Publications by authors named "Koutaro Yokote"

293 Publications

Background characteristics and diabetes remission after laparoscopic sleeve gastrectomy in Japanese patients with type 2 diabetes stratified by BMI: subgroup analysis of J-SMART.

Diabetol Int 2021 Jul 2;12(3):303-312. Epub 2021 Jan 2.

Center of Diabetes, Endocrine and Metabolism, Toho University Sakura Medical Center, 564-1, Shimoshizu, Sakura-City, Chiba 285-8741 Japan.

Aim: The J-SMART study was the first national survey of Japanese patients undergoing laparoscopic sleeve gastrectomy (LSG). We performed a subgroup analysis of J-SMART focusing on the differences in patient background and diabetes remission between patients with BMI 32-34.9 kg/m and those with higher BMI.

Methods: In this multi-institutional retrospective study at 10 certified bariatric institutions, 203 Japanese with type 2 diabetes (T2D) and BMI of 32 kg/m or higher were analyzed (mean age: 49.2 years, BMI: 43.8 kg/m, HbA1c: 7.6%). Patients were stratified into five groups according to preoperative BMI.

Results: Background characteristics in BMI 32.0-34.9 group were higher adjusted HbA1c, higher visceral/subcutaneous fat area ratio, higher prevalence of diabetic retinopathy, higher frequency of insulin use and lower serum C-peptide. Although 2-year percent total weight loss (21.7%) and diabetes complete remission (CR) rate (52.4%) were lower in BMI 32.0-34.9 group, diabetes improvement rate was 81.0%, and the decrease in HbA1c and number of antidiabetic drugs were comparable or greater than those with higher BMI. Higher BMI and no insulin use were significant independent predictors of diabetes CR. No significant independent predictor was identified for diabetes improvement.

Conclusion: The patients with 32-34.9 kg/m were characterized by more severe visceral obesity, T2D and the complications, and lower intrinsic insulin secretion capacity. LSG should be considered as a treatment option for patients with BMI 32-34.9 kg/m, to improve diabetes control.
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http://dx.doi.org/10.1007/s13340-020-00487-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172703PMC
July 2021

Serum anti-DIDO1, anti-CPSF2, and anti-FOXJ2 antibodies as predictive risk markers for acute ischemic stroke.

BMC Med 2021 Jun 9;19(1):131. Epub 2021 Jun 9.

Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.

Background: Acute ischemic stroke (AIS) is a serious cause of mortality and disability. AIS is a serious cause of mortality and disability. Early diagnosis of atherosclerosis, which is the major cause of AIS, allows therapeutic intervention before the onset, leading to prevention of AIS.

Methods: Serological identification by cDNA expression cDNA libraries and the protein array method were used for the screening of antigens recognized by serum IgG antibodies in patients with atherosclerosis. Recombinant proteins or synthetic peptides derived from candidate antigens were used as antigens to compare serum IgG levels between healthy donors (HDs) and patients with atherosclerosis-related disease using the amplified luminescent proximity homogeneous assay-linked immunosorbent assay.

Results: The first screening using the protein array method identified death-inducer obliterator 1 (DIDO1), forkhead box J2 (FOXJ2), and cleavage and polyadenylation specificity factor (CPSF2) as the target antigens of serum IgG antibodies in patients with AIS. Then, we prepared various antigens including glutathione S-transferase-fused DIDO1 protein as well as peptides of the amino acids 297-311 of DIDO1, 426-440 of FOXJ2, and 607-621 of CPSF2 to examine serum antibody levels. Compared with HDs, a significant increase in antibody levels of the DIDO1 protein and peptide in patients with AIS, transient ischemic attack (TIA), and chronic kidney disease (CKD) but not in those with acute myocardial infarction and diabetes mellitus (DM). Serum anti-FOXJ2 antibody levels were elevated in most patients with atherosclerosis-related diseases, whereas serum anti-CPSF2 antibody levels were associated with AIS, TIA, and DM. Receiver operating characteristic curves showed that serum DIDO1 antibody levels were highly associated with CKD, and correlation analysis revealed that serum anti-FOXJ2 antibody levels were associated with hypertension. A prospective case-control study on ischemic stroke verified that the serum antibody levels of the DIDO1 protein and DIDO1, FOXJ2, and CPSF2 peptides showed significantly higher odds ratios with a risk of AIS in patients with the highest quartile than in those with the lowest quartile, indicating that these antibody markers are useful as risk factors for AIS.

Conclusions: Serum antibody levels of DIDO1, FOXJ2, and CPSF2 are useful in predicting the onset of atherosclerosis-related AIS caused by kidney failure, hypertension, and DM, respectively.
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http://dx.doi.org/10.1186/s12916-021-02001-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188684PMC
June 2021

Generation of disease-specific and CRISPR/Cas9-mediated gene-corrected iPS cells from a patient with adult progeria Werner syndrome.

Stem Cell Res 2021 May 23;53:102360. Epub 2021 Apr 23.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan; Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba, Japan. Electronic address:

Adult progeria Werner syndrome (WS), a rare autosomal recessive disorder, is characterized by accelerated aging symptoms after puberty. The causative gene, WRN, is a member of the RecQ DNA helicase family and is predominantly involved in DNA replication, repair, and telomere maintenance. Here, we report the generation of iPS cells from a patient with WS and correction of the WRN gene by the CRISPR/Cas9-mediated method. These iPSC lines would be a valuable resource for deciphering the pathogenesis of WS.
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http://dx.doi.org/10.1016/j.scr.2021.102360DOI Listing
May 2021

Association between glycemic control and cardiovascular events in older Japanese adults with diabetes mellitus: An analysis of the Japanese medical administrative database.

J Diabetes Investig 2021 May 14. Epub 2021 May 14.

Data Science Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.

Aims/introduction: The relationship between glycated hemoglobin (HbA1c) and cardiovascular events in older adults was investigated using a Japanese administrative medical database.

