[show abstract][hide abstract] ABSTRACT: Concept of Diabetes Mellitus:Diabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its pathogenesis involves both genetic and environmental factors. The long-term persistence of metabolic disorders can cause susceptibility to specific complications and also foster arteriosclerosis. Diabetes mellitus is associated with a broad range of clinical presentations, from being asymptomatic to ketoacidosis or coma, depending on the degree of metabolic disorder.Classification (Tables 1 and 2, and Figure 1):Table 1. Etiological classification of diabetes mellitus and glucose metabolism disorders Note: Those that cannot at present be classified as any of the above are called unclassifiable.The occurrence of diabetes-specific complications has not been confirmed in some of these conditions.I. Type 1 (destruction of pancreatic β-cells, usually leading to absolute insulin deficiency) A. Autoimmune B. IdiopathicII. Type 2 (ranging from predominantly insulin secretory defect, to predominantly insulin resistance with varying degrees of insulin secretory defect)III. Due to other specific mechanisms or diseases (see Table 2 for details) A. Those in which specific mutations have been identified as a cause of genetic susceptibility (1) Genetic abnormalities of pancreatic β-cell function (2) Genetic abnormalities of insulin action B. Those associated with other diseases or conditions (1) Diseases of exocrine pancreas (2) Endocrine diseases (3) Liver disease (4) Drug- or chemical-induced (5) Infections (6) Rare forms of immune-mediated diabetes (7) Various genetic syndromes often associated with diabetesIV. Gestational diabetes mellitusTable 2. Diabetes mellitus and glucose metabolism disorders due to other specific mechanisms and diseases The occurrence of diabetes-specific complications has not been confirmed in some of these conditions.A. Those in which specific mutations have been identified as a cause of genetic susceptibilityB. Those associated with other diseases or conditions(1) Genetic abnormalities of pancreatic β-cell function Insulin gene (abnormal insulinemia, abnormal proinsulinemia, neonatal diabetes mellitus) HNF 4 gene (MODY1) Glucokinase gene (MODY2) HNF 1 gene (MODY3) IPF-1 gene (MODY4) HNF 1β gene (MODY5) Mitochondria DNA (MIDD) NeuroD1 gene (MODY6) Kir6.2 gene (neonatal diabetes mellitus) SUR1 gene (neonatal diabetes mellitus) Amylin Others (2) Genetic abnormalities of insulin action Insulin receptor gene (type A insulin resistance, leprechaunism, Rabson–Mendenhall syndrome etc.) Others(1) Diseases of exocrine pancreas Pancreatitis Trauma/pancreatectomy Neoplasm Hemochromatosis Others (2) Endocrine diseases Cushing’s syndrome Acromegaly Pheochromocytoma Glucagonoma Aldosteronism Hyperthyroidism Somatostatinoma Others (3) Liver disease Chronic hepatitis Liver cirrhosis Others (4) Drug- or chemical-induced Glucocorticoids Interferon Others (5) Infections Congenital rubella Cytomegalovirus Others (6) Rare forms of immune-mediated diabetes Anti-insulin receptor antibodies Stiffman syndrome Insulin autoimmune syndrome Others (7) Various genetic syndromes often associated with diabetes Down syndrome Prader-Willi syndrome Turner syndrome Klinefelter syndrome Werner syndrome Wolfram syndrome Ceruloplasmin deficiency Lipoatrophic diabetes mellitus Myotonic dystrophy Friedreich ataxia Laurence-Moon-Biedl syndrome OthersFigure 1. A scheme of the relationship between etiology (mechanism) and patho-physiological stages (states) of diabetes mellitus. Arrows pointing right represent worsening of glucose metabolism disorders (including onset of diabetes mellitus). Among the arrow lines, indicates the condition classified as ‘diabetes mellitus’. Arrows pointing left represent improvement in the glucose metabolism disorder. The broken lines indicate events of low frequency. For example, in type 2 diabetes mellitus, infection can lead to ketoacidosis and require temporary insulin treatment for survival. Also, once diabetes mellitus has developed, it is treated as diabetes mellitus