Publications by authors named "Hirotaka Watada"

381 Publications

Short-term physical inactivity induces diacylglycerol accumulation and insulin resistance in muscle via lipin1 activation.

Am J Physiol Endocrinol Metab 2021 Nov 1. Epub 2021 Nov 1.

Department of Metabolism & Endocrinology, Juntendo University, Tokyo, Japan.

Physical inactivity impairs muscle insulin sensitivity. However, its mechanism is unclear. To model physical inactivity, we applied 24-h hind-limb cast immobilization (HCI) to mice with normal or high fat diet (HFD), and evaluated intramyocellular lipids and the insulin signaling pathway in the soleus muscle. While 2-wk HFD alone did not alter intramyocellular diacylglycerol (IMDG) accumulation, HCI alone increased it by 1.9-fold and HCI after HFD further increased it by 3.3-fold. Parallel to this, we found increased PKCε activity, reduced insulin-induced 2-deoxy-glucose (2-DOG) uptake, and reduced phosphorylation of IRβ and Akt, key molecules for insulin signaling pathway. Lipin1, which converts phosphatidic acid to diacylglycerol, showed increase of its activity by HCI, and dominant-negative lipin1 expression in muscle prevented HCI-induced IMDG accumulation and impaired insulin-induced 2-DOG uptake. Further, 24-h leg cast immobilization in human increased lipin1 expression. Thus, even short-term immobilization increases IMDG and impairs insulin sensitivity in muscle via enhanced lipin1 activity.
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http://dx.doi.org/10.1152/ajpendo.00254.2020DOI Listing
November 2021

Insulin resistance and muscle weakness are synergistic risk factors for silent lacunar infarcts: the Bunkyo Health Study.

Sci Rep 2021 Oct 26;11(1):21093. Epub 2021 Oct 26.

Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Insulin resistance and muscle weakness are risk factors for silent lacunar infarcts (SLI), but it is unclear whether they are still independent risk factors when adjusted for each other. In addition, the effect of their combination on SLI is completely unknown. We evaluated SLI, insulin sensitivity, and knee extensor muscle strength by magnetic resonance imaging, PREDIM, and dynamometer, respectively, in 1531 elderly people aged 65-84 years living in an urban area of Tokyo. Among the study subjects, 251 (16.4%) had SLI. Impaired insulin sensitivity (High; 1.00 [reference], Medium; 1.53 [95% confidence interval (CI) 0.94-2.48], Low; 1.86 [1.02-3.39], p for trend 0.047) and reduced muscle strength (High; 1.00 [reference], Medium; 1.40 [0.98-2.02], Low; 1.49 [1.04-2.15], p for trend 0.037) were independently associated with increased risk for SLI in the fully adjusted model. In terms of combined, subjects classified as having the lowest insulin sensitivity and lowest strength were 4.33 times (95% CI 1.64-11.45) more likely to have a SLI than those classified as having the highest insulin sensitivity and highest strength. Impaired insulin sensitivity and reduced muscle strength were independently associated with higher risk of SLI in elderly subjects, and their combination synergistically increased this risk.
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http://dx.doi.org/10.1038/s41598-021-00377-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548532PMC
October 2021

Incidence rates and predictors of microvascular and macrovascular complications in patients with type 2 diabetes: Results from the longitudinal global discover study.

Am Heart J 2022 Jan 16;243:232-239. Epub 2021 Oct 16.

Division of Cardiology, Saint Luke's Mid America Heart Institute, Kansas City, Missouri; Department of Medicine, University of Missouri, Kansas City, Missouri; The George Institute for Global Health and University of New South Wales, Sydney, Australia.

Background: Micro- and macrovascular complications are a major cause of morbidity and mortality in people with type 2 diabetes (T2D). We sought to understand the global incidence rates and predictors of these complications.

Methods: We examined the incidence of vascular complications over 3 years of follow-up in the DISCOVER study-a global, observational study of people with T2D initiating second-line glucose-lowering therapy. Hierarchical Cox proportional hazards regression models examined factors associated with development of micro- and macrovascular complications during follow-up.

Results: Among 11,357 people with T2D from 33 countries (mean age 56.9 ± 11.7 years, T2D duration 5.7 ± 5.1 years, HbA1c 8.4 ± 1.7%), 19.0% had a microvascular complication at enrolment (most commonly neuropathy), and 13.2% had a macrovascular complication (most commonly coronary disease). Over 3 years of follow-up, 16.0% developed an incident microvascular complication, and 6.6% had an incident macrovascular complication. At the end of 3 years of follow-up, 31.5% of patients had at least one microvascular complication, and 16.6% had at least one macrovascular complication. Higher HbA1c and smoking were associated with greater risk of both incident micro- and macrovascular complications. Known macrovascular complications at baseline was the strongest predictor for development of new microvascular complications (HR 1.40, 95% CI 1.21 -1.61) and new macrovascular complications (HR 3.39, 95% CI 2.84 -4.06).

Conclusions: In this global study, both the prevalence and 3-year incidence of vascular complications were high in patients with relatively short T2D duration, highlighting the need for early risk-factor modification.
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http://dx.doi.org/10.1016/j.ahj.2021.10.181DOI Listing
January 2022

Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes.

Biomedicines 2021 Sep 3;9(9). Epub 2021 Sep 3.

Department of Metabolism & Endocrinology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.

Background: Decreased insulin clearance could be a relatively upstream abnormality in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Previous studies have shown that sodium-glucose cotransporter 2 inhibitor (SGLT2i) increases insulin-C-peptide ratio, a marker of insulin clearance, and improves metabolic parameters. We evaluated the effects of the SGLT2i tofogliflozin on metabolic clearance rate of insulin (MCRI) with a hyperinsulinemic euglycemic clamp study, the gold standard for measuring systemic insulin clearance.

Methods: Study participants were 12 Japanese men with type 2 diabetes. We evaluated MCRI and tissue-specific insulin sensitivity with a hyperinsulinemic euglycemic clamp (insulin infusion rate, 40 mU/m·min) before and immediately after a single dose ( = 12) and 8 weeks ( = 9) of tofogliflozin. We also measured ectopic fat in muscle and liver and the abdominal fat area using H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively, before and after 8 weeks of tofogliflozin.

