Comparison of the effects of sitagliptin and dapagliflozin on time in range in Japanese patients with type 2 diabetes stratified by body mass index: A sub-analysis of the DIVERSITY-CVR study.

AIMS: To compare the effects of baseline background characteristics in patients treated with dapagliflozin and sitagliptin in the DIVERSITY-CVR study and to analyse the time in range (TIR), a metric for glycaemic control. MATERIALS AND METHODS: This prospective, randomized, multicentre study included 340 Japanese patients with early-stage type 2 diabetes. To examine the effects of dapagliflozin and sitagliptin on glycaemic variability, we re-examined the primary endpoint (glycated haemoglobin [HbA1c] < 7.0%, body weight loss ≥ 3.0%, and avoidance of hypoglycaemia) achievement rate in participants stratified by baseline background characteristics. RESULTS: Sitagliptin was significantly superior in achieving HbA1c level <7.0% in the lower body mass index (BMI) group (71.1% vs. 43.6%; P < 0.05), with no significant differences in other subgroups. In the lower BMI group, the rate of achievement of TIR > 70% after 24-week treatment was significantly higher with sitagliptin than with dapagliflozin (91.9% vs. 69.4%; P < 0.05). In contrast, dapagliflozin was superior to sitagliptin in achieving TIR > 70% in the higher BMI group (85.7% vs. 52.9%; P < 0.01). CONCLUSION: In Japanese patients with early-stage type 2 diabetes, sitagliptin was associated with improved TIR in patients with a lower BMI. Dapagliflozin was effective in patients with a higher BMI.

Aldosterone-to-Renin Ratio Is Associated with Diabetic Nephropathy in Type 2 Diabetic Patients: A Single-Center Retrospective Study.

BACKGROUND It is well established that primary aldosteronism (PA) and aldosterone-to-renin ratio (ARR) are associated with kidney disease. The aim of this study was to retrospectively investigate the relationship between ARR, urinary albumin excretion (UAE), and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes from a single center. MATERIAL AND METHODS We included 70 patients with type 2 diabetes, UAE ≤100 mg/day, not taking renin-aldosterone system inhibitors, did not meet the diagnostic criteria for PA, and had an ARR <20. The patients were divided into 3 groups: the normal low (NL) group (33 patients) with a UAE <10 mg/day, the normal (N) group (22 patients) with a UAE of 10-29 mg/day, and the microalbuminuria (M) group (15 patients) with a UAE of 30-100 mg/day. The ARR, plasma renin activity (PRA), and plasma aldosterone (PAC) were compared among groups. RESULTS The ARR was highest in group M (10.1±4.6), 6.5±0.3 in group NL, and 7.0±2.7 in group N. The PRA and PAC were significantly lower in group M (P<0.001). The ARR showed a significant positive correlation with log UAE (r=0.37, P<0.001) and a significant negative correlation with eGFR (r=-0.33, P<0.01). CONCLUSIONS High levels of aldosterone relative to renin, which did not fulfill confirmatory criteria for PA, may be one of the risk factors for the development of diabetic nephropathy in patients with diabetes. The present results are supported by previous research showing that an increased ARR without PA was a risk factor for kidney disease.

A prospective randomized study comparing effects of empagliflozin to sitagliptin on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes: the ASSET study.

BACKGROUND: While the cardioprotective benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been established in patients with cardiovascular disease (CVD), their advantages over other anti-diabetic drugs at earlier stages remain unclear. We compared the cardioprotective effects of empagliflozin, an SGLT2 inhibitor, with those of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, focusing on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes mellitus (T2DM) without CVD complications. METHODS: This was a prospective, randomized, open-label, blinded-endpoint, parallel-group trial that enrolled 44 Japanese patients with T2DM. The patients were randomized for 12-week administration of empagliflozin or sitagliptin. Pericardial fat accumulation and myocardial triglyceride content were evaluated by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. Echocardiography, 123I-ß-methyl-iodophenyl pentadecanoic acid myocardial scintigraphy, and laboratory tests were performed at baseline and after the 12-week treatment period. RESULTS: The patients were middle-aged (50.3 ± 10.7 years, mean ± standard deviation) and overweight (body mass index 29.3 ± 4.9 kg/m2). They had a short diabetes duration (3.5 ± 3.2 years), HbA1c levels of 7.1 ± 0.8%, and preserved cardiac function (ejection fraction 73.8 ± 5.0%) with no vascular complications, except for one baseline case each of diabetic nephropathy and peripheral arterial disease. After the 12-week treatment, no differences from baseline were observed between the two groups regarding changes in pericardial, epicardial, and paracardial fat content; myocardial triglyceride content; cardiac function and mass; and cardiac fatty acid metabolism. However, considering cardiometabolic biomarkers, high-density lipoprotein cholesterol and ketone bodies, including ß-hydroxybutyric acid, were significantly increased, whereas uric acid, plasma glucose, plasma insulin, and homeostasis model assessment of insulin resistance were significantly lower in the empagliflozin group than in the sitagliptin group (p < 0.05). CONCLUSIONS: Although the effects on cardiac fat and function were not statistically different between the two groups, empagliflozin exhibited superior effects on cardiometabolic biomarkers, such as uric acid, high-density lipoprotein cholesterol, ketone bodies, and insulin sensitivity. Therefore, when considering the primary preventive strategies for CVD, early supplementation with SGLT2 inhibitors may be more beneficial than DPP-4 inhibitors, even in patients with early-stage T2DM without current CVD complications. CLINICAL TRIAL REGISTRATION: UMIN000026340; registered on February 28, 2017. https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000030257.

