The PDE5 inhibitor udenafil ameliorates nonalcoholic fatty liver disease by improving mitochondrial function.

Nonalcoholic fatty liver disease (NAFLD) refers to a series of diseases, including simple steatosis, caused by the excessive accumulation of fat in hepatocytes, nonalcoholic steatohepatitis with inflammation and fibrosis, and more advanced forms of cirrhosis. The pathogenic mechanisms underlying fatty liver and the progression from simple fatty liver to hepatitis and cirrhosis remain unclear. One potentially unifying mechanism may be a dysregulation of free fatty acid oxidation. The oversupply of fatty acids to the liver can result in mitochondrial dysfunction leading to the accumulation of lipids in the liver. Interestingly, there have been several reports showing that inhibitors of phosphodiesterase 5 (PDE5) can increase mitochondrial biogenesis, preserve mitochondrial function in vitro. And, we have recently demonstrated that the phosphodiesterase type 5 inhibitor udenafil improves insulin sensitivity by increasing mitochondrial function in adipocytes. In this study, we aimed to examine the effects of the PDE5 inhibitor udenafil on NAFLD in the ob/ob mouse model. Treatment of ob/ob mice for 6 weeks with udenafil reduced fat mass and fasting glucose. Importantly, udenafil caused a reduction in lipid accumulation in the liver of these mice, including hepatic triglyceride (TG) and cholesterol levels. Mechanistically, udenafil decreased the proinflammatory cytokines in the liver. Also, udenafil increased the levels in the liver of the important lipolytic enzymes and the levels of several mitochondrial ß-oxidation related genes. Similar effects were seen in udenafil treated primary hepatocytes. We believe that our study makes a significant contribution to the literature because the results from our study suggest that udenafil may be an effective treatment for NAFLD by improving mitochondrial function.

Comparison of the Efficacy and Safety of Insulin Detemir Administered Once Daily According to Two Titration Algorithms (3-0-3 and 2-4-6-8) in Patients with Type 2 Diabetes Mellitus.

BACKGROUND: This study was conducted to compare glycaemic control with insulin detemir administered according to two titration algorithms (3-0-3 and 2-4-6-8) after 20 weeks of treatment in subjects with type 2 diabetes mellitus inadequately controlled on metformin. METHODS: This was a 20-week, randomised, multicentre, open-labelled, treat-to-target trial. Forty-six patients were randomised in a 1:1 manner to either the 3-0-3 (G3, n=23) or 2-4-6-8 (G2, n=23) algorithm. The primary endpoint was change of haemoglobin A1c (HbA1c), and the secondary safety endpoint included hypoglycaemic events. RESULTS: After 20 weeks, HbA1c decreased similarly in the G3 and G2 groups, with a mean change of -0.9% from baseline. The mean change in fasting plasma glucose was numerically similar in both groups. The hypoglycaemia event rate per 100-patient-years of exposure (r) in the G2 group (r=1,427) was higher than that in the G3 group (r=807). CONCLUSION: Both treatment groups had numerically similar HbA1c reductions. A trend towards fewer hypoglycaemia episodes after dose stabilisation was seen with the simpler G3. Clinically, this may be an important observation, as a simpler titration algorithm may support self-management and maintenance of insulin therapy.

A comparison study on efficacy, insulin sensitivity and safety of Glimepiride/Metformin fixed dose combination versus glimepiride single therapy on type 2 diabetes mellitus patients with basal insulin therapy.

AIM: The aim of this study was to analyze the efficacy, insulin sensitivity and safety in the event of administering sulfonylurea-based drugs and metformin in combination with basal insulin. METHODS: A randomized, open-label, parallel, 16-week trial was conducted across four study centers. The 97 type 2 diabetic patients were selected and randomized into two groups, the insulin glargine plus fixed-dose combination glimepiride 1 mg and metformin 500 mg twice daily group (the G/M group) and the insulin glargine plus glimepiride 4 mg once daily group (the G group). The primary endpoint evaluated was change in HbA1c. The secondary endpoints evaluated were changes in fasting blood glucose (FPG), 2-h post prandial glucose (PPG 2 h), insulin, and C-peptide levels. RESULTS: The G/M group was found to have experienced a significantly greater decrease in HbA1c, as well as PPG 2 h compared to the G group. While no significant intergroup difference was found regarding FPG in the ITT, the G/M group in the PP set experienced a significantly greater decrease in FPG. CONCLUSION: Comparison of combined therapy consisting of either the G/M group or the G group indicated that both forms of therapy are relatively safe but that the former more effectively decreases blood glucose levels.