Results: MCRI did not change after a single dose of tofogliflozin (594.7 ± 67.7 mL/min·m and 608.3 ± 90.9 mL/min·m, = 0.61) or after 8 weeks (582.5 ± 67.3 mL/min·m and 602.3 ± 67.0 mL/min·m, = 0.41). The 8-week treatment significantly improved glycated hemoglobin and decreased body weight (1.7%) and the subcutaneous fat area (6.4%), whereas insulin sensitivity and ectopic fat in muscle and liver did not change significantly.

Conclusions: MCRI did not change after a single dose or 8 weeks of tofogliflozin. Increased MCRI does not precede a decrease in body fat or improved glycemic control.
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http://dx.doi.org/10.3390/biomedicines9091154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472728PMC
September 2021

A Pilot Study of Intervention With a Mobile Application Visualizing the Macronutrient Content for Type 2 Diabetes at a Japanese Center.

J Clin Med Res 2021 Aug 30;13(8):425-433. Epub 2021 Aug 30.

Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Background: Estimating the nutritional content of food is essential for self-management in people with type 2 diabetes mellitus, but it is a difficult skill to learn. The aim of this study was to investigate how diabetes management was impacted by the ability of patients to search for items they ate from a database of 26,300 different foods, and to visualize nutritional intake using the Japanese mobile application (app) "Calomeal."

Methods: This was a single-arm, single-center, pilot study. Eighteen outpatients with type 2 diabetes mellitus used the "Calomeal" app for 3 months. The primary endpoint was change in hemoglobin A1c (HbA1c). Secondary endpoints were changes in body weight (BW), lipid parameters, and quality of life scores.

Results: The baseline characteristics of the study subjects were as follows: age: 53.4 ± 7.8 years; male/female ratio: 11/7; HbA1c: 7.9 (7.58 - 8.23)%; and body mass index (BMI): 25.17 (21.63 - 28.59) kg/m. Significant reductions in HbA1c and BMI were observed over 3 months (HbA1c: 7.9 (7.58 - 8.23)% to 7.6 (7.3 - 8.23)%, P = 0.0410; BMI: 25.17 (21.63 - 28.59) to 24.54 (21.57 - 27.81) kg/m, P = 0.0057). Reductions in HbA1c and BMI both correlated with decreased carbohydrate intake estimated by the mobile app.

Conclusions: Japanese patients who used their smartphones to visualize their nutritional intake using the "Calomeal" app demonstrated improved short-term glycemic control and BMI. Although the validity of the results should be tested in future randomized controlled trials, this approach may be a clinical option for improving self-management in Japanese patients with type 2 diabetes mellitus.
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http://dx.doi.org/10.14740/jocmr4558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425790PMC
August 2021

Relationship between blood glucose variability in ambulatory glucose profile and standardized continuous glucose monitoring metrics: Subanalysis of a prospective cohort study.

Diabetes Obes Metab 2021 Sep 9. Epub 2021 Sep 9.

Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Aim: To clarify the relationship between ambulatory glucose profile (AGP) indexes and standardized continuous glucose monitoring (CGM) metrics in patients with type 2 diabetes (T2D).

Methods: This is an exploratory, cross-sectional analysis of baseline data collected from a prospective, multicentre, 5-year follow-up observational study conducted and published previously by our group. The study participants were 999 outpatients with T2D who used CGM at baseline, and had no apparent history of cardiovascular disease. We investigated the relationship between average interquartile range (IQR) and time in range (TIR). We also calculated, for the first time, the cutoff values to achieve the TIR target values.

Results: In both the TIR more than 70% and TIR more than 90% achievement groups, the average IQR was notably small compared with the non-achievement groups. Particularly in comparison of the TIR quartiles, the average IQR became significantly smaller as the TIR became larger. The average IQR correlated negatively with TIR, and the cutoff values for TIR of more than 70% achievement and TIR of more than 90% achievement were an average IQR (>70%/>90%) of 2.13/1.85 mmol/L.

Conclusion: Our results showed a negative correlation between TIR and the range of blood glucose variations visually represented in AGP. The results also showed that the range of blood glucose variations in AGP is associated with indices of intraday and interday blood glucose variations and also with hypoglycaemia. Our results may provide new perspectives in the assessment and application of AGP in the clinical setting.
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http://dx.doi.org/10.1111/dom.14550DOI Listing
September 2021

Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice.

Diabetologia 2021 Dec 9;64(12):2803-2816. Epub 2021 Sep 9.

Laboratory of Developmental Biology & Metabolism, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.

Aims/hypothesis: Pancreatic polypeptide (PP) cells, which secrete PP (encoded by the Ppy gene), are a minor population of pancreatic endocrine cells. Although it has been reported that the loss of beta cell identity might be associated with beta-to-PP cell-fate conversion, at present, little is known regarding the characteristics of Ppy-lineage cells.

Methods: We used Ppy-Cre driver mice and a PP-specific monoclonal antibody to investigate the association between Ppy-lineage cells and beta cells. The molecular profiles of endocrine cells were investigated by single-cell transcriptome analysis and the glucose responsiveness of beta cells was assessed by Ca imaging. Diabetic conditions were experimentally induced in mice by either streptozotocin or diphtheria toxin.

Results: Ppy-lineage cells were found to contribute to the four major types of endocrine cells, including beta cells. Ppy-lineage beta cells are a minor subpopulation, accounting for 12-15% of total beta cells, and are mostly (81.2%) localised at the islet periphery. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorised into two groups (i.e. Ppy-lineage and non-Ppy-lineage beta cells). These subpopulations of beta cells demonstrated distinct characteristics regarding their functionality and gene expression profiles. Ppy-lineage beta cells had a reduced glucose-stimulated Ca signalling response and were increased in number in experimental diabetes models.

Conclusions/interpretation: Our results indicate that an unexpected degree of beta cell heterogeneity is defined by Ppy gene activation, providing valuable insight into the homeostatic regulation of pancreatic islets and future therapeutic strategies against diabetes.

Data Availability: The single-cell RNA sequence (scRNA-seq) analysis datasets generated in this study have been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE166164 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166164 ).
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http://dx.doi.org/10.1007/s00125-021-05560-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563568PMC
December 2021

Defective autophagy in vascular smooth muscle cells enhances the healing of abdominal aortic aneurysm.