Efficacy of dapagliflozin versus sitagliptin on cardiometabolic risk factors in Japanese patients with type 2 diabetes: a prospective, randomized study (DIVERSITY-CVR).

BACKGROUND: Few prospective studies have compared the cardiovascular benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors. We aimed to clarify the efficacy of dapagliflozin versus sitagliptin for modulating cardiometabolic risk factors including high glycated hemoglobin (HbA1c) levels, hypoglycemia, and body weight. METHODS: This prospective, randomized, open-label, blinded-endpoint, parallel-group trial enrolled 340 Japanese patients with early-stage type 2 diabetes receiving metformin alone or no glucose-lowering agents, who were randomized to receive dapagliflozin or sitagliptin for 24 weeks. The primary endpoint was the proportion of patients who achieved the composite endpoint of HbA1c level maintenance < 7.0% (53 mmol/mol), avoidance of hypoglycemia (maintenance of sensor glucose ≥ 3.0 mmol/L or ≥ 54 mg/dL), and ≥ 3.0% body weight loss from baseline. Secondary endpoints included components of the primary endpoint, other metabolic indices, and glucose variability indices measured using flash glucose monitoring. RESULTS: Clinical characteristics of patients were age, 58.1 ± 12.2 years; known duration of diabetes, 5.8 ± 6.1 years; body weight, 74.7 ± 14.2 kg; body mass index, 27.9 ± 4.1 kg/m2; and HbA1c level, 7.8 ± 0.8% at baseline. The achievement ratio of primary endpoint was significantly higher in the dapagliflozin group than in the sitagliptin group (24.4% vs. 13.8%, P < 0.05). While the rates of HbA1c level maintenance < 7.0% (53 mmol/mol) and avoidance of hypoglycemia were comparable between the groups (49.4 vs. 50.0% and 88.7 vs. 92.3% for dapagliflozin vs. sitagliptin, respectively), body weight loss of ≥ 3.0% was significantly achieved in the dapagliflozin group (54.4 vs. 19.6%, P < 0.001). Moreover, dapagliflozin was superior to sitagliptin regarding several secondary endpoints that modulate cardiometabolic risk, namely reducing fasting plasma glucose, insulin, uric acid, increasing high-density lipoprotein cholesterol, and suppressing the increase in serum creatinine and the decrease in estimated glomerular filtration rate. On the other hand, sitagliptin was superior to dapagliflozin in suppressing glucose variability. CONCLUSIONS: Compared to sitagliptin, dapagliflozin was significantly more effective at improving cardiometabolic risk factors, suggesting that SGLT2 inhibitors might be more suitable than DPP-4 inhibitors for preventing cardiovascular events in patients with early-stage but inadequately controlled type 2 diabetes. Trial registration Trial number, UMIN000028014; registered on June 30, 2017.

Practical use of insulin degludec/insulin aspart in a multinational setting: beyond the guidelines.