regardless of improvement in glucose metabolism, therefore, the arrow lines pointing left are filled in black. In such cases, a broken line is used, because complete normalization of glucose metabolism is rare.Download figure to PowerPointThe classification of glucose metabolism disorders is principally derived from etiology, and includes staging of pathophysiology based on the degree of deficiency of insulin action. These disorders are classified into four groups: (i) type 1 diabetes mellitus; (ii) type 2 diabetes mellitus; (iii) diabetes mellitus due to other specific mechanisms or diseases; and (iv) gestational diabetes mellitus. Type 1 diabetes is characterized by destruction of pancreatic β-cells. Type 2 diabetes is characterized by combinations of decreased insulin secretion and decreased insulin sensitivity (insulin resistance). Glucose metabolism disorders in category (iii) are divided into two subgroups; subgroup A is diabetes in which a genetic abnormality has been identified, and subgroup B is diabetes associated with other pathologic disorders or clinical conditions. The staging of glucose metabolism includes normal, borderline and diabetic stages depending on the degree of hyperglycemia occurring as a result of the lack of insulin action or clinical condition. The diabetic stage is then subdivided into three substages: non-insulin- requiring, insulin-requiring for glycemic control, and insulin-dependent for survival. The two former conditions are called non-insulin-dependent diabetes and the latter is known as insulin-dependent diabetes. In each individual, these stages may vary according to the deterioration or the improvement of the metabolic state, either spontaneously or by treatment.Diagnosis (Tables 3–7 and Figure 2):Table 3. Criteria of fasting plasma glucose levels and 75 g oral glucose tolerance test 2-h value Normal rangeDiabetic range*Casual plasma glucose ≥200 mg/dL (≥11.1 mmol/L) and HbA1c≥6.5% are also regarded as to indicate diabetic type.Even for normal type, if 1-h value is 180 mg/dL (10.0 mmol/L), the risk of progression to diabetes mellitus is greater than for <180 mg/dL (10.0 mmol/L) and should be treated as with borderline type (follow-up observation, etc.). Fasting plasma glucose level of 100–109 mg/dL (5.5–6.0 mmol/L) is called ‘high-normal’: within the range of normal fasting plasma glucose.Plasma glucose level after glucose load in oral glucose tolerance test (OGTT) is not included in casual plasma glucose levels. The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%).Fasting value<110 mg/dL (6.1 mmol/L)≥126 mg/dL (7.0 mmol/L)75 g OGTT 2-h value<140 mg/dL (7.8 mmol/L)≥200 mg/dL (11.1 mmol/L)Evaluation of OGTTNormal type: If both values belong to normal range*Diabetic type: If any of the two values falls into diabetic rangeBorderline type Neither normal nor diabetic typesTable 4. Procedures for diagnosing diabetes mellitus *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). **Hyperglycemia must be confirmed in a non-stressful condition. OGTT, oral glucose tolerance test.Clinical diagnosis (1) At initial examination, a ‘diabetic type’ is diagnosed if any of the following criteria are met: (i) fasting plasma glucose level ≥126 mg/dL (7.0 mmol/L), (ii) 75 g OGTT 2-h value ≥200 mg/dL (11.1 mmol/L), (iii) casual plasma glucose level ≥200 mg/dL (11.1 mmol/L) or (iv) *HbA1c≥6.5%. Re-examination is carried out at another date and diabetes mellitus is diagnosed if ‘diabetic type’ is confirmed again**. However, diagnosis cannot be made on the basis of a repeated HbA1c test alone. If the same blood sample is confirmed to be diabetic type by both plasma glucose and HbA1c levels (any of [i] to [iii] plus [iv]), then diabetes mellitus can be diagnosed from the initial test (2) If plasma glucose level shows diabetic type (any of [i] to [iii]) and either of the following conditions exists, diabetes mellitus can be diagnosed immediately at the initial examination • The presence of typical symptoms of diabetes mellitus (thirst, polydipsia, polyuria, weight loss) • The