Diabetes Research and Clinical Practice (DIABETES RES CLIN PR)

Publications in this journal

• Article: Role of vascular reactive oxygen species in development of vascular abnormalities in diabetes.

  Seok Man Son
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  ABSTRACT: Macrovascular and microvascular diseases are currently the principal causes of morbidity and mortality in patients with diabetes. Oxidative stress has been postulated to be a major contributor to the pathogenesis of these events. There is considerable evidence that many biochemical pathways adversely affected by hyperglycemia and other substances that are found at elevated levels in diabetic patients are associated with the generation of reactive oxygen species, ultimately leading to increased oxidative stress in a variety of tissues. In the absence of an appropriate compensation by the endogenous antioxidant defense network, increased oxidative stress leads to the activation of stress-sensitive intracellular signaling pathways and the formation of gene products that cause cellular damage and contribute to the late complications of diabetes. It has recently been suggested that diabetic subjects with vascular complications may have a defective cellular antioxidant response against the oxidative stress generated by hyperglycemia. This raises the concept that antioxidant therapy may be of great interest in these patients. Although our understanding of how hyperglycemia-induced oxidative stress ultimately leads to tissue damage has advanced considerably in recent years, effective therapeutic strategies to prevent or delay the development of this damage remain limited. Thus, further investigations of therapeutic interventions to prevent or delay the progression of diabetic vascular complications are needed.
  Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1:S65-70.
• Article: Normal mortality in the elderly with diabetes under strict glycemic and blood pressure control: outcome of 6-year prospective study.

  Masafumi Katakura, Motoji Naka, Teruki Kondo, Mitsuhisa Komatsu, Keishi Yamauchi, Kiyoshi Hashizume, Toru Aizawa
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  ABSTRACT: Mortality, macroangiopathic events and end-stage renal disease (ESRD) in the elderly under long-term, intensive multifactorial diabetes control were prospectively investigated. Three hundred and eighty-eight elderly patients (> or =65 years) with type 2 diabetes (the mean age 72.9 years, men/women ratio 176/212) were followed-up for 6 years with HbA1c 7.0%, BP 145/80 mmHg and total cholesterol<240 mg/dl as targets. The mean baseline HbA1c was 6.8%, BP 137/74 mmHg and total cholesterol 196 mg/dl, and corresponding values upon closing 6.9%, 134/72 mmHg and 188 mg/dl respectively. Mortality rate was 19.6%/6 years (1.01 times that of age- and sex-matched general population), and macroangiopathic events developed in 142 (36.6%) and ESRD in 9 (2.3%). Independent risk factors: low glomerular filtration rate (GFR) (P<0.001), prior stroke (P=0.002), age (P=0.001) and DeltaBMI (P=0.001) for mortality; prior stroke (P<0.001) and coronary events (P=0.042), high LDL-cholesterol (P=0.004), low GFR (P=0.028), and past maximum BMI (P=0.032) and age (P=0.019) for macroangiopathy; low GFR (P<0.001) for ESRD. No smoking was an independent protective factor for mortality (P=0.008). In conclusion, normal mortality was attained in the elderly under intensive mutifactorial diabetes control. Renal dysfunction, prior stroke, high LDL-cholesterol, and prior obesity were prominent risks for mortality, macroangiopathy and/or ESRD.
  Diabetes Research and Clinical Practice 10/2007; 78(1):108-14.
• Article: Effect of aging on insulin secretory function and expression of beta cell function-related genes of islets.

  Sung-Hee Ihm, Hong Ju Moon, Jun Goo Kang, Cheol Young Park, Ki Won Oh, In Kyung Jeong, Yang-Seok Oh, Sung Woo Park
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  ABSTRACT: Recently, the glucose-stimulated insulin release of isolated human islets has been shown to deteriorate progressively with advancing donor age. This decline in beta cell function with aging may contribute to the increasing development of IGT and type 2 diabetes and also to the progressive nature of the disease. This study was to see whether there is any change in expression of beta cell function-related genes in islets with aging. Islets were isolated from young (2-month old) and old (22-24-month old) LETO rats and C57BL/6N mice. The in vitro GSIR index was significantly lower in islets from old mice compared with young mice. In real-time RT-PCR, PDX-1, insulin, GLUT2 and prohormone convertase 1/3 gene expression in islets was markedly lower in old rats (33%, 13%, 20% and 34%, respectively) and old mice (56%, 42%, 28% and 22%, respectively) compared with young animals. On the other hand, genes not specifically related to beta cell-specific function, such as caspase 3, superoxide dismutase 2 and glycerol kinase were not significantly different in expression in islets according to age. In conclusion, with increasing age, insulin secretory function of islets deteriorates accompanied with a decrease in expression of beta cell-specific genes including PDX-1.
  Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1:S150-4.
• Article: Cross-sectional association between BMI, glycemic control and energy intake in Japanese patients with type 2 diabetes. Analysis from the Japan Diabetes Complications Study.