Insulin degludec/insulin aspart (IDegAsp) is a fixed-ratio co-formulation of insulin degludec, which provides long-lasting basal insulin coverage, and insulin aspart, which targets postprandial glycaemia. This review provides expert opinion on the practical clinical use of IDegAsp, including: dose timings relative to meals, when and how to intensify treatment from once-daily (OD) to twice-daily (BID) dose adjustments, and use in special populations (including hospitalized patients). IDegAsp could be considered as one among the choices for initiating insulin treatment, preferential to starting on basal insulin alone, particularly for people with severe hyperglycaemia and/or when postprandial hyperglycaemia is a major concern. The recommended starting dose of IDegAsp is 10 units with the most carbohydrate-rich meal(s), followed by individualized dose adjustments. Insulin doses should be titrated once weekly in two-unit steps, guided by individualized fasting plasma glucose targets and based on patient goals, preferences and hypoglycaemia risk. Options for intensification from IDegAsp OD are discussed, which should be guided by HbA1c, prandial glucose levels, meal patterns and patient preferences. Recommendations for switching to IDegAsp from basal insulin, premixed insulins OD/BID, and basal-plus/basal-bolus regimens are discussed. IDegAsp can be co-administered with other antihyperglycaemic drugs; however, sulphonylureas frequently need to be discontinued or the dose reduced, and the IDegAsp dose may need to be decreased when sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists are added. Considerations around the initiation or continuation of IDegAsp in hospitalized individuals are discussed, as well as in those undergoing medical procedures.

Efficacy of intermittent empagliflozin supplementation on dietary self-management and glycaemic control in patients with poorly controlled type 2 diabetes: A 24-week randomized controlled trial.

AIMS: To explore the effects of intermittent use of empagliflozin, a sodium-glucose co-transporter-2 inhibitor, on dietary self-management and glycaemic control in patients with inadequately controlled type 2 diabetes. MATERIALS AND METHODS: We conducted a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial of 50 patients with type 2 diabetes, treated with no more than three oral antidiabetic drugs (glycated haemoglobin [HbA1c] ≥52 mmol/mol but <86 mmol/mol). The participants were randomized to take 10 mg/d empagliflozin either every day (regular group, n = 25) or on the day on which they considered they had overeaten (intermittent group, n = 25) for 24 weeks. We limited empagliflozin prescription to half of the required period in the intermittent group. The primary endpoint was change in HbA1c at the end of the 24-week treatment period relative to baseline. The secondary outcomes included changes in body weight, daily energy intake and diabetes treatment-related quality of life (QoL). Energy intake was assessed using a diet-specific validated questionnaire rather than actual assessments of food intake. RESULTS: The intake rate of empagliflozin was 96.7 ± 7.2% for the regular group and 45.7 ± 7.0% for the intermittent group. Interestingly, ΔHbA1c was identical in the two groups (-0.64 ± 0.19% and - 0.65 ± 0.17%, respectively). Body weight decreased (-2.72 ± 0.52 and - 1.50 ± 0.45 kg, respectively) and diabetes treatment-related QoL increased significantly from baseline in both groups. Energy intake, however, decreased significantly only in the intermittent group (-221.0 ± 108.3 kcal/d). CONCLUSIONS: Intermittent empagliflozin supplementation is a useful therapeutic option that empowers dietary self-management, improves glycaemic control and is accompanied by body weight loss and an increase in diabetes treatment-related QoL in patients with inadequately controlled type 2 diabetes.

Whole hepatic lipid volume quantification and color mapping by multi-slice and multi-point magnetic resonance imaging.

AIM: Current approaches for hepatic steatosis assess only a small point within the liver and might cause inaccuracy for longitudinal observation. We aimed to establish a reliable non-invasive method for whole hepatic lipid content evaluation. METHODS: A total of 52 patients with hepatic steatosis underwent liver biopsy. Hepatic lipid content was assessed by Dixon in-phase/out-of-phase magnetic resonance imaging and proton magnetic resonance spectroscopy. Using multi-slice and multi-point magnetic resonance imaging, we calculated the lipid intensity of every voxel throughout the liver and showed the color-mapped lipid distributions. This new analysis could also quantify the whole hepatic lipid and whole liver volumes absolutely. The diagnostic performance of hepatic lipid content between the new analysis and proton magnetic resonance spectroscopy methods was compared by receiver operating characteristic curve analysis referring to the steatosis scores of the liver biopsy. RESULTS: Areas under the receiver operating characteristic for the diagnosis of steatosis scores ≥1, ≥2, and ≥3 using magnetic resonance imaging and proton magnetic resonance spectroscopy were 0.86 (95% confidence interval [CI] 0.70-1.00) and 0.98 (95% CI 0.93-1.00), 0.94 (95% CI 0.87-1.00) and 0.93 (95% CI 0.86-1.00), and 0.95 (95% CI 0.89-1.00) and 0.97 (95% CI 0.93-1.00), respectively, showing comparable diagnostic accuracies. However, color mapping showed some inconsistencies between the methods. CONCLUSIONS: We described a non-invasive and repeatable evaluation method of whole hepatic lipid accumulation with absolute quantification and color mapping. Hepatic steatosis was accurately evaluated regardless of heterogeneous lipid accumulation. The whole hepatic lean volume, reflecting the hepatic parenchymal condition, can also be determined by this method.

