Iron overload may be critical for liver dysfunction in anorexia nervosa, and the role of haematocrit-adjusted albumin in assessing nutritional status: a case report.

BACKGROUND: Anorexia nervosa (AN) is frequently associated with liver dysfunction, but the precise mechanism remains undefined. Since the nutritional marker albumin has a low correlation with changes in body weight in AN, and patients with AN often have dehydration as a complication, we also examined whether haematocrit (HCT)-adjusted serum albumin could be a better nutritional marker in AN. CASE PRESENTATION: We describe a 15-year-old girl with severe weight loss and liver damage whose liver enzymes normalized after 1.5 months of hospitalization and weight gain. We found a significant correlation between body weight (BW) and HCT-adjusted serum albumin (Spearman's rank correlation coefficient (rs) = 0.66, P = 5.28 × 10-3) and between BW and alanine aminotransferase (ALT) (rs = -0.825, P = 8.45 × 10-5). After division by HCT, correlations between serum albumin and ALT (rs = -0.835, P = 5.24 × 10-5) and between the iron-storage protein ferritin and the liver enzyme gamma-glutamyl transferase (rs = 1.0, P = 0.017) were also statistically significant. CONCLUSION: These results suggest that improvement of the nutritional status in AN could relieve liver dysfunction and facilitate iron transport. Since a decrease in the iron-transport protein transferrin presumably increases labile non-transferrin-bound iron, resulting in excess reactive oxygen species production, a defect in iron transport due to malnutrition could be one of the causes of liver injury in AN. In addition, HCT-adjusted albumin could be a better marker than its raw data to assess changes in nutritional status in AN.

Association of high proprotein convertase subtilisin/kexin type 9 antibody level with poor prognosis in patients with diabetes: a prospective study.

In addition to pathogenic autoantibodies, polyclonal autoantibodies with unknown physiological roles and pathogenicity are produced in the body. Moreover, serum antibodies against the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, which is integral to cholesterol metabolism, have also been observed. PCSK9 was also reported to be associated with insulin secretion and diabetes mellitus (DM). Therefore, we aimed to examine the clinical significance of PCSK9 antibodies (PCSK9-Abs) levels. We measured blood PCSK9-Abs and PCSK9 protein levels in 109 healthy donors (HDs) and 274 patients with DM (type 2 DM: 89.8%) using an amplified luminescence proximity homogeneous assay-linked immunosorbent assay. Subsequently, patients with DM were followed up (mean: 4.93 years, standard deviation: 2.77 years, maximum: 9.58 years, minimum: 0.07 years) to examine associations between antibody titers and mortality, myocardial infarction, stroke onset, and cancer. The primary endpoint of this study was to examine whether PCSK9-Abs can be a prognostic marker for overall mortality among the patients with diabetes. The secondary endpoint was to examine the relationship between PCSK9-Abs and clinical parameters. Although both PCSK9-Abs and PCSK9 protein levels were significantly higher in the DM group than in the HD group (p < 0.008), PCSK9-Abs and PCSK9 protein levels showed no correlation in either group. Mortality was significantly associated with higher PCSK9-Ab levels, but unrelated to PCSK9 protein levels. After investigating for potential confounding factors, higher PCSK9-Ab levels were still associated with increased mortality among the patients with DM. PCSK9-Abs may be a novel prognostic marker for overall mortality in patients with diabetes, and further studies are warranted to verify its usefulness.

A case of doxorubicin and cyclophosphamide therapy-induced type 1 diabetes: a case report.

BACKGROUND: Patients receiving immune checkpoint inhibitors have been reported to develop autoimmune endocrine diseases, including type 1 diabetes, although few drugs have been shown to induce type 1 diabetes. Additionally, it is important to note that drugs other than immune checkpoint inhibitors could lead to the development of type 1 diabetes. CASE PRESENTATION: A 54-year-old Filipino female patient underwent surgery for left-sided breast cancer. Postoperative chemotherapy was initiated, including doxorubicin (Adriamycin) and cyclophosphamide therapy. The patient was brought to our hospital by ambulance after consciousness disturbance following three courses of doxorubicin and cyclophosphamide therapy and was hospitalized. Her blood glucose and hemoglobin A1c levels were 1661 mg/dL and 11.9%, respectively. The patient was diagnosed with diabetic ketoacidosis after arterial blood gas analysis indicated a blood pH of 7.120. Her insulin secretion was impaired, and her anti-glutamic acid decarboxylase antibody test result was significantly positive. CONCLUSIONS: The present case shows that doxorubicin and cyclophosphamide therapy may cause unexpected adverse responses, such as type 1 diabetes, though rarely, and highlights the importance of careful patient follow-up. This report is the first to present a case of type 1 diabetes that suddenly developed after doxorubicin and cyclophosphamide treatment.

