Prolonged impacts of sodium glucose cotransporter-2 inhibitors on metabolic dysfunction-associated steatotic liver disease in type 2 diabetes: a retrospective analysis through magnetic resonance imaging.

The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in people with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) have been suggested in several reports based on serological markers, imaging data, and histopathology associated with steatotic liver disease. However, evidence regarding their long-term effects is currently insufficient. In this retrospective observational study, 34 people with T2D and MASLD, treated with SGLT2 inhibitors, were examined by proton density fat fraction derived by magnetic resonance imaging (MRI-PDFF) and other clinical data before, one year after the treatment. Furthermore, 22 of 34 participants underwent MRI-PDFF five years after SGLT2 inhibitors were initiated. HbA1c decreased from 8.9 ± 1.8% to 7.8 ± 1.0% at 1 year (p = 0.006) and 8.0 ± 1.1% at 5 years (p = 0.122). Body weight and fat mass significantly reduced from baseline to 1 and 5 year(s), respectively. MRI-PDFF significantly decreased from 15.3 ± 7.8% at baseline to 11.9 ± 7.6% (p = 0.001) at 1 year and further decreased to 11.3 ± 5.7% (p = 0.013) at 5 years. Thus, a 5-year observation demonstrated that SGLT2 inhibitors have beneficial effects on liver steatosis in people with T2D and MASLD.

Novel time-resolved reporter mouse reveals spatial and transcriptional heterogeneity during alpha cell differentiation.

AIMS/HYPOTHESIS: Glucagon-expressing pancreatic alpha cells have attracted much attention for their plasticity to transdifferentiate into insulin-producing beta cells; however, it remains unclear precisely when, and from where, alpha cells emerge and what regulates alpha cell fate. We therefore explored the spatial and transcriptional heterogeneity of alpha cell differentiation using a novel time-resolved reporter system. METHODS: We established the mouse model, 'Gcg-Timer', in which newly generated alpha cells can be distinguished from more-differentiated cells by their fluorescence. Fluorescence imaging and transcriptome analysis were performed with Gcg-Timer mice during the embryonic and postnatal stages. RESULTS: Fluorescence imaging and flow cytometry demonstrated that green fluorescence-dominant cells were present in Gcg-Timer mice at the embryonic and neonatal stages but not after 1 week of age, suggesting that alpha cell neogenesis occurs during embryogenesis and early neonatal stages under physiological conditions. Transcriptome analysis of Gcg-Timer embryos revealed that the mRNAs related to angiogenesis were enriched in newly generated alpha cells. Histological analysis revealed that some alpha cells arise close to the pancreatic ducts, whereas the others arise away from the ducts and adjacent to the blood vessels. Notably, when the glucagon signal was suppressed by genetic ablation or by chemicals, such as neutralising glucagon antibody, green-dominant cells emerged again in adult mice. CONCLUSIONS/INTERPRETATION: Novel time-resolved analysis with Gcg-Timer reporter mice uncovered spatiotemporal features of alpha cell neogenesis that will enhance our understanding of cellular identity and plasticity within the islets. DATA AVAILABILITY: Raw and processed RNA sequencing data for this study has been deposited in the Gene Expression Omnibus under accession number GSE229090.

ATP6AP2 is robustly expressed in pancreatic ß cells and neuroendocrine tumors, and plays a role in maintaining cellular viability.

ATP6AP2, also known as (pro)renin receptor, has been shown to be expressed in several tissues including pancreatic ß cells. Whereas ATP6AP2 plays an important role in regulating insulin secretion in mouse pancreatic ß cells, the expression profiles and roles of ATP6AP2 in human pancreatic endocrine cells and neuroendocrine tumor cells remain unclear. Here in this study, we investigated the expression profiles of ATP6AP2 in pancreatic endocrine cells, and found that ATP6AP2 is robustly expressed in pancreatic insulinoma cells as well as in normal ß cells. Although ATP6AP2 was also expressed in low-grade neuroendocrine tumors, it was not or faintly detected in intermediate- and high-grade neuroendocrine tumors. Knockdown experiments of the Atp6ap2 gene in rat insulinoma-derived INS-1 cells demonstrated decreased cell viability accompanied by a significant increase in apoptotic cells. Taken together, these findings suggest that ATP6AP2 plays a role in maintaining cellular homeostasis in insulinoma cells, which could lead to possible therapeutic approaches for endocrine tumors.