  Hirohito Sone, Yukio Yoshimura, Sachiko Tanaka, Satoshi Iimuro, Yasuo Ohashi, Hideki Ito, Hiroaki Seino, Shun Ishibashi, Yasuo Akanuma, Nobuhiro Yamada
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  ABSTRACT: Although, weight loss is associated with improved glycemic control in diabetic patients, the relationships between patient weight, daily energy intake (EI), and glycemic or other control status have been poorly investigated. Baseline characteristics of the Japan Diabetes Complications Study, a representative cohort of Japanese diabetic patients, were used for quartile analysis stratified according to patient body mass index (BMI) and EI. Despite a 1.4-fold discrepancy in BMI between the highest and the lowest quartiles, no significant linear trend in HbA(1C) levels or EI between quartiles was seen, although, waist/hip ratio, blood pressure, total cholesterol and triglycerides increased and HDL cholesterol decreased with the increase in BMI. Quartile analysis, according to EI, revealed a 1.8-fold elevation in EI between the lowest and the highest quartile. Nevertheless, the differences in patient BMI between the lowest and the highest quartile were no more than 3% and there were no significant linear trends among the four quartiles in most parameters including HbA(1C), blood pressure, serum lipids. These results revealed only very limited cross-sectional correlations among BMI, EI and other parameters suggesting that it is necessary to consider much wider variations in ideal weight and optimal dietary prescription when making assessments of diabetic patients.
  Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1:S23-9.
• Article: Genetics of type 1 diabetes in Asian and Caucasian populations.

  Hiroshi Ikegami, Yumiko Kawabata, Shinsuke Noso, Tomomi Fujisawa, Toshio Ogihara
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  ABSTRACT: Among candidate genes for type 1 diabetes, HLA, INS, CTLA4, PTPN22 and SUMO4 have been shown to be associated with the disease in Caucasian populations. To clarify the similarities and differences in the contribution of these genes to type 1 diabetes between Asian and Caucasian populations, association of these genes with type 1 diabetes was studied in a large number of samples in Japanese and Korean populations. Class II HLA was strongly associated with type 1 diabetes in both Asian and Caucasian populations, but haplotypes associated with type 1 diabetes were markedly different due to difference in the presence and absence of haplotypes in each population. INS was consistently associated with type 1 diabetes in both Japanese and Caucasian populations, but frequency of disease-associated haplotype was markedly high in Japanese general population. CTLA4 was associated with type 1 diabetes only in a subset of patients with type 1 diabetes complicated with AITD in Japanese. A variant (R620W) of PTPN22 was associated with type 1 diabetes and other autoimmune diseases in Caucasians, but the variant was absent in Asians. SUMO4 was associated with type 1 diabetes in Asians, but not in Caucasian, suggesting a genetic heterogeneity among diverse ethnic groups. Trans-racial study with a large number of samples in both Asian and Caucasian populations will contribute to genetic dissection of type 1 diabetes and identification of causative variants.
  Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1:S116-21.
• Article: Study of iron metabolism disturbances in an animal model of insulin resistance.