presence of definite diabetic retinopathy (3) If it can be confirmed that either of the above conditions 1 or 2 existed in the past, diabetes mellitus must be diagnosed or suspected even if present test values do not meet the above conditions (4) If diabetes mellitus is suspected but the diagnosis cannot be made by the above (1) to (3), the patient should be followed-up (5) The following points should be kept in mind when selecting the method of determination in initial examination and re-examination • If HbA1c is used at initial examination, another method of determination is required for diagnosis at re-examination. As a rule, both plasma glucose level and HbA1c should be measured • If casual plasma glucose level is ≥200 mg/dL (11.1 mmol/L) at the initial test, a different test method is desirable for re-examination • In the case of disorders and conditions in which HbA1c may be inappropriately low, plasma glucose level should be used for diagnosis (Table 5)Epidemiological study For the purpose of estimating the frequency of diabetes mellitus, determination of ‘diabetic type’ from a single test can be considered to represent ‘diabetes mellitus’. Whenever possible, the criteria to be used are HbA1c≥6.5% or OGTT 2-h value ≥200 mg/dL (11.1 mmol/L)Health screening It is important to detect diabetes mellitus and identify high risk groups without overlooking anyone. Therefore, besides measuring plasma glucose and HbA1c, clinical information such as family history and obesity should be referredTable 5. Disorders and conditions associated with low HbA1c values AnemiaLiver diseaseDialysisMajor hemorrhageBlood transfusionChronic malariaHemoglobinopathyOthersTable 6. Situations where a 75-g oral glucose tolerance test is recommended *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%).Strongly recommended (suspicion of present diabetes mellitus cannot be ruled out) Fasting plasma glucose level is 110–125 mg/dL (6.1–6.9 mmol/L) Casual plasma glucose level is 140–199 mg/dL (7.8–11.0 mmol/L) *HbA1c is 6.0–6.4% (excluding those having overt symptoms of diabetes mellitus)Testing is desirable (high risk of developing diabetes mellitus in the future; Testing is especially advisable for patients with risk factors for arteriosclerosis such as hypertension, dyslipidemia and obesity.) Fasting plasma glucose level is 100–109 mg/dL (5.5–6.0 mmol/L) *HbA1c is 5.6–5.9% Strong family history of diabetes mellitus or present obesity regardless of above criteriaTable 7. Definition and diagnostic criteria of gestational diabetes mellitus (IADPSG Consensus Panel, Reference 42, partly modified with permission of Diabetes Care).Definition of gestational diabetes mellitus Glucose metabolism disorder with first recognition or onset during pregnancy, but that has not developed into diabetes mellitusDiagnostic criteria of gestational diabetes mellitus Diagnosed if one or more of the following criteria is met in a 75 g OGTT Fasting plasma glucose ≥92 mg/dL (5.1 mmol/L) 1-h value ≥180 mg/dL (10.0 mmol/L) 2-h value ≥153 mg/dL (8.5 mmol/L) However, diabetes mellitus that is diagnosed according to ‘Clinical diagnosis’ outlined in Table 4 is excluded from gestational diabetes mellitusFigure 2. Flow chart outlining steps in the clinical diagnosis of diabetes mellitus. *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%).Download figure to PowerPointCategories of the State of Glycemia: Confirmation of chronic hyperglycemia is essential for the diagnosis of diabetes mellitus. When plasma glucose levels are used to determine the categories of glycemia, patients are classified as having a diabetic type if they meet one of the following criteria: (i) fasting plasma glucose level of ≥126 mg/dL (≥7.0 mmol/L); (ii) 2-h value of ≥200 mg/dL (≥11.1 mmol/L) in 75 g oral glucose tolerance test (OGTT); or (iii) casual plasma glucose level of ≥200 mg/dL (≥11.1 mmol/L). Normal type is defined as fasting plasma glucose level of <110 mg/dL (<6.1 mmol/L) and 2-h value of <140 mg/dL (<7.8 mmol/L) in OGTT. Borderline type (neither diabetic nor normal