PIONEER REAL Japan: Baseline characteristics of a multicenter, prospective, real-world study of oral semaglutide in adults with type 2 diabetes in clinical practice in Japan.

AIMS/INTRODUCTION: PIONEER REAL Japan was a non-interventional, multicenter, prospective study investigating oral semaglutide in adults with type 2 diabetes in routine clinical practice. We report baseline characteristics of participants enrolled in this study. MATERIALS AND METHODS: Adults aged ≥20 years with type 2 diabetes but no previous treatment with injectable glucose-lowering medication were enrolled. Participants initiated oral semaglutide at their treating physician's discretion and were followed for 34-44 weeks. Participants were stratified into <75-year-old and ≥75-year-old subgroups. RESULTS: A total of 624 participants initiated the study. The mean (standard deviation) age was 64.1 years (14.1), the mean (standard deviation) body weight was 72.4 kg (16.1), and the mean (standard deviation) body mass index was 27.5 kg/m2 (5.0). Participants had a median (interquartile range) type 2 diabetes duration of 9.3 years (4.2, 15.2) and mean (standard deviation) glycated hemoglobin 7.7% (1.1). Most (75.6%) participants were taking glucose-lowering medications at baseline; the most common was metformin (51.9%). The main reasons for initiating oral semaglutide were glycemic control and weight loss. Most (86.0%) participants had an individualized target for glycemic control of glycated hemoglobin ≤7%. The <75-year-old subgroup was heavier (mean [standard deviation] body mass index 28.6 kg/m2 [5.2] vs 25.1 kg/m2 [3.4]) but had comparable glycated hemoglobin levels (mean [standard deviation] 7.7% [1.2] vs 7.8% [1.0]) to the ≥75-year-old subgroup. CONCLUSIONS: PIONEER REAL Japan describes the characteristics of individuals with type 2 diabetes prescribed oral semaglutide. The baseline characteristics provide insights into Japanese individuals with type 2 diabetes prescribed oral semaglutide in clinical practice.

Japanese 17q12 Deletion Syndrome with Complex Clinical Manifestations.

17q12 deletion syndrome is a rare chromosomal anomaly with variable phenotypes, caused by the heterozygous deletion of chromosome 17q12. We herein report a 35-year-old Japanese patient with chromosomal 17q12 deletion syndrome identified by de novo deletion of the 1.46 Mb segment at the 17q12 band by genetic analyses. He exhibited a wide range of phenotypes, such as maturity-onset diabetes of the young (MODY) type 5, structural or functional abnormalities of the kidney, liver, and pancreas; facial dysmorphic features, electrolyte disorders; keratoconus, and acquired perforating dermatosis. This case report provides valuable resources concerning the clinical spectrum of rare 17q12 deletion syndrome.

Primary aldosteronism patients with previous cardiovascular and cerebrovascular events have high aldosterone responsiveness to ACTH stimulation.

Aldosterone secretion in primary aldosteronism (PA) is often regulated by adrenocorticotropic hormone (ACTH) in addition to its autonomous secretion. However, the clinical characteristics and risk of cardiovascular and cerebrovascular (CCV) events in PA patients with aldosterone responsiveness to ACTH stimulation remain unclear. This study aimed to investigate the prevalence of CCV events in PA patients with high aldosterone responsiveness to ACTH stimulation. A retrospective cross-sectional study was conducted as part of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Disease project. PA patients with adrenal venous sampling (AVS) between January 2006 and March 2019 were enrolled. The ACTH-stimulated plasma aldosterone concentration (PAC) of the inferior vena cava during AVS was used to evaluate aldosterone responsiveness to ACTH. We analyzed the relationship between responsiveness and previous CCV events. Logistic regression analysis demonstrated that the ΔPAC (the difference between the PAC measurements before and after ACTH stimulation) significantly increased the odds of previous CCV events in PA patients after adjusting for classical CCV event risk factors, baseline PAC and duration of hypertension (relative PAC: odds ratio [OR], 2.896; 95% confidence interval [CI], 0.989-8.482; ΔPAC: OR, 2.344; 95% CI, 1.149-4.780; ACTH-stimulated PAC: OR, 2.098; 95% CI, 0.694-6.339). This study clearly demonstrated that aldosterone responsiveness to ACTH is closely related to previous CCV events. The responsiveness of the PAC to ACTH could be useful in predicting CCV event risk.Registration Number in UMIN-CTR is UMIN000032525.