Materials And Methods: Anonymized medical data on patients with diabetes mellitus aged ≥65 years for the period from January 2010 to December 2019 were extracted from the EBM Provider database. The primary end-point was a composite of cardiovascular events, whereas the other end-points included severe hypoglycemia and fracture. The association between cardiovascular events and HbA1c at the index date (i.e., approximately 10 months after initial diabetes mellitus diagnosis) was evaluated using the Cox proportional hazards model.

Results: Among the 3,186,751 patients in the database, 3,946 older adults with diabetes mellitus were eligible for inclusion and were subsequently grouped according to HbA1c quartiles at the index date. Cardiovascular events occurred in 142 patients. Patients with HbA1c in the highest quartile had significantly higher risk of hospitalization for cardiovascular disease than those with HbA1c in the lowest quartile (hazard ratio 1.948; 95% confidence interval 1.252-3.031, P = 0.003). However, the events risk was similar across subgroups with HbA1c <7.2%. The incidence of hypoglycemia and fracture was not significantly associated with the level of glycemic control.

Conclusions: Among older adults with diabetes mellitus, those with poor glycemic control were at higher risk for cardiovascular events compared with those with better glycemic control. However, strict glycemic control had no effect on cardiovascular risk in patients with HbA1c <7.2%.
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http://dx.doi.org/10.1111/jdi.13575DOI Listing
May 2021

Favorable Effects of 24-Week Whole-Body Vibration on Glycemic Control and Comprehensive Diabetes Therapy in Elderly Patients with Type 2 Diabetes.

Diabetes Ther 2021 Jun 12;12(6):1751-1761. Epub 2021 May 12.

Tokuyama Clinic, Chiba, Japan.

Background: Elderly patients with type 2 diabetes (T2DM) are vulnerable to treatment-inducible hypoglycemia, falls, and depressive symptoms. Although it is challenging for elderly patients to adhere to regular exercise, its positive effect on functional ability, glycemic control, and mental wellness offers comprehensive diabetes treatment. In the present study, we aimed to investigate a novel exercise approach for the elderly, focusing on whole-body vibration (WBV).

Methods: This retrospective cohort study was conducted in a primary-care setting at a medical fitness center affiliated with the incorporated medical institution of THY (TOTAL HEALTH YARD). Fourteen (WBV group) and 12 (control group) elderly patients with T2DM undergoing and not undergoing our WBV program, respectively, for > 6 months were analyzed. Primary endpoints were the functional ability changes, evaluated by Timed Up and Go (TUG), Sit-to-Stand test (SST), gait length, and grip test. Secondary endpoints were global glycemic control and questionnaires, namely the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and Geriatric Depression Scale (GDS). All records of exercise adherence and any adverse events were followed.

Results: Significant improvements in TUG and SST were found only in the WBV group [TUG: 7.1 ± 0.9, 7.1 ± 0.8 to 7.0 ± 1.0, 6.6 ± 0.9 (s), P = 0.63, 0.01; SST: 10.4 ± 1.9, 11.3 ± 2.4 to 9.7 ± 2.3, 9.5 ± 2.1 (s), P = 0.62, P < 0.01, control vs. WBV group, respectively]. The WBV group demonstrated significant improvement of hemoglobin A1C levels (7.2 ± 0.8 to 6.9 ± 0.5, P < 0.01) and DTSQ and GDS scores, while the control group did not. There were no hypoglycemic events during the study. The WBV program adherence was 93.3 ± 8.0%.

Conclusion: We demonstrated the favorable effect of WBV training on balance, diabetes treatment, and mood. Therefore, WBV training can be proposed as comprehensive therapy in a safe manner and potentially has a positive effect on health-related quality of life in elderly patients with T2DM.
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http://dx.doi.org/10.1007/s13300-021-01068-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179879PMC
June 2021

Characteristics of benign adrenocortical adenomas with 18F-FDG PET accumulation.

Eur J Endocrinol 2021 Jun 5;185(1):155-165. Epub 2021 Jun 5.

Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Introduction: Although 18F-FDG PET was originally developed to evaluate benign and malignant tumors, the frequency of detection of benign adrenocortical adenomas showing FDG-PET accumulation has increased. However, the details of FDG-PET-accumulated benign adrenocortical adenomas have not been elucidated.

Methods: To elucidate the pathophysiology of FDG-PET-positive cortisol-producing adrenal tumors, we performed clinicopathological and genetic analyses of adrenocortical adenomas examing FDG-PET in 30 operated patients with unilateral cortisol-producing adrenal tumors (26 adrenal adenomas and 4 adrenal cancers).

Results: All adrenocortical carcinomas and 17/26 (65%) benign adrenocortical adenomas showed high FDG accumulation (SUVmax ≥ 3). In adrenocortical adenomas with high FDG accumulation (SUVmax ≥ 3), SUVmax showed a positive correlation with the CT Hounsfield units. A higher SUVmax showed a clear black adenoma appearance with predominantly compact cells, which exhibited high T1 and T2 signals, a lack of signal drop on out-of-phase imaging on MRI, and less accumulation on 131-I adsterol scintigraphy. Furthermore, RNA-sequencing analysis revealed significant increases in the lysosomal and autophagy pathways and metabolic pathways, including glycolysis through glucose transporter (GLUT) 1 and 3, in black adenomas with high-level FDG accumulation.

Discussion: A black adenoma is blackish due to lipofuscin, which accumulates as a result of damaged mitochondria or proteins that escape lysosomal degradation or autophagy. Since FDG in PET is taken up via GLUTs, alteration of the intracellular metabolic dynamics associated with mitochondrial damage in black adenomas may increase PET accumulation.