STAT3 suppression and ß-cell ablation enhance α-to-ß reprogramming mediated by Pdx1.

As diabetes results from the absolute or relative deficiency of insulin secretion from pancreatic ß cells, possible methods to efficiently generate surrogate ß cells have attracted a lot of efforts. To date, insulin-producing cells have been generated from various differentiated cell types in the pancreas, such as acinar cells and α cells, by inducing defined transcription factors, such as PDX1 and MAFA, yet it is still challenging as to how surrogate ß cells can be efficiently generated for establishing future regenerative therapies for diabetes. In this study, we demonstrated that the exogenous expression of PDX1 activated STAT3 in α cells in vitro, and STAT3-null PDX1-expressing α cells in vivo resulted in efficient induction of α-to-ß reprogramming, accompanied by the emergence of α-cell-derived insulin-producing cells with silenced glucagon expression. Whereas ß-cell ablation by alloxan administration significantly increased the number of α-cell-derived insulin-producing cells by PDX1, STAT3 suppression resulted in no further increase in ß-cell neogenesis after ß-cell ablation. Thus, STAT3 modulation and ß-cell ablation nonadditively enhance α-to-ß reprogramming induced by PDX1, which may lead to the establishment of cell therapies for curing diabetes.

Synchronous primary malignancies in ovarian cancer and liver angiosarcoma.

•A case of concurrent primary ovarian clear cell adenocarcinoma and liver angiosarcoma is detailed herein.•If a liver tumor is found together with ovarian cancer, it is necessary to determine whether this is a primary hepatic malignancy or metastatic liver cancer.•It is important to make a definitive diagnosis by performing a liver biopsy when appropriate.

Complete resection after pembrolizumab treatment followed by salvage surgery in stage IVB endometrial cancer: A case report.

INTRODUCTION: There is little evidence regarding the treatment of stage IVB endometrial cancer. Therefore, chemotherapy is more likely to be chosen as the initial and first-line treatment. Pembrolizumab is a new treatment choice for unresectable endometrial cancer after first-line chemotherapy failure. PRESENTATION OF CASE: Herein, we report the case of a 56-year-old patient diagnosed with stage IVB endometrial cancer. After eight cycles of first-line chemotherapy, computed tomography (CT) revealed relapse with re-enlargement of the para-aortic lymph nodes. Since the primary tumour had high microsatellite instability, we switched to pembrolizumab treatment. Pembrolizumab was effective but could not be continued due to adverse events after 10 cycles. Positron emission tomography-CT revealed active cancer in the uterus and para-aortic lymph nodes. DISCUSSION: Since pembrolizumab treatment had to be discontinued, we performed salvage surgery, which achieved complete tumour removal, and the patient has had no evidence of disease for 16 months. CONCLUSION: This is the first case of complete surgical resection after administering pembrolizumab as a second-line treatment for advanced endometrial cancer.

Effects of luseogliflozin on the secretion of islet hormones and incretins in patients with type 2 diabetes.

The insufficient activity of insulin and the hyperactivity of glucagon are responsible for glucose intolerance in patients with type 2 diabetes. Whereas sodium-glucose cotransporter-2 (SGLT2) inhibitors improve blood glucose levels in patients with type 2 diabetes, their effects on the secretion profiles of glucagon and incretins remain unclear. Therefore, to investigate the effects of the SGLT2 inhibitor luseogliflozin on metabolic and endocrine profiles, 19 outpatients with type 2 diabetes were administered luseogliflozin for 12 weeks. It is of note that all subjects were treated only with diet and exercise therapy, and we were able to investigate the effects of luseogliflozin separately from the effects of other antidiabetic agents. Body weight, body fat mass, fat-free mass, and muscle mass were significantly reduced after 12 weeks of luseogliflozin administration. Glycosylated hemoglobin significantly decreased from the baseline of 8.2% ± 0.8% to 7.3% ± 0.7% (p < 0.0001). The meal tolerance test demonstrated that luseogliflozin significantly recovered glucose tolerance, accompanied by improved insulin resistance and ß-cell function, whereas glucagon secretion was unaffected. Furthermore, GLP-1 secretion was significantly increased after luseogliflozin administration. Thus, luseogliflozin improved metabolic and endocrine profiles accompanied by increased GLP-1 secretion in type 2 diabetic patients without any antidiabetic medication, but did not affect glucagon secretion.