Impact of Participant Characteristics on Clinical Outcomes with iGlarLixi in Type 2 Diabetes: Post Hoc Analysis of SPARTA Japan.

INTRODUCTION: The real-world SPARTA Japan study confirmed the effectiveness and safety of the fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) once daily over 6 months in Japanese people with type 2 diabetes (T2D). This post hoc analysis examined the impact of participant characteristics on the achievement of age-defined glycaemic targets with iGlarLixi therapy. METHODS: The retrospective, observational SPARTA Japan study included adults with T2D who initiated iGlarLixi. In this analysis, data from insulin-naïve and insulin-experienced participants were separately assessed to compare glycated haemoglobin (HbA1c), body weight and safety outcomes between those who achieved ('achieved' group) and those who did not achieve ('not-achieved' group) age-defined glycaemic targets after 6 months of iGlarLixi. The not-achieved group was further stratified by whether or not their iGlarLixi dose was increased during treatment. RESULTS: In total, 418 participants were included in this analysis (138 insulin naïve and 280 insulin experienced). Among both insulin-naïve and insulin-experienced participants, those in the achieved group were older and had lower baseline HbA1c than those in the not-achieved group. Compared with the not-achieved group, the achieved group showed significantly greater HbA1c reductions from baseline (in both insulin-naïve and insulin-experienced participants) and significantly greater body weight reductions (in insulin-naïve participants), despite some participants in the not-achieved group receiving significantly higher insulin glargine doses than those in the achieved group. In both insulin-naïve and insulin-experienced participants, the incidence of hypoglycaemia and gastrointestinal-related adverse events was similar in the achieved and not-achieved groups. In a multivariate analysis, glycaemic target achievement was significantly more likely in older individuals and those who lost weight during iGlarLixi treatment. CONCLUSIONS: Achievement of age-defined glycaemic targets with iGlarLixi treatment for 6 months was significantly affected by increased age and body weight loss, regardless of prior insulin exposure. TRIAL REGISTRATION: UMIN-CTR Trials Registry, UMIN000044126; registered 10 May 2021.

iGlarLixi is an injectable product used to treat type 2 diabetes that contains a fixed combination of two drugs, insulin glargine (at a concentration of 100 U/mL) and lixisenatide. The SPARTA Japan study investigated the effectiveness of controlling blood glucose levels and the safety of iGlarLixi in Japanese people when taken once daily for over 6 months as part of their routine medical care. The analysis reported in this article looked back at data from SPARTA Japan to assess whether certain characteristics of the people who took part in the study affected how well blood glucose targets were met. People who had previously taken insulin and those who had not were identified, and their results were assessed separately. The people were divided into those who had met their blood glucose level target (with the target defined as the glycated haemoglobin level for each person based on their age) and those who had not met their target. It was found that people who achieved their blood glucose target while receiving iGlarLixi were more likely to be older, to have had a lower glycated haemoglobin level before starting iGlarLixi, and to have lost weight during treatment than those who did not achieve their target, whether or not they had previously been treated with insulin. Side effects of excessively low blood glucose levels or gastrointestinal upset with iGlarLixi treatment occurred in a similar number of people who achieved or did not achieve their blood glucose target.

Long-term safety and efficacy of SGLT2 inhibitor use in older east Asians with type 2 diabetes.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been shown in cardiovascular outcome trials to reduce the risk of heart failure and major adverse cardiovascular as well as renal events in individuals with type 2 diabetes. Moreover, clinical evidence indicates that SGLT2i use reduces heart failure and chronic kidney disease (CKD) in east Asian patients with type 2 diabetes. Thus, SGLT2is might seem to be the preferred treatment for older patients with type 2 diabetes even in the presence of multiple comorbidities. However, older patients with type 2 diabetes may well have impaired physiological function, making the risk of certain adverse events higher than that in the general population. While a randomized clinical trial has been conducted to evaluate changes in skeletal muscle mass and function as well as those in cognitive function with SGLT2i use in older Japanese individuals with type 2 diabetes who are otherwise healthy, the safety of SGLT2is remains to be established among older individuals with type 2 diabetes also having impaired activity of daily living and/or cognitive impairment. Even so, international and domestic consensus reports recommend SGLT2is for patients with type 2 diabetes and heart failure, CKD, and/or cardiovascular diseases, and SGLT2is are being widely prescribed by general practitioners to older individuals with type 2 diabetes with little regard to the patient's comorbidities. We maintain that SGLT2i use in older patients with type 2 diabetes should be prescribed cautiously in consideration of the pathophysiology of the disease and the presence of complications and comorbidities as well as the individual's lifestyle.

