in TIR 0.52; 95% CI 0.06, 0.98; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.12; 95% CI -0.22, -0.02; Hochberg-adjusted p value 0.038). TIR and CV at baseline were also significantly associated with the annual change in thickened-lesion GSM (regression coefficient per 10% increase in TIR 0.95; 95% CI 0.12, 1.79; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.19; 95% CI -0.36, -0.01; Hochberg-adjusted p value 0.038). Participants who achieved target CGM-derived metrics at baseline, as proposed by an international consensus, showed significant annual changes in mean GSM compared with those who did not (0.94±6.88 vs -0.21±6.19 units/year, p=0.007). CONCLUSIONS/INTERPRETATION: TIR and CV were significantly associated with changes in the tissue characteristics of the carotid artery wall. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, number UMIN000032325.

Coronary Artery Vorticity to Predict Functional Plaque Progression in Participants with Type 2 Diabetes Mellitus.

Purpose: To investigate whether vorticity could predict functional plaque progression better than high-risk plaque (HRP) and lesion length (LL) in individuals with type 2 diabetes mellitus. Materials and Methods: This single-center prospective study included 61 participants (mean age, 61 years ± 9 [SD]; 43 male participants) who underwent serial coronary CT angiography at 2 years, with 20%-70% stenosis at initial CT between October 2015 and March 2020. The number of the following HRP characteristics was recorded: low attenuation, positive remodeling, spotty calcification, and napkin-ring sign. Vorticity was calculated using a mesh-free simulation. A decrease in CT fractional flow reserve larger than 0.05 indicated functional progression. Models using HRP and LL and vorticity were compared using receiver operating characteristic curve analysis. Results: Of the 94 vessels evaluated, 25 vessels (27%) showed functional progression. Vessels with functional progression showed higher vorticity at distal stenosis (984 sec-1; IQR: 730-1253 vs 443 sec-1; IQR: 295-602; P < .001) than vessels without progression. The area under the receiver operating characteristic curve of vorticity (0.91; 95% CI: 0.84, 0.97) was higher than that of HRP and LL (0.69; 95% CI: 0.56, 0.82; P < .01). Diagnostic accuracy of vorticity (85%; 80 of 94 vessels; 95% CI: 76, 92) was higher than that of HRP and LL (72%; 68 of 94 vessels; 95% CI: 62, 81; P = .004). Conclusion: In participants with type 2 diabetes mellitus, vorticity at distal stenosis was a better predictor of functional plaque progression than HRP and LL.Keywords: Coronary Artery, Vorticity, Functional Plaque Progression, Type 2 Diabetes, Vasculature, CT Angiography, Computational Fluid Dynamics, Fractional Flow Reserve Supplemental material is available for this article. © RSNA, 2023.

Long-term efficacy and safety of early alogliptin initiation in subjects with type 2 diabetes: an extension of the SPEAD-A study.

We previously reported in the study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-A) that alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuated the progression of carotid atherosclerosis in subjects with type 2 diabetes and no history of cardiovascular disease. This extension study of the SPEAD-A trial investigated whether early alogliptin initiation improved long-term cardiovascular outcomes. The SPEAD-A trial randomized 341 subjects with type 2 diabetes to either alogliptin or conventional treatment to investigate the effects of alogliptin on atherosclerosis. All subjects who completed that trial were eligible for this prospective, observational cohort study. The primary endpoint was the first occurrence of a major cardiovascular event, defined as death due to any cause, acute myocardial infarction, or stroke. During the 520-week follow-up period, composite primary outcome events occurred in only a few subjects in each group [8 (5.4%) in the alogliptin group and 9 in the conventional treatment group (5.9%)]. There were no significant differences in the incidence rate of the primary outcome between the two groups. Post hoc Poisson regression analysis showed no significant difference between the two groups in the incidence rate of composite recurrence events for the same outcomes as the primary endpoint. On the other hand, this incidence rate was significantly lower in subjects who received DPP-4 inhibitors before an initial cardiovascular event than in those who did not (5.8 vs. 13.3 per 1000 person-years, respectively, p = 0.04). Early initiation of alogliptin was not associated with a reduced risk of composite cardiovascular disease, which could be attributed to fewer events and/or the addition of DPP-4 inhibitors during the follow-up period.

Diabetic ketoacidosis due to a sensor defect of FreeStyle Libre: A case report.

The FreeStyle Libre Flash Glucose Monitoring System allows users to obtain sensor glucose values by scanning with the reader or their mobile phone. We report a case of a 59-year-old man with type 1 diabetes mellitus who developed diabetic ketoacidosis due to a sensor defect. After replacing the sensor with a new one, the glucose value shown in the device was much lower than usual, which made him consider that he was hypoglycemic. Accordingly, he reduced his insulin dose and eventually developed diabetic ketoacidosis. He was unaware of the discrepancy due to the lack of self-monitoring of his blood glucose, although he was educated to do. In sum, glucose monitoring with the FreeStyle Libre is helpful; however, it is necessary to remind the patient that a sensor defect leading to a severe complication frequently happens.

Establishment of Pancreatic ß-Cell-Specific Gene Knockout System Based on CRISPR-Cas9 Technology With AAV8-Mediated gRNA Delivery.

The Cre-loxP system provides valuable resources to analyze the importance of tissue-specific gene knockout (KO), including pancreatic ß-cells associated with the pathogenesis of diabetes. However, it is expensive and time consuming to generate transgenic mice harboring floxed genes of interest and cross them with cell-specific Cre expression mice. We establish a ßCas9 system with mice expressing Cas9 in pancreatic ß-cells and adeno-associated virus 8 (AAV8)-mediated guide RNA (gRNA) delivery based on CRISPR-Cas9 technology to overcome those shortcomings. Interbreeding CAG-loxP-STOP-loxP (LSL)-Cas9 with Ins1-Cre mice generates normal glucose-tolerant ßCas9 mice expressing Cas9 with fluorescent reporter EGFP specifically in ß-cells. We also show significant ß-cell-specific gene KO efficiency with AAV8-mediated delivery of gRNA for EGFP reporter by intraperitoneal injection in the mice. As a proof of concept, we administered AAV8 to ßCas9 mice for expressing gRNA for Pdx1, a culprit gene of maturity-onset diabetes of the young 4. As reported previously, we demonstrate that those mice show glucose intolerance with transdifferentiation of Pdx1 KO ß-cells into glucagon-expressing cells. We successfully generated a convenient ß-cell-specific gene KO system with ßCas9 mice and AAV8-mediated gRNA delivery.