Multiple endocrine neoplasia type 1 with MEN1 variant of unknown significance, in a patient after the diagnosed of pancreatic neuroendocrine neoplasia.

Duodenopancreatic neuroendocrine neoplasia (DP-NEN) is in approximately 10% of cases of multiple endocrine neoplasia type 1 (MEN1). We encountered a case in which the onset of NEN led to suspicion and diagnosis of MEN1. Although genetic testing showed MEN1 variant of uncertain significance (VUS), we considered it pathological from the clinical course, promoting the provision of genetic counseling and screening for relatives. MEN1 has a variety of clinical manifestations, and DP-NENs are the second-most common manifestation after primary hyperparathyroidism (pHPT). It is important to assume that MEN1 is an underlying cause of NEN.

Inhibition of IL-33 signaling ameliorate hepatic fibrosis with decreasing MCP-1 in a mouse model of diabetes and non-alcoholic steatohepatitis; comparison for luseogliflozin, an SGLT2 inhibitor.

Non-alcoholic fatty liver disease (NAFLD) is increasing globally, and seeking therapeutic molecule targets is urgent. Several studies have demonstrated that IL-33 plays an important role in the progression of Non-alcoholic steatohepatitis (NASH) with fibrosis and the proliferation of hepatocellular carcinoma (HCC). However, whether the inhibition of IL-33 signaling prevents NAFLD from progressing to NASH and HCC has not been clarified. We investigated the effects of a novel antibody, IL-33RAb, and luseogliflozin, a SGLT2 inhibitor, when administered to a model mouse for NASH and HCC, and their effects were compared to investigate the mechanisms of how IL-33 is involved in the pathogenesis of NASH progression. Compared with the positive control of luseogliflozin, inhibition of IL-33 signaling ameliorated decreasing hepatic fibrosis via decreasingαSMA and MCP-1, and also partially suppressed the progression of the HCC cell line in in vitro experiments. These findings suggest that inhibition of IL-33 possibly prevents progression from NASH to HCC, and their effect may be a newly arrived therapeutic agent.

Relationship between reduced heart rate variability and increased arterial stiffness evaluated by the cardio-ankle vascular index in people with type 2 diabetes.

Objective: Cardiac autonomic neuropathy (CAN) is an independent risk factor for cardiovascular mortality and also is associated with a high risk of lethal arrhythmias and sudden death in people with type 1 or 2 diabetes. Heart rate variability (HRV) is an index of cardiac autonomic function. To investigate the relationship between HRV and arterial stiffness evaluated by the cardio-ankle vascular index (CAVI), a relatively new marker for arterial stiffness and a predictor of cardiovascular disease, in patients with type 2 diabetes. Materials and methods: We studied consecutive 313 patients with type 2 diabetes in a cross-sectional design. HRV was estimated by the coefficient of variation of 100 R-R intervals (CVR-R) at rest and during deep breathing (DB). The difference in CVR-R was defined as CVR-R during DB minus CVR-R at rest. Arterial stiffness was evaluated by CAVI, which is independent of blood pressure (BP). A CAVI greater than or equal to 9.0 was defined as significant arterial stiffening. Results: Linear regression analysis showed that CAVI correlated positively with age, duration of diabetes, urinary albumin creatinine ratio (UACR), CVR-R during DB, and the difference in CVR-R and negatively with body mass index (BMI), estimated glomerular filtration rate, and sensory nerve conduction velocity and action potential of the sural nerve. Multivariate analysis found that age, BMI, systolic blood pressure, UACR, and CVR-R during DB were independently associated with arterial stiffness determined by CAVI. The CVR-R at rest and during deep breathing was significantly lower in the patients with arterial stiffness than in those without it. Conclusion: Low HRV estimated by CVR-R during DB is closely associated with arterial stiffness measured by CAVI in people with type 2 diabetes, suggesting that arterial stiffness associated with CAN may be an independent risk factor for cardiovascular disease in people with type 2 diabetes. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-022-00604-y.

Increased Number of Mucosal-Associated Invariant T Cells Is Associated with the Inhibition of Nonalcoholic Fatty Liver Disease in High Fat Diet-Fed Mice.

Nonalcoholic fatty liver disease (NAFLD) is an emerging worldwide health concern. The disease may involve immune cells including T cells, but little is known about the role(s) of the innate-like T cells in the liver. Furthermore, the most abundant innate-like T cells in the human liver are mucosal-associated invariant T (MAIT) cells, but the involvement of MAIT cells in NAFLD remains largely unexplored because of their paucity in mice. In this study, we used a novel mouse line, Vα19, in which the number of MAIT cells is equivalent to or greater than that in humans. Compared with the control mice, Vα19 mice fed a high-fat diet (HFD) exhibited a reduction in lipid accumulation, NAFLD activity score, and transcripts relevant to lipogenesis. In addition, serum triglyceride and non-esterified fatty acids were lower in Vα19 mice fed normal chow or HFD. In contrast, the Vα19 mice showed little or no change in glucose tolerance, insulin sensitivity, inflammation in adipose tissues, or intestinal permeability compared with the controls, irrespective of diet. These results suggest that the presence of MAIT cells is associated with reduced lipogenesis and lipid accumulation in the liver; however, further studies are needed to clarify the role of MAIT cells in hepatic lipid metabolism.

Serum high-molecular-weight adiponectin and response to dapagliflozin in patients with type 2 diabetes and non-alcoholic fatty liver disease.

