Serum levels of soluble dipeptidyl peptidase-4 in type 2 diabetes are associated with severity of liver fibrosis evaluated by transient elastography (FibroScan) and the FAST (FibroScan-AST) score, a novel index of non-alcoholic steatohepatitis with significant fibrosis.

AIM: To investigate the relationship in people with type 2 diabetes between serum soluble dipeptidyl peptidase-4 (sDDP-4) and degree of liver fibrosis assessed as the liver stiffness measurement (LSM) and FAST (FibroScan-AST) score, both of which were measured by transient elastography (FibroScan). SUBJECTS AND METHODS: In this cross-sectional study, we examined 115 patients with type 2 diabetes. With transient elastography (FibroScan), we assessed the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) as measures of hepatic steatosis and liver fibrosis, respectively. We calculated the FAST score, which identifies progressive non-alcoholic steatohepatitis (NASH), from CAP, LSM, and the serum aspartate aminotransferase level. Significant hepatic steatosis was defined as CAP ≥280 dB/m; and significant liver fibrosis, as LSM ≥ 8.0 kPa. LSM was divided into 3 severity levels: significant fibrosis (8.0 to <9.7 kPa); advanced fibrosis, (9.7 to <13.0 kPa); and liver cirrhosis (≥ 13.0 kPa). RESULTS: Serum sDPP-4 correlated positively with liver enzymes, CAP, LSM, and FAST score. Multivariate analysis showed that LSM remained to be an independent factor for serum sDDP-4. Serum sDPP-4 was significantly higher in patients with LSM ≥ 8.0 kPa than in those with LSM <8.0 kPa and was significantly elevated in patients who are at risk for non-alcoholic steatohepatitis (NASH) with fibrosis (FAST score ≥ 035 or 0.67). Patients with both hepatic steatosis and liver fibrosis had the highest serum sDPP-4. CONCLUSION: Serum sDPP-4 was strongly associated with severity of liver fibrosis evaluated by LSM and the FAST score and was markedly elevated in diabetic patients with LSM ≥ 13.0 kPa indicating probable cirrhosis.

Genetic alteration of ARMC5 in a patient diagnosed with meningioma and primary macronodular adrenal hyperplasia: a case report.

A monoallelic germline alteration of ARMC5 causes primary bilateral macronodular adrenal hyperplasia (PBMAH) with Cushing's syndrome via its subsequent somatic alteration on the other allele as the second hit. PBMAH is sometimes complicated with meningioma. Dependency of such a multi-organ disease on the second hit mechanism was reported before, but this finding has not been confirmed yet. We describe a case of a 65-year-old female with PBMAH, carrying a heterozygous germline alteration of ARMC5, p.R267*, complicated with meningioma associated with somatic loss of heterozygosity (LOH) of the unaffected allele. Pathogenic alterations of ARMC5 may also contribute to the development of meningioma by the two-hit mechanism.

Teneligliptin, a DPP-4 Inhibitor, Decreases Plasma Levels of Inflammatory Chemokines During a Standard Meal Test in Patients With Type 2 Diabetes.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) rapidly inactivates incretin hormones and several chemokines, thus influencing chemokine function. There have recently been several reports that DPP-4 inhibitor therapy is associated with an increased risk of bullous pemphigoid (BP), an autoimmune skin disease. Previous studies have demonstrated an increase of CCL11/Eotaxin, a DPP-4 substrate, in serum and blister fluid from patients with BP. Serum levels of CCL22/macrophage-derived chemokine (MDC) and CXCL10/IP-10, other DPP-4 substrates, are also elevated in BP patients. MATERIALS AND METHODS: In patients with type 2 diabetes, we investigated the effect of treatment with teneligliptin (a DPP-4 inhibitor) for 24 weeks on plasma levels of CCL11/Eotaxin, CCL22/MDC and CXCL10/IP-10 during a meal test. Ten consecutive patients with type 2 diabetes who showed inadequate glycemic control by metformin and/or sulfonylureas were recruited. A standard meal test was performed at baseline and after 24 weeks of treatment with teneligliptin at 20 mg/day. Blood samples were collected at 0, 30, 60 and 120 minutes after ingestion of the meal. In addition to plasma levels of the 3 chemokine, plasma DPP-4 enzyme activity and soluble DPP-4 antigen were measured. RESULTS: Treatment with teneligliptin decreased hemoglobin A1c and reduced fasting plasma DPP-4 activity by 90.1% compared with baseline. Unexpectedly, plasma levels of all 3 chemokines (including CCL11/Eotaxin) were not increased after teneligliptin treatment, and instead were significantly lower at every point during the meal test. CONCLUSIONS: Teneligliptin reduced the plasma concentrations of 3 chemokines (DPP-4 substrates) that may be related to the occurrence of DPP4 inhibitor-associated BP (UMIN000012508).

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.

Efficacy of Additional Canagliflozin Administration to Type 2 Diabetes Patients Receiving Insulin Therapy: Examination of Diurnal Glycemic Patterns Using Continuous Glucose Monitoring (CGM).

INTRODUCTION: The efficacy of administering a sodium-glucose cotransporter 2 inhibitor during insulin therapy has not been established. In this study, we examined its effects based on diurnal glycemic patterns using continuous glucose monitoring (CGM). METHODS: The subjects were 15 patients who had received insulin therapy for 1 year or more. A CGM device was attached to all subjects for 1 week. The administration of canagliflozin at 100 mg was started 4 days after attachment. The mean glucose concentrations, standard deviation (SD), mean amplitude of glycemic excursions (MAGE), mean of daily difference of blood glucose (MODD), and area under the curve (AUC) (≥180, <70 mg h/dL) after the start of administration were compared with the pretreatment values. In addition, we compared changes in the number of insulin units between basal and bolus insulin. Furthermore, we investigated the influence of canagliflozin on oxidative stress markers and cytokines using 8-hydroxy-2'-deoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α), and adiponectin as parameters. RESULTS: The mean glucose concentrations decreased from 161.1 to 139.1 mg/dL (P < 0.01). The SD decreased from 36.5 to 29.6 mg/dL (P = 0.05). The MAGE decreased from 89.2 to 77.4 mg/dL (P < 0.01), and the MODD decreased from 34.3 to 25.5 mg/dL (P < 0.05). All parameters showed significant improvements in diurnal changes. AUC of ≥180, i.e., the total area of blood glucose levels at or above 180 on the blood glucose curve of CGM, decreased from 339.1 to 113.6 mg/dL (P < 0.05). AUC of <70, i.e., the total area of blood glucose levels below 70 on the blood glucose curve of CGM, slightly decreased from 1.6 to 0.3 mg/dL (P = 0.08). The total number of basal insulin units decreased from 128 to 76, and that of bolus insulin decreased from 266 to 154; the dose of insulin could be markedly decreased. In addition, the mean 8-OHdG level decreased from 11.4 to 10.8 ng/mg Cre (P < 0.05), and the mean TNF-α level decreased from 2.31 to 1.79 pg/mL (P = 0.10). The mean adiponectin level increased from 5.01 to 5.53 µg/mL (P < 0.05). CONCLUSION: Canagliflozin improved blood glucose changes in type 2 diabetes using insulin. In addition, the results suggest its antioxidant actions. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN no. 000019429).