Minoru Takemoto

Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey

Aim:u2003 Werner syndrome (WS) is an autosomal recessive disorder of progeroid symptoms and signs. It is caused by mutations in the WRN gene, which encodes a RecQ DNA helicase. The aim of this study was to revise the diagnostic criteria for Japanese Werner syndrome.

A low-grade increase of serum pancreatic exocrine enzyme levels by dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes

A potential adverse effect of dipeptidyl peptidase-4 inhibitors (DPP-4i) on the pancreas remains controversial. We evaluated the DPP-4i effects on pancreatic amylase and lipase activity in patients with type 2 diabetes. These enzymes were slightly but significantly increased, suggesting DPP-4i cause a low-grade inflammatory change in the exocrine pancreas.

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 ≤2u2009mg/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 24u2009weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12u2009weeks, sitagliptin reduced HbA1c by −0.44% (pu2009<u20090.001) relative to αGI. At 24u2009weeks, the reduction was almost identical between the groups (−0.091%, pu2009=u20090.47). 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.nnA 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 …

Metabolic predictors of ischemic heart disease and cerebrovascular attack in elderly diabetic individuals: difference in risk by age.

BackgroundHigh LDL-cholesterol (LDL-C) and glucose levels are risk factors for ischemic heart disease (IHD) in middle-aged diabetic individuals; however, the risk among the elderly, especially the very elderly, is not well known. The aim of this study was to identify factors that predict IHD and cerebrovascular attack (CVA) in the elderly and to investigate their differences by age.MethodsWe performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5u2009years of follow-up. A total of 4,014 patients with type 2 diabetes and without previous IHD or CVA (1,936 women; age 67.4u2009±u20099.5u2009years, median 70u2009years; <65u2009years old, nu2009=u20091,261; 65 to 74u2009years old, nu2009=u20091,731; andu2009≥u200975u2009years old, nu2009=u20091,016) were recruited on a consecutive outpatient basis from 40 hospitals throughout Japan. Lipids, glucose, and other factors related to IHD or CVA risk, such as blood pressure (BP), were investigated using the multivariate Cox hazard model.ResultsOne hundred fifty-three cases of IHD and 104 CVAs (7.8 and 5.7/1,000 people per year, respectively) occurred over 5.5u2009years. Lower HDL-cholesterol (HDL-C) and female gender were correlated with IHD in patients ≥75u2009years old (hazard ratio (HR):0.629, Pu2009<u20090.01 and 1.132, Pu2009<u20090.05, respectively). In contrast, systolic BP (SBP), HbA1C, LDL-C and non-HDL-C were correlated with IHD in subjects <65u2009years old (Pu2009<u20090.05), and the LDL-C/HDL-C ratio was correlated with IHD in all subjects. HDL-C was correlated with CVA in patients ≥75u2009years old (HR: 0.536, Pu2009<u20090.01). Kaplan-Meier estimator curves showed that IHD occurred more frequently in patients <65u2009years old in the highest quartile of the LDL-C/HDL-C ratio. In patients ≥75u2009years old, IHD and CVA were both the most frequent among those with the lowest HDL-C levels.ConclusionsIHD and CVA in late elderly diabetic patients were predicted by HDL-C. LDL-C, HbA1C, SBP and non-HDL-C are risk factors for IHD in the non-elderly. The LDL-C/HDL-C ratio may represent the effects of both LDL-C and HDL-C. These age-dependent differences in risk are important for developing individualized strategies to prevent atherosclerotic disease.Trial registrationUMIN-CTR, UMIN00000516