Physiol Rep 2021 Sep;9(17):e15000

Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Autophagy is an evolutionarily conserved cellular catabolic process essential for cell homeostasis, and thus its failure is associated with several diseases. While autophagy has been reported to play a role in vascular smooth muscle cells (SMCs) in vascular disorders, its precise role in the pathogenesis of abdominal aortic aneurysm (AAA) has not yet been elucidated. In this study, we investigated the role of SMC autophagy in AAA formation. As a mouse model of AAA, we used control apolipoprotein E-deficient (apoeKO) mice and Atg7cKO (SMC-specific Atg7-deficient mice):apoeKO mice administered angiotensin II for 4 weeks. Intriguingly, Kaplan-Meier curves showed that the survival rates of Atg7cKO:apoeKO mice were significantly higher than those of apoeKO mice. The hematoma area in AAA of Atg7cKO:apoeKO mice was smaller than in apoeKO mice despite the lack of a significant difference in AAA incidence between the two groups. Furthermore, the amount of granulomatous tissues was significantly larger and the collagen-positive area within AAA was significantly larger in Atg7cKO:apoeKO mice than in apoeKO mice. In accordance with these findings, SMCs cultured from Atg7cKO mice showed increased expression of collagens, independent of angiotensin II action. Taken together, our data suggest that defective autophagy in SMCs elicits AAA healing that may underlie the better survival rate under dyslipidemia and angiotensin II infusion.
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http://dx.doi.org/10.14814/phy2.15000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422599PMC
September 2021

Efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes: A post hoc subgroup analysis of the PIONEER 1, 3, 4 and 8 trials.

Diabetes Obes Metab 2021 Dec 27;23(12):2785-2794. Epub 2021 Sep 27.

Toranomon Hospital, Tokyo, Japan.

Aims: To evaluate, through exploratory post hoc subgroup analyses, the efficacy and safety of oral semaglutide versus comparators in Japanese patients enrolled in the global PIONEER 1, 3, 4 and 8 clinical trials.

Materials And Methods: Patients were randomized to once-daily oral semaglutide 3, 7 or 14 mg or comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg). Change from baseline in glycated haemoglobin (HbA1c) and body weight, and proportions of patients attaining HbA1c <7.0% (53 mmol/mol) and body weight loss ≥5%, were analysed at week 26 for all Japanese patients in each trial separately using the treatment policy estimand (regardless of treatment discontinuation or rescue medication use). Adverse events (AEs) were analysed descriptively.

Results: Reductions in HbA1c from baseline in Japanese patients were 1.0% to 1.2% (11.3 mmol/mol to 13.3 mmol/mol) and 1.4% to 1.7% (15.7 mmol/mol to 18.3 mmol/mol) for oral semaglutide 7 mg and 14 mg, respectively. HbA1c reductions were similar or greater than with comparators. Body weight reductions were 1.0% to 2.7% and 3.7% to 4.7% for oral semaglutide 7 mg and 14 mg, respectively, and were generally greater with oral semaglutide than comparators. As expected, the main class of AEs was gastrointestinal, and these AEs comprised most commonly mild-to-moderate constipation, nausea and diarrhoea.

Conclusions: Oral semaglutide appears efficacious and well tolerated in Japanese patients across the type 2 diabetes spectrum.
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http://dx.doi.org/10.1111/dom.14536DOI Listing
December 2021

The Influence of Tofogliflozin on Treatment-Related Quality of Life in Patients with Type 2 Diabetes Mellitus.

Diabetes Ther 2021 Sep 6;12(9):2499-2515. Epub 2021 Aug 6.

Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.

Introduction: Treatment-related quality of life (QOL) is an important aspect of diabetes management. We evaluated the influence of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, tofogliflozin, on treatment-related QOL in Japanese patients with type 2 diabetes mellitus (T2DM).

Methods: This is the prespecified subanalysis study of the "Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)" trial. Treatment-related QOL was evaluated at baseline, week 26, week 52, and week 104 after the initiation of the study using the Diabetes Therapy-Related QOL questionnaire (DTR-QOL). Among the 340 patients in the original UTOPIA study, a total of 252 patients (127, tofogliflozin group; 125, conventional treatment group) who completed the DTR-QOL questionnaire at baseline were the study subjects of the current subanalysis.

Results: The tofogliflozin and conventional treatment groups exhibited almost comparable baseline clinical characteristics, while the use of antihypertensive drugs and lipid-lowering agents was significantly lower in the tofogliflozin treatment group than in the conventional treatment group. Tofogliflozin treatment increased the total score of DTR-QOL7 from baseline (P < 0.001), while conventional treatment did not change it. There were statistically significant differences in delta change in the total DTR-QOL7 score and DTR-QOL7 Q4, Q5, Q6, and Q7 scores from the baseline to week 104 between the treatment groups. Delta changes in HbA1c (Spearman's correlation coefficient, ρ =  - 0.30, P < 0.001), fasting blood glucose (ρ =  - 0.16, P = 0.031), BMI (ρ =  - 0.19, P = 0.008), and waist circumference (ρ =  - 0.17, P = 0.024) at week 104 were negatively associated with delta change in the total QOL7 score.

Conclusions: Our data indicated that tofogliflozin treatment improved treatment-related QOL compared to conventional treatment in Japanese patients with T2DM, in accordance with the improvement of major cardiovascular risk factors.

Trial Registration: UMIN000017607.
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http://dx.doi.org/10.1007/s13300-021-01125-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385006PMC
September 2021

The Multi-Domain Intervention Trial in Older Adults With Diabetes Mellitus for Prevention of Dementia in Japan: Study Protocol for a Multi-Center, Randomized, 18-Month Controlled Trial.

Front Aging Neurosci 2021 12;13:680341. Epub 2021 Jul 12.

Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Obu, Japan.