type) is defined as falling between the diabetic and normal values. According to the current revision, in addition to the earlier listed plasma glucose values, hemoglobin A1c (HbA1c) has been given a more prominent position as one of the diagnostic criteria. That is, (iv) HbA1c≥6.5% is now also considered to indicate diabetic type. The value of HbA1c, which is equivalent to the internationally used HbA1c (%) (HbA1c [NGSP]) defined by the NGSP (National Glycohemoglobin Standardization Program), is expressed by adding 0.4% to the HbA1c (JDS) (%) defined by the Japan Diabetes Society (JDS).Subjects with borderline type have a high rate of developing diabetes mellitus, and correspond to the combination of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) noted by the American Diabetes Association (ADA) and WHO. Although borderline cases show few of the specific complications of diabetes mellitus, the risk of arteriosclerosis is higher than those of normal type. When HbA1c is 6.0–6.4%, suspected diabetes mellitus cannot be excluded, and when HbA1c of 5.6–5.9% is included, it forms a group with a high risk for developing diabetes mellitus in the future, even if they do not have it currently.Clinical Diagnosis: 1 If any of the criteria for diabetic type (i) through to (iv) is observed at the initial examination, the patient is judged to be ‘diabetic type’. Re-examination is conducted on another day, and if ‘diabetic type’ is reconfirmed, diabetes mellitus is diagnosed. However, a diagnosis cannot be made only by the re-examination of HbA1c alone. Moreover, if the plasma glucose values (any of criteria [i], [ii], or [iii]) and the HbA1c (criterion [iv]) in the same blood sample both indicate diabetic type, diabetes mellitus is diagnosed based on the initial examination alone. If HbA1c is used, it is essential that the plasma glucose level (criteria [i], [ii] or [iii]) also indicates diabetic type for a diagnosis of diabetes mellitus. When diabetes mellitus is suspected, HbA1c should be measured at the same time as examination for plasma glucose.2 If the plasma glucose level indicates diabetic type (any of [i], [ii], or [iii]) and either of the following conditions exists, diabetes mellitus can be diagnosed immediately at the initial examination.• The presence of typical symptoms of diabetes mellitus (thirst, polydipsia, polyuria, weight loss)• The presence of definite diabetic retinopathy3 If it can be confirmed that the above conditions 1 or 2 existed in the past, diabetes mellitus can be diagnosed or suspected regardless of the current test results.4 If the diagnosis of diabetes cannot be established by these procedures, the patient is followed up and re-examined after an appropriate interval.5 The physician should assess not only the presence or absence of diabetes, but also its etiology and glycemic stage, and the presence and absence of diabetic complications or associated conditions.Epidemiological Study: For the purpose of estimating the frequency of diabetes mellitus, ‘diabetes mellitus’ can be substituted for the determination of ‘diabetic type’ from a single examination. In this case, HbA1c≥6.5% alone can be defined as ‘diabetes mellitus’.Health Screening: It is important not to misdiagnose diabetes mellitus, and thus clinical information such as family history and obesity should be referred to at the time of screening in addition to an index for plasma glucose level.Gestational Diabetes Mellitus: There are two hyperglycemic disorders in pregnancy: (i) gestational diabetes mellitus (GDM); and (ii) diabetes mellitus. GDM is diagnosed if one or more of the following criteria is met in a 75 g OGTT during pregnancy:1 Fasting plasma glucose level of ≥92 mg/dL (5.1 mmol/L)2 1-h value of ≥180 mg/dL (10.0 mmol/L)3 2-h value of ≥153 mg/dL (8.5 mmol/L)However, diabetes mellitus that is diagnosed by the clinical diagnosis of diabetes mellitus defined earlier is excluded from GDM. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00074.x, 2010)
Journal of Diabetes Investigation. 09/2010; 1(5):212 - 228.