  Guillaume Le Guenno, Emilie Chanséaume, Marc Ruivard, Béatrice Morio, Andrzej Mazur
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  ABSTRACT: The relationship between iron and insulin-resistance (IR) is documented by the positive correlation between iron stores and IR. Moreover, some patients exhibited a hepatic iron overload associated with IR (HIO-IR) but the mechanism involved in this overload is not known. Thus, we studied the iron metabolism disturbances in an animal model of IR and the influence of provoked hyperglycemia/hyperinsulinemia on plasma iron parameters. Wistar rats were fed a control or a high-fat/high-energy (HF/HE) diet. Plasma glucose, insulin, iron, transferrin and transferrin saturation (TS) were measured during intra-peritoneal glucose test tolerance (IPGTT) compared to saline. Hemogram, tissue iron concentrations and hepatic hepcidin mRNA expression were determined at the end of experiment. HF/HE rats exhibited higher body and liver weights, increased IR-index and hemoglobin concentration. Iron content was lower in the spleen of HF/HE rats and tended to decrease in the liver as compared to controls. Transferrin values were higher and these of TS lower in HF/HE group. The hepcidin mRNA was 3.5-fold lower in HF/HE rats than in controls. IPGTT had no effect on iron status parameters in both groups. As reflected by higher hemoglobin concentration, IR could increase erythropoïesis which enhances iron requirement. Iron stores and TS value decreased leading to a down-regulation of hepcidin expression which increased iron absorption. Hepcidin expression should be investigated in metabolic syndrome and hepatic iron overload associated with IR.
  Diabetes Research and Clinical Practice 10/2007; 77(3):363-70.
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  Available from: koreamed.org

  Article: The metabolic syndrome in young Korean women with polycystic ovary syndrome.

  Hwi Ra Park, Youngju Choi, Hye-Jin Lee, Jee-Young Oh, Young Sun Hong, Yeon-Ah Sung
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  ABSTRACT: Polycystic ovary syndrome (PCOS) is characterized by insulin resistance and consequent hyperinsulinemia. Insulin resistance also plays an important role in the metabolic syndrome (MS). We conducted a cross-sectional study to determine the prevalence of the MS in young Korean women with PCOS and whether it is associated insulin resistance. One hundred and seventeen young women with PCOS (age: 26+/-5, 16-39 years) were evaluated for the frequency of MS according to the modified Adult Treatment Panel III. Total testosterone (T), free T, androstenedione, dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) were measured, and insulin sensitivity was evaluated by euglycemic hyperinsulinemic clamp technique. The prevalence of MS in women with PCOS was 14.5%, nearly 3.5-fold higher than in age-matched women in Korean urban population (4.3%) [J.-Y. Oh, Y.-A. Sung, Y.S. Hong, E. Barrett-Conner, Prevalence and factor analysis of metabolic syndrome in an urban Korean population, Diabetes Care 27 (2004) 2027-2032]. The most frequently occurring component of MS was low HDL cholesterol (45%), and the least frequent was high fasting serum glucose level (0.9%). PCOS women with MS had significantly higher free T, and lower SHBG compared with those without MS. And women with MS showed significantly lower M-value and higher fasting/post-glucose load insulin levels. M-value was still significantly lower in women with MS even after the adjustment for BMI. MS is frequent in young Korean women with PCOS and it reflects more severe insulin resistance. These results suggest the importance of early and regular screening of metabolic disturbance in even young women with PCOS.
  Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1:S243-6.
• Article: Rationale and usefulness of newly devised abbreviated diagnostic criteria and staging for diabetic polyneuropathy.

  Hitoshi Yasuda, Mitsuru Sanada, Kanako Kitada, Tomoya Terashima, Hyoh Kim, Yoshio Sakaue, Masashi Fujitani, Hiromichi Kawai, Kengo Maeda, Atsunori Kashiwagi
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  ABSTRACT: In order to establish a diagnostic criteria for diabetic polyneuropathy (DP) for daily practice, usefulness of the abbreviated diagnostic criteria proposed by Diabetic Neuropathy Study Group in Japan was examined in 131 diabetic patients in admission and outpatient clinic. The prerequisite condition includes: (1) diagnosed as diabetes and (2) other neuropathies than diabetic neuropathy can be excluded. The criteria should meet any of the following three items: (1) sensory symptoms considered to be due to DP, (2) bilaterally decreased or absent ankle reflex and (3) decreased vibratory sensation in bilateral medial malleoli. Using this criteria, sensitivity (68%) and specificity (74%) were obtained by evaluating nerve conduction study as gold standard, suggesting usefulness of the criteria for diagnosis of DP especially for daily practice. Staging of DP is now sought to establish the consensus for the specific therapy for its stage. Thirty-one diabetic patients in admission was evaluated to examine usefulness of the newly devised staging system of DP. Staging was almost consistent between the new staging system and Dyck's staging (gold standard) and nerve function deteriorated with increasing stage, suggesting that usefulness and rationale of this staging system is well substantiated.
  Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1:S178-83.
• Article: Relationship between smoking, white blood cell count and metabolic syndrome in Japanese women.