The Japan-Multi-domain Intervention Trial for Prevention of Dementia in Older Adults with Diabetes (J-MIND-Diabetes) is an 18-month, multi-centered, open-labeled, randomized controlled trial designed to identify whether multi-domain intervention targeting modifiable risk factors for dementia could prevent the progression of cognitive decline among older adults with type 2 diabetes mellitus (T2DM). This manuscript describes the study protocol for the J-MIND-Diabetes trial. Subjects of this trial will comprise a total of 300 T2DM outpatients aged 70-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the stratified permuted-block randomization methods. The intervention group will participate in multi-domain intervention programs aimed at: (1) management of metabolic and vascular risk factors; (2) physical exercise and self-monitoring of physical activity; (3) nutritional guidance; and (4) social participation. The control group will receive usual T2DM care and general instructions on dementia prevention. The primary and secondary outcomes will be assessed at baseline, at 6- and 18-month follow-up. The primary outcome is change from baseline at 18 months in a global composite score combining several neuropsychological domains, including global cognitive function, memory, attention, executive function, processing speed and language. Secondary outcomes include: (1) cognitive changes in neuropsychological tests; (2) changes in geriatrics assessments; (3) metabolic control and diabetic complications; (4) changes in blood and urinary markers. This trial will be the first trial to demonstrate the effectiveness of multi-domain intervention in preventing cognitive decline in older adults with T2DM at increased risk of dementia in Japan. UMIN000035911; Registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) 18 February 2019. (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000040908).
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http://dx.doi.org/10.3389/fnagi.2021.680341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312849PMC
July 2021

Comparison of Brain Volume Measurements Made with 0.3- and 3-T MR Imaging.

Magn Reson Med Sci 2021 Jul 22. Epub 2021 Jul 22.

Department of Radiology, Juntendo University Graduate School of Medicine.

The volumes of intracranial tissues of 40 healthy volunteers acquired from 0.3- and 3-T scanners were compared using intraclass correlation coefficients, correlation analyses, and Bland-Altman analyses. We found high intraclass correlation coefficients, high Pearson's correlation coefficients, and low percentage biases in all tissues and most of the brain regions, although small differences were observed in some areas. These findings may support the validity of brain volumetry with low-field magnetic resonance imaging.
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http://dx.doi.org/10.2463/mrms.tn.2020-0034DOI Listing
July 2021

Health-related quality of life in patients with type 2 diabetes initiating a second-line glucose-lowering therapy: The DISCOVER study.

Diabetes Res Clin Pract 2021 Oct 22;180:108974. Epub 2021 Jul 22.

Peking University People's Hospital, Beijing, China.

Aim: To investigate factors associated with health-related quality of life (HRQoL) in patients with type 2 diabetes mellitus (T2D) at initiation of second-line glucose-lowering therapy.

Methods: DISCOVER is a 3-year, prospective observational study of patients with T2D initiating second-line glucose-lowering therapy, conducted in 38 countries. HRQoL at baseline was assessed using the physical and mental component summary (PCS; MCS) scores of the 36-Item Short Form Health Survey version 2 (SF-36v2) in 31 countries (n = 8309) and the Hypoglycaemia Fear Survey-II (HFS-II) in 23 countries (n = 6516). Factors associated with differences in HRQoL were assessed using multivariable hierarchical regression models.

Results: Mean PCS and MCS scores were 48.0 (standard deviation [SD]: 7.8) and 45.5 (SD: 10.4), respectively. Factors associated with significantly lower SF-36v2 scores included being female, having a history of macrovascular complications and first-line treatment with oral combinations (vs metformin monotherapy). Mean HFS-II behaviour and worry scores were 8.2 (SD: 9.9) and 7.3 (SD: 11.8), respectively. Increased fear of hypoglycaemia was significantly associated with lower SF-36v2 scores.

Conclusions: Several patient-, disease- and treatment-related characteristics correlated with HRQoL, indicating that a multifactorial approach is needed to maintain HRQoL in patients with T2D.
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http://dx.doi.org/10.1016/j.diabres.2021.108974DOI Listing
October 2021

Early versus late intensification of glucose-lowering therapy in patients with type 2 diabetes: Results from the DISCOVER study.

Diabetes Res Clin Pract 2021 Aug 10;178:108947. Epub 2021 Jul 10.

Juntendo University, Tokyo, Japan.

Aims: To assess the effects of glycated haemoglobin (HbA) levels at time of glucose-lowering treatment intensification in DISCOVER, a global observational study of patients with type 2 diabetes (T2D) initiating second-line therapy. Outcomes of interest were glycaemic control, hypoglycaemia, and need for further intensification during 3 years of follow-up.

Methods: We included patients who intensified treatment (add-on or insulin initiation) upon initiation of second-line therapy (baseline). Outcomes were assessed according to baseline HbA: HbA ≤ 7·5% (early intensification) or HbA > 7·5% (late intensification). Factors associated with early or late intensification were assessed using multivariate logistic regression.

Results: Of the 9575 patients included, 3275 (34·2%) intensified treatment early and 6300 (65·8%) intensified treatment late. During follow-up, mean (SD) HbA was lower in the early- than in the late-intensification group (6·9% [0·95%] vs 7·5% [1·28%] at 36 months). More patients had HbA < 7·0% in the early- than in the late-intensification group (61·8% vs 37·9% at 36 months; p < 0·001). The risk of further intensification was higher in the late-intensification group (hazard ratio 1·88 [95% confidence interval 1·68-2·09]). Occurrence of hypoglycaemia was similar in both groups.

Conclusions: Late intensification of glucose-lowering therapy after first-line treatment failure reduces the likelihood of reaching recommended treatment goals.
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http://dx.doi.org/10.1016/j.diabres.2021.108947DOI Listing
August 2021

What are the factors associated with long-term glycaemic control in patients with type 2 diabetes and elevated glycated haemoglobin (≥7.0%) at initiation of second-line therapy? Results from the DISCOVER study.

Diabetes Obes Metab 2021 10 2;23(10):2336-2343. Epub 2021 Aug 2.

University of Leicester, Leicester, UK.

Aims: Glycaemic control is a cornerstone of type 2 diabetes (T2D) management. We assessed factors associated with good long-term glycaemic control in patients with glycated haemoglobin (HbA1c) ≥7.0% at initiation of second-line glucose-lowering therapy, using data from DISCOVER, a global, prospective, 3-year observational study of patients with T2D.

Materials And Methods: This analysis included patients with HbA1c ≥7.0% at baseline (initiation of second-line therapy). Multivariable regression models assessed factors associated with having HbA1c <7.0% at 3 years in two distinct groups: patients with (a) HbA1c ≥7.0% and <9.0%, and (b) HbA1c ≥9.0% at baseline.