[show abstract][hide abstract] ABSTRACT: Leptin, the product of the ob gene, plays important roles in the regulation of food intake and body weight through its receptor in the hypothalamus. To identify novel transcripts induced by leptin, we performed cDNA subtraction based on selective suppression of the polymerase chain reaction by using mRNA prepared from the forebrain of leptin-injected ob/ob mice. One of the genes isolated was a mouse homolog of human negative regulatory element-binding protein (NREBP). Its expression was markedly increased by leptin in the growth hormone secretagogue-receptor (GHS-R)-positive neurons of the arcuate nucleus and ventromedial hypothalamic nucleus. The promoter region of GHS-R contains one NREBP binding sequence, suggesting that NREBP regulates GHS-R transcription. Luciferase reporter assays showed that NREBP repressed GHS-R promoter activity in a hypothalamic neuronal cell line, GT1-7, and its repressive activity was abolished by the replacement of negative regulatory element in GHS-R promoter. Overexpression of NREBP reduced the protein expression of endogenous GHS-R without affecting the expression of ob-Rb in GT1-7 cells. To determine the functional importance of NREBP in the hypothalamus, we assessed the effects of NREBP on ghrelin action. Although phosphorylation of AMP-activated protein kinase α (AMPKα) was induced by ghrelin in GT1-7 cells, NREBP repressed ghrelin-induced AMPKα phosphorylation. These results suggest that leptin-induced NREBP is an important regulator of GHS-R expression in the hypothalamus and provides a novel molecular link between leptin and ghrelin signaling.
Journal of Biological Chemistry 09/2010; 285(48):37884-94. · 4.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ghrelin inhibits insulin secretion partly via induction of IA-2beta. However, the orexigenic effect of ghrelin is mediated by the AMP-activated protein kinase (AMPK)-uncoupling protein 2 (UCP2) pathway. Here, we demonstrate that ghrelin's inhibitory effect on insulin secretion also occurs through the AMPK-UCP2 pathway. Ghrelin increased AMPK phosphorylation and UCP2 mRNA expression in MIN6 insulinoma cells. Overexpression or downregulation of UCP2 attenuated or enhanced insulin secretion, respectively. Furthermore, AMPK activator had a similar effect to ghrelin on UCP2 and insulin secretion in MIN6 cells. In conclusion, ghrelin's inhibitory effect on insulin secretion is partly mediated by the AMPK-UCP2 pathway, which is independent of the IA-2beta pathway.
[show abstract][hide abstract] ABSTRACT: Recent advances in genome research have enabled the identification of new genomic variations that are associated with type 2 diabetes mellitus (T2DM). Via fine mapping of SNPs in a candidate region of chromosome 21q, the current study identifies potassium inwardly-rectifying channel, subfamily J, member 15 (KCNJ15) as a new T2DM susceptibility gene. KCNJ15 is expressed in the beta cell of the pancreas, and a synonymous SNP, rs3746876, in exon 4 (C566T) of this gene, with T allele frequency among control subjects of 3.1%, showed a significant association with T2DM affecting lean individuals in three independent Japanese sample sets (p = 2.5 x 10(-7), odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.76-3.67) and with unstratified T2DM (p = 6.7 x 10(-6), OR = 1.76, 95% CI = 1.37-2.25). The diabetes risk allele frequency was, however, very low among Europeans in whom no association between this variant and T2DM could be shown. Functional analysis in human embryonic kidney 293 cells demonstrated that the risk allele of the synonymous SNP in exon 4 increased KCNJ15 expression via increased mRNA stability, which resulted in the higher expression of protein as compared to that of the nonrisk allele. We also showed that KCNJ15 is expressed in human pancreatic beta cells. In conclusion, we demonstrated a significant association between a synonymous variant in KCNJ15 and T2DM in lean Japanese patients with T2DM, suggesting that KCNJ15 is a previously unreported susceptibility gene for T2DM among Asians.
The American Journal of Human Genetics 01/2010; 86(1):54-64. · 11.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Our goal was to ascertain the prevalence of pruritus in diabetic and nondiabetic subjects and the relevance of symptoms, signs, and nerve functions of diabetic polyneuropathy (DPN) of pruritus.
A large-scale survey of 2,656 diabetic outpatients and 499 nondiabetic subjects was performed. In diabetic subjects, the relationship between pruritus and age, sex, diabetic duration, A1C, Achilles tendon reflex (ATR), and abnormal sensation in legs was evaluated. In 105 diabetic subjects, nerve conduction studies, quantitative vibratory threshold (QVT), heart rate variability, and a fall of systolic blood pressure at a head-up tilt test (DeltaBP) were performed, and the relationships between pruritus and nerve functions were evaluated.