Lifestyle factors associated with a rapid decline in the estimated glomerular filtration rate over two years in older adults with type 2 diabetes-Evidence from a large national database in Japan.

BACKGROUND: The present study investigated lifestyle risk factors from metabolic syndrome-related lifestyles for a rapid decline in the estimated glomerular filtration rate (eGFR) among adults aged 40-74 years with treated and untreated type 2 diabetes. METHODS AND RESULTS: This study analyzed data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan, encompassing the period from fiscal year (FY) 2017 to FY2020. We established FY2018 as our baseline year. The subjects of this study were adults aged 40-74 in FY2018(baseline) who had type 2 diabetes and underwent specific health checkups in FY2020. We excluded adults with a medical record of kidney dialysis between FY2017 and FY2018, records of suspected type 1 diabetes between FY2017 and FY2020, or a baseline eGFR >85 mL/min/1.73 m2 or missing eGFR data as of FY2020. Eventually we analyzed 573,860 individuals. The outcome variable was a rapid decline in eGFR (≥30%) during the follow-up. Exposure lifestyle factors included skipping breakfast, late-night dinners, regular smoking, a high alcohol intake, non-refreshing sleep, and a lack of habitual exercise. Logistic regression models were stratified by age (40-59 and 60-74 years) and baseline eGFR levels (60-85, 30-59, and <30 mL/min/1.73 m2). Covariates included sex, a history of heart disease, a history of stroke, a history of renal failure, anemia, low-density lipoprotein, systolic blood pressure, hemoglobin A1C, body mass index, antidiabetic medications, antihypertension drugs, lipid-lowering drugs, the oral adsorbent Kremezin, non-steroidal anti-inflammatory drugs, and drugs for the treatment of renal anemia. A rapid decline in eGFR was detected in approximately 1.3% of participants (7,683 cases). In the baseline eGFR >30 subgroups (60-85 or 30-59 mL/min/1.73 m2), skipping breakfast and regular smoking were associated with a rapid decline in eGFR in both age groups, while a lack of habitual exercise and late-night dinners in the 60-74 age group and non-refreshing sleep in the 40-59 age group were identified as risk factors. Additionally, skipping breakfast was a risk factor for a rapid decline in eGFR in the 60-74 age group regardless of baseline eGFR levels. In the baseline eGFR <30 mL/min/1.73 m2 subgroup, skipping breakfast and non-refreshed sleep were risk factors for a rapid decline in eGFR. CONCLUSIONS: We found specific lifestyle risk factors were associated with a rapid eGFR decline among people with type 2 diabetes from a nationwide database in Japan. The associations varied by baseline eGFR level, age, and sex. Lifestyle modifications may effectively prevent the aggravation of diabetic kidney disease.

Glucokinase Variant Proteins Are Resistant to Fasting-Induced Uridine Diphosphate Glucose-Dependent Degradation in Maturity-Onset Diabetes of the Young Type 2 Patients.

We previously reported that glucokinase undergoes ubiquitination and subsequent degradation, a process mediated by cereblon, particularly in the presence of uridine diphosphate glucose (UDP-glucose). In this context, we hereby present evidence showcasing the resilience of variant glucokinase proteins of maturity-onset diabetes of the young type 2 (MODY2) against degradation and, concomitantly, their influence on insulin secretion, both in cell lines and in the afflicted MODY2 patient. Hence, glucose-1-phodphate promotes UDP-glucose production by UDP-glucose pyrophosphorylase 2; consequently, UDP-glucose-dependent glucokinase degradation may occur during fasting. Next, we analyzed glucokinase variant proteins from MODY2 or persistent hyperinsulinemic hypoglycemia in infancy (PHHI). Among the eleven MODY2 glucokinase-mutated proteins tested, those with a lower glucose-binding affinity exhibited resistance to UDP-glucose-dependent degradation. Conversely, the glucokinaseA456V-mutated protein from PHHI had a higher glucose affinity and was sensitive to UDP-glucose-dependent degradation. Furthermore, in vitro studies involving UDP-glucose-dependent glucokinase variant proteins and insulin secretion during fasting in Japanese MODY2 patients revealed a strong correlation and a higher coefficient of determination. This suggests that UDP-glucose-dependent glucokinase degradation plays a significant role in the pathogenesis of glucose-homeostasis-related hereditary diseases, such as MODY2 and PHHI.