PDE 5 inhibitor improves insulin sensitivity by enhancing mitochondrial function in adipocytes.

Adipocytes are involved in many metabolic disorders. It was recently reported that phosphodiesterase type 5 (PDE5) is expressed in human adipose tissue. In addition, PDE5 inhibitors have been shown to improve insulin sensitivity in humans. However, the mechanism underlying the role of PDE5 inhibitors as an insulin sensitizer remains largely unknown. The present study was undertaken to investigate the role of the PDE5 inhibitor udenafil in insulin signaling in adipocytes and whether this is mediated through the regulation of mitochondrial function. To study the mechanism underlying the insulin sensitizing action of PDE5 inhibitors, we evaluated quantitative changes in protein or mRNA levels of mitochondrial oxidative phosphorylation (OxPhos) complex, oxygen consumption rate (OCR), and fatty acid oxidation with varying udenafil concentrations in 3T3-L1 cells. Our cell study suggested that udenafil enhanced the insulin signaling pathway in 3T3-L1 cells. Following udenafil treatment, basal mitochondrial OCR, maximal OxPhos capacity, and OxPhos gene expression significantly increased. Finally, we examined whether udenafil can affect the fatty acid oxidation process. Treatment of 3T3-L1 cells with udenafil (10 and 20 µM) significantly increased fatty acid oxidation rate in a dose-dependent manner. In addition, the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) significantly increased. We demonstrated that the PDE5 inhibitor udenafil enhances insulin sensitivity by improving mitochondrial function in 3T3-L1 cells. This might be the mechanism underlying the PDE5 inhibitor-enhanced insulin signaling in adipocytes. This also suggests that udenafil may provide benefit in the treatment of type 2 diabetes and other related cardiovascular diseases.

The value of red blood cell distribution width in subclinical hypothyroidism.

OBJECTIVE: Therefore, we evaluated the relationship between the subclinical hypothyroidism and red cell distribution width (RDW) levels in a healthy population. SUBJECTS AND METHODS: The medical records of 23,343 consecutive health subjects were reviewed. Subjects were classified into four thyroid stimulating hormone (TSH) groups to determine the correlation between TSH and other variables in detail (0.3 to < 2.5 mU/L, 2.5 to < 5 mU/L, 5 to < 7.5 mU/L, and ≥ 7.5 mU/L). RESULTS: In the multivariate linear regression analysis, RDW was associated with TSH levels, and e-GFR was inversely associated with TSH levels, respectively (standardized beta coefficient = 0.102, -0.019; p < 0.001, p < 0.001). After adjusting for age and sex, in the four groups, TSH levels were significantly correlated with RDW, estimated glomerular filtration rate (e-GFR), and free thyroxine (fT4) levels in all groups. Furthermore in the 4 th group, RDW levels were more strongly associated with TSH levels than in the other groups (p = 0.006). CONCLUSIONS: RDW levels are correlated with euthyroid and subclinical thyroid status. Notably, RDW is more correlated with subclinical hypothyroidism than the euthyroid status. This study presents the relationship between the RDW levels and thyroid function using TSH level in a large healthy population.

The value of red blood cell distribution width in subclinical hypothyroidism / O valor da amplitude de distribuição de eritrócitos no hipotireoidismo subclínico

Objective : Therefore, we evaluated the relationship between the subclinical hypothyroidism and red cell distribution width (RDW) levels in a healthy population. Subjects and methods : The medical records of 23,343 consecutive health subjects were reviewed. Subjects were classified into four thyroid stimulating hormone (TSH) groups to determine the correlation between TSH and other variables in detail (0.3 to < 2.5 mU/L, 2.5 to < 5 mU/L, 5 to < 7.5 mU/L, and ≥ 7.5 mU/L). Results : In the multivariate linear regression analysis, RDW was associated with TSH levels, and e-GFR was inversely associated with TSH levels, respectively (standardized beta coefficient = 0.102, -0.019; p < 0.001, p < 0.001). After adjusting for age and sex, in the four groups, TSH levels were significantly correlated with RDW, estimated glomerular filtration rate (e-GFR), and free thyroxine (fT4) levels in all groups. Furthermore in the 4 th group, RDW levels were more strongly associated with TSH levels than in the other groups (p = 0.006). Conclusions : RDW levels are correlated with euthyroid and subclinical thyroid status. Notably, RDW is more correlated with subclinical hypothyroidism than the euthyroid status. This study presents the relationship between the RDW levels and thyroid function using TSH level in a large healthy population. .