Although the prevalence of truncal pruritus of unknown origin (TPUO) in diabetic subjects was significantly higher than that in age-matched nondiabetic subjects (11.3 vs. 2.9%, P = 0.0001), the prevalence of other pruritus was not different between the two groups. Multiple logistic regression analysis revealed that abnormal sensation and ATR areflexia were independent risk factors for TPUO in age, sex, duration of diabetes, and A1C. DeltaBP in diabetic subjects with TPUO was significantly impaired compared with that in those without TPUO. Larger DeltaBP was identified as a significant risk factor of TPUO independent of other nerve dysfunctions by multiple logistic regression analysis.
TPUO is significantly more frequent in diabetic than in nondiabetic individuals. TPUO is significantly associated with symptoms and signs of DPN, including impaired blood pressure response in a head-up tilt test. TPUO, therefore, might be a newly recognized symptom of DPN.
Diabetes care 01/2010; 33(1):150-5. · 8.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chronic kidney disease (CKD) and metabolic syndrome have been recognized as risk factors for cardiovascular disease. However, there is no information comparing their impact on macroangiopathy in diabetic patients. Thus, we studied the prevalence of CKD and metabolic syndrome in Japanese type 2 diabetic patients and then compared their impact on peripheral arterial disease (PAD) in type 2 diabetic patients.
This study focused on Japanese type 2 diabetic patients without hemodialysis (n = 1014). Patients with albuminuria, including microalbuminuria and/or an estimated glomerular filtration rate less than 60 mL/min/1.73(2), were diagnosed as having CKD. PAD was defined as ankle-brachial blood pressure index less than 0.9.
The prevalence of CKD and metabolic syndrome was 47.1% and 39.6%, respectively. In four age- and duration-matched groups classified by the presence or absence of CKD and metabolic syndrome, the prevalence of PAD was significantly higher in groups with CKD alone than those with metabolic syndrome alone, and the high prevalence in the groups with CKD was not influenced by the coexistence with metabolic syndrome.
This study indicates that CKD has more powerful impact on PAD than metabolic syndrome in type 2 diabetic patients.
Metabolic syndrome and related disorders 07/2009; 7(4):323-6.
[show abstract][hide abstract] ABSTRACT: The Met55Val polymorphism in the small ubiquitin-like modifier 4 (SUMO4) gene has been associated with susceptibility not only to type 1 diabetes, but also to type 2 diabetes and diabetic nephropathy. We tried to confirm the association with susceptibility to type 2 diabetes and to investigate its role in diabetic vascular complications. The polymorphism was genotyped in two independent Japanese samples (Wakayama and Tokyo) by the TaqMan method. Susceptibility to type 2 diabetes and prevalence of diabetic vascular complications (coronary heart disease, cerebral infarction, retinopathy, and nephropathy) were evaluated by case-control study and multivariate logistic regression analysis, respectively. There were no significant differences in the frequency of alleles or genotypes between patients and controls. The Val allele, however, was associated with higher prevalence of coronary heart disease in patients in both groups (Wakayama, n=423, odds ratio, 1.64; 95% confidence interval, 1.02-2.64; P=0.041; Tokyo, n=451, odds ratio, 1.58; 95% CI, 1.07-2.34; P=0.021, in an additive model, respectively). No significant associations were observed with other diabetic vascular complications. Although association of the polymorphism with susceptibility to type 2 diabetes or nephropathy was not replicated, an association of the polymorphism with risk of coronary heart disease in type 2 diabetes is suggested.