Erdheim-Chester Disease With BRAF V600E Mutation and Central Diabetes Insipidus Successfully Treated With Glucocorticoid.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by xanthoma/xanthogranuloma infiltration in various organs and a broad spectrum of clinical presentations, including bone lesions, central diabetes insipidus and renal failure. BRAF V600E mutation is seen in almost half of the cases of ECD; the BRAF inhibitor vemurafenib is recommended treatment in the United States and the European Union. However, the indication for vemurafenib in Japan is limited to unresectable malignant melanoma with BRAF mutation. Although glucocorticoids, interferon, chemotherapy, and radiation therapy are treatment options, no standard therapy for ECD has yet been established in Japan. We describe here a patient with central diabetes insipidus and retroperitoneal lesions who was successfully treated with prednisolone. Glucocorticoid therapy is therefore a plausible alternative for ECD with BRAF V600E mutation when the BRAF inhibitor vemurafenib cannot be used.

Correction: A consensus statement from the Japan Diabetes Society (JDS): a proposed algorithm for pharmacotherapy in people with type 2 diabetes.

[This corrects the article DOI: 10.1007/s13340-022-00605-x.].

Gastric inhibitory polypeptide receptor antagonism suppresses intramuscular adipose tissue accumulation and ameliorates sarcopenia.

BACKGROUND: Intramuscular adipose tissue (IMAT) formation derived from muscle fibro-adipogenic progenitors (FAPs) has been recognized as a pathological feature of sarcopenia. This study aimed to explore whether genetic and pharmacological gastric inhibitory polypeptide (GIP) receptor antagonism suppresses IMAT accumulation and ameliorates sarcopenia in mice. METHODS: Whole body composition, grip strength, skeletal muscle weight, tibialis anterior (TA) muscle fibre cross-sectional area (CSA) and TA muscle IMAT area were measured in young and aged male C57BL/6 strain GIP receptor (Gipr)-knockout (Gipr-/- ) and wild-type (Gipr+/+ ) mice. FAPs isolated from lower limb muscles of 12-week-old Gipr+/+ mice were cultured with GIP, and their differentiation into mature adipocytes was examined. Furthermore, TA muscle IMAT area and fibre CSA were measured in untreated Gipr-/- mice and GIP receptor antagonist-treated Gipr+/+ mice after glycerol injection into the TA muscles. RESULTS: Body composition analysis revealed that 104-week-old Gipr-/- mice had a greater proportion of lean tissue mass (73.7 ± 1.2% vs. 66.5 ± 2.7%, P < 0.05 vs. 104-week-old Gipr+/+ mice) and less adipose tissue mass (13.1 ± 1.3% vs. 19.4 ± 2.6%, P < 0.05 vs. 104-week-old Gipr+/+ mice). Eighty-four-week-old Gipr-/- mice exhibited increases in grip strength (P < 0.05), weights of TA (P < 0.05), soleus (P < 0.01), gastrocnemius (P < 0.05) and quadriceps femoris (P < 0.01) muscles, and average TA muscle fibre CSA (P < 0.05) along with a reduction in TA muscle IMAT area assessed by the number of perilipin-positive cells (P < 0.0001) compared with 84-week-old Gipr+/+ mice. Oil Red O staining analysis revealed 1.6- and 1.7-fold increased adipogenesis in muscle FAPs cultured with 10 and 100 nM of GIP (P < 0.01 and P < 0.001 vs. 0 nM of GIP, respectively). Furthermore, both untreated Gipr-/- mice and GIP receptor antagonist-treated Gipr+/+ mice for 14 days after glycerol injection into the TA muscles at 12 weeks of age showed reduced TA muscle IMAT area (1.39 ± 0.38% and 2.65 ± 0.36% vs. 6.54 ± 1.30%, P < 0.001 and P < 0.01 vs. untreated Gipr+/+ mice, respectively) and increased average TA muscle fibre CSA (P < 0.01 and P < 0.05 vs. untreated Gipr+/+ mice, respectively). CONCLUSIONS: GIP promotes the differentiation of muscle FAPs into adipocytes and its receptor antagonism suppresses IMAT accumulation and promotes muscle regeneration. Pharmacological GIP receptor antagonism may serve as a novel therapeutic approach for sarcopenia.