Increased glycated albumin levels in patients with acromegaly related to glucose fluctuation caused by growth hormone excess but not albumin metabolism.

Acromegaly is often complicated by impaired glucose tolerance. The accuracy of glycated hemoglobin (HbA1c) and glycated albumin (GA) levels in representing glycemic profiles in patients with endocrine disorders, such as acromegaly, is unclear. This retrospective study reviewed data from patients whose GA levels had been recorded. 14 patients with acromegaly without diabetes mellitus (DM) (the acromegaly group), 15 patients with severe adult GH deficiency without DM (the growth hormone deficiency (GHD) group), and 55 nondiabetic patients (the control group) were included in this study. GA levels were significantly increased in the acromegaly group compared with the control and GHD groups, but no significant differences were observed between the control and GHD groups. The three groups were matched using propensity score matching (13 patients with acromegaly, 13 with GHD, and 13 control patients). Nonetheless, the results after matching were the same as those before matching. GA levels in the acromegaly group were significantly associated with plasma glucose (PG) levels at 0, 30, and 120 min after a 75-g oral glucose tolerance test (OGTT). Further, GH levels at 120 min after a 75-g OGTT in the acromegaly group were significantly correlated with GA levels and the difference in PG levels at baseline and 30 min. Our findings suggest that increases in PG levels attributable to excess GH after glucose loading are related to increases in GA levels in patients with acromegaly without DM. Hence, both HbA1c and GA should be checked to accurately assess impaired glucose tolerance in patients with acromegaly.

Improved AcroQoL scores in acromegaly after sagittal split ramus osteotomy with Le Fort I osteotomy.

SUMMARY: Acromegaly is associated with a low quality of life (QoL), which is partially attributable to appearance. However, appearance changes are only partially reversible with treatments of growth hormone excess. This case study describes a 41-year-old Japanese man who presented with mandibular prognathism. Acromegaly was suspected because of the patient's facial features. Subsequent examination revealed a pituitary tumour with elevated levels of growth hormone and insulin-like growth factor 1 (IGF1), confirming a diagnosis of acromegaly. We assessed his QoL with the acromegaly QoL questionnaire (AcroQoL) before transsphenoidal surgery, and all AcroQoL scores were low. Although the pituitary adenoma was resected, his serum IGF1 levels started to increase again and MRI identified a residual pituitary lesion. After lanreotide and pegvisomant injection therapies improved his serum IGF1 levels, we reassessed his AcroQoL scores, however, the results showed worsening scores regarding appearance and personal relationships, and the patient expressed interest in surgery for mandibular prognathism. We performed sagittal split ramus osteotomy (SSRO) with Le Fort I osteotomy, thus, the patient's AcroQoL scores improved. This case shows that SSRO with Le Fort I osteotomy for mandibular prognathism, rather than control of serum IGF1 level alone, improved the patient's AcroQoL score, especially for both psychological well-being and approval of appearance. Acromegaly has many complications, including its negative impact on patients' perception of their appearance and patients' QoL can be improved using multiple options, in addition to controlling growth hormone levels. LEARNING POINTS: The patient's AcroQoL scores worsened despite biochemical normalization of IGF-1 levels. Mandibular prognathism due to acromegaly can be successfully operated by performing sagittal split ramus osteotomy with Le Fort I osteotomy. Frequent monitoring of AcroQoL scores and appropriate response to negative results can improve the overall QoL.

A case of adrenocortical adenoma harboring venous thrombus mimicking adrenal malignancy.