Conclusion: Black adrenal adenomas should be considered with adrenal tumors showing PET accumulation and low lipid contents.
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http://dx.doi.org/10.1530/EJE-20-1459DOI Listing
June 2021

Effect of empagliflozin on cardiorenal outcomes and mortality according to body mass index: A subgroup analysis of the EMPA-REG OUTCOME trial with a focus on Asia.

Diabetes Obes Metab 2021 May 5. Epub 2021 May 5.

Boehringer Ingelheim Norway KS, Asker, Norway.

Aim: To investigate whether the cardiorenal benefits of the sodium-glucose co-transporter-2 inhibitor empagliflozin are affected by body mass index (BMI) in type 2 diabetes patients with established cardiovascular (CV) disease, including Asians.

Methods: In this exploratory analysis of the EMPA-REG OUTCOME trial, we used Cox regression to evaluate the effects of empagliflozin on all-cause mortality, hospitalization for heart failure (HHF) or CV death, and incident or worsening nephropathy by baseline BMI category.

Results: Of the 7020 participants (1517 Asians [21.6%]), 934 (13.3%), 2465 (35.1%) and 3621 (51.6%) had a BMI of less than 25, 25 to less than 30, and 30 kg/m or higher, respectively. Overall, hazard ratios for empagliflozin versus placebo for all-cause mortality, HHF or CV death, and incident or worsening nephropathy were 0.68 (95% CI 0.57, 0.82), 0.66 (0.55, 0.79) and 0.61 (0.53, 0.70), respectively, and were consistent across BMI categories (P values for interaction between treatment and BMI were .6772, .3087 and .6265, respectively). Results were similar in Asians using these BMI categories and categories of less than 24, 24 to less than 28, and 28 kg/m or higher.

Conclusion: Empagliflozin reduced cardiorenal and mortality risk regardless of BMI at baseline, including in Asians with a lower BMI.
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http://dx.doi.org/10.1111/dom.14415DOI Listing
May 2021

Effects of pemafibrate on glucose metabolism markers and liver function tests in patients with hypertriglyceridemia: a pooled analysis of six phase 2 and phase 3 randomized double-blind placebo-controlled clinical trials.

Cardiovasc Diabetol 2021 05 4;20(1):96. Epub 2021 May 4.

Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan.

Background: Increased risk of cardiovascular events is associated not only with dyslipidemias, but also with abnormalities in glucose metabolism and liver function. This study uses pooled analysis to explore the in-depth effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) already known to decrease elevated triglycerides, on glucose metabolism and liver function in patients with hypertriglyceridemia.

Methods: We performed a post-hoc analysis of six phase 2 and phase 3 Japanese randomized double-blind placebo-controlled trials that examined the effects of daily pemafibrate 0.1 mg, 0.2 mg, and 0.4 mg on glucose metabolism markers and liver function tests (LFTs). Primary endpoints were changes in glucose metabolism markers and LFTs from baseline after 12 weeks of pemafibrate treatment. All adverse events and adverse drug reactions were recorded as safety endpoints.

Results: The study population was 1253 patients randomized to placebo (n = 298) or pemafibrate 0.1 mg/day (n = 127), 0.2 mg/day (n = 584), or 0.4 mg/day (n = 244). Participant mean age was 54.3 years, 65.4 % had BMI ≥ 25 kg/m, 35.8 % had type 2 diabetes, and 42.6 % had fatty liver. Fasting glucose, fasting insulin, and HOMA-IR decreased significantly in all pemafibrate groups compared to placebo. The greatest decrease was for pemafibrate 0.4 mg/day: least square (LS) mean change from baseline in fasting glucose - 0.25 mmol/L; fasting insulin - 3.31 µU/mL; HOMA-IR - 1.28. ALT, γ-GT, ALP, and total bilirubin decreased significantly at all pemafibrate doses vs. placebo, with the greatest decrease in the pemafibrate 0.4 mg/day group: LS mean change from baseline in ALT - 7.6 U/L; γ-GT - 37.3 U/L; ALP - 84.7 U/L; and total bilirubin - 2.27 µmol/L. Changes in HbA1c and AST did not differ significantly from placebo in any pemafibrate groups in the overall study population. The decreases from baseline in LFTs and glucose metabolism markers except for HbA1c were notable among patients with higher baseline values. FGF21 increased significantly in all pemafibrate groups compared to placebo, with the greatest increase in the pemafibrate 0.4 mg/day group. Adverse event rates were similar in all groups including placebo.

Conclusions: In patients with hypertriglyceridemia, pemafibrate can improve glucose metabolism and liver function, and increase FGF21, without increasing adverse event risk.
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http://dx.doi.org/10.1186/s12933-021-01291-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097867PMC
May 2021

Central administration of sodium-glucose cotransporter-2 inhibitors increases food intake involving adenosine monophosphate-activated protein kinase phosphorylation in the lateral hypothalamus in healthy rats.

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

Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

Introduction: Sodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake.

Research Design And Methods: We administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Intraperitoneal administration of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin.

Results: Bolus ICV injection of tofogliflozin induced a robust increase in food intake starting at 1.5 hours postinjection, and lasting for 5 days. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. ICV dapagliflozin and empagliflozin significantly enhanced food intake, although the strength of these effects varied among drugs. Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. ICV tofogliflozin increased phosphorylation of AMPK and c-fos expression in the lateral hypothalamus.

Conclusions: SGLT2 inhibitors in the CNS increase food intake. SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area.
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http://dx.doi.org/10.1136/bmjdrc-2020-002104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061802PMC
April 2021

Current Status of Familial LCAT Deficiency in Japan.

J Atheroscler Thromb 2021 Apr 18. Epub 2021 Apr 18.

Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute.

Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of the acyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM 136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) and corneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia, proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal opacity. A clinical research project aiming at gene/cell therapy is currently underway.
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http://dx.doi.org/10.5551/jat.RV17051DOI Listing
April 2021

Fibroblasts from different body parts exhibit distinct phenotypes in adult progeria Werner syndrome.