Mechanisms of sleep deprivation-induced hepatic steatosis and insulin resistance in mice.

Sleep deprivation is associated with increased risk for type 2 diabetes mellitus. However, the underlying mechanisms of sleep deprivation-induced glucose intolerance remain elusive. The aim of this study was to investigate the mechanisms of sleep deprivation-induced glucose intolerance in mice with a special focus on the liver. We established a mouse model of sleep deprivation-induced glucose intolerance using C57BL/6J male mice. A single 6-h sleep deprivation by the gentle handling method under fasting condition induced glucose intolerance. Hepatic glucose production assessed by a pyruvate challenge test was significantly increased, as was hepatic triglyceride content (by 67.9%) in the sleep deprivation group, compared with freely sleeping control mice. Metabolome and microarray analyses were used to evaluate hepatic metabolites and gene expression levels and to determine the molecular mechanisms of sleep deprivation-induced hepatic steatosis. Hepatic metabolites, such as acetyl coenzyme A, 3ß-hydroxybutyric acid, and certain acylcarnitines, were significantly increased in the sleep deprivation group, suggesting increased lipid oxidation in the liver. In contrast, fasted sleep-deprived mice showed that hepatic gene expression levels of elongation of very long chain fatty acids-like 3, lipin 1, perilipin 4, perilipin 5, and acyl-CoA thioesterase 1, which are known to play lipogenic roles, were 2.7, 4.5, 3.7, 2.9, and 2.8 times, respectively, those of the fasted sleeping control group, as assessed by quantitative RT-PCR. Sleep deprivation-induced hepatic steatosis and hepatic insulin resistance seem to be mediated through upregulation of hepatic lipogenic enzymes.

Rationale and design of study of dapagliflozin versus sitagliptin treatment efficacy on prevention of cardiovascular risk factors in type 2 diabetes patients: the DIVERSITY-CVR study.

BACKGROUND: Recent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors reduced the cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM) compared to placebo in contrast to no reduction with dipeptidyl peptidase 4 (DPP4) inhibitors. However, there are no comparative studies on the effects of SGLT2 inhibitors and DPP4 inhibitors on HbA1c, body weight and hypoglycemia as risk factors of cardiovascular diseases. The aim of the present ongoing study is to compare the effects of dapagliflozin, a SGLT2 inhibitor, with those of sitagliptin, a DPP4 inhibitor, on cardiovascular risk factors in T2DM patients with inadequate glycemic control. METHODS: The study of dapagliflozin versus sitagliptin treatment efficacy on prevention of cardiovascular risk factors in T2DM patients (DIVERSITY-CVR study) is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative study. A total of 340 T2DM patients treated with metformin alone or with no glucose-lowering agents (hemoglobin A1c ≥ 7.0 and < 10.0%) will be randomized into the dapagliflozin group (5-10 mg/day, n = 170) and the sitagliptin group (50-100 mg/day, n = 170), and treated for 24 weeks. The primary endpoint is the rate of achieving a composite endpoint of the following three items at 24th week; (1) HbA1c < 7.0%; (2) body weight loss of ≥ 3.0% from baseline; (3) avoidance of hypoglycemia. Hypoglycemia will be monitored using the flash glucose monitoring system. The secondary outcomes include each component of the primary endpoint, plus indices of lipid metabolism, and evaluations related to safety. CONCLUSIONS: There is lack of solid information on differences in the therapeutic effects of SGLT2 inhibitors and DPP4 inhibitors on multiple risk factors for cardiovascular diseases. It is anticipated that the results of the DIVERSITY-CVR study provides useful clinical data on the management of patients with T2DM, including reducing the risk of CVD. The results of this study will become available in 2019. Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000028014). Registered 30 June 2017.

Glycaemic control, hypoglycaemia, and weight change with insulin glargine 300 U/mL versus insulin glargine 100 U/mL in Japanese adults with type 2 diabetes: A 12-month comparison by concomitant sulphonylurea and/or glinide use.