Diabetes research and clinical practice 05/2009; 85(1):85-9. · 2.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: A novel frameshift mutation attributable to 14-nucleotide insertion in hepatocyte nuclear factor-1alpha (HNF-1alpha) encoding a truncated HNF-1alpha (G554fsX556) with 76-amino acid deletion at its carboxyl terminus was identified in a Thai family with maturity-onset diabetes of the young (MODY). The wild-type and mutant HNF-1alpha proteins were expressed by in vitro transcription and translation (TNT) assay and by transfection in HeLa cells. The wild-type and mutant HNF-1alpha could similarly bind to human glucose-transporter 2 (GLUT2) promoter examined by electrophoretic mobility shift assay (EMSA). However, the transactivation activities of mutant HNF-1alpha on human GLUT2 and rat L-type pyruvate kinase (L-PK) promoters in HeLa cells determined by luciferase reporter assay were reduced to approximately 55-60% of the wild-type protein. These results suggested that the functional defect of novel truncated HNF-1alpha (G554fsX556) on the transactivation of its target-gene promoters would account for the beta-cell dysfunction associated with the pathogenesis of MODY.
Biochemical and Biophysical Research Communications 04/2009; 383(1):68-72. · 2.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Prediction of the disease status is one of the most important objectives of genetic studies. To select the genes with strong evidence of the association with type 2 diabetes mellitus, we validated the associations of the seven candidate loci extracted in our earlier study by genotyping the samples in two independent sample panels. However, except for KCNQ1, the association of none of the remaining seven loci was replicated. We then selected 11 genes, KCNQ1, TCF7L2, CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX, GCKR, HNF1B, KCNJ11 and PPARG, whose associations with diabetes have already been reported and replicated either in the literature or in this study in the Japanese population. As no evidence of the gene-gene interaction for any pair of the 11 loci was shown, we constructed a prediction model for the disease using the logistic regression analysis by incorporating the number of the risk alleles for the 11 genes, as well as age, sex and body mass index as independent variables. Cumulative risk assessment showed that the addition of one risk allele resulted in an average increase in the odds for the disease of 1.29 (95% CI=1.25-1.33, P=5.4 x 10(-53)). The area under the receiver operating characteristic curve, an estimate of the power of the prediction model, was 0.72, thereby indicating that our prediction model for type 2 diabetes may not be so useful but has some value. Incorporation of data from additional risk loci is most likely to increase the predictive power.
Journal of Human Genetics 03/2009; 54(4):236-41. · 2.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest Pvalue (6.7 x 10(-13), odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (OR = 1.40; 95% CI = 1.34-1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of beta-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.
[show abstract][hide abstract] ABSTRACT: Although brachial-ankle pulse wave velocity (baPWV) is a non-invasive method of detecting arteriosclerosis, it is affected by changes in blood pressure (BP). Cardio-ankle vascular index (CAVI) is a new method for estimating arteriosclerosis, and it has been reported to be less influenced by BP. We investigated the influence of BP changes on CAVI and the correlation of CAVI to clinical factors and carotid arteriosclerosis. CAVI and baPWV in 35 non-diabetic and 33 diabetic subjects were measured in increased BP (after stair climbing) and rested BP (after 10min of rest). Intima-media thickness (IMT) of carotid arteries was measured by ultrasoundsonography. We achieved the following results: CAVI did not show a significant change with a change in BP in both non-diabetic and diabetic subjects. On the contrary, baPWV was significantly influenced by BP changes. Carotid artery IMT had a significant positive correlation with CAVI and baPWV. Multiple regression analysis revealed that significant risk factors of high baPWV were age and systolic BP. On the contrary, significant risk factors of high CAVI were age and hemoglobin A1c, while systolic BP was not relevant. Our findings suggest that CAVI is independent of BP and useful as an indicator of early arteriosclerosis in diabetic subjects.
Diabetes research and clinical practice 06/2008; 80(2):265-70. · 2.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: This multinational study was conducted to investigate the association between a mitochondrial DNA (mtDNA) T16189C polymorphism and type 2 diabetes in Asians. The mtDNA 16189C variant has been reported to be associated with insulin resistance and type 2 diabetes. However, a recent meta-analysis concluded that it is negatively associated with type 2 diabetes in Europids. Since the phenotype of an mtDNA mutant may be influenced by environmental factors and ethnic differences in the nuclear and mitochondrial genomes, we investigated the association between the 16189C variant and type 2 diabetes in Asians.