Aging (Albany NY) 2021 02 24;13(4):4946-4961. Epub 2021 Feb 24.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chuo-Ku, Chiba 260-8670, Japan.

Werner syndrome (WS), also known as adult progeria, is characterized by accelerated aging symptoms from a young age. Patients with WS experience painful intractable skin ulcers with calcifications in their extremities, subcutaneous lipoatrophy, and sarcopenia. However, there is no significant abnormality in the trunk skin, where the subcutaneous fat relatively accumulates. The cause of such differences between the limbs and trunk is unknown. To investigate the underlying mechanism behind these phenomena, we established and analyzed dermal fibroblasts from the foot and trunk of two WS patients. As a result, WS foot-derived fibroblasts showed decreased proliferative potential compared to that from the trunk, which correlated with the telomere shortening. Transcriptome analysis showed increased expression of genes involved in osteogenesis in the foot fibroblasts, while adipogenic and chondrogenic genes were downregulated in comparison with the trunk. Consistent with these findings, the adipogenic and chondrogenic differentiation capacity was significantly decreased in the foot fibroblasts . On the other hand, the osteogenic potential was mutually maintained and comparable in the foot and trunk fibroblasts. These distinct phenotypes in the foot and trunk fibroblasts are consistent with the clinical symptoms of WS and may partially explain the underlying mechanism of this disease phenotype.
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http://dx.doi.org/10.18632/aging.202696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950285PMC
February 2021

A novel podocyte protein, R3h domain containing-like, inhibits TGF-β-induced p38 MAPK and regulates the structure of podocytes and glomerular basement membrane.

J Mol Med (Berl) 2021 Jun 23;99(6):859-876. Epub 2021 Feb 23.

Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan.

Not only in kidney glomerular physiological function but also glomerular pathology especially in diabetic condition, glomerular podocytes play pivotal roles. Therefore, it is important to increase our knowledge about the genes and proteins expressed in podocytes. Recently, we have identified a novel podocyte-expressed gene, R3h domain containing-like (R3hdml) and analyzed its function in vivo as well as in vitro. Transforming growth factor-β (TGF-β) signaling regulated the expression of R3hdml. And R3hdml inhibited p38 mitogen-activated protein kinase phosphorylation, which was induced by TGF-β, leading to the amelioration of podocyte apoptosis. Furthermore, a lack of R3hdml in mice significantly worsened glomerular function in streptozotocin (STZ)-induced diabetes, while overexpression of R3hdml ameliorated albuminuria in STZ-induced diabetes. Our results surmise that the functional analyses of R3hdml may lead to the development of novel therapeutic strategies for diabetic nephropathy in the future. KEY MESSAGES: • A novel podocyte expressed protein R3h domain containing-like was identified. • R3HDML inhibits podocyte apoptosis by inhibiting TGF-β-mediated p38 MAPK signaling. • Overexpression of R3HDML ameliorates albuminuria in STZ-induced diabetes mice. • R3HDML may prove to be a novel therapeutic strategy for diabetic nephropathy.
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http://dx.doi.org/10.1007/s00109-021-02050-wDOI Listing
June 2021

Once-Weekly Semaglutide in Adults with Overweight or Obesity.

N Engl J Med 2021 03 10;384(11):989. Epub 2021 Feb 10.

From the Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool (J.P.H.W.), University College London Centre for Obesity Research, Division of Medicine, University College London (R.L.B.), the National Institute of Health Research, UCLH Biomedical Research Centre (R.L.B.), the Centre for Weight Management and Metabolic Surgery, University College London Hospital (R.L.B.), and the Department of Diabetes and Endocrinology, Guy's and St. Thomas' NHS Foundation Trust (B.M.M.), London, and the Diabetes Research Centre, University of Leicester (M.D.) and the NIHR Leicester Biomedical Research Centre (M.D.), Leicester - all in the United Kingdom; Novo Nordisk, Søborg, Denmark (S.C., M.T.D.T., N.Z.); the Department of Endocrinology, Diabetology, and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium (L.F.V.G.); the Departments of Internal Medicine/Endocrinology and Population and Data Sciences, University of Texas Southwestern Medical Center (I.L.), and the Dallas Diabetes Research Center at Medical City (J.R.) - both in Dallas; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.A.W.); York University, McMaster University and Wharton Weight Management Clinic, Toronto (S.W.); the Department of Endocrinology, Hematology, and Gerontology, Graduate School of Medicine, Chiba University and Department of Diabetes, Metabolism, and Endocrinology, Chiba University Hospital, Chiba, Japan (K.Y.); and the Division of Endocrinology, Feinberg School of Medicine, Northwestern University, Chicago (R.F.K.).

Background: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

Methods: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

Results: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

Conclusions: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).
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http://dx.doi.org/10.1056/NEJMoa2032183DOI Listing
March 2021

Distinct Differences in Lipoprotein Particle Number Evaluation between GP-HPLC and NMR: Analysis in Dyslipidemic Patients Administered a Selective PPARα Modulator, Pemafibrate.

J Atheroscler Thromb 2021 Feb 2. Epub 2021 Feb 2.

Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University.

Aim: We established a method to evaluate the lipid concentrations, size and particle numbers (PNs) of lipoprotein subclasses by gel permeation chromatography (GP-HPLC). Nuclear magnetic resonance (NMR) is widely used to analyze these parameters of lipoprotein subclasses, but differences of the two methods are unknown. Current study compared the PNs of each lipoprotein subclass measured by GP-HPLC and NMR, and assessed the effect of a selective PPARα modulator, pemafibrate.

