The Effects of Imeglimin on Muscle Strength in Patients with Type 2 Diabetes: A Prospective Cohort Study.

INTRODUCTION: A bidirectional relationship has been observed between type 2 diabetes mellitus and sarcopenia, especially among older adults. While previous studies have reported that imeglimin improves mitochondrial function, they have not assessed its effects on muscle strength in patients with type 2 diabetes. Therefore, we aimed to investigate the effects of imeglimin on muscle strength in patients with type 2 diabetes. METHODS: In this prospective cohort study, we recruited consenting patients with type 2 diabetes (20-75 years). Changes in lean body mass (LBM), fat mass, quadriceps muscle strength, and grip strength from baseline (week 0) to week 24 were evaluated and compared between patients treated with imeglimin therapy (group I) and those who did not take imeglimin (controls, group C). RESULTS: We recruited 27 patients treated with imeglimin (group I) and 29 controls (group C), and 50 of them completed the study (group I: n = 23; group C: n = 27). The change in LBM, total body fat mass, or skeletal muscle index from baseline to week 24 did not differ significantly between the two groups. However, group I exhibited a significantly higher percent change in quadriceps knee extension strength from baseline to week 24 than group C (13 ± 19% and 2.1 ± 14%, p = 0.022). Conversely, the difference in percent change in grip strength was not significant. Multivariable analysis showed that imeglimin use was significantly associated with a percent change in quadriceps knee extension strength, independent of age, sex, body mass index, and skeletal mass index (ß = 0.325, p = 0.0014). CONCLUSIONS: Imeglimin positively affected muscle strength in patients with type 2 diabetes without altering LBM. Therefore, imeglimin exerts a unique effect on skeletal muscles in humans. Further randomized controlled trials are needed to validate these findings. TRIAL REGISTRATION: This research was registered in the University Hospital Medical Information Network (UMIN, UMIN000054715).

Correction: Patients with gestational diabetes mellitus may be treated in both early and late pregnancy, especially in patients with pre-pregnancy overweight: A cross-sectional study in Japan.

[This corrects the article DOI: 10.1007/s13340-023-00646-w.].

Histopathological analysis of tumor microenvironment in adrenocortical carcinoma: Possible effects of in situ disorganized glucocorticoid production on tumor immunity.

Adrenocortical carcinoma (ACC) patients with glucocorticoid excess have been reported to be associated with decreased tumor-infiltrating immune cells, but the effects of in situ glucocorticoid production on tumor immunity have remained unknown. In addition, ACC was also known to harbor marked intra-tumoral heterogeneity of steroidogenesis or disorganized steroidogenesis. Therefore, in this study, we immune-profiled tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) and pivotal steroidogenic enzymes of glucocorticoid biosynthesis (CYP17A and CYP11B1) to explore the potential effects of in situ glucocorticoid production and intra-tumoral heterogeneity/disorganized steroidogenesis on tumor immunity of ACC. We also studied the correlations of the status of tumor immunity with that of angiogenesis and tumor grade to further explore the tumor tissue microenvironment of ACC. TILs (CD3, CD4, CD8, and FOXP3), TAMs (CD68 and CD163), key steroidogenic enzymes of glucocorticoid (CYP17A and CYP11B1), angiogenesis (CD31 and vasohibin-1 (VASH-1)), tumor grade (Ki-67 and Weiss score) were immunohistochemically evaluated in 34 ACCs. Increased CYP17A immunoreactivity in the whole tumor area was significantly positively correlated with FOXP3-positive TILs (p = 0.021) and negatively with CD4/CD3 ratio (p = 0.001). Increased CYP11B1 immunoreactivity in the whole tumor area was significantly positively correlated with CD8/CD3 (p = 0.039) and CD163/CD68 ratios (p = 0.006) and negatively with CD4-positive TILs (p = 0.036) and CD4/CD3 ratio (p = 0.001). There were also significant positive correlations between CYP17A and CD8 (r = 0.334, p < 0.001) and FOXP3-positive TILs (r = 0.414, p < 0.001), CD8/CD3 ratio (r = 0.421, p < 0.001), and CD68-positive TAMs (r = 0.298, p < 0.001) in randomly selected areas. Significant positive correlations were also detected between CYP11B1 and CD8/CD3 ratio (r = 0.276, p = 0.001) and negative ones detected between CYP11B1 and CD3- (r = -0.259, p = 0.002) and CD4-positive TILs (r = -0.312, p < 0.001) in those areas above. Increased micro-vessel density (MVD) -VASH-1 was significantly positively correlated with CD68- (p = 0.015) and CD163-positive TAMs (p = 0.009) and CD163/CD68 ratio and the high VASH-1 with CD163-positive TAMs (p = 0.042). Ki-67 labeling index was significantly positively correlated with MAD-VASH-1 (p = 0.006) and VASH-1 (p = 0.006) status. Results of our present study indicated that in situ glucocorticoid production did influence the status of tumor immunity in ACC. In particular, increased levels of CYP17A and CYP11B1, both involved in glucocorticoid producing immunoreactivity played different effects on tumor immunity, i.e., reflecting the involvement of intra-tumoral heterogeneity and disorganized steroidogenesis of ACC, which also did indicate the importance of in situ approaches when analyzing tumor immunity of ACC.