The Incidence and Risk Factors of Hyponatremia in Pulmonary Tuberculosis.

Context: The syndrome of inappropriate antidiuresis (SIAD) with euvolemic hyponatremia may occur in patients with pulmonary tuberculosis (PTB), but little is known about the clinical characteristics of SIAD-associated hyponatremia in PTB patients. Objective: This study aimed to investigate the frequency and risk factors of hyponatremia in PTB patients. Methods: In this retrospective chart review, we examined the incidence and severity of hyponatremia in PTB patients. Multivariate analysis was conducted to identify risk factors for hyponatremia in PTB patients. Results: Of the 161 patients who were screened, after excluding patients with hyperglycemia and renal failure, we enrolled and analyzed data from 113 participants. Hyponatremia occurred in 40.7% patients (<135 mEq/L). Univariate analysis revealed that the presence of hyponatremia was associated with old age, female sex, low body mass index, high glycosylated hemoglobin, C-reactive protein (CRP), and N-terminal pro-brain natriuretic peptide. Multivariable analysis indicated that hyponatremia was strongly associated with old age (odds ratio, 1.06; 95% CI, 1.03-1.09 for every 1-year age increase) and CRP values (odds ratio, 1.15; 95% CI, 1.03-1.30 for every 1-mg/dL increase in CRP). For 86 patients with blood cortisol measurements, the cortisol level was significantly high in the hyponatremia group. Conclusions: Hyponatremia was less frequently associated with hyperglycemia, heart failure, renal failure, and other diseases that cause euvolemic hyponatremia; thus, PTB patients may have euvolemic hyponatremia due to SIAD. Administration of hypertonic saline or fluid restriction should be considered in PTB patients with hyponatremia.

Comparison of Visceral Fat Reduction by Ipragliflozin and Metformin in Elderly Type 2 Diabetes Patients: Sub-Analysis of a Randomized-Controlled Study.

INTRODUCTION: To compare the effects of ipragliflozin, a sodium-glucose transporter 2 inhibitor, with those of metformin on visceral fat (as well as muscles and bones) in Japanese elderly patients with type 2 diabetes (T2D), we conducted a sub-analysis of a prospective, multicenter, blinded-endpoint randomized-controlled study. METHODS: In total, 103 patients with T2D (body mass index ≥ 22 kg/m2; glycated hemoglobin, 7-10%) and being treated with sitagliptin (a dipeptidyl peptidase-4 inhibitor) were included and randomized to receive ipragliflozin or metformin. The primary outcome was the change in visceral fat area measured using computed tomography 24 weeks following treatment. The secondary outcomes included changes in subcutaneous and total fat area, muscle volume, bone density measured using computed tomography, handgrip strength, bone markers, plasma glucose, insulin, homeostasis model assessment (HOMA)2-beta, HOMA2-R, glycated hemoglobin, lipid panel, uric acid, blood pressure, adiponectin, and high-sensitivity C-reactive protein. All patients aged 65-74 years were selected for sub-analysis. RESULTS: The sub-analysis included 15 and 14 patients in the ipragliflozin and metformin groups, respectively. The patients' backgrounds were well balanced. Visceral fat area reduction was greater in the ipragliflozin group than in the metformin group (- 10.58% vs. - 6.93%; P = 0.034). There were significant differences in the changes in bone absorption markers, uric acid, and total cholesterol levels between the groups. CONCLUSION: Ipragliflozin significantly reduced the visceral fat area compared with metformin when added to sitagliptin in elderly patients with T2D. Long-term and large-scale studies are required to elucidate whether ipragliflozin is suitable for elderly patients. TRIAL REGISTRATION: The study was registered at https://www.umin.ac.jp/ctr/ (UMIN-ID: UMIN 000015170).

Effects of ipragliflozin versus metformin in combination with sitagliptin on bone and muscle in Japanese patients with type 2 diabetes mellitus: Subanalysis of a prospective, randomized, controlled study (PRIME-V study).