Methods: Lipoprotein profiles of 212 patients with dyslipidemia who participated in the phase 2 clinical trial of a selective PPARα modulator, pemafibrate, were analyzed by two methods, GP-HPLC and NMR, which were performed with LipoSEARCH (Skylight Biotech) and LipoProfile 3 (LabCorp), respectively. GP-HPLC evaluated the PNs of 18 subclasses, consisting of CM, VLDL1-5, LDL1-6, and HDL1-6. NMR evaluated the PNs of 9 subclasses, consisting of large VLDL & CM, medium VLDL, small VLDL, IDL, large LDL, small LDL, large HDL, medium HDL and small HDL.

Results: Three major classes, total CM&VLDL, total LDL and total HDL were obtained by grouping of corresponding subclasses in both methods and PNs of these classes analyzed by GP-HPLC were correlated positively with those by NMR. The correlation coefficients in total CM&VLDL, total LDL and total HDL between GP-HPLC and NMR was 0.658, 0.863 and 0.798 (all p<0.0001), respectively. The PNs of total CM&VLDL, total LDL and total HDL analyzed by GP-HPLC was 249.5±51.7nM, 1,679±359 nM and 13,273±1,564 nM, respectively, while those by NMR was 124.6±41.8 nM, 1,514±386 nM and 31,161±4,839 nM, respectively. A marked difference in the PNs between the two methods was demonstrated especially in total HDL.The number of apolipoprotein (Apo) B molecule per one ApoB-containing lipoprotein particle, total CM&VLDL plus total LDL, was 1.10±0.05 by GP-HPLC, while 1.32±0.18 by NMR. The number of ApoA-I per one HDL particle was 3.40±0.17 by GP-HPLC, but only 1.46±0.15 by NMR, much less than reported previously.From the phase 2 clinical trial, randomizing 212 patients to pemafibrate 0.025-0.2 mg BID, fenofibrate 100 mg QD, or placebo groups, pemafibrate reduced the PNs of CM, large VLDL1-VLDL3 and medium VLDL4, but not small VLDL5 by GP-HPLC. It significantly decreased the PNs of smaller LDL and larger HDL particles, but increased those of larger LDL and smaller HDL particles. In contrast, NMR showed marked variations in the effect of pemafibrate on lipoprotein PNs, and no significant size-dependent changes.

Conclusions: GP-HPLC evaluates the lipoprotein PNs more accurately than NMR and can be used for assessing the effects of lipid-lowering drugs on lipoprotein subclasses.
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http://dx.doi.org/10.5551/jat.60764DOI Listing
February 2021

DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes.

Blood Adv 2021 01;5(2):438-450

Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Dihydroorotate dehydrogenase (DHODH) catalyzes a rate-limiting step in de novo pyrimidine nucleotide synthesis. DHODH inhibition has recently been recognized as a potential new approach for treating acute myeloid leukemia (AML) by inducing differentiation. We investigated the efficacy of PTC299, a novel DHODH inhibitor, for myelodysplastic syndrome (MDS). PTC299 inhibited the proliferation of MDS cell lines, and this was rescued by exogenous uridine, which bypasses de novo pyrimidine synthesis. In contrast to AML cells, PTC299 was inefficient at inhibiting growth and inducing the differentiation of MDS cells, but synergized with hypomethylating agents, such as decitabine, to inhibit the growth of MDS cells. This synergistic effect was confirmed in primary MDS samples. As a single agent, PTC299 prolonged the survival of mice in xenograft models using MDS cell lines, and was more potent in combination with decitabine. Mechanistically, a treatment with PTC299 induced intra-S-phase arrest followed by apoptotic cell death. Of interest, PTC299 enhanced the incorporation of decitabine, an analog of cytidine, into DNA by inhibiting pyrimidine production, thereby enhancing the cytotoxic effects of decitabine. RNA-seq data revealed the marked downregulation of MYC target gene sets with PTC299 exposure. Transfection of MDS cell lines with MYC largely attenuated the growth inhibitory effects of PTC299, suggesting MYC as one of the major targets of PTC299. Our results indicate that the DHODH inhibitor PTC299 suppresses the growth of MDS cells and acts in a synergistic manner with decitabine. This combination therapy may be a new therapeutic option for the treatment of MDS.
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http://dx.doi.org/10.1182/bloodadvances.2020001461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839369PMC
January 2021

The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells.

Sci Rep 2021 Jan 22;11(1):2074. Epub 2021 Jan 22.

Department of Hematology, Chiba University Hospital, Chiba, Japan.

The novel small molecule PTC596 inhibits microtubule polymerization and its clinical development has been initiated for some solid cancers. We herein investigated the preclinical efficacy of PTC596 alone and in combination with proteasome inhibitors in the treatment of multiple myeloma (MM). PTC596 inhibited the proliferation of MM cell lines as well as primary MM samples in vitro, and this was confirmed with MM cell lines in vivo. PTC596 synergized with bortezomib or carfilzomib to inhibit the growth of MM cells in vitro. The combination treatment of PTC596 with bortezomib exerted synergistic effects in a xenograft model of human MM cell lines in immunodeficient mice and exhibited acceptable tolerability. Mechanistically, treatment with PTC596 induced cell cycle arrest at G2/M phase followed by apoptotic cell death, associated with the inhibition of microtubule polymerization. RNA sequence analysis also revealed that PTC596 and the combination with bortezomib affected the cell cycle and apoptosis in MM cells. Importantly, endoplasmic reticulum stress induced by bortezomib was enhanced by PTC596, providing an underlying mechanism of action of the combination therapy. Our results indicate that PTC596 alone and in combination with proteasome inhibition are potential novel therapeutic options to improve outcomes in patients with MM.
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http://dx.doi.org/10.1038/s41598-021-81577-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822878PMC
January 2021

Time gap between the onset and diagnosis in Werner syndrome: a nationwide survey and the 2020 registry in Japan.

Aging (Albany NY) 2020 12 29;12(24):24940-24956. Epub 2020 Dec 29.

Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

Patients with Werner syndrome present with diverse signs of aging that begin in adolescence. A Japanese nationwide survey was conducted to establish a registry that could clarify the disease profile of patients with Werner syndrome. The questionnaires were sent to 7888 doctors. The survey identified 116 patients diagnosed with Werner syndrome based on the diagnosis criteria. Forty patients were enrolled in the registry. Data on clinical symptoms, treatment information, and laboratory examination from patients who provided informed consent were collected. The data at enrollment were analyzed. The patients' average age at enrollment was 50.1±7.5 years. The mean onset age was 26.1±9.5 years, but the mean age at diagnosis was 42.5±8.6 years. Average height and weight of the study patients were lower than those of Japanese individuals. Almost all patients experienced hair change and cataracts. More than 60% of patients presented with glycolipid abnormalities. Overall, 15% of patients had a history of foot amputation. Approximately 30% of the patients' parents had a consanguineous marriage. The average grip strength, walking speed, and skeletal muscle mass index met the diagnostic criteria for sarcopenia. The registry revealed that there are opportunities for early diagnosis and intervention; therefore, sensitization about the disease is needed.
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http://dx.doi.org/10.18632/aging.202441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803551PMC
December 2020

Association of urinary free cortisol with bone formation in patients with mild autonomous cortisol secretion.

Clin Endocrinol (Oxf) 2021 Apr 17;94(4):544-550. Epub 2020 Dec 17.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

Context: Mild autonomous cortisol secretion (ACS) is associated with an increased risk of vertebral fractures (VFx). However, the influence of this condition on bone turnover or its association with mild ACS is still controversial.

Objective: This study aimed to evaluate the impact of mild ACS on bone quality among patients living with the disease.

Design And Setting: A retrospective study was conducted using data from 55 mild ACS and 12 nonfunctioning adrenal tumour (NFT) patients who visited Chiba University Hospital, Japan, from 2006 to 2018.

Patients And Main Outcome Measures: We analysed clinical features and bone-related factors, including bone mineral density (BMD) and VFx, performed blood tests to assess bone metabolism markers in patients with mild ACS and NFT, and assessed the associations between bone-related markers and endocrinological parameters in patients with mild ACS.

Results: No significant differences between mild ACS and NFT patients were observed with respect to the presence or absence of VFx and BMD. Urinary free cortisol (UFC) was higher in mild ACS patients with VFx than those without (p = .037). The T-score and young adult mean (YAM) of the BMD of the femoral neck in mild ACS patients with a body mass index <25 were positively correlated with dehydroepiandrosterone sulphate levels (ρ: 0.42, p = .017; ρ: 0.40, p = .024, respectively). Pearson's correlation analysis showed that bone-specific alkaline phosphatase was negatively correlated with UFC in the patients with mild ACS (ρ: -0.37, p = .026).

Conclusions: These results suggest that urinary free cortisol may be useful for predicting bone formation in mild ACS patients.
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http://dx.doi.org/10.1111/cen.14385DOI Listing
April 2021

Sodium-Glucose Cotransporter 2 Inhibitors Improve Chronic Diabetic Macular Edema.

Case Rep Ophthalmol Med 2020 12;2020:8867079. Epub 2020 Nov 12.

Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Purpose: Diabetic macular edema (DME) is a vision-threatening condition that develops in diabetic patients. The first-line therapy for DME is intravitreal injections of antivascular endothelial growth factor (anti-VEGF) agents; however, the high frequency of repeat injections, invasiveness of the procedure, and high cost are drawbacks for this treatment. The purpose of this report is to present our findings in 3 patients with chronic DME whose edema was resolved soon after oral doses of sodium-glucose cotransporter-2 (SGLT2) inhibitors were used. . Case 1 was a 66-year-old woman diagnosed with moderate nonproliferative diabetic retinopathy (DR) with DME that had developed a decade earlier. The DME persisted for 4 years in the left eye. The addition of oral empagliflozin, a SGLT2 inhibitor, led to a marked improvement of the DME after one month, and this improvement continued over two years. Case 2 was a 68-year-old woman who was diagnosed with preproliferative DR with bilateral DME. The addition of oral dapagliflozin led to the improvement of the DME after two months, and this improvement continued over one year. Case 3 was a 61-year-old woman who was diagnosed with moderate nonproliferative DR with DME. Oral luseogliflozin was given which led to better glycemic control, and her left central retinal thickness (CRT) was markedly reduced after only two weeks. This reduction was maintained in her left eye for six months without any additional ophthalmic procedures.

Conclusions: Although this study involved only three cases, our findings indicate that SGLT2 inhibitors might have possible efficacy for chronic DME.
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http://dx.doi.org/10.1155/2020/8867079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683151PMC
November 2020

Management guideline for Werner syndrome 2020 8. Calcification in tendons associated with Werner syndrome.

Geriatr Gerontol Int 2021 Feb 1;21(2):163-165. Epub 2020 Dec 1.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

Aim: To clarify the diagnostic value of the calcification in the Achilles tendon for Werner syndrome.

Methods: Calcification of the Achilles tendon in the plain radiograph was investigated in 92 patients with Werner syndrome provided from the nationwide secondary survey in 2010. And the same investigation was performed for 2151 feet in 1853 patients without Werner syndrome, who underwent foot and ankle surgeries at the department of orthopaedic surgery in Nara Medical University from 2004 to 2015.

Result And Conclusion: Achilles tendon calcification was observed in 70 (76.1%) out of 92 patients with Werner syndrome, whereas that was observed only in 19 feet (0.88%) without Werner syndrome, accompanied by 1 to 4 calcified masses with a maximum diameter ranging from 9.7mm to 63.2mm. The frequency of Achilles tendon calcification in patients with Werner syndrome is far higher than that of patients without Werner syndrome. Achilles tendon calcification could be included in the diagnostic criteria for Werner syndrome. Geriatr Gerontol Int 2021; 21: 163-165.
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http://dx.doi.org/10.1111/ggi.14084DOI Listing
February 2021

Management guideline for Werner syndrome 2020 1. Dyslipidemia and fatty liver associated with Werner syndrome.