  Nobukazu Ishizaka, Yuko Ishizaka, Ei-Ichi Toda, Ryozo Nagai, Kazuhiko Koike, Hideki Hashimoto, Minoru Yamakado
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  ABSTRACT: We found that cigarette smoking increased white blood cell count, and individuals which increased white blood cell count more likely to have metabolic syndrome in Japanese men. We investigated whether similar relationship can be observed also in women. We analyzed the data from 16,383 Japanese women who underwent general health screening. Age-adjusted logistic regression analysis showed that current smoking was positively associated with a highest white blood cell count quartile with an odds ratio of 2.40 (95% CI: 2.16-2.68, P<0.0001). The white blood cell count showed a graded association with metabolic syndrome. On the other hand, the association between current smoking and metabolic syndrome was no longer significant after subdividing the individuals into groups according to the white blood cell quartile. These data collectively suggested that the association between current smoking and metabolic syndrome is heavily confounded by certain factors that increase the circulating white blood cell count in Japanese women, as in men.
  Diabetes Research and Clinical Practice 10/2007; 78(1):72-6.
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  Available from: hua.edu.vn

  Article: Short-chain aldehyde-derived ligands for RAGE and their actions on endothelial cells.

  Yasuhiko Yamamoto, Hideto Yonekura, Takuo Watanabe, Shigeru Sakurai, Hui Li, Ai Harashima, Khin Mar Myint, Mari Osawa, Akihiko Takeuchi, Masayoshi Takeuchi, Hiroshi Yamamoto
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  ABSTRACT: The formation and accumulation of advanced glycation endproducts (AGE) have been implicated in the development of diabetic vascular complications. Their biological responses are known to be mediated by the receptor for AGE (RAGE). Recently, AGE have been proposed to be derived not only from the classical Maillard reaction but also from other pathways of sugar autoxidation and metabolism. Here, we report the identification of glyceraldehydes (Gcer)- and glycolaldehyde (Gcol)-derived AGE as RAGE ligands and their presence in vivo. The apparent dissociation constants assessed by surface-plasmon resonance (SPR) analysis with purified human RAGE proteins were 360 nM for Gcer-AGE and 1.35 microM for Gcol-AGE. The radiolabeled-ligand binding assay with RAGE-expressing COS-7 cells revealed similar association kinetics. Competitive SPR assay with antibodies specific to the respective AGE fractions demonstrated abundant existence of both Gcer- and Gcol-AGE in RAGE affinity-purified proteins from human sera. The serum contents of Gcer- and Gcol-AGE in a diabetic patient were about twice as high as those in a healthy control. Functionally, Gcer- and Gcol-AGE upregulated the endothelial cell levels of mRNA for vascular endothelial growth factor (VEGF) and the secretion of its protein product into the culture media and DNA synthesis in a dose-dependent manner. Further, these endothelial responses were augmented by RAGE overexpression. The results suggest that RAGE engagement of Gcer- and Gcol-AGE may elicit angiogenesis through the induction of autocrine VEGF, thereby contributing to the development and progression of diabetic angiopathies.
  Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1:S30-40.
• Article: Functional association of the morphogenic factors with the clusterin for the pancreatic beta-cell differentiation.