AIM: To explore if clinical effects and hypoglycaemia risks associated with insulin glargine 300 U/mL (Gla-300) and 100 U/mL (Gla-100) differed by sulphonylurea and/or glinide (SU/G) treatment. METHODS: A post hoc subgroup analysis of 12-month treatment data from the EDITION Japan 2 trial, a randomized, open-label, phase 3 study of Japanese people with type 2 diabetes receiving once-daily Gla-300/Gla-100 + oral antihyperglycaemic drugs. Participants previously receiving SU/G (+SU/G) were compared with those not taking SU/G (-SU/G). Endpoints included HbA1c, hypoglycaemia and body weight. RESULTS: For +SU/G (n = 152, 63%), HbA1c was reduced from baseline to month 12 for Gla-300 (8.1% to 7.6%) and Gla-100 (8.2% to 7.8%). For -SU/G (n = 89, 37%), reductions were 7.8% to 7.4%, and 7.9% to 7.5% for Gla-300 and Gla-100, respectively. A lower annualized rate of hypoglycaemia with Gla-300 versus Gla-100 was observed at night (00:00-05:59 hours; p = 0.0001) and any time of day (24 hour; p = 0.0015). Irrespective of the insulin used, the incidence and rate of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia appeared higher in +SU/G versus -SU/G; overall, a reduced incidence of nocturnal hypoglycaemia, and rate of hypoglycaemia at any time, was observed in -SU/G versus +SU/G. In the -SU/G subgroup, body weight gain differences were observed between Gla-300 and Gla-100 (p < 0.0001). CONCLUSIONS: Participants with prior and continued SU/G use had similar therapeutic responses with basal insulin but greater risk of hypoglycaemia than those not using SU/G; hypoglycaemia risk was lower with Gla-300 than Gla-100 in both subgroups.

Effects of linagliptin versus voglibose on treatment-related quality of life in patients with type 2 diabetes: sub-analysis of the L-STEP study.

Treatment-related quality of life (QOL) is an important aspect of diabetes management. However, no studies have compared the influence of dipeptidyl peptidase-4 inhibitors versus alpha-glucosidase inhibitors on treatment-related QOL. This prespecified sub-analysis of the Linagliptin Study of Effects on Postprandial blood glucose (L-STEP) compared the effects of linagliptin (5 mg once daily) and voglibose (0.2 mg/meal thrice daily) on treatment-related QOL in Japanese patients with type 2 diabetes (T2DM) inadequately controlled with diet and exercise therapy. Among 366 subjects in the original study, 182 in the linagliptin group and 173 in the voglibose group were included in this analysis. The outcome of this study was change in QOL as assessed by the Diabetes Therapy-Related Quality of Life 17 (DTR-QOL17) questionnaire from baseline to week 12. Compared with baseline data, total DTR-QOL17 scores were significantly higher after 12 weeks of linagliptin and voglibose treatment. The change in the total DTR-QOL17 score and the score of one domain, burden on social activities and daily activities, was significantly greater in the linagliptin group than in the voglibose group. In addition, only linagliptin treatment was identified as a factor associated with an increased total DTR-QOL17 score. Linagliptin is superior to voglibose in terms of improving treatment-related QOL in Japanese patients with T2DM.

Follicular thyroglobulin induces cathepsin H expression and activity in thyrocytes.

Thyroglobulin (Tg) stored in thyroid follicles exerts a potent negative-feedback effect on each step of pre-hormone biosynthesis, including Tg gene transcription and iodine uptake and organification, by suppressing the expression of specific transcription factors that regulate these steps. Pre-hormones are stored in the follicular colloid before being reabsorbed. Following lysosomal proteolysis of its precursor, thyroid hormone (TH) is released from thyroid follicles. Although the suppressive effects of follicular Tg on each step of pre-hormone biosynthesis have been extensively characterized, whether follicular Tg accumulation also affects hormone reabsorption, proteolysis, and secretion is unclear. In this study we explored whether follicular Tg can regulate the expression and function of the lysosomal endopeptidases cathepsins. We found that in the rat thyroid cell line FRTL-5 follicular Tg induced cathepsin H mRNA and protein expression, as well as cathepsin H enzyme activity. Double immunofluorescence staining showed that Tg endocytosis promoted cathepsin H translocalization into lysosomes where it co-localized with internalized Tg. These results suggest that cathepsin H is an active participant in lysosome-mediated pre-hormone degradation, and that follicular Tg stimulates mobilization of pre-hormones by activating cathepsin H-associated proteolysis pathways.

Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study.