Geriatr Gerontol Int 2021 Feb 1;21(2):133-138. Epub 2020 Dec 1.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

For the purpose of examining the characteristics of dyslipidemia and fatty liver in patients with Werner syndrome in Japan in recent years, we searched all case reports of Japanese Werner syndrome reported on Medical Online and PubMed since 1996, and collected and examined the data and clinical features described in these reports. In addition, as there are few descriptions of treatment methods in these reports from Medical Online and PubMed, we analyzed 12 cases for which detailed data on treatment methods are available at Chiba University. Geriatr Gerontol Int 2021; 21: 133-138.
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http://dx.doi.org/10.1111/ggi.14095DOI Listing
February 2021

Steroid metabolites for diagnosing and predicting clinicopathological features in cortisol-producing adrenocortical carcinoma.

BMC Endocr Disord 2020 Nov 23;20(1):173. Epub 2020 Nov 23.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background: Approximately 60% of adrenocortical carcinomas (ACC) are functional, and Cushing's syndrome is the most frequent diagnosis that has been revealed to have a particularly poor prognosis. Since 30% of ACC present steroid hormone-producing disorganization, measurement of steroid metabolites in suspected ACC is recommended. Previous reports demonstrated that steroid hormone precursors or their urine metabolites, which can be assessed using liquid chromatography tandem mass spectrometry (LC-MS/MS) or gas chromatography mass spectrometry (GC-MS) respectively, are useful for distinguishing ACC from cortisol-producing adenomas (CPA); however, despite high precision, LC-MS/MS and GC-MS require a highly trained team, are expensive and have limited capacity.

Methods: Here, we examined 12 serum steroid metabolites using an immunoassay, which is a more rapid and less costly method than LC-MS/MS, in cortisol-producing ACC and CPA. Further, the correlation of each steroid metabolite to the classification stage and pathological status in ACC was analyzed.

Results: Reflecting disorganized steroidogenesis, the immunoassay revealed that all basal levels of steroid precursors were significantly increased in cortisol-producing ACC compared to CPA; in particular, 17-hydroxypregnenolone (glucocorticoid and androgen precursor) and 11-deoxycorticosterone (mineralocorticoid precursor) showed a large area under the ROC curve with high sensitivity and specificity when setting the cut-off at 1.78 ng/ml and 0.4 mg/ml, respectively. Additionally, a combination of androstenedione and DHEAS also showed high specificity with high accuracy. In cortisol-producing ACC, 11-deoxycortisol (glucocorticoid precursor) showed significant positive correlations with predictive prognostic factors used in ENSAT classification, while testosterone showed significant positive correlations to the Ki67-index in both men and women.

Conclusion: Less expensive and more widely available RIA and ECLIA may also biochemically distinguish ACC from CPA and may predict the clinicopathological features of ACC.
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http://dx.doi.org/10.1186/s12902-020-00652-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686776PMC
November 2020

Management guideline for Werner syndrome 2020. 6. Skin ulcers associated with Werner syndrome: Prevention and non-surgical and surgical treatment.

Geriatr Gerontol Int 2021 Feb 22;21(2):153-159. Epub 2020 Nov 22.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

Aim: To provide guidelines on the diagnosis, treatment, and prevention of skin ulcers in Werner syndrome.

Methods: This article was based on literature from 1996, when WRN was identified as a gene responsible for Werner syndrome, and we evaluated several authentic clinical cases of genetically diagnosed patients. There were 63 patients with Werner syndrome in the Japanese reports retrieved from Medical Online between January 1996 and December 2017. There were 56 patients with Werner syndrome in English reports written by Japanese authors and retrieved from PubMed during the same period.

Results: Records on skin ulcers were found in 27 (43%) out of 63 patients and 22 (40%) out of 56 patients from the Japanese and English reports, respectively. The reported ulcers were often located at the distal one-third of the lower legs. There were 8 patients with callosities in the foot in the Japanese reports and 9 patients in the English reports. A skin ulcer in Werner syndrome is generally intractable. Weight-bearing ulcers or callosity should be critically assessed in surgical procedures because they have effects on patient pain and gait. By adopting a recently advanced technique to facilitate wound healing, the cases of ulcers that were difficult to treat and those requiring major operations can be closed with minimally invasive surgery.

Conclusions: Skin ulcers in Werner syndrome are refractory, and they lead to reduced quality of life of patients. A callosity in Werner syndrome is an important therapeutic target for the prevention of ulcers. Geriatr Gerontol Int 2021; 21: 153-159.
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http://dx.doi.org/10.1111/ggi.14096DOI Listing
February 2021

Management guideline for Werner syndrome 2020. 3. Diabetes associated with Werner syndrome.

Geriatr Gerontol Int 2021 Feb 9;21(2):142-145. Epub 2020 Nov 9.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

Aims: To evaluate the characteristics of diabetes associated with Werner syndrome.

Methods: A literature search was done with search term "Werner syndrome" and "Diabetes".

Results And Conclusions: Prevalence of diabetes is extremely high in Werner syndrome. Diabetes associated with Werner syndrome is classified as "accompanied with other diseases and conditions and the one occurring mainly in association with other genetic syndromes." This type of diabetes is marked by accumulated visceral fat and high insulin resistance, despite low body mass index. Thiazolidine derivatives and metformin are effective for glycemic control. New antidiabetic drugs, such as dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, could be potentially beneficial for patients with Werner syndrome. Furthermore, the establishment of diet therapy as well as exercise therapy is warranted. Geriatr Gerontol Int 2021; 21: 142-145.
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http://dx.doi.org/10.1111/ggi.14083DOI Listing
February 2021

Management guideline for Werner syndrome 2020. 2. Sarcopenia associated with Werner syndrome.