  So-Yoon Kim, Song Lee, Bon-Hong Min, In-Sun Park
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  ABSTRACT: Several differentiation or morphogenic factors have known to be involved in the developmental process of endocrine pancreas. However, mechanism of action and functional relation of these molecules are not well elucidated particularly in beta-cell formation from adult pancreatic stem cells. We hypothesized that adult pancreatic stem cells could be activated by the functional resumption of the morphogenic factors that were involved in embryonic development of pancreas in the duct system under the specific conditions such as tissue injuries. Besides the well-established genes including Pdx-1 and Ngn-3, we propose the nestin and clusterin as the new morphogenic factors for beta-cell neogenesis and their functional associations. We found extensive in vivo formation of ductules showing a higher replicating ability following the experimental tissue injury. These neogenic ductules were lined with low epithelial cells positive for the nestin, which has been known as neuronal stem cell marker. In in vitro culture, the nestin-rich epithelial cells of the neogenic ductules also displayed extensive self-replication leading to monolayer of epithelial cell explants and transformed into the insulin secreting beta cells as well as duct cells. Thus, we depicted them as nestin-positive duct stem (NPDS) cells. We found a neogenesis specific protein 'clusterin' in the regenerating pancreatic tissues with concomitant increase of Pdx-1 and Ngn-3 expression. The protein is expressed predominantly in the neogenic pancreas undergoing differentiation. In vitro over-expression of the clusterin gene strongly induces beta-cell transformation from neogenic ductal cells. Insulin expression, both insulin mRNA and peptide levels, was increased and showed glucose dependent manner by ectopic expression of clusterin upon the culture of neogenic ductules when compared to the mock-transfected control, implying that the duct cells transformed functional beta cells. We observed that clusterin over-expression led to up-regulation of Pdx-1 and Ngn-3, and clusterin levels were increased upon the transfection of cDNAs of Pdx-1 or Ngn-3, suggesting a close functional association of these morphogenic factors. In conclusion, we suggest that adult pancreatic stem cells can be recapitulated for neogenesis of insulin secreting beta cells not only by reactivation Pdx-1 and Ngn-3, the classical differentiation factors for pancreas development, but also by the intervention of new morphogenic factors including nestin and clusterin. In particular, by modulation of Pdx-1 and Ngn-3, clusterin induces remarkable differentiation of the functional beta cells secreting insulin in response to glucose stimulation.
  Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1:S122-6.
• Article: A long-term effect of epalrestat on motor conduction velocity of diabetic patients: ARI-Diabetes Complications Trial (ADCT).

  Kempei Matsuoka, Nobuo Sakamoto, Yasuo Akanuma, Nigishi Hotta, Motoaki Shichiri, Takayoshi Toyota, Yoshitomo Oka, Ryuzo Kawamori, Yukio Shigeta
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  ABSTRACT: In order to study a long-term effect along with adverse action of epalrestat, an aldose reductase inhibitor, a randomized, prospective study was conducted over the period of 3 years at 112 facilities. Six hundred and three diabetic patients with median motor conduction velocity (MCV)>40 m/s, HbA1c<9% were randomly allocated to epalrestat (50 mg/day p.o. ac, t.i.d.) group (E group: n=289, age: 61+/-9.8 y.o.) and a control group (C group: n=305, age: 61+/-9.1 y.o.). MCV was measured once a year for 3 years. MCV (m/s, M+/-S.D.) on baseline, 1 year and 3 years, was 52.0+/-4.5, 52.2+/-4.9, 52.1+/-4.6 in E group and 53.3+/-4.4, 52.4+/-4.2, 52.0+/-4.6 in C group, respectively. After 3 years, difference from the baseline was significant (p<0.0001, E versus C). Among the subjects with HbA1c<7.0%, C group showed marked deterioration of MCV while in E group, there was no significant deterioration (p<0.001). Although, the subjects with pre-proliferative or proliferative retinopathy, there was no difference between E and C groups for 3 years, in subjects with background retinopathy or without retinopathy, deterioration rate of E group was significantly less than that of C group (p<0.0001). Epalrestat was found to prevent deterioration of MCV especially in well-controlled patients without advanced complications. No remarkable side effects serious enough to discontinue the study was observed.
  Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1:S263-8.
• Article: Estimation of influence of gastric emptying on shape of glucose concentration-time profile measured in oral glucose tolerance test.

  Ladislav Dedík, Mária Durisová, Adela Penesová, Daniela Miklovicová, Martina Tvrdonová
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  ABSTRACT: To develop a model for simulations of processes in the oral glucose tolerance test (OGTT), using tools of the theory of dynamic systems. Frequent sampling OGTT was performed in 13 healthy subjects (6 males and 7 females). Subsequently, employing glucose and insulin concentration-time profiles of the subjects, the model was developed. In all subjects the model was able to simulate influences of the insulin plasma concentration and gastric emptying rate on glucose concentration and to determine time profiles of glucose fractions retained in stomach. The approach presented represents an opportunity for building models for data analyses in OGTT.
  Diabetes Research and Clinical Practice 10/2007; 77(3):377-84.
• Article: Negative and positive feedback regulation of insulin in glucose-stimulated Ca2+ response in pancreatic beta cells.