BACKGROUND: Recent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors can potentially reduce the risk of cardiovascular mortality in patients with type 2 diabetes mellitus (T2DM). However, there is little or no information on the therapeutic effects of SGLT2 inhibitors on the progression of atherosclerosis. This dapagliflozin effectiveness on vascular endothelial function and glycemic control (DEFENCE) study was designed to determine the effects of dapagliflozin, a SGLT2 inhibitor, on endothelial function in patients with early-stage T2DM. METHODS: DEFENCE is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial. Between October 2015 and August 2016, 80 T2DM patients treated with 750 mg of metformin (hemoglobin A1c ≥6.0 and <8.0%, n = 80) were enrolled and randomized to receive either 1500 mg/day metformin (the metformin group, n = 40), or 750 mg/day metformin supplemented with 5 mg/day dapagliflozin (the dapagliflozin group, n = 40), for 16 weeks. The primary endpoint was a change in flow-mediated dilation (FMD) from baseline to the end of the 16-week treatment period. The secondary outcomes include changes in indexes of glycemic control, lipid metabolism, and oxidative stress, body composition, and safety evaluation. RESULTS: Although FMD tended to improve only in the dapagliflozin group, ΔFMD was comparable between the two groups. Analysis of patients with HbA1c >7.0% showed significant improvement of FMD in the dapagliflozin group than metformin group (P < 0.05). HbA1c, fasting plasma glucose, plasma glucagon, and body weight significantly decreased in both groups. Interestingly, urine 8-hydroxy-2'-deoxyguanosin, a biomarker of oxidative stress, was significantly lower in the dapagliflozin group than metformin group at 16 weeks (P < 0.001). CONCLUSIONS: Dapagliflozin add-on therapy to metformin for 16 weeks improved endothelial function, as assessed by FMD, in patients with inadequately controlled early-stage T2DM. Improvement in oxidative stress may contribute to the improvement in FMD. Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000018754).

A case of idiopathic normal pressure hydrocephalus in an elder diabetic patient.

The clinical entity idiopathic normal pressure hydrocephalus (iNPH) is characterized by dementia, urinary incontinence, gait ataxia. An 80-year old man with a past history of Type 2 diabetes mellitus admitted to our hospital. Combination of twice Aspart and Aspart premixed30/70 insulin were used. Although, he was unable to inject insulin by himself recently. On physical examination, he walked in a mildly wide based manner. According to his family, urinary incontinence was existed. Laboratory data were as follows: Postrandial blood glucose 243 mg/dl and glycated hemoglobin 8.0% (NGSP). Brain magnetic resonance imaging (MRI) scans showed thinning of the corpus callosum with enlargement of the lateral ventricles on a colonal image. Evan's ratio was 0.29. The revised version of Hasegawa's Dementia scale (HDS-R) was 10. The patient showed no evidence a related antecedent event, such as head trauma, intracerebral hemorrhage and meningitis. Thus, he was diagnosed as having possible Idiopathic normal pressure hydrocephalus (iNPH). The following several psychological tests and walking test were applied. Before and after the tap, he was evaluated using the HDS-R, Mini mental state examination (MMSE), Timed Up and Go test (TUG). Insulin was replaced by glargine, and Sitagliptin was added. On the 31 day, the patient underwent Ventriculo-perioneal shunt. Laboratoly data and memory impairment were also improved. 8 month's later, HbA1c was 7.5%. iNPH occurs in the elderly and is characterized by a clinical triad of gait disturbance, urinary incontinence and dementia. In the present case, thinning of the corpus callosum with enlargement of the lateral ventricles was detected by MRI. 49% of iNPH patients had Diabetes mellitus. However, we were unable to detect a relationship iNPH and Diabetes mellitus. Cognitive impairment may interfere with the insulin therapy. In the present case, failure of insulin self-injection was the first clinical sign to appear. We were able to reduce dose of insulin. We conclude that iNPH is a treatable disorder, especially when treatment is started early in the course of the disease.

A case of lean polycystic ovary syndrome with early stage of type 1 diabetes successfully treated with metformin.

Polycystic ovary syndrome (PCOS) is common in obese women with insulin resistant type 2 diabetes for which metformin treatment is getting established in addition to clomiphene. However, lean PCOS patients are sometimes accompanied with type 1 diabetes. It remains unclear whether these patients are insulin resistant and whether metformin is effective for them. A 32-year-old woman, who suffered from acne, hirsutism, and menstrual disorders since age 29, was diagnosed as PCOS by serum high LH levels and polycystic ovary on echography. Interestingly, her body mass index (BMI) had consistently been 21.0 kg/m2 since age 20. She was first treated with clomiphene for one year for infertility but it did not improve her menstrual cycle nor did she get pregnant during that period. She was then assessed with diabetes mellitus and subsequently diagnosed as type 1 diabetes with mild hyperglycemia (HbA1c 6.0%). Since her insulin secretion was still well preserved, to assess insulin sensitivity, hyperinsulinemic-euglycemic clamp test was performed and showed her to be insulin resistant. Low dose insulin and low dose metformin treatment was started without clomiphene. After her ovulation and menstrual cycle were ameliorated only one month later, her treatment was supplemented with clomiphene for the next three months enabling her to at last become pregnant. This report highlights the efficacy of metformin in lean PCOS with type 1 diabetes. Insulin therapy is essential for type 1 diabetes but hyperinsulinemia potentially exacerbates PCOS through hyperandrogenism. Metformin is therefore recommended for treatment of lean PCOS with type 1 diabetes as well as common obese PCOS with type 2 diabetes.