Results: In total, 7575 patients with baseline HbA1c ≥7.0% were included (2233 with baseline HbA1c ≥9.0%). At 6 months, 43.7% and 24.2% of patients had an HbA1c level <7.0% in groups a and b, respectively; the corresponding proportions at 3 years were 45.8% and 29.3%. Having HbA1c <7.0% at 6 months (vs. ≥7.0%) was the strongest predictor of having HbA1c <7.0% at 3 years in both group a and group b [odds ratio (95% confidence interval): 2.01 (1.77-2.27) and 2.68 (2.10-3.41), respectively]. Longer T2D duration was associated with a decreased likelihood of having HbA1c <7.0% at 3 years.

Conclusions: In patients with poor glycaemic control at initiation of second-line therapy, early attainment of HbA1c <7.0% appears predictive of long-term glycaemic control, suggesting that timely modification of treatment strategies in patients with elevated HbA1c after 6 months is important to minimize therapeutic inertia.
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http://dx.doi.org/10.1111/dom.14476DOI Listing
October 2021

A Claims-Based Cohort Study on the Treatment Patterns of Japanese Patients with Type 2 Diabetes Mellitus and the Association of Early First Physician Visit with Time to Prescription of Oral Hypoglycemic Agents.

Diabetes Ther 2021 Jul 20;12(7):2035-2047. Epub 2021 Jun 20.

Department of Public Health and Epidemiology, Meiji Pharmaceutical University, Tokyo , Japan.

Introduction: This study aimed to investigate the relationships between timing of the first physician visit after detection of an abnormal glycated hemoglobin (HbA1c) value at routine annual check and the time to antidiabetic treatment prescription; and understand treatment patterns in patients newly diagnosed with type 2 diabetes mellitus (T2DM).

Methods: This retrospective, longitudinal, observational cohort study examined data from JMDC Inc., an administrative claims database. Patients with HbA1c value of at least 6.5% at routine annual check, aged 20 years or older, and prescribed at least one antidiabetic drug were included. This cohort was classified into early physician visit and delayed physician visit groups based on the timing of the first physician visit relative to the median. Patients were monitored from the date of first HbA1c checkup of at least 6.5% to the date of first physician visit with an HbA1c test, and from the date of the first physician visit to the date of prescription of first-line and second-line T2DM treatments. The time to first prescription of antidiabetic treatment for the two groups was then compared.

Results: Of 4798 eligible patients, 54.8% were prescribed first-line T2DM therapy less than 2 months from the first physician visit for T2DM diagnosis. A lower percentage of the early group compared with the delayed group required T2DM pharmacological therapy in less than 2 months (46.1% vs. 63.4%). The early group had a longer median time to prescription of first-line therapy [92 days vs. 15 days, p < 0.0001; hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.24, 1.39] and second-line therapy (1599 days vs. 1315 days, p < 0.0001; HR 1.22, 95% CI 1.11, 1.34) compared with the delayed group.

Conclusion: In Japanese patients with T2DM, early physician visit after abnormal HbA1c detection at routine annual check is associated with a longer period before T2DM medication requirement, and may improve disease course.
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http://dx.doi.org/10.1007/s13300-021-01090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266984PMC
July 2021

Inceptor intercepts insulin signaling in pancreatic β-cells.

Authors:
Hirotaka Watada

J Diabetes Investig 2021 Sep 4;12(9):1540-1541. Epub 2021 Jul 4.

Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/jdi.13596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409865PMC
September 2021

ALDH2 rs671 Is Associated With Elevated FPG, Reduced Glucose Clearance and Hepatic Insulin Resistance in Japanese Men.

J Clin Endocrinol Metab 2021 08;106(9):e3573-e3581

Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.

Context: A recent meta-analysis of genome-wide association studies data from East Asians identified aldehyde dehydrogenase 2 (ALDH2) rs671 as a susceptibility variant for type 2 diabetes in males.

Objective: To investigate the association between ALDH2 rs671 and metabolic characteristics.

Methods: We studied 94 nonobese, nondiabetic, Japanese men. Using a 2-step hyperinsulinemic-euglycemic clamp, we evaluated insulin sensitivity in muscle and liver. Intrahepatic lipid and fat distribution were measured using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively. We divided participants into a risk-carrying group with ALDH2 rs671 G/G (n = 53) and a nonrisk-carrying group with ALDH2 rs671 G/A or A/A (n = 41).

Results: The risk-carrying group had significantly higher levels of alcohol consumption (18.4 [interquartile range, IQR, 10.4-48.9]) vs 12.1 (IQR, 1.3-29.0) g/day; P = .003), elevated fasting plasma glucose (FPG) (97.5 ± 7.9 vs 93.5 ± 6.2 mg/dL; P = .010), lower hepatic insulin sensitivity (61.7 ± 20.5% vs 73.1 ± 15.9%; P = .003), and lower fasting glucose clearance (0.84 ± 0.8 dL·m-2·min-1 vs 0.87 ± 0.09 dL·m-2·min-1; P = .047) than the nonrisk-carrying group, while insulin resistance in muscle and body fat distribution were similar. The single linear correlation analysis revealed significant correlations between alcohol consumption and hepatic insulin sensitivity (r = -0.262, P = .011), fasting glucose clearance (r = -0.370, P < .001), or FPG (r = 0.489, P < .001). The multiple regression analysis revealed that both ALDH2 rs671 G/G genotype and alcohol consumption were significant independent correlates for hepatic insulin sensitivity, whereas only alcohol consumption was a significant independent correlate for fasting glucose clearance.

Conclusion: Our data suggest that high-alcohol intake-dependent and independent hepatic insulin resistance and reduced fasting glucose clearance due to high alcohol intake could be a relatively upstream metabolic abnormality in ALDH2 rs671 G/G carriers.
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http://dx.doi.org/10.1210/clinem/dgab324DOI Listing
August 2021

Associations of continuous glucose monitoring-assessed glucose variability with intima-media thickness and ultrasonic tissue characteristics of the carotid arteries: a cross-sectional analysis in patients with type 2 diabetes.

Cardiovasc Diabetol 2021 05 4;20(1):95. Epub 2021 May 4.

Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Background: The association between glucose variability and the progression of atherosclerosis is not completely understood. We aimed to evaluate the associations of glucose variability with the progression of atherosclerosis in the early stages.