Dietary and Nutritional Guidelines for People with Diabetes.

Diabetes is a disease in which lifestyle-based interventions, including recommendations for a healthy diet, play a critical role, and many countries have established their own nutritional guidelines [...].

Oral Semaglutide under Human Protocols and Doses Regulates Food Intake, Body Weight, and Glycemia in Diet-Induced Obese Mice.

The first oral form of the glucagon-like peptide-1 receptor agonist, oral semaglutide, has recently been launched and potently controls glycemia and body weight in subjects with type 2 diabetes. This drug carries the absorption enhancer and requires specific protocols of administration. The mechanism of action of oral semaglutide is not fully understood, for which an appropriate experimental model is required. This study explores the metabolic effects of oral semaglutide in mice under human protocols and doses. Oral semaglutide was bolus and once daily injected into high-fat diet-induced obese (DIO) mice under human protocols, followed by monitoring blood glucose, food intake, and body weight. Oral semaglutide 0.23 mg/kg, a comparable human dose (14 mg) in a small volume of water under human protocols rapidly decreased blood glucose and food intake and continuously reduced food intake and weight gain for 3 days in DIO mice. At 0.7 mg/kg (42 mg), this drug was somewhat more potent. Oral semaglutide with human protocols and doses rapidly reduces blood glucose and food intake and continuously suppresses feeding and weight in DIO mice. This study establishes mice as a model suitable for analyzing the mechanism of anti-obesity/diabetes actions of oral semaglutide.

Unmasked insulinoma occasioned by severe hypoglycemic coma immediately postpartum: a case report.

BACKGROUND: Insulinoma in women during pregnancy and postpartum is very rare; approximately 65% of cases are diagnosed early in pregnancy and ~ 35% immediately after delivery, few being found in middle or late pregnancy, likely due to increased insulin resistance seen after early-stage pregnancy. We successfully treated a case of insulinoma in which severe hypoglycemic coma immediately after delivery occasioned detailed investigation and diagnosis. CASE PRESENTATION: Our patient experienced hypoglycemic coma in the 3rd month of pregnancy (initially considered due to her hyperemesis gravidarum) that improved spontaneously during the gestational period. No abnormalities of plasma glucose or body weight were found in regular checkups during her pregnancy; however, recurrence of hypoglycemic coma after delivery led us to suspect insulinoma. While contrast enhanced computer tomography and endoscopic ultrasonography (EUS) initially failed to detect a tumor in the pancreas, selective arterial calcium stimulation test revealed an insulin-secreting tumor localized in the pancreatic body. She then underwent spleen-preserving distal pancreatectomy; a 10-mm tumor positive for chromogranin A, synaptophysin and insulin was identified. CONCLUSIONS: Although pregnancy can mask insulinoma-associated symptoms and make diagnosis challenging, hypoglycemic episodes during early pregnancy, which were observed in this case, are suggestive of insulinoma. Importantly, in this case, accurate preoperative localization of the tumor enabled prompt curative surgery after delivery. Thus, clinical vigilance for the occurrence of insulinoma and its localization is appropriate for pregnant women suffering severe hypoglycemia.

Effect of Roxadustat on Thyroid Function in Patients With Renal Anemia.

CONTEXT: Roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, a recently developed class of drugs for treatment of anemia in chronic kidney disease (CKD), is reported to have a structure unlike that of other HIF-PH inhibitors but similar to that of triiodothyronine and bind to the thyroid hormone receptor in vitro. However, reports on the effects of roxadustat on thyroid function are limited and not detailed, and it remains unknown whether other HIF-PH inhibitors also affect thyroid function. OBJECTIVE: To compare the effect of roxadustat with daprodustat, another HIF-PH inhibitor, on thyroid function in patients with renal anemia in CKD. METHODS: This retrospective observational study included a total of 26 patients with anemia in CKD who were treated with roxadustat or daprodustat; thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were measured before and after treatment with the drugs. RESULTS: After initiation of roxadustat, TSH showed a significant decrease (2.4732 [1.7858-4.9016] µIU/mL before treatment and 0.659 [0.112-2.005] µIU/mL after treatment, P < .05); FT4 showed a significant decrease (0.93 [0.84-1.05] ng/dL before treatment and 0.70 [0.53-0.85] ng/dL after treatment, P < .01). After daprodustat initiation, neither TSH nor FT4 showed a significant change (TSH: 3.044 [1.853-4.171] µIU/mL before treatment and 2.893 [1.866-4.894] µIU/mL after treatment, P = .635; FT4 was 0.93 [0.81-1.00] ng/dL before treatment and 0.97 [0.87-1.05] ng/dL after treatment, P = .328). CONCLUSION: Roxadustat decreases TSH and FT4 levels while daprodustat does not.