Efficacy and safety of repaglinide added to sitagliptin in Japanese patients with type 2 diabetes: A randomized 24-week open-label clinical trial.

Although sitagliptin and repaglinide monotherapies improve postprandial hyperglycemia, the long-term effects and safety of their combination has not been examined. In this randomized 24-week trial of Japanese patients with poor control (HbA1c 7.0-8.5%) by sitagliptin, we divided 40 patients randomly into two equal groups of the repaglinide add-on to sitagliptin (ADD-ON, n=20), or sitagliptin switched to repaglinide (SWITCH, n=20). The meal tolerance test was carried out at weeks 0 and 24. The primary outcomes were changes in HbA1c and area under the curves (AUC) of glucose from the baseline to week 24. The mean change in HbA1c from baseline to week 24 was larger in the ADD-ON (-0.87±0.63%, mean±SD), compared with the SWITCH (0.03±0.65%, p=0.000). Significant improvements were noted in the mean changes in fasting glucose and AUCs of glucose in the ADD-ON vs. SWITCH (p=0.007 and p=0.000). Insulin secretion relative to glucose elevation (ISG; defined as AUC insulin/AUC glucose) increased significantly in the ADD-ON, although the mean change in fasting insulin level was significantly decreased in the ADD-ON (p=0.015 and p=0.026). The AUC of glucagon was significantly lower at 24-week relative to baseline in the ADD-ON, but was not significant in the two groups (p=0.047 and p=0.056, respectively). The combination therapy produced significant reductions in HbA1c, AUC of glucose and fasting glucose compared with switching to repaglinide without weight gain or severe hypoglycemia. The improved glycemic control with this combination therapy may be at least in part due to augmentation of repaglinide-induced insulin secretion by sitagliptin.

[Factors associated with malnutrition in community-dwelling disabled elderly--the KANAGAWA-AICHI Disabled Elderly Cohort (KAIDEC) Study].

AIM: This study aimed to identify factors associated with malnutrition in community-dwelling disabled elderly. METHODS: A cross-sectional study of baseline data for 1,142 community-dwelling elderly (81.2±8.7 years) from of the KANAGAWA-AICHI Disabled Elderly Cohort (KAIDEC) study was conducted. The data included the participants' demographic characteristics, nutritional status (Mini Nutritional Assessment short-form: MNA-SF), dysphagia status (Dysphagia Severity scale: DSS), comorbidity, basic activities of daily living (bADL), hospitalization with in the past three months and care level according to the Long-Term Care Insurance program. The participants were considered to be in malnutrition or at risk of malnutrition if their MNA-SF score was 0-7 or 8-11, respectively. The chi square test, analysis of variance, Jonckheere-Terpstra trend test and logistic regression analysis were used for the statistical analysis. RESULTS: A total of 16.7% of the participants were classified as having malnutrition. In addition, a higher prevalence of malnutrition was associated with a higher care level in the long-term care insurance program, and malnutrition was associated with a lower bADL score, the presence of dysphagia and dementia and hospitalization with in the past three months. CONCLUSIONS: The present study demonstrated that malnutrition in community-dwelling disabled elderly is associated with a lower bADL score, the presence of dysphagia and dementia and hospitalization with in the past three months.

Glucose Tolerance and the Risk Factors for Transmission in Japanese SARS-CoV-2/WA-1/2020 Epicenter: A Retrospective Study.