AIMS/INTRODUCTION: Recent randomized clinical trials have suggested that sodium-glucose cotransporter 2 inhibitors might reduce cardiovascular events and heart failure, and have renal protective effects. Despite these remarkable benefits, the effects of sodium-glucose cotransporter 2 inhibitors on bone and muscle are unclear. MATERIALS AND METHODS: A subanalysis of a randomized controlled study was carried out to evaluate the effects of the sodium-glucose cotransporter 2 inhibitor, ipragliflozin, versus metformin on bone and muscle in Japanese patients with type 2 diabetes mellitus (baseline body mass index ≥22 kg/m2 and hemoglobin A1c 7-10%) who were already receiving sitagliptin. These patients were randomly administered ipragliflozin 50 mg or metformin 1,000-1,500 mg daily. The effects of these medications on the bone formation marker, bone alkali phosphatase; the bone resorption marker, tartrate-resistant acid phosphatase 5b (TRACP-5b); handgrip strength; abdominal cross-sectional muscle area; and bone density of the fourth lumbar vertebra were evaluated. RESULTS: After 24 weeks of treatment, the changes in bone density of the fourth lumbar vertebra, handgrip strength and abdominal cross-sectional muscle area were not significantly different between the two groups. However, TRACP-5b levels increased in patients treated with ipragliflozin compared with patients treated with metformin (median 11.94 vs -10.30%, P < 0.0001), showing that ipragliflozin can promote bone resorption. CONCLUSIONS: There were no adverse effects on bone or muscle when sitagliptin was used in combination with either ipragliflozin or metformin. However, ipragliflozin combination increased the levels of TRACP-5b. A long-term study is required to further understand the effects of this TRACP-5b increase caused by ipragliflozin.

Comparing the effects of ipragliflozin versus metformin on visceral fat reduction and metabolic dysfunction in Japanese patients with type 2 diabetes treated with sitagliptin: A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study (PRIME-V study).

A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium-dependent glucose transporter-2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%-10%, and body mass index (BMI) ≥ 22 kg/m2 . Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000-1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (-12.06% vs. -3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)-resistance, and increased HDL-cholesterol levels. Metformin significantly reduced HbA1c and LDL-cholesterol levels and increased HOMA-beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase-4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors.

Pituitary adenylate cyclase-activating polypeptide protects glomerular podocytes from inflammatory injuries.

Diabetic nephropathy (DN) is a leading cause of end-stage kidney disease; however, there are few treatment options. Inflammation plays a crucial role in the initiation and/or progression of DN. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide, which was originally isolated from the ovine hypothalamus and reportedly has diverse biological functions. It has been reported that PACAP has renoprotective effects in different models of kidney pathology. However, the specific cell types within the kidney that are protected by PACAP have not yet been reported. In this study, we localized VPAC1, one of the PACAP receptors, to glomerular podocytes, which also reportedly has crucial roles not only in glomerular physiology but also in pathology. PACAP was effective in the downregulation of proinflammatory cytokines, such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-6, which had been induced by the activation of toll-like receptor (TLR) with lipopolysaccharide. PACAP also had downregulated the expression of MCP-1 through the protein kinase A signaling pathway; this led to the attenuation of the activation of extracellular signal-regulated kinase and nuclear factor-kappa B signaling. Our results suggested that PACAP could be a possible treatment option for DN through the use of anti-inflammation effects on glomerular podocytes.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with alpha-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on metformin or pioglitazone alone (Study for an Ultimate Combination Therapy to Control Diabetes with Sitagliptin-1): A multicenter, randomized, open-label, non-inferiority trial.

AIMS/INTRODUCTION: To assess the efficacy and safety of sitagliptin compared with α-glucosidase inhibitors in Japanese patients with type 2 diabetes inadequately controlled by metformin or pioglitazone alone. MATERIALS AND METHODS: In the present multicenter, randomized, open-label, parallel-group, active-controlled, non-inferiority trial, 119 patients aged 20-79 years with type 2 diabetes who had glycated hemoglobin 6.9-8.8% on stable metformin (500-1,500 mg/day) or pioglitazone (15-30 mg/day) alone were randomly assigned (1:1) to receive the addition of sitagliptin (50 mg/day) or an α-glucosidase inhibitor (0.6 mg/day voglibose or 150 mg/day miglitol) for 24 weeks. The primary end-point was change in glycated hemoglobin from baseline to week 12. All data were analyzed according to the intention-to-treat principle. RESULTS: After 12 weeks, reductions in adjusted mean glycated hemoglobin from baseline were -0.70% in sitagliptin and -0.21% in the α-glucosidase inhibitor groups respectively; between-group difference was -0.49% (95% confidence interval -0.66 to -0.32, P < 0.0001), meeting the predefined non-inferiority criterion (0.25%) and showing statistical significance. This statistical significance also continued after 24 weeks. Although sitagliptin did not affect bodyweight, α-glucosidase inhibitors decreased bodyweight significantly from baseline (-0.39 kg; P = 0.0079). Gastrointestinal disorders were significantly lower with sitagliptin than with an α-glucosidase inhibitor (6 [10.3%] patients vs 23 [39.7%]; P = 0.0003). Minor hypoglycemia occurred in two patients (3.5%) in each group. CONCLUSIONS: Sitagliptin showed greater efficacy and better tolerability than an α-glucosidase inhibitor when added to stable doses of metformin or pioglitazone. These findings support the use of sitagliptin in Japanese patients with type 2 diabetes inadequately controlled by insulin-sensitizing agents. This trial was registered with UMIN (no. 000004675).