A better baseline renal function is associated with a better response to sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes. Low serum adiponectin is associated with visceral fat accumulation and hepatic steatosis. We investigated the relationship between baseline serum adiponectin and glycemic response to dapagliflozin in patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). In a randomized, active-controlled, open-label trial, 57 patients with type 2 diabetes and NAFLD were randomized to either the dapagliflozin (5 mg/d) group or the control group. Both groups were treated for 24 weeks. Serum high-molecular-weight (HMW) adiponectin was measured with an ELISA kit. Visceral fat area (VFA) was measured by dual bioelectrical impedance analysis. Hepatic steatosis was assessed by the controlled attenuation parameter (CAP) measured by a transient elastography (FibroScan). Treatment with dapagliflozin significantly decreased HbA1c from 8.4%±1.5% at baseline to 7.4%±1.2% at 24 weeks. Both VFA and CAP decreased in the dapagliflozin group. Baseline serum HMW adiponectin was negatively correlated with changes in HbA1c from baseline to 24 weeks with dapagliflozin therapy. In the multivariate analysis, baseline HbA1c (ß=-0.559, p=0.002) and serum HMW adiponectin (ß=0.471, p=0.010) were independent determinants for the change (reduction) in HbA1c. In the dapagliflozin group, the change in HbA1c was positively correlated with the changes of CAP, but negatively correlated with the change in serum HMW adiponectin. In conclusion, a lower serum level of HMW adiponectin was associated with a better response to dapagliflozin in patients with type 2 diabetes and NAFLD.Trial registration numberUMIN000022155.

Concurrent variant type 3 autoimmune polyglandular syndrome and pulmonary arterial hypertension in a Japanese woman.

We describe a very rare case of concurrent variant type 3 autoimmune polyglandular syndrome (APS) and pulmonary arterial hypertension (PAH). A previously healthy 65-year-old Japanese woman was referred to our university hospital with a 2-month history of general fatigue and hyperglycemia. Laboratory tests revealed severe hyperglycemia (plasma glucose 543 mg/dL and HbA1c 10.7%) with ketonuria (3+). Glutamic acid decarboxylase (GAD) and IA-2 antibodies were positive, and the serum C peptide level was markedly decreased to 0.2 ng/mL. Accordingly, type 1 diabetes was diagnosed. Hashimoto's thyroiditis was also diagnosed because she had a diffuse goiter and a mild hypothyroidism (TSH 8.20 µU/mL, and FT4 0.80 ng/mL) with positive autoantibodies for thyroid peroxidase and thyroglobulin. There was neither adrenal insufficiency nor hypocalcemia. In addition, chest X ray showed a suspicious PAH by a dilation of both pulmonary arteries, especially right descending artery, and right heart catheterization confirmed the presence of PAH. HLA Class II genotyping revealed DRB1-DQB1*0901-*0303, a common susceptibility haplotype in Japanese patients with type 3 APS or acute-onset type 1 diabetes. The combination of variant type 3 APS and PAH is extremely rare and to the best of knowledge, this is the first case reported in a Japanese patient.

Effect of growth hormone replacement therapy on plasma diacron-reactive oxygen metabolites and endothelial function in Japanese patients: The GREAT clinical study.

Patients with growth hormone deficiency (GHD) have an increased risk of atherosclerosis and vascular mortality. Evidence suggests that endothelial dysfunction is involved in all stages of atherogenesis. This study examined the effect of growth hormone (GH) replacement therapy on diacron-reactive oxygen metabolites (d-ROMs) and endothelial function in Japanese patients with GHD, using peripheral arterial tonometry. This was an open-label, prospective, case-control study. Nine patients with GHD who had not previously received any GH replacement therapy were enrolled. The following parameters were evaluated at baseline (before treatment), and after 24 weeks of GH replacement therapy: endothelial function using the reactive hyperemia index (RHI; EndoPAT® system), d-ROMs, blood pressure, and fasting lipid levels. Plasma GH and insulin-like growth factor-1 (IGF-1) levels were measured at baseline and after 24 weeks of GH replacement therapy. We also enrolled eight controls with pituitary disease but no GH deficiency. Over 24 weeks of GH replacement therapy, the serum IGF-1 levels normalized with significant improvement in the RHI (from 1.65 ± 0.33 to 1.92 ± 0.26, p < 0.05) and decreased d-ROM levels (from 356.8 ± 64.1 to 303.1 ± 43.3 U.CARR, p < 0.05). There were no significant improvements in the RHI or d-ROM levels in controls. GH replacement therapy in Japanese patients with GHD may be mediated by the reduced oxidative stress and the d-ROMs associated with the treatment.

The effects of intermittent use of the SGLT-2 inhibitor, dapagliflozin, in overweight patients with type 2 diabetes in Japan: a randomized, crossover, controlled clinical trial.

BACKGROUND: This study examined the effects of short-term administration of the sodium glucose cotransporter 2 (SGLT-2) inhibitor, dapagliflozin, on visceral fat area (VFA) in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this randomized, crossover, controlled clinical trial, overweight patients with type 2 diabetes were randomized to treatment with 5 mg dapagliflozin for the first (n = 27) or second 12-week study period (n = 29). The parameters evaluated at baseline and after 12 and 24 weeks included blood pressure, hemoglobin A1c (HbA1c), body composition, VFA, and subcutaneous fat area (SFA). RESULTS: In both groups, dapagliflozin administration improved the levels of HbA1c, body weight, blood pressure, total fat mass, and VFA. Cessation of dapagliflozin, however, reversed the improvements in HbA1c, blood pressure, body weight, and SFA levels, whereas reductions in VFA and total fat mass levels were somewhat maintained even after 12 weeks without treatment. CONCLUSIONS: Dapagliflozin led to decreases in VFA and, consequently, body weight after a short treatment period. However, these effects were largely reversed by the cessation of dapagliflozin, suggesting that this agent should be administered continuously to maintain clinical usefulness in overweight patients with type 2 diabetes.