Purpose: The severe pathogenic ancient-type COVID-19, SARS-CoV-2/WA-1/2020 was the predominant gene variant in early 2020 in Japan, however, its transmissibility was uncertain. The period before the public commenced using any personal protective equipment (PPE) was evaluating to describe the transmissibility of the SARS-CoV-2/WA-1/2020. We analyzed the secondary attack rate (SAR) among close contacts and the risk factor for SAR. Methods: This retrospective cohort study included a total of 539 patients who were anticipated for the SARS-CoV-2/WA-1/2020 infection at Toho University Medical Center Omori Hospital from February to May 2020. We selected 54 patients with 1) exclude other pathogens infection, 2) include "Three Cs" condition: crowded places between distance< 6 feet, closed spaces indoor and close contact settings involving contact >15min with a person tested positive for SARS-CoV-2/WA-1/2020 without PPE. We evaluated alternative infection risks: the body mass index (BMI) and diabetes (DM) status (non-DM, pre-DM, and DM) as demographic determinants of transmissibility and infectivity of SARS-CoV2/WA-1/2020 cases during the incubation period. Results: The calculated SAR was 79.3%. BMI was significantly associated with the PCR positivity rate, which was significant in the univariate (CI 95%, 1.02-1.51; P = 0.03) and multivariate (CI 95%, 1.02-1.60; P = 0.03) analyses. Comparing the different BMI groups, the highest BMI group (25.5-35.8 kg/m2) had an elevated risk of SAR compared to the lowest BMI group (14.0-22.8 kg/m2), with an odds ratio of 1.41 (95% CI, 1.02-1.59; P = 0.03). There were no significant differences in the risk of SAR among different DM statuses. Conclusion: The transmissibility of SARS-CoV2/WA-1/2020 was high (79.3%) among household members without PPE who had "Three Cs" exposure. Although pre-DM and established DM did not confer a risk for transmissibility, higher BMI was associated with an increased risk of SAR. Trial Registration: UMIN Clinical Trials Registry, UMIN0000 50905.

[Place and cause of death in community-dwelling disabled elderly people].

AIM: To examine the place and cause of death in community-dwelling disabled elderly people. METHODS: The baseline data of 1,875 participants and their caregivers in the Nagoya Longitudinal Study for Frail Elderly were used for the analysis. Cox proportional hazard models were used to assess the associations between the variables and the place of death during the 3-year follow-up period. RESULTS: During the observation period of three years, 454 died (hospital death: 347, home death: 107). In total, the rates of pneumonia-, cancer- and heart failure-related death were 22.7%, 14.5%, and 13.2%, respectively. Among the home deaths, 22.4% were age-related deaths and 18.7% were heart failure-related deaths. Females, older, and participants with dementia were more likely to die at home, while those with cancer or a spouse caregiver were more likely to die in the hospital. There were no differences in the levels of caregiver burden or formal service use between the cases of home and hospital death. Multivariate Cox hazard models revealed that home death was associated with an older age and the absence of diabetes mellitus and cancer at baseline. CONCLUSIONS: We demonstrated that death at home among community-dwelling disabled elderly is associated with an older age, and the absence of diabetes mellitus and cancer. Due to the lack of important factors that should be addressed, a further study is required in the future.

A Case of Acute-Onset Type 1 Diabetes Mellitus with Diabetic Ketoacidosis Triggered by COVID-19.

BACKGROUND It is well known that diabetes mellitus contributes to COVID-19 severity. Recently, there have been reports of an increase in the number of children with type 1 diabetes after the COVID-19 pandemic. CASE REPORT A 52-year-old woman presented to the Emergency Department with disturbance of consciousness, accompanied by a 1-day history of thirst, a fever of 38°C, and breathlessness. She had a positive coronavirus antigen test. Her initial vital signs assessment showed a heart rate of 120 beats per minute, blood pressure 90/50 mmHg, temperature 37.3°C, and respiratory rate 30 breaths/minute with an oxygen saturation of 100% with 10 L oxygen inhalation. Her initial laboratory test results showed a blood glucose level of 1507 mg/dl, HbA1c of 10.1%, ketone 2+, and blood gas pH 7.113. The patient was diagnosed with diabetic ketoacidosis (DKA). There were mild inflammatory findings with blood CRP 0.14 mg/dl and a white cell count of 12 400/µL, but no pneumonia on a chest CT scan. Therefore, the patient was diagnosed with COVID-19 and DKA. The patient was positive for anti-glutamic acid decarboxylase (anti-GAD antibody) and had markedly low levels 24-h urine C-peptide (CPR). She was diagnosed with acute-onset type 1 diabetes mellitus, as her blood examination showed a postprandial blood glucose level of 100 mg/dl and HbA1c of 5.7% 2 months before admission. After admission, fluid replacement and continuous intravenous insulin infusion therapy were started, and blood glucose and blood gas pH improved over 10 h. CONCLUSIONS There have been reports of cases of type 1 diabetes consequences of COVID-19, but the mechanism has not been elucidated.