Patients with gestational diabetes mellitus may be treated in both early and late pregnancy, especially in patients with pre-pregnancy overweight: A cross-sectional study in Japan.

The significance of diagnosing gestational diabetes mellitus (GDM) in early pregnancy is controversial. We used the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria to investigate whether clinical background and neonatal outcomes differ depending on when GDM is diagnosed in early or late pregnancy. This was a single-center, observational study conducted between November 2012 and March 2020 at St. Marianna University Hospital (Kawasaki, Japan). We compared the background and perinatal outcomes of patients with GDM depending on the time of diagnosis (at < 24 gestational weeks or ≥ 24 weeks). Insulin sensitivity index, homeostasis model assessment of insulin resistance, and ß-cell function were calculated from a 75-g oral glucose tolerance test. Stratified analysis was performed by pre-pregnancy BMI in patients with early GDM. As a result, in the 507 patients, 89.9% gave birth at our hospital. The pre-pregnancy BMI was significantly higher in patients with early GDM than in those with late GDM (the median [interquartile range], 22.7 [20.3, 26.3] and 21.5 [19.3, 23.8] kg/m2, respectively; p = 0.001). Perinatal outcomes were not different between the two groups. However, in the subgroup analysis of patients with early GDM, the prevalence of large-for-gestational-age infants was significantly higher in the group with overweight (15.4% vs 2.1%, respectively; p = 0.008). In conclusion, patients with GDM using the IADPSG criteria in early pregnancy may be treated, especially in patients with pre-pregnancy overweight.

A rare case of multiple paragangliomas in the head and neck, retroperitoneum and duodenum: A case report and review of the literature.

Pheochromocytomas and paragangliomas (PGLs) are rare non-epithelial neuroendocrine neoplasms of the adrenal medulla and extra-adrenal paraganglia respectively. Duodenal PGL is quite rare and there are only two previous reports. Herein, we report a case of multiple catecholamines (CAs)-producing PGLs in the middle ear, retroperitoneum, and duodenum, and review the literature of duodenal PGLs. A 40-year-old man complained right-ear hearing loss, and an intracranial tumor was suspected. Magnetic resonance imaging of the head revealed a 3-cm mass at the right transvenous foramen, which was surgically resected following preoperative embolization. The pathological diagnosis was a sympathetic PGL of the right middle ear. Six years later, family history of PGL with germline mutation of succinate dehydrogenase complex iron sulfur subunit B, SDHB: c.268C>T (p.Arg90Ter) was clarified. The patient had elevated levels of plasma and urine CAs again. Abdominal computed tomography scanning revealed two retroperitoneal tumors measuring 30-mm at the anterior left renal vein and 13-mm at near the ligament of Treitz. The larger tumor was laparoscopically resected, but the smaller tumor was not identified by laparoscopy. After the operation, the patient remained hypertensive, and additional imaging tests suggested a tumor localized in the duodenum. The surgically resected tumor was confirmed to be a duodenal PGL. After that, the patient remained hypertension free, and urinary levels of noradrenaline and normetanephrine decreased to normal values. No recurrence or metastasis has been found at 1 year after the second operation. CAs secretion from PGLs in unexpected location, like the duodenum of our patient, may be overlooked and leads to a hypertensive crisis. In such cases, comprehensive evaluation including genetic testing, fluorodeoxyglucose-positron emission tomography scanning, and measurement of CAs will be useful for detecting PGLs. Most previous reports on duodenal PGL were gangliocytic PGL which has been renamed composite gangliocytoma/neuroma and neuroendocrine tumor, and defined the different tumor from duodenal PGL. We reviewed and discussed duodenal PGLs in addition to multiple PGLs associated with SDHB mutation.

Effects of resistance training using elastic bands on muscle strength with or without a leucine supplement for 48 weeks in elderly patients with type 2 diabetes.