Atorvastatin ameliorates podocyte injury in patients with type 2 diabetes complicated with dyslipidemia.

We examined the effects of atorvastatin on urinary podocyte excretion. Thirteen patients with type 2 diabetes receiving 2.5mg of rosuvastatin were recruited and the medication was switched to 10mg of atorvastatin for a 24-week period. With the switch to atorvastatin, the urinary excretion of podocytes was significantly reduced.

The reduced form of coenzyme Q10 improves glycemic control in patients with type 2 diabetes: an open label pilot study.

Coenzyme Q10 (CoQ10) provides the energy for vital cellular functions and is known to act as an antioxidant. We conducted an open label study to examine the clinical effects of supplementation of the reduced form of CoQ10, ubiquinol, in addition to conventional glucose-lowering agents in patients with type 2 diabetes. Nine subjects (3 males and 6 females) with type 2 diabetes and receiving conventional medication were recruited. The subjects were assigned to receive an oral dose of 200 mg ubiquinol daily for 12 weeks. The effect of ubiquinol on blood pressure, lipid profile, glycemic control, oxidative stress, and inflammation were examined before and after ubiquinol supplementation. In addition, five healthy volunteers were also assigned to receive an oral dose of 200 mg ubiquinol daily for 4 weeks to examine the effects of ubiquinol on insulin secretion. In patients with diabetes, there were no differences with respect to blood pressure, lipid profile, oxidative stress marker, and inflammatory markers. However, there were significant improvements in glycosylated hemoglobin (53.0 ± 4.3 to 50.5 ± 3.7 mmol/mol, P = 0.01) (7.1 ± 0.4 to 6.8 ± 0.4%, P = 0.03). In healthy volunteers, the insulinogenic index (0.65 ± 0.29 to 1.23 ± 0.56, P = 0.02) and the ratio of proinsulin to insulin were significantly improved (3.4 ± 1.8 to 2.1 ± 0.6, P = 0.03). The results of our study are consistent with the suggestion that the supplementation of ubiquinol in subjects with type 2 diabetes, in addition to conventional antihyperglycemic medications, improves glycemic control by improving insulin secretion without any adverse effects

An angiotensin II type 1 receptor blocker prevents renal injury via inhibition of the Notch pathway in Ins2 Akita diabetic mice.

Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse) and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1) is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor ß and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.

The roles of transforming growth factor-ß and Smad3 signaling in adipocyte differentiation and obesity.

We aimed at elucidating the roles of transforming growth factor (TGF)-ß and Smad3 signaling in adipocyte differentiation (adipogenesis) and in the pathogenesis of obesity. TGF-ß/Smad3 signaling in white adipose tissue (WAT) was determined in genetically obese (ob/ob) mice. The effect of TGF-ß on adipogenesis was evaluated in mouse embryonic fibroblasts (MEF) isolated both from WT controls and Smad3 KO mice by Oil red-O staining and gene expression analysis. Phenotypic analyses of high-fat diet (HFD)-induced obesity in Smad3 KO mice compared to WT controls were performed. TGF-ß/Smad3 signaling was elevated in WAT from ob/ob mice compared to the controls. TGF-ß significantly inhibited adipogenesis in MEF, but the inhibitory effects of TGF-ß on adipogenesis were partially abolished in MEF from Smad3 KO mice. TGF-ß inhibited adipogenesis independent from the Wnt and ß-catenin pathway. Smad3 KO mice were protected against HFD-induced insulin resistance. The size of adipocytes from Smad3 KO mice on the HFD was significantly smaller compared to the controls. In conclusion, the TGF-ß/Smad3 signaling pathway plays key roles not only in adipogenesis but also in development of insulin resistance.