Methods: We conducted a cross-sectional analysis to investigate the associations of glucose variability, assessed by continuous glucose monitoring, with intima-media thickness (IMT) and gray-scale median (GSM) of the carotid arteries, which are different indicators for the progression of atherosclerosis. We used baseline data from a hospital-based multicenter prospective observational cohort study among Japanese patients with type 2 diabetes without a history of cardiovascular diseases aged between 30 and 80 years. Continuous glucose monitoring was performed by Freestyle Libre Pro, and glucose levels obtained every 15 min for a maximum of eight days were used to calculate the metrics of glucose variability. IMT and GSM were evaluated by ultrasonography, and the former indicates thickening of intima-media complex in the carotid artery wall, while the latter indicates tissue characteristics.

Results: Among 600 study participants (age: 64.9 ± 9.2 (mean ± SD) years; 63.2%: men; HbA1c: 7.0 ± 0.8%), participants with a larger intra- and inter-day glucose variability had a lower GSM and most of these associations were statistically significant. No trend based on glucose variability was shown regarding IMT. Standard deviation of glucose (regression coefficient, β = - 5.822; 95% CI - 8.875 to - 2.768, P < 0.001), glucose coefficient of variation (β = - 0.418; - 0.685 to - 0.151, P = 0.002), mean amplitude of glycemic excursion (β = - 1.689; - 2.567 to - 0.811, P < 0.001), mean of daily differences (β = - 6.500; - 9.758 to - 3.241, P < 0.001), and interquartile range (β = - 4.289; - 6.964 to - 1.614, P = 0.002) had a statistically significant association with mean-GSM after adjustment for conventional cardiovascular risk factors, including HbA1c. No metrics of glucose variability had a statistically significant association with IMT.

Conclusions: Continuous glucose monitoring-assessed glucose variability was associated with the tissue characteristics of the carotid artery wall in type 2 diabetes patients without cardiovascular diseases.
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http://dx.doi.org/10.1186/s12933-021-01288-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097791PMC
May 2021

Inappropriate intensification of glucose-lowering treatment in older patients with type 2 diabetes: the global DISCOVER study.

BMJ Open Diabetes Res Care 2021 05;9(1)

Institute for Biometrics and Epidemiology, German Diabetes Center Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Dusseldorf, Germany.

Introduction: Although individualized target glycated hemoglobin (HbA) levels are recommended in older people with type 2 diabetes, studies report high levels of potential overtreatment. We aimed to investigate the proportion of older patients (aged ≥65 years) who potentially received an inappropriately intensive treatment (HbA level <7.0% (53.0 mmol/mol)) in a global study. Factors associated with intensive glycemic management and using glucose-lowering medications associated with a high risk of hypoglycemia (high-risk medications (insulin, sulfonylureas, and meglitinides)) were also assessed.

Research Design And Methods: DISCOVER is a 3-year observational study program of 15 992 people with type 2 diabetes initiating second-line glucose-lowering therapy in 38 countries. Data were collected at baseline (initiation of second-line therapy) and at 6, 12, and 24 months. Factors associated with an inappropriately intensive treatment or using high-risk medications were assessed using a hierarchical regression model.

Results: Of the 3344 older patients with baseline HbA data in our analytic cohort, 23.5% received inappropriate treatment intensification. Among those who had follow-up HbA data, 55.2%, 54.2%, and 53.5% were inappropriately tightly controlled at 6, 12, and 24 months, respectively, with higher proportions in high-income than in middle-income countries. The proportion of patients receiving high-risk medications was higher in middle-income countries than in high-income countries. Gross national income (per US$5000 increment) was associated with increased odds of inappropriately intensive treatment but with decreased odds of receiving high-risk medications.

Conclusions: A large proportion of older DISCOVER patients received an inappropriately intensive glucose-lowering treatment across the 2 years of follow-up, with substantial regional variation. The use of high-risk medications in these patients is particularly concerning.
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http://dx.doi.org/10.1136/bmjdrc-2020-001585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098925PMC
May 2021

Associations between continuous glucose monitoring-derived metrics and diabetic retinopathy and albuminuria in patients with type 2 diabetes.

BMJ Open Diabetes Res Care 2021 04;9(1)

Department of Metabolism & Endocrinology, Juntendo University School of Medicine Graduate School of Medicine, Bunkyo-ku, Japan.

Introduction: Preventing the development and progression of diabetic microvascular complications through optimal blood glucose control remains an important challenge. Whether metrics based on continuous glucose monitoring are useful for the management of diabetic microvascular complications is not entirely clear.

Research Design And Methods: This is an exploratory analysis of an ongoing prospective, multicenter, 5-year follow-up observational study. Study participants included 999 outpatients with type 2 diabetes who underwent continuous glucose monitoring at baseline. Associations between continuous glucose monitoring-derived metrics and the severity of diabetic retinopathy or albuminuria were investigated using multivariable proportional odds models.

Results: The overall prevalence of diabetic retinopathy was 22.2%. Multivariate analysis with proportional odds models demonstrated that continuous glucose monitoring-derived metrics related to intraday and interday glucose variability are significantly associated with the severity of diabetic retinopathy, even after adjusting for various possible risk factors. However, significant relationships were not observed after adjusting for hemoglobin A1c (HbA1c) levels. The prevalence of microalbuminuria and macroalbuminuria was 20.3% and 6.7%, respectively. Similarly, multivariate analysis demonstrated that those metrics are significantly associated with the severity of albuminuria. These relationships remained significant even after further adjusting for HbA1c levels.

Conclusions: Continuous glucose monitoring-derived metrics related to intraday and interday glucose variability are significantly associated with the severity of diabetic retinopathy or albuminuria in patients with type 2 diabetes. Thus, evaluating these metrics might possibly be useful for risk assessment of diabetic microvascular complications. UMIN000032325.
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http://dx.doi.org/10.1136/bmjdrc-2020-001923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061826PMC
April 2021

Associations between second-line glucose-lowering combination therapies with metformin and HbA1c, body weight, quality of life, hypoglycaemic events and glucose-lowering treatment intensification: The DISCOVER study.

Diabetes Obes Metab 2021 08 3;23(8):1823-1833. Epub 2021 May 3.

AstraZeneca, Gaithersburg, Maryland, USA.

Aim: To explore the effects of second-line combination therapies with metformin on body weight, HbA1c and health-related quality of life, as well as the risks of hypoglycaemia and further treatment intensification in the DISCOVER study, a 3-year, prospective, global observational study of patients with type 2 diabetes initiating second-line glucose-lowering therapy.