Empagliflozin is associated with lower cardiovascular risk compared with dipeptidyl peptidase-4 inhibitors in adults with and without cardiovascular disease: EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study results from Europe and Asia.

BACKGROUND: Studies that have reported lower risk for cardiovascular outcomes in users of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are limited by residual cofounding and lack of information on prior cardiovascular disease (CVD). This study compared risk of cardiovascular events in patients within routine care settings in Europe and Asia with type 2 diabetes (T2D) initiating empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) stratified by pre-existing CVD and history of heart failure (HF). METHODS AND RESULTS: Adults initiating empagliflozin and DPP-4i in 2014-2018/19 from 11 countries in Europe and Asia were compared using propensity score matching and Cox proportional hazards regression to assess differences in rates of primary outcomes: hospitalisation for heart failure (HHF), myocardial infarction (MI), stroke; and secondary outcomes: cardiovascular mortality (CVM), coronary revascularisation procedure, composite outcome including HHF or CVM, and 3-point major adverse cardiovascular events (MACE: MI, stroke and CVM). Country-specific results were meta-analysed and pooled hazard ratios (HR) with 95% confidence intervals (CI) from random-effects models are presented. In total, 85,244 empagliflozin/DPP4i PS-matched patient pairs were included with overall mean follow-up of 0.7 years. Among those with pre-existing CVD, lower risk was observed for HHF (HR 0.74; 95% CI 0.64-0.86), CVM (HR 0.55; 95% CI 0.38-0.80), HHF or CVM (HR 0.57; 95% CI 0.48-0.67) and stroke (HR 0.79; 95% CI 0.67-0.94) in patients initiating empagliflozin vs DPP-4i. Similar patterns were observed among patients without pre-existing CVD and those with and without pre-existing HF. CONCLUSION: These results from diverse patient populations in routine care settings across Europe and Asia demonstrate that initiation of empagliflozin compared to DPP-4i results in favourable cardioprotective effects regardless of pre-existing CVD or HF status.

Efficacy and safety of the sodium-glucose co-transporter-2 inhibitor empagliflozin in elderly Japanese adults (≥65 years) with type 2 diabetes: A randomized, double-blind, placebo-controlled, 52-week clinical trial (EMPA-ELDERLY).

AIM: Use of sodium-glucose co-transporter-2 inhibitors (SGLT2is) for glycaemic control is increasing in individuals with type 2 diabetes (T2D) for their additional benefits on heart failure and chronic kidney disease. However, SGLT2is generally reduce body weight, which might promote sarcopenia in older individuals. We evaluated the effects of the SGLT2i empagliflozin on muscle mass and strength in addition to glucose control in elderly adults with T2D. MATERIALS AND METHODS: Individuals with T2D aged ≥65 years with body mass index ≥22 kg/m2 and glycated haemoglobin (HbA1c) 7.0%-10.0% were randomized 1:1 to once-daily empagliflozin 10 mg or placebo for 52 weeks. The primary endpoint was change from baseline in HbA1c at week 52. Secondary endpoints included changes from baseline in muscle mass and strength. RESULTS: Of the 129 individuals randomized, 72.4% were men, mean age 74.1 years, body mass index 25.6 kg/m2 and HbA1c 7.6%. The placebo-adjusted mean change from baseline in HbA1c at week 52 with empagliflozin was -0.57% [95% confidence interval (CI) -0.78, -0.36]. Change in body weight was -3.26 kg and -0.90 kg with empagliflozin and placebo, respectively (placebo-adjusted difference: -2.37 kg; 95% CI -3.07, -1.68). Placebo-adjusted change in muscle mass was -0.61 kg (95% CI -1.61, 0.39), fat mass -1.84 kg (95% CI -2.65, -1.04) and grip strength -0.3 kg (95% CI -1.1, 0.5). CONCLUSIONS: Empagliflozin improved glucose control and reduced body weight without compromising muscle mass or strength in elderly adults with T2D in this trial.

Device-supported automated basal insulin titration in adults with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.