Objetivo : Avaliamos a relação entre o hipotireoidismo subclínico e os níveis de distribuição do tamanho dos eritrócitos (RWD) em uma população saudável. Pacientes e métodos : Foram revisadas as fichas médicas de 23.343 sujeitos saudáveis consecutivos. Os sujeitos foram classificados em quatro grupos de nível de hormônio tireoestimulante (TSH) para se determinar a correlação entre o TSH e outras variáveis, em detalhe (0,3 a < 2,5 mU/L; 2,5 a < 5 mU/L; 5 a < 7,5 mU/L; e ≥ 7,5 mU/L). Resultados : Na análise de regressão linear múltipla, a distribuição do tamanho dos eritrócitos (RWD) foi associada aos níveis de TSH, e a taxa estimada de filtração glomerular (e-GFR) foi inversamente associada aos níveis de TSH, respectivamente (coeficiente betapadronizado = 0,102; -0,019; p < 0,001; p < 0,001). Depois do ajuste para idade e sexo, nos quatro grupos, os níveis de TSH se correlacionaram significativamente com os níveis de RDW, e-GFR e tiroxina livre (fT4) em todos os grupos. Além disso, no quarto grupo, os níveis de RDW estiveram mais fortemente associados aos níveis de TSH do que nos outros grupos (p = 0,006). Conclusões : Os níveis de RDW estão correlacionados com o estado eutiroide e com o hipotireoidismo subclínico. Notavelmente, a RDW é mais correlacionada com o hipotireoidismo subclínico do que com o estado eutiroide. Este estudo apresenta uma relação entre os níveis de RDW e a função tiroidiana por meio da concentração de TSH em um grande número de indivíduos saudáveis. .

A case of parasite invasion of the intestinal tract: a missed diagnosis in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits in the absence of any organic cause. As the clinical manifestations are very diverse and associated with nonspecific symptoms, research seeking to identify organic causes to rule out IBS and to enable differential diagnosis is required. A 24-year-old man was referred to our hospital for specialized management of IBS. He had a 7-month history of intermittent epigastric and lower abdominal pain. On the basis of clinical examination, he was diagnosed with IBS and administered medication at a primary clinic. However, his symptoms did not improve after treatment. We performed capsule endoscopy at our hospital and identified a parasite (Ancylostoma duodenale) in the proximal jejunum. We therefore report a case of parasitic infection found by additional examination while evaluating symptoms associated with a previous diagnosis of refractory IBS.

Effect of granulocyte colony-stimulating factor on the peripheral nerves in streptozotocin-induced diabetic rat.

There are controversial reports about the effect of granulocyte colony-stimulating factor (G-CSF) in peripheral nerve protection. Therefore, the present study aimed to investigate the effect of G-CSF on peripheral nerves in streptozotocin (STZ) induced diabetic rats. After STZ or vehicle injection, rats were divided into five groups (n=6) as follows: normal+vehicle, normal+G-CSF (50 µg/kg for 5 days), diabetes mellitus (DM)+vehicle, DM+G-CSF (50 µg/kg for 5 days), and DM+G-CSF extension (50 µg/kg for 5 days and followed by two injections per week up to 24 weeks). Our results showed that the current perception threshold was not significantly different among experimental groups. G-CSF treatment inhibited the loss of cutaneous nerves and gastric mucosal small nerve fibers in morphometric comparison, but statistical significance was not observed. The present results demonstrated that G-CSF has no harmful but minimal beneficial effects with respect to peripheral nerve preservation in diabetic rats.

Therapeutic Potential of Dioscorea Extract (DA-9801) in Comparison with Alpha Lipoic Acid on the Peripheral Nerves in Experimental Diabetes.

DA-9801, a mixture of extracts from Dioscorea japonica Thunb. and Dioscorea nipponica Makino, was reported to have neurotrophic activity. Therefore, we investigated the therapeutic potential of DA-9801, in comparison with alpha lipoic acid (ALA), for peripheral nerves preservation in experimental diabetes. Experimental animals were divided into 4 groups, and each group was designated according to the type of treatment administered as follows: normal, DM, DM+DA-9801, and DM+ALA. After 16 weeks, response thresholds to tactile and thermal stimuli were higher in DM+DA-9801 group than in nontreated DM group. This degree of increase in DM+DA-9801 group indicates more therapeutic potency of DA-9801 than ALA. Western blot analysis showed more significant increase in NGF and decrease in TNF-α and IL-6 in DM+DA-9801 group than in DM or DM+ALA groups (P < 0.05). IENF density was reduced less significantly in the DM+DA-9801 group than in other DM groups (7.61 ± 0.32, 4.2 ± 0.26, and 6.5 ± 0.30 in DM+DA-9801, DM, and DM+ALA, resp., P < 0.05). Mean myelinated axonal area in the sciatic nerves was significantly greater in DM+DA-9801 group than in other DM groups (69.2 ± 5.76, 54.0 ± 6.32, and 63.1 ± 5.41 in DM+DA-9801, DM, and DM+ALA, resp., P < 0.05). Results of this study demonstrated potential therapeutic applications of DA-9801 for the treatment of diabetic peripheral neuropathy.