Type 2 diabetes is associated with sarcopenia. Resistance training and appropriate nutritional therapy are reported to be effective for muscle strength and mass. This study aimed to evaluate the effect of resistance training using elastic bands at home combined with a leucine-rich amino acid supplement on muscle strength, physical function, and muscle mass in elderly type 2 diabetes. We conducted a 48-week prospective single-center randomized controlled trial in 60 patients who were randomly allocated to one of three groups: control (C), resistance exercise (R), and resistance exercise plus supplement (RL). R and RL groups performed daily bodyweight resistance training with elastic bands exercises at home, and the RL group also took 6 g of a leucine-rich amino acid supplement daily. Knee extension strength (muscle strength), grip strength, usual gait speed (physical function), muscle mass, and cognitive function were assessed at 0 and 48 weeks. Although the change in knee extension strength from baseline was significantly increased by 6.4 Nm (95% CI 1.0, 11.7) in the RL group (p = 0.036), no significant difference was observed among the three groups (p = 0.090). Physical function, muscle mass, and cognitive function also had no changes during the study period among the three groups. No additive effect of a leucine-rich amino acid supplement on muscle strength or mass was observed. Although a post hoc analysis comparing with or without resistance training (C group vs. R + RL group) found that knee extension strength was significantly increased (p = 0.028), and cognitive decline was less (p = 0.046) than in the C group.

Differing Effect of the Sodium-Glucose Cotransporter 2 Inhibitor Ipragliflozin on the Decrease of Fat Mass vs. Lean Mass in Patients With or Without Metformin Therapy.

BACKGROUND: We previously reported changes of body composition determined by dual-energy X-ray absorptiometry after treatment with ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. In that study, mean body weight was decreased by 3.5 kg (4.3% of the baseline value) after ipragliflozin treatment at 50 mg/day, with fat mass and lean mass showing similar reductions of 1.7 and 1.8 kg, respectively. A long-term decrease of lean mass in patients treated with SGLT2 inhibitors may be associated with loss of skeletal muscle, which could potentially have an impact on quality of life. METHODS: In this post hoc analysis, we investigated whether changes of body composition were influenced by other medications for diabetes in 20 patients (11 men and nine women) who received ipragliflozin for 24 weeks. RESULTS: When we divided the patients into two subgroups with or without metformin treatment, fat mass showed a significant decrease in the ipragliflozin + metformin subgroup and a significantly greater decrease compared to the ipragliflozin subgroup (2.0 kg; 95% confidence interval (CI): 0.1 - 3.9; P = 0.038). Lean mass was significantly decreased in the ipragliflozin subgroup, but the decrease showed no significant difference from that in the ipragliflozin + metformin subgroup (1.9 kg; 95% CI: -4.1 - 0.3; P = 0.087). No significant differences of body composition changes were observed with other antidiabetic agents. CONCLUSIONS: More desirable weight reduction due to preferential fat loss and less muscle loss may be achieved by combining an SGLT2 inhibitor with metformin.

Association of the muscle/fat mass ratio with insulin resistance in gestational diabetes mellitus.

This study assessed the association of muscle mass with insulin resistance, evaluated from the insulin sensitivity index (ISI), in Japanese patients with gestational diabetes mellitus (GDM). Consecutive patients with GDM (n = 96) admitted to St. Marianna University Hospital between October 2015 and March 2018 for initial education and glycemic control were enrolled in a prospective observational study. Insulin resistance was evaluated by measuring the ISI and body composition was assessed by bioelectrical impedance analysis. The subjects were aged 34.4 ± 4.8 years (mean ± SD) and their body mass index (BMI) before pregnancy was 22.3 ± 4.0 kg/m2. Fifty-three patients (55.2%) had a history of diabetes in first-degree relatives. The ISI was 7.2 ± 3.3, appendicular skeletal muscle mass (ASM) was 17.0 ± 2.1 kg, and fat mass (FM) was 18.8 ± 8.2 kg. The ASM/FM ratio was 1.02 ± 0.34. There was a positive correlation between FM and ASM (r = 0.734, p < 0.001). To adjust for confounders when evaluating the association of ASM with ISI, multivariate analysis was conducted using age, family history of diabetes, and BMI as variables. In this analysis, the ASM/FM ratio showed a significant positive correlation with ISI (ß = 0.303, p = 0.020). These findings suggest that inadequate ASM/FM ratio is important for the development of insulin resistance in Japanese patients with GDM. Excessive emphasis on dieting rather than health might increase the risk of GDM by reducing the muscle mass below the level that maintains normal glucose metabolism.