  Sung Hee-Park, Bora Lim, Won-Ki Baek, Jae-Hoon Bae, Dae-Kyu Song
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  ABSTRACT: Secreted insulin from pancreatic beta cells exerts autocrine and paracrine effects within the islets. The present study has evaluated how exogenous insulin participates in cytosolic Ca(2+) response to high glucose, according to glucose concentration at which insulin is applied. When 100 nM insulin was pretreated to the bath solution containing islet cells in the presence of basal level of glucose, the elevation of cytosolic Ca(2+) concentration ([Ca(2+)](c)) by subsequently applied 10mM glucose was remarkably attenuated. In contrast, the glucose-stimulated [Ca(2+)](c) elevation was more potentiated when insulin was superimposed on the high glucose stimulation. These insulin actions were modestly inhibited by the application of LY294002, the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, but not completely, suggesting that another mechanism is also involved. By 100 nM insulin, phosphorylated form of AMP-activated protein kinases (p-AMPK) was dramatically decreased in basal glucose but increased in high glucose, when compared with their reciprocal controls. These results may suggest that the extent of AMPK activation may be a tool for insulin receptors to monitor blood glucose level, with which insulin-induced insulin receptor activation determines the way to go negatively or positively toward [Ca(2+)](c).
  Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1:S143-9.
• Article: Association between high levels IL-8 and Staphylococcus aureus-specific IgA antibodies in subjects with type 1 diabetes mellitus from Argentina.

  S Satorres, L Alcaraz, S Di Genaro
  Diabetes Research and Clinical Practice 10/2007; 77(3):489-91.
• Article: A comparison of mealtime insulin aspart and human insulin in combination with metformin in type 2 diabetes patients.

  L Pala, E Mannucci, I Dicembrini, C M Rotella
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  ABSTRACT: This randomized, open-label, cross-over study compares the efficacy of mealtime rapid-acting analog insulin aspart with human insulin, in combination with metformin. A total of 30 patients with type 2 diabetes, inadequately controlled (HbA(1c)>7.5%) with oral hypoglycemic agents (OHAs), were assigned to human insulin 30 min before meals or aspart immediately before meals, both with metformin 500 mg t.i.d. for 90 days. Patients then switched to the alternate insulin. At 90 and 180 days, blood glucose and lipids were measured at baseline and every 30 min after test meals, for 3h. HbA(1c) and hypoglycemic events were also assessed. After 3 months, HbA(1c) was significantly reduced with aspart, but not human insulin (-0.4+/-0.7% versus +0.1+/-0.7%, p<0.05). During meal tests, blood glucose area under the curve (AUC) was significantly lower with aspart than human insulin (1240+/-476 min/mmol/l versus 1588+/-766 min/mmol/l, p<0.01). AUCs for lipids were similar for both treatments. Neither group experienced serious hypoglycemic events. These results encourage treatment with mealtime insulin aspart plus metformin, in type 2 diabetes patients with postprandial hyperglycemia inadequately controlled by OHAs alone.
  Diabetes Research and Clinical Practice 10/2007; 78(1):132-5.
• Article: Both Pdx-1 and NeuroD1 genes are requisite for the maintenance of insulin gene expression in ES-derived differentiated cells.

  Koichi Saitoh, Eiji Yamato, Satsuki Miyazaki, Jun-Ichi Miyazaki
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  ABSTRACT: Embryonic stem (ES) cells can differentiate into many cell types. Recent reports have shown that ES cells can differentiate into insulin-producing cells. We have established an ES cell line in which exogenous Pdx-1 expression was precisely regulated by the Tet-off system integrated into the ROSA26 locus and succeeded to produce insulin-producing cells. The Pdx-1 expressing final differentiated insulin-positive cells can be maintained for more than 2 months. However, in spite of their induced expression of Pdx-1, the repeated passages of cells lost their capacity to express insulin and NeuroD1 gene. Forced expression of NeuroD1 gene by adenoviral vector in these cells restored the expression of insulin. These results suggested that maintenance of the property of insulin-producing cells derived from ES cells could be achieved by synergistic expression of Pdx-1 and NeuroD1.
  Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1:S138-42.
• Article: Role of PDX-1 and MafA as a potential therapeutic target for diabetes.