Subacute thyroiditis presenting as acute psychosis: a case report and literature review.

We describe herein an unusual case of subacute thyroiditis presenting as acute psychosis. An 18-year-old male presented at the emergency department due to abnormal behavior, psychomotor agitation, sexual hyperactivity, and a paranoid mental state. Laboratory findings included an erythrocyte sedimentation rate of 36 mm/hr (normal range, 0 to 9), free T4 of 100.0 pmol/L (normal range, 11.5 to 22.7), and thyroid stimulating hormone of 0.018 mU/L (normal range, 0.35 to 5.5). A technetium-99m pertechnetate scan revealed homogeneously reduced activity in the thyroid gland. These results were compatible with subacute thyroiditis, and symptomatic conservative management was initiated. The patient's behavioral abnormalities and painful neck swelling gradually resolved and his thyroid function steadily recovered. Although a primary psychotic disorder should be strongly considered in the differential diagnosis, patients with an abrupt and unusual onset of psychotic symptoms should be screened for thyroid abnormalities. Furthermore, transient thyroiditis should be considered a possible underlying etiology, along with primary hyperthyroidism.

Risk factors of severe infections in patients with rheumatoid arthritis treated with leflunomide.

OBJECTIVES: To determine the risk of severe infection requiring or complicating hospitalization associated with leflunomide therapy in patients with rheumatoid arthritis (RA). METHODS: We performed a retrospective study of RA patients who were prescribed leflunomide between 2004 and 2011. Background clinical and laboratory features were compared between patients who suffered severe leflunomide-associated infections and those who did not. RESULTS: Since January 2005, 401 RA patients have started on leflunomide. Among those, 33 (8.2%) developed severe infections: pneumonia, oral candidiasis, pyelonephritis, pulmonary tuberculosis, cellulitis, disseminated herpes zoster, tonsillitis, and pulmonary cryptococcosis. Logistic regression showed that age at entry, the presence of DM, and daily dosage of corticosteroid were associated with development of severe infections. CONCLUSIONS: These results showed that some patients with RA who were taking leflunomide developed severe infections requiring hospitalization, and that older age, DM, and a higher daily dosage of corticosteroid were risk factors associated with leflunomide-associated severe infections.

Graves' Disease that Developed Shortly after Surgery for Thyroid Cancer.

Graves' disease is an autoimmune disorder that may present with various clinical manifestations of hyperthyroidism. Patients with Graves' disease have a greater number of thyroid nodules and a higher incidence of thyroid cancer compared with patients with normal thyroid activity. However, cases in which patients are diagnosed with recurrence of Graves' disease shortly after partial thyroidectomy for thyroid cancer are very rare. Here we report a case of hyperthyroid Graves' disease that occurred after partial thyroidectomy for papillary thyroid cancer. In this case, the patient developed hyperthyroidism 9 months after right hemithyroidectomy, and antithyroglobulin autoantibody and thyroid stimulating hormone receptor stimulating autoantibody were positive. Therefore, we diagnosed Graves' disease on the basis of the laboratory test results and thyroid ultrasonography findings. The patient was treated with and maintained on antithyroid drugs. The mechanism of the recurrence of Graves' disease in this patient is still unclear. The mechanism may have been the improper response of the immune system after partial thyroidectomy. To precisely determine the mechanisms in Graves' disease after partial thyroidectomy, further studies based on a greater number of cases are needed.

Papillary Thyroid Carcinoma: Four Cases Required Caution during Long-Term Follow-Up.

Due to the increased prevalence of papillary thyroid carcinoma (PTC), difficult cases and unexpected events have become more common during long-term follow-up. Herein we reported four cases that exhibited poor progress during long-term follow-up. All the cases were diagnosed with PTC and treated with total thyroidectomy before several years, and the patients had been newly diagnosed with recurrent and metastatic PTC. These four cases included recurred PTC with invasion of large blood vessels, a concomitant second malignancy, malignant transformation, and refractoriness to treatment. Physicians should closely monitor patients to promptly address unforeseen circumstances during PTC follow-up, including PTC recurrence and metastasis. Furthermore, we suggest that the development of a management protocol for refractory or terminal PTC is also warranted.