Materials And Methods: Adjusted changes from baseline in weight, HbA1c and 36-item Short Form Health Survey version 2 (SF-36v2) summary scores at 6, 12, 24 and 36 months were assessed using linear mixed models. Risk of hypoglycaemia and further intensification were assessed using interval censored analyses.

Results: At baseline, 7613 patients received metformin in combination with a sulphonylurea (SU; 40.9%), a dipeptidyl peptidase-4 (DPP-4) inhibitor (48.3%), a sodium-glucose co-transporter-2 (SGLT-2) inhibitor (8.3%) or a glucagon-like peptide-1 (GLP-1) receptor agonist (2.4%). After 36 months, all combinations showed similar reductions in HbA1c (0.8%-1.0%), however, metformin plus a DPP-4 inhibitor, an SGLT-2 inhibitor or a GLP-1 receptor agonist was associated with greater weight loss (1.9, 2.9 and 5.0 kg, respectively) than metformin plus an SU (1.3 kg, P < .0001). Proportions of further treatment intensification were similar across combinations (19.9%-26.2%). Patients prescribed metformin plus an SU more often reported one or more hypoglycaemic events (11.9%) than other combinations (3.9%-6.4%, P < .0001). SF-36v2 summary scores were typically lowest among patients prescribed metformin and an SU.

Conclusions: Combinations of metformin with an SU were associated with the lowest weight reduction, highest risk of hypoglycaemia and lower SF-36v2 scores.
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http://dx.doi.org/10.1111/dom.14400DOI Listing
August 2021

Prevalence and progression of chronic kidney disease among patients with type 2 diabetes: Insights from the DISCOVER study.

Diabetes Obes Metab 2021 08 3;23(8):1956-1960. Epub 2021 May 3.

Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA.

We report the prevalence and change in severity of chronic kidney disease (CKD) in DISCOVER, a global, 3-year, prospective, observational study of patients with type 2 diabetes (T2D) initiating second-line glucose-lowering therapy. CKD stages were defined according to estimated glomerular filtration rate (eGFR). Overall, 7843 patients from 35 countries had a baseline serum creatinine measurement. Of these (56.7% male; mean age: 58.1 years; mean eGFR: 87.5 mL/min/1.73 m ), baseline prevalence estimates for stage 0-1, 2, 3 and 4-5 CKD were 51.4%, 37.7%, 9.4% and 1.4%, respectively. A total of 5819 patients (74.2%) also had at least one follow-up serum creatinine measurement (median time between measurements: 2.9 years, interquartile range: 1.9-3.0 years). Mean eGFR decreased slightly to 85.7 mL/min/1.73 m over follow-up. CKD progression (increase of ≥1 stage) occurred in 15.7% of patients, and regression (decrease of ≥1 stage) in 12.0%. In summary, a substantial proportion of patients with T2D developed CKD or had CKD progression after the initiation of second-line therapy. Renal function should be regularly monitored in these patients, to ensure early CKD diagnosis and treatment.
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http://dx.doi.org/10.1111/dom.14401DOI Listing
August 2021

GH-induced LH hyporesponsiveness as a potential mechanism for hypogonadism in male patients with acromegaly.

Endocr J 2021 Aug 9;68(8):953-968. Epub 2021 Apr 9.

Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo 105-8470, Japan.

Male patients with acromegaly frequently have hypogonadism. However, whether excess GH affects gonadal function remains unclear. We retrospectively compared clinical features affecting total testosterone (TT) and free testosterone (FT) levels between 112 male patients with acromegaly and 100 male patients with non-functioning pituitary adenoma (NFPA) without hyperprolactinemia. Median maximum tumor diameter (14.4 vs. 26.5 mm) and suprasellar extension rate (33 vs. 100%) were lower in acromegaly, but LH, FSH, TT, and FT were not significantly different. In acromegaly, TT was less than 300 ng/dL in 57%, and FT was below the age-specific reference range in 77%. TT and FT were negatively correlated with GH, IGF-1, and the tumor size, and positively correlated with LH. In NFPA, they were positively correlated with IGF-1, LH, FSH, ACTH, cortisol, and free T4, reflecting hypopituitarism. Multiple regression analysis showed that TT and FT had the strongest correlation with GH in acromegaly, and with LH in NFPA. Surgical remission was achieved in 87.5% of 56 follow-up patients with acromegaly. TT and FT increased in 80.4 and 87.5%, respectively, with a significant increase in LH. In acromegaly, the degree of postoperative increase in TT(FT) correlated with the fold increase of TT(FT)/LH ratio, a potential parameter of LH responsiveness, but not with fold increase of LH, whereas in NFPA it correlated with both. These results suggest that excessive GH is the most relevant factor for hypogonadism in male acromegaly, and may cause impaired LH responsiveness as well as the suppression of LH secretion.
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http://dx.doi.org/10.1507/endocrj.EJ20-0596DOI Listing
August 2021

Olfactory dysfunction predicts the development of dementia in older patients with type 2 diabetes.

Diabetes Res Clin Pract 2021 Apr 9;174:108740. Epub 2021 Mar 9.

Department of Metabolism & Endocrinology, 2-1-1 Hongo, Bunkyoku, Tokyo 113-8421, Japan; Center for Therapeutic Innovations in Diabetes, 2-1-1 Hongo, Bunkyoku, Tokyo 113-8421, Japan; Center for Molecular Diabetology, 2-1-1 Hongo, Bunkyoku, Tokyo 113-8421, Japan; Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyoku, Tokyo 113-8421, Japan.

Aims: Olfactory dysfunction is associated with the transition from normal cognition to dementia in persons without type 2 diabetes. This study aimed to investigate whether olfactory dysfunction could be an early marker of future dementia in older patients with type 2 diabetes.

Methods: This exploratory study included 151 older Japanese outpatients with type 2 diabetes who did not have a diagnosis of probable dementia at baseline. A multivariate logistic regression model was used to determine whether Open Essence (OE) test score at baseline is associated with the development of probable dementia.

Results: Over 3 years, approximately 9% of the study subjects developed probable dementia. Subjects with olfactory dysfunction at baseline developed probable dementia more frequently than those without. Multivariate logistic regression showed that lower OE test score, higher age, lower Mini-Mental State Examination (MMSE) score, higher total protein concentration, and more frequent use of a sulfonylurea are significantly associated with the development of probable dementia. Stepwise multivariate regression analysis demonstrated that change in OE test score over 3 years is significantly associated with change in MMSE score.