Advances in imaging technology and its widespread use have increased the number of identified patients with bilateral adrenal incidentalomas. The pathology of bilateral adrenal incidentalomas is gradually elucidated by its increased frequency. Although there is no consensus regarding the optimal management of bilateral adrenal lesions, adrenal lesions that are a suspected adrenocortical carcinoma on the basis of radiological imaging require surgical resection. We report a clinically interesting case of a 59-year-old female with adrenocortical adenoma harboring venous thrombus that mimicked adrenal malignancy. She was referred for evaluation of asymptomatic asymmetric lesions on both adrenal glands. Abdominal computed tomography and magnetic resonance imaging showed a 4.7-cm-diameter heterogenous lesion with peripheral enhancement in the right adrenal gland and a 2.0-cm-diameter homogenous lesion in the left adrenal gland. Adrenal scintigraphy with 131I-adosterol exhibited marked accumulation in the left lesion and slight accumulation in the middle inferior portion of the right lesion. Endocrine data revealed subclinical Cushing syndrome, and the patient underwent right laparoscopic adrenalectomy. The serum cortisol level was not suppressed on an overnight dexamethasone suppression test after the adrenalectomy. The resected tumor revealed a cortisol-producing adrenocortical adenoma harboring an organized and re-canalized venous thrombus, which was associated with focal papillary endothelial hyperplasia. This case illustrates the difficulty with preoperatively diagnosing this heterogeneously enhanced large benign adrenal lesion and differentiating it from adrenocortical carcinoma or angiosarcoma.

Suprabasin-derived bioactive peptides identified by plasma peptidomics.

Identification of low-abundance, low-molecular-weight native peptides using non-tryptic plasma has long remained an unmet challenge, leaving potential bioactive/biomarker peptides undiscovered. We have succeeded in efficiently removing high-abundance plasma proteins to enrich and comprehensively identify low-molecular-weight native peptides using mass spectrometry. Native peptide sequences were chemically synthesized and subsequent functional analyses resulted in the discovery of three novel bioactive polypeptides derived from an epidermal differentiation marker protein, suprabasin. SBSN_HUMAN[279-295] potently suppressed food/water intake and induced locomotor activity when injected intraperitoneally, while SBSN_HUMAN[225-237] and SBSN_HUMAN[243-259] stimulated the expression of proinflammatory cytokines via activation of NF-κB signaling in vascular cells. SBSN_HUMAN[225-237] and SBSN_HUMAN[279-295] immunoreactivities were present in almost all human organs analyzed, while immunoreactive SBSN_HUMAN[243-259] was abundant in the liver and pancreas. Human macrophages expressed the three suprabasin-derived peptides. This study illustrates a new approach for discovering unknown bioactive peptides in plasma via the generation of peptide libraries using a novel peptidomic strategy.

Effects of canagliflozin on body composition and hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease.

AIMS/INTRODUCTION: Non-alcoholic fatty liver disease is frequently associated with type 2 diabetes, and constitutes an important risk factor for the development of hepatic fibrosis and hepatocellular carcinoma. Because there remains no effective drug therapy for non-alcoholic fatty liver disease associated with type 2 diabetes, we evaluated the efficacy of sodium-glucose cotransporter 2 inhibitor. METHODS AND MATERIALS: In the present pilot, prospective, non-randomized, open-label, single-arm study, we evaluated the effect of 100 mg canagliflozin administered once daily for 12 months on serological markers, body composition measured by bioelectrical impedance analysis method and hepatic fat fraction measured by magnetic resonance imaging in type 2 diabetes patients with non-alcoholic fatty liver disease. RESULTS: Canagliflozin significantly reduced body and fat mass, and induced a slight decrease in lean body or muscle mass that did not reach significance at 6 and 12 months. Reductions in fat mass in each body segment (trunk, arms and legs) were evident, whereas those in lean body mass were not. The hepatic fat fraction was reduced from a baseline of 17.6 ± 7.5% to 12.0 ± 4.6% after 6 months and 12.1 ± 6.1% after 12 months (P < 0.0005 and P < 0.005), whereas serum liver enzymes and type IV collagen concentrations improved. From a mean baseline hemoglobin A1c of 8.7 ± 1.4%, canagliflozin significantly reduced hemoglobin A1c after 6 and 12 months to 7.3 ± 0.6% and 7.7 ± 0.7% (P < 0.0005 and P < 0.01). CONCLUSIONS: Canagliflozin reduced body mass, fat mass and hepatic fat content without significantly reducing muscle mass.