Background: Technological advances make it possible to use device-supported, automated algorithms to aid basal insulin (BI) dosing titration in patients with type 2 diabetes. Methods: A systematic review and meta-analysis of randomized controlled trials were performed to evaluate the efficacy, safety, and quality of life of automated BI titration versus conventional care. The literature in Medline, Embase, Web of Science, and the Cochrane databases from January 2000 to February 2022 were searched to identify relevant studies. Risk ratios (RRs), mean differences (MDs), and their 95% confidence intervals (CIs) were calculated using random-effect meta-analyses. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Findings: Six of the 7 eligible studies (889 patients) were included in meta-analyses. Low- to moderate-quality evidence suggests that patients who use automated BI titration versus conventional care may have a higher probability of reaching a target of HbA1c <7.0% (RR, 1.82 [95% CI, 1.16-2.86]); and a lower level of HbA1c (MD, -0.25% [95% CI, -0.43 to -0.06%]). No statistically significant differences were detected between the two groups in fasting glucose results, incidences of hypoglycemia, severe or nocturnal hypoglycemia, and quality of life, with low to very low certainty for all the evidence. Interpretation: Automated BI titration is associated with small benefits in reducing HbA1c without increasing the risk of hypoglycemia. Future studies should explore patient attitudes and the cost-effectiveness of this approach. Funding: Sponsored by the Chinese Geriatric Endocrine Society.

Efficacy and Safety of 6-Month High Dietary Protein Intake in Hospitalized Adults Aged 75 or Older at Nutritional Risk: An Exploratory, Randomized, Controlled Study.

The aim of this study was to investigate the effects of increased dietary protein in daily-life settings in Japan for 6 months on the activities of daily living (ADL) in adults aged 75 or older at nutritional risk. The study was an open-label, exploratory, randomized controlled trial conducted at seven hospitals in Japan. The study participants were adults aged 75 or older who were hospitalized for treatable cancer, pneumonia, fractures, and/or urinary-tract infection at nutritional risk. The primary outcome was change in grip strength, skeletal muscle, and ADL indices (Barthel index, Lawton score). One hundred sixty-nine patients were randomly assigned to the intensive care (IC) or standard care (SC) group; the protein intake goals (g/kgw/day) were 1.5 for IC and 1.0 for SC. There was a significant improvement in grip strength only in the IC group (1.1 kg: 95% CI 0.1 to 2.1) (p = 0.02). While the skeletal muscle index and ADL indices were not significantly improved in either group, the improvement ratio tended to be greater in the IC group. There was no decrease in renal function in either group. Thus, intervention of increased dietary protein in daily-life settings for 6 months in adults aged 75 or older with treatable cancer, pneumonia, fractures, and/or urinary-tract infection and at nutritional risk may be effective in ameliorating loss of muscle strength.

Blockade of glucagon increases muscle mass and alters fiber type composition in mice deficient in proglucagon-derived peptides.

AIMS/INTRODUCTION: Glucagon is secreted from pancreatic α-cells and plays an important role in amino acid metabolism in liver. Various animal models deficient in glucagon action show hyper-amino acidemia and α-cell hyperplasia, indicating that glucagon contributes to feedback regulation between the liver and the α-cells. In addition, both insulin and various amino acids, including branched-chain amino acids and alanine, participate in protein synthesis in skeletal muscle. However, the effect of hyperaminoacidemia on skeletal muscle has not been investigated. In the present study, we examined the effect of blockade of glucagon action on skeletal muscle using mice deficient in proglucagon-derived peptides (GCGKO mice). MATERIALS AND METHODS: Muscles isolated from GCGKO and control mice were analyzed for their morphology, gene expression and metabolites. RESULTS: GCGKO mice showed muscle fiber hypertrophy, and a decreased ratio of type IIA and an increased ratio of type IIB fibers in the tibialis anterior. The expression levels of myosin heavy chain (Myh) 7, 2, 1 and myoglobin messenger ribonucleic acid were significantly lower in GCGKO mice than those in control mice in the tibialis anterior. GCGKO mice showed a significantly higher concentration of arginine, asparagine, serine and threonine in the quadriceps femoris muscles, and also alanine, aspartic acid, cysteine, glutamine, glycine and lysine, as well as four amino acids in gastrocnemius muscles. CONCLUSIONS: These results show that hyperaminoacidemia induced by blockade of glucagon action in mice increases skeletal muscle weight and stimulates slow-to-fast transition in type II fibers of skeletal muscle, mimicking the phenotype of a high-protein diet.