  Hideaki Kaneto, Takeshi Miyatsuka, Yoshio Fujitani, Hirofumi Noguchi, Ki-Ho Song, Kun-Ho Yoon, Taka-Aki Matsuoka
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  ABSTRACT: Pancreatic and duodenal homeobox factor-1 (PDX-1) plays a crucial role in pancreas development, beta-cell differentiation, and maintaining mature beta-cell function. During pancreas development, PDX-1 expression is maintained in precursor cells, and later it becomes restricted to beta-cells. In mature beta-cells, PDX-1 regulates gene expression of various beta-cell-related factors including insulin. Also, PDX-1 has potency to induce insulin-producing cells from non-beta-cells in various tissues, and PDX-1-VP16 fusion protein more efficiently induces insulin-producing cells, especially in the presence of NeuroD or Ngn3. MafA is a recently isolated beta-cell-specific transcription factor which functions as a potent activator of insulin gene transcription. During pancreas development, MafA expression is first detected at the beginning of the principal phase of insulin-producing cell production. Furthermore, MafA markedly enhances insulin gene promoter activity and ameliorates glucose tolerance in diabetic mice, especially in the presence of PDX-1 and NeuroD. Taken together, PDX-1 and MafA play a crucial role in inducing surrogate beta-cells and could be a therapeutic target for diabetes.
  Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1:S127-37.
• Article: Survey of dietary habits in obese patients with type 2 diabetes treated with either OHA or insulin injections in Japan.

  Yasuko Uchigata, Yasuhiko Iwamoto
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  ABSTRACT: A questionnaire survey on meal/snack intake and timing in obese patients with type 2 diabetes treated with either oral hypoglycemic agents (OHA) or insulin injections was performed in order to elucidate their dietary habits, using a method independent of the treating physician. The OHA and insulin groups recruited from all over Japan showed no differences in any factors except the duration of diabetes. Daily calorie intake was not correlated with gender, BMI, medication or HbA1c. However, calorie intake was the highest at dinner, followed by lunch and breakfast. Only for dinner was the calorie intake significantly higher for the OHA group than for the insulin group. Of the patients, 8.6, 4.2 and 1.3% skipped breakfast, lunch or dinner, respectively. However, there was no significant difference in the abstention ratio for the three meals or between the two treatment groups. It was remarkable that at least 90% or more reported the habitual ingestion of snacks. The snack time ranged from 6:00 a.m. to midnight. There was no marked difference in the proportion of patients having snacks between the two treatment groups. The outcomes such as deviations in calorie intake among the three meals, skipping meals and snacking in this survey may reflect the current dietary habits of obese patients with type 2 diabetes, especially under medical treatment.
  Diabetes Research and Clinical Practice 10/2007; 77(3):371-6.
• Article: Haptoglobin polymorphism and diabetic retinopathy in Brazilian patients.

  Vânia P A Wobeto, Endrigo T Rosim, Mônica B Melo, Luís Eduardo P Calliari, Maria de Fátima Sonati
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  ABSTRACT: Haptoglobin (Hp) is an acute phase protein with antioxidant and immunomodulatory properties. Three main genotypes/phenotypes (Hp1-1, Hp2-1 and Hp2-2) show distinct efficiencies in these activities and have been associated with susceptibility and outcome in several diseases, including diabetes mellitus (DM). It has been suggested that Hp polymorphism may influence the development of retinopathy, an important microvascular complication in DM. In order to investigate this association in a Brazilian population, we determined the Hp genotypes of 317 diabetic patients with at least 10 years of disease. The patients were classified as DM-type 1 and 2, with and without diabetic retinopathy (DR). The Hp genotype frequencies of the different patient groups and of a control group consisting of 142 healthy individuals who had previously been studied were compared. No significant differences were observed for the three Hp genotypes. Hemoglobin A1c levels, systolic blood pressure (SBP), diastolic blood pressure (DBP) and duration of diabetes, which are potential risk factors for DR, were also compared. Again no significant differences were observed for the three Hp genotypes. Thus, we conclude that this polymorphism is not associated with the presence of DR in the Brazilian population studied here.
  Diabetes Research and Clinical Practice 10/2007; 77(3):385-8.