Conclusions: Our study suggested that olfactory dysfunction precedes the development of probable dementia in older patients with type 2 diabetes.
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http://dx.doi.org/10.1016/j.diabres.2021.108740DOI Listing
April 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Ex vivo conditioning of peripheral blood mononuclear cells of diabetic patients promotes vasculogenic wound healing.

Stem Cells Transl Med 2021 Jun 18;10(6):895-909. Epub 2021 Feb 18.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

The quality and quantity of endothelial progenitor cells (EPCs) are impaired in patients with diabetes mellitus patients, leading to reduced tissue repair during autologous EPC therapy. This study aimed to address the limitations of the previously described serum-free Quantity and Quality Control Culture System (QQc) using CD34+ cells by investigating the therapeutic potential of a novel mononuclear cell (MNC)-QQ. MNCs were isolated from 50 mL of peripheral blood of patients with diabetes mellitus and healthy volunteers (n = 13 each) and subjected to QQc for 7 days in serum-free expansion media with VEGF, Flt-3 ligand, TPO, IL-6, and SCF. The vascular regeneration capability of MNC-QQ cells pre- or post-QQc was evaluated with an EPC colony-forming assay, FACS, EPC culture, tube formation assay, and quantitative real time PCR. For in vivo assessment, 1 × 10 pre- and post-MNC-QQc cells from diabetic donors were injected into a murine wound-healing model using Balb/c nude mice. The percentage of wound closure and angio-vasculogenesis was then assessed. This study revealed vasculogenic, anti-inflammatory, and wound-healing effects of MNC-QQ therapy in both in vitro and in vivo models. This system addresses the low efficiency and efficacy of the current naïve MNC therapy for wound-healing in diabetic patients. As this technique requires a simple blood draw, isolation, and peripheral blood MNC suspension culture for only a week, it can be used as a simple and effective outpatient-based vascular and regenerative therapy for patients with diabetes mellitus.
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http://dx.doi.org/10.1002/sctm.20-0309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133343PMC
June 2021

Efficacy and safety of the fixed-ratio combination of insulin degludec and liraglutide by baseline glycated hemoglobin, body mass index and age in Japanese individuals with type 2 diabetes: A subgroup analysis of two phase III trials.

J Diabetes Investig 2021 Sep 24;12(9):1610-1618. Epub 2021 Mar 24.

Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan.

Aims/introduction: To assess efficacy and safety of insulin degludec/liraglutide (IDegLira) in Japanese participants with type 2 diabetes across different baseline characteristics.

Materials And Methods: Data from two randomized controlled trials were used: DUAL I Japan (n = 819 insulin-naïve participants) and DUAL II Japan (n = 210 insulin-experienced participants). Outcomes were assessed according to baseline glycated hemoglobin ( HbA ; <8.0%, ≥8.0-<9.0%, ≥9.0%), body mass index (<25, ≥25-<30, ≥30 kg/m ) and age (<65, ≥65 years).

Results: In DUAL I Japan, reductions in HbA with IDegLira versus degludec and liraglutide were observed across all subgroups (treatment differences: -0.48% to -0.72% vs degludec, -0.29% to -0.73% vs liraglutide). Results were similar with IDegLira versus degludec in DUAL II Japan (treatment differences: -0.82% to -1.61%). Treatment-by-subgroup interactions were significant for IDegLira versus liraglutide for baseline HbA and age in DUAL I Japan, and for IDegLira versus degludec for baseline HbA in DUAL II Japan. In DUAL I Japan, IDegLira was associated with less weight gain than degludec in most subgroups. In DUAL II Japan, IDegLira was associated with a small mean weight loss (except for baseline HbA ≥9.0%) versus a small gain for degludec (except for age ≥65 years subgroup); treatment-by-subgroup interactions were not significant. Total daily insulin dose was lower with IDegLira versus degludec across all categories, except for age >65 years in DUAL II Japan.

Conclusions: IDegLira reduced HbA in Japanese participants with type 2 diabetes across baseline HbA , body mass index and age categories, without unexpected safety issues.
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http://dx.doi.org/10.1111/jdi.13525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409843PMC
September 2021

Type 2 diabetes and heart failure: insights from the global DISCOVER study.

ESC Heart Fail 2021 04 11;8(2):1711-1716. Epub 2021 Feb 11.

Saint Luke's Mid America Heart Institute, 4401 Wornall Rd, Kansas City, MO, 64111, USA.

Aims: Heart failure (HF) is increasingly recognized as a major cause of morbidity and mortality in patients with type 2 diabetes (T2D), but the global epidemiology and treatment of HF in T2D are not well defined. This study aimed to examine the global prevalence of HF and the incidence of HF over 3 years of follow-up in patients with T2D [by presence and absence of co-existing coronary artery disease (CAD)].

Methods And Results: DISCOVER was a 3 year, prospective, observational study of T2D patients enrolled at initiation of second-line glucose-lowering therapy. Among 14 057 patients with T2D from 36 countries, 289 (2.1%) had a diagnosis of HF at enrolment; median prevalence across countries was 2.0% (inter-quartile range 1.0-3.1%). Patients with HF at baseline were more likely to be older [HF vs. no HF: 67 ± 12 vs. 57 ± 12 years, standardized difference (StDiff) = 84%] and have longer duration of T2D (8.1 ± 7.2 vs. 5.6 ± 5.2 years, StDiff = 40%), CAD (44% vs. 6%, StDiff = 97%), atrial fibrillation (21% vs. 1%, StDiff = 66%), and kidney disease (23% vs. 4%, StDiff = 55%). Patients with HF were less likely to be on metformin (66% vs. 79%, StDiff = 28%) and thiazolidinediones (5.5% vs. 10.6%, StDiff = 19%) but had similar use of other glucose-lowering medications. Among 9313 patients with follow-up data, there were 70 incident cases of HF, which translates to an incidence of 2.6 cases per 1000 person years. Of these incident HF cases, 60% occurred in the absence of pre-existing or concomitant CAD, and 73% were diagnosed in the outpatient setting.

Conclusions: In a large, global cohort of patients with T2D, the majority of incident cases of HF occurred in outpatients and in the absence of known CAD. These findings highlight the need for greater awareness of HF risk in patients with T2D.
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http://dx.doi.org/10.1002/ehf2.13235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006680PMC
April 2021
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