The presence of the mtDNA 16189C variant was determined in 2,469 patients with type 2 diabetes and 1,205 non-diabetic individuals from Korea, Japan, Taiwan, Hong Kong and China. An additional meta-analysis including previously published Asian studies was performed. Since mtDNA nucleotide position 16189 is very close to the mtDNA origin of replication, we performed DNA-linked affinity chromatography and reverse-phase liquid chromatography/tandem mass spectrometry and chromatin immunoprecipitation to identify protein bound to the 16189 region.
Analysis of participants from five Asian countries confirmed the association between the 16189C variant and type 2 diabetes [odds ratio (OR) 1.256, 95% CI 1.08-1.46, p=0.003]. Inclusion of data from three previously published Asian studies (type 2 diabetes n=3,283, controls n=2,176) in a meta-analysis showed similar results (OR 1.335, 95% CI 1.18-1.51, p=0.000003). Mitochondrial single-stranded DNA-binding protein (mtSSB) was identified as a candidate protein bound to the 16189 region. Chromatin immunoprecipitation in cybrid cells showed that mtSSB has a lower binding affinity for the 16189C variant than the wild-type sequence.
The mtDNA 16189C variant is associated with an increased risk of type 2 diabetes in Asians.
[show abstract][hide abstract] ABSTRACT: Catecholamines strongly promote lipolysis and thermogenesis, and play a central role in the regulation of body fat content. The beta1 adrenergic receptor (BAR-1) is a major mediator of catecholamine-induced lipolysis and thermogenesis. To explore whether mutations in the BAR-1 gene contribute to morbid obesity in Japanese, we scanned for mutations in the coding sequence of the gene in 50 morbid obese [body mass index (BMI)>==35.0kg/m(2); 99.7th percentile] Japanese subjects. Direct DNA sequencing was performed following polymerase chain reaction (PCR) amplification. Two common polymorphisms, Gly49Arg and Arg389Ser, were detected in these subjects. The frequencies of these polymorphisms, as determined by PCR-restriction fragment length polymorphism (RFLP) analysis, showed no significant difference between 180 severely obese subjects (BMI>==30.0kg/m(2); 97th percentile) and 132 control (BMI<25.0kg/m(2)) subjects. This study represents the first investigations of genetic variations of BAR-1 in relationship to morbid obesity and suggests mutations in the BAR-1 coding sequence is not likely a major cause of morbid obesity at least in Japanese.
Diabetes research and clinical practice 05/2008; 80(2):213-7. · 2.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: Prevalence of metabolic syndrome (MetS) in type 2 diabetes and its association with vascular complications were studied in 637 Japanese type 2 diabetic patients. MetS was diagnosed using criteria proposed by the Japanese study group for the definition of MetS in 2005. The prevalence of MetS in patients studied was higher in males (45.9%) than females (28.0%). The prevalence of MetS was 53.0% in males and 35.4% in females in patients with duration of less than 10 years, and decreased with an increase in duration. Upon comparing patients groups complicated with and without MetS, we determined the MetS group had significantly higher levels of fasting serum C-peptide and high-sensitivity C-reactive protein, and a significantly lower level of serum adiponectin. However, the prevalence of coronary heart disease, brain infarction, or peripheral arterial disease was not significantly different between these groups. On the other hand, the prevalence of microangiopathy in the group with MetS was significantly higher than in that without MetS, and became significantly higher along with an increase in duration. This study clarifies the prevalence of MetS in Japanese type 2 diabetic patients, and suggests that MetS is associated with microangiopathy rather than macroangiopathy in Japanese type 2 diabetic patients.
Diabetes research and clinical practice 03/2008; 79(2):310-7. · 2.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: A genome-wide association study in the French population has detected that novel single-nucleotide polymorphisms (SNPs) in the IDE-KIF11-HHEX gene locus and the SLC30A8 gene locus are associated with susceptibility to type 2 diabetes.
We investigated whether SNPs in these loci were associated with type 2 diabetes in Japanese.
Two SNPs, rs7923837 and rs1111875, in the IDE-KIF11-HHEX gene locus and one SNP, rs13266634, in the