Geriatr Gerontol Int 2021 Feb 9;21(2):139-141. Epub 2020 Nov 9.

Department of Endocrinology, Hematolog and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

Aim: Sarcopenia is defined as a condition that combines decreased skeletal muscle mass with weakness or decreased physical function. It is well known that in older adults, the presence of sarcopenia is a risk of frailty, falls and physical dysfunction. Patients with Werner syndrome are characterized by visceral fat accumulation and thin limbs, but the prevalence of sarcopenia in patients with Werner syndrome has not been investigated.

Methods: A literature search was conducted using Werner syndrome and skeletal muscle as keywords. We also analyzed data from our 7 Werner syndrome patients.

Results: A literature search on the relationship between Werner syndrome and skeletal muscle yielded only one article reported from Japan. According to this paper, a decrease in skeletal muscle mass (appendicular skeletal muscle index) was observed in all 9 Werner syndromes investigated. On the other hand, in our 7 Werner syndrome patients, their appendicular skeletal muscle indexes were below the standard value except for one male patient who had continued resistance exercise.

Conclusion: The decrease in skeletal muscle mass frequently occurs in patients with Werner syndrome. However, resistance exercise may prevent the appearance of sarcopenia and requires early intervention in patients with Werner syndrome. Geriatr Gerontol Int 2021; 21: 139-141.
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http://dx.doi.org/10.1111/ggi.14076DOI Listing
February 2021

Management guideline for Werner syndrome 2020. 4. Osteoporosis associated with Werner syndrome.

Geriatr Gerontol Int 2021 Feb 5;21(2):146-149. Epub 2020 Nov 5.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

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http://dx.doi.org/10.1111/ggi.14078DOI Listing
February 2021

Management guideline for Werner syndrome 2020. 7. Skin ulcer associated with Werner syndrome: Dermatological treatment.

Geriatr Gerontol Int 2021 Feb 3;21(2):160-162. Epub 2020 Nov 3.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

Skin ulcers in Werner's syndrome often arise from hyperkeratotic lesions and trauma to pressure points such as the plantar region, and are more difficult to treat than wound healing in healthy individuals. Multiple factors contribute to the intractable skin ulcers in Werner's syndrome, including skin thinning, sclerosis, fatty tissue loss, impaired blood flow, calcification, and excessive pressure due to osteoarticular deformity. Treatment includes topical application of a keratolytic agent for keratosis around the ulcer. Treatment of ulcers is the same as for normal ulcers, and if the ulcer is associated with infection and necrotic tissue, surgical debridement with a scalpel or scissors should be performed as much as possible after washing with saline or mildly warm water or with an antibacterial agent. Topical medications that promote softening and debridement of the necrotic tissue are used with careful control of moisture in the wound. Topical agents that promote granulation should be used in wounds where necrotic tissue has been removed without infection. Dressings to maintain a moist environment in the wound may also be useful. If the wound does not improve with conservative treatment, surgical treatment should be considered. Geriatr Gerontol Int 2021; 21: 160-162.
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http://dx.doi.org/10.1111/ggi.14077DOI Listing
February 2021

Determinants and impact of physical impairment in patient-reported outcomes among older patients with type 2 diabetes mellitus in Japan.

Curr Med Res Opin 2021 Mar 23;37(3):393-402. Epub 2020 Nov 23.

Kita-Harima Medical Center,Ono,Japan.

Objective: To investigate the predictive factors associated with physical impairment among older patients with type 2 diabetes mellitus (T2DM) in Japan and to examine the potential impact of physical impairment on patient-reported health outcomes in this population.

Methods: A cross-sectional analysis was conducted using patient-reported data from the 2012-2014 Japan National Health and Wellness Survey. Physical impairment was measured using the Physical Component Summary (PCS) score of the Short-Form 36-Item Health Survey (SF-36) three-component model (using Japanese norms). Older T2DM patients (≥65 years old;  = 1511) were dichotomized into physically impaired (PCS ≤ 25th percentile;  = 378) and non-physically impaired (PCS > 25th percentile;  = 1133). Work productivity (absenteeism, presenteeism and overall work impairment), activity impairment and healthcare resource utilization were compared between these groups.

Results: Age, female sex, low and high body mass index (BMI), diabetes-related complications, cardiovascular events, unawareness of having hypoglycemic events in the past 3 months, and lack of regular exercise were significant factors associated with physical impairment in multivariable analysis. The physically impaired group reported significantly more regular outpatient visits (13.48 vs. 10.16, respectively,  < .001), 1% or greater absenteeism (16.7% vs. 4.1%,  = .005), greater presenteeism (27.8% vs. 12.2%,  = .001), overall work impairment (30.0% vs. 13.0%,  = .001) and overall activity impairment (39.5% vs. 17.2%,  .001) than the non-physically-impaired group after adjusting for covariates.

Conclusions: This study identified age, BMI, diabetes-related comorbidities, history of cardiovascular events and lack of exercise as key predictors associated with physical impairment in older patients with T2DM in Japan, which predicted low work productivity as well as activity impairment. This study provides support that physical impairment in patients with T2DM may lead to low work productivity and activity impairment.

Supplemental data for this article is available online at https://doi.org/10.1080/03007995.2020.1846170.
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http://dx.doi.org/10.1080/03007995.2020.1846170DOI Listing
March 2021

Management guideline for Werner syndrome 2020. 5. Infection associated with Werner syndrome.

Geriatr Gerontol Int 2021 Feb 1;21(2):150-152. Epub 2020 Nov 1.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

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http://dx.doi.org/10.1111/ggi.14073DOI Listing
February 2021

Preface to Management guideline for Werner syndrome 2020.

Geriatr Gerontol Int 2021 Feb 29;21(2):131-132. Epub 2020 Oct 29.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

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http://dx.doi.org/10.1111/ggi.14074DOI Listing
February 2021