Shunichiro Onishi

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

We aimed at elucidating the roles of transforming growth factor (TGF)-β and Smad3 signaling in adipocyte differentiation (adipogenesis) and in the pathogenesis of obesity. TGF-β/Smad3 signaling in white adipose tissue (WAT) was determined in genetically obese (ob/ob) mice. The effect of TGF-β 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-β/Smad3 signaling was elevated in WAT from ob/ob mice compared to the controls. TGF-β significantly inhibited adipogenesis in MEF, but the inhibitory effects of TGF-β on adipogenesis were partially abolished in MEF from Smad3 KO mice. TGF-β inhibited adipogenesis independent from the Wnt and β-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-β/Smad3 signaling pathway plays key roles not only in adipogenesis but also in development of insulin resistance.

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

Japanese diabetic patients with Werner syndrome exhibit high incidence of cancer

To the Editor Diabetes is associated with the occurrence and progression of malignant tumors [1, 2]. Werner syndrome (WS), an autosomal recessive disorder classified as a progeroid syndrome, occurs because of mutation of the WRN gene encoding a RecQ-type DNA helicase. Because WS patients often have diabetes and malignant tumors, we initiated a nation-wide epidemiological survey in Japan to clarify the current relationship between the prevalence of diabetes and malignant tumors in them. We sent 6921 survey sheets to hospitals with[200 beds. This survey confirmed 336 new WS patients; detailed clinical data were obtained for 163 patients with diabetes, malignant tumors, or both [3]. These patients were categorized as diabetic (n = 102) and non-diabetic (n = 61). The correlation between diabetes and epithelial tumors (cancers) or non-epithelial tumors was examined using the chi-square test. The proportions of patients grouped according to age were 1.2, 9.8, 23.3, 62.6, and 1.8 % for patients in their 20s, 30s, 40s, 50s, and 60s, respectively. The prevalence of cancers and non-epithelial tumors was 11.7 and 19.0 %, respectively. No significant difference was observed in the morbidity rates of non-epithelial tumors in diabetic or non-diabetic patients (21.6 vs. 21.3 %, p = 0.485). However, diabetic patients showed significantly higher cancer prevalence than non-diabetic patients (16.6 vs. 4.9 %, p = 0.013). The types of malignant tumors in these patients and their prevalence rates are shown in Table 1. The prevalence of non-epithelial tumors and cancers is similar in WS patients [4]; non-epithelial tumors are seldom observed in the general population. Insulin resistance is related to the high cancer prevalence in diabetic patients [5]. Diabetes in WS patients is usually caused by high insulin resistance [6], which may contribute to cancer development. WS patients usually die in their 40s [4]. However, in our study, more than 60 % WS patients were in their 50s, which confirmed that the average life expectancy of Japanese WS patients has increased by 5–10 years. Because cancer incidence has increased with age, aging may be a risk factor for cancer development, especially in diabetic WS patients. Thus, our results demonstrate that diabetic WS patients show high cancer prevalence. It is therefore important to monitor the development of not only non-epithelial tumors but also cancers in these patients, especially when WS is complicated with diabetes. Communicated by Renato Lauro.

Incidence and Characteristics of Metabolic Disorders and Vascular Complications in Individuals with Werner Syndrome in Japan

1. Shin A, Kim J, Park S. Gastric cancer epidemiology in Korea. J Gastric Cancer 2011;11:135–140. 2. GLOBOCAN 2008. Cancer Incidence, Mortality and Prevalence Worldwide in 2008. World Health Organization [on-line]. Available at http://globocan. iarc.fr/ Accessed December 2011. 3. Lee J, Demissie K, Lu SE et al. Cancer incidence among Korean-American immigrants in the United States and native Koreans in South Korea. Cancer Control 2007;14:78–85. 4. Hwang HS, Won CW, Lee DH. Clinical behavior of geriatricians regarding periodic screening for gastro-intestinal cancers in older adults. J Korean Geriatr Soc 2008;12:35–41. 5. Lee KS, Oh DK, Han MA et al. Gastric cancer screening in Korea: Report on the national cancer screening program in 2008. Cancer Res Treat 2011;43:83–88.

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 α-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on sulfonylurea alone (SUCCESS-2): a multicenter, randomized, open-label, non-inferiority trial.

We assessed the efficacy and safety of sitagliptin compared with α‐glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2 mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active‐controlled, non‐inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24 weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12 weeks, sitagliptin reduced HbA1c by −0.44% (p < 0.001) relative to αGI. At 24 weeks, the reduction was almost identical between the groups (−0.091%, p = 0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia.

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 β 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.

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.

Sitagliptin Improves Postprandial Hyperglycemia by Inhibiting Glucagon Secretion in Werner Syndrome With Diabetes

Werner syndrome (WS) is a typical progeria syndrome and often leads to diabetes (1). Here, we report a case in which sitagliptin, a dipeptidyl peptidase-4 inhibitor, normalized the postprandial glucagon secretion and improved postprandial blood glucose levels. A 54-year-old female was admitted to our hospital. She developed bilateral cataracts at 35 years of age. Thereafter, at 44 years of age, because of her progeria-like face, she underwent genetic testing and was diagnosed with WS (mutation 4/6, compound heterozygote). At 49 years of age, she developed diabetes. Her height was 144 cm, weight 30.4 kg, and BMI 14.6 kg/m2. Her visceral fat area was 124.8 cm2. At the time of the hospitalization, she was prescribed 30 mg pioglitazone daily. The initial …

Sitagliptin Successfully Ameliorates Glycemic Control in Werner Syndrome With Diabetes

Werner syndrome (WS) is an autosomal recessive disorder caused by a mutation in the WRN gene, and it is considered to be a representative type of progeroid syndrome (1). Patients with WS often exhibit insulin resistance, which is associated with the accumulation of visceral fat and disadipocytokinemia. We and others have previously reported that pioglitazone, a peroxisome proliferator–activated receptor γ ligand, improved glycemic control and insulin sensitivity with normalization of disadipocytokine levels in patients with WS (2,3). Here we describe a diabetic subject with WS that had good glycemic control with pioglitazone initially but worsened because of abdominal obesity and increasing visceral fat area. Sitagliptin, an inhibitor of dipeptidyl peptidase-4, was then administered, which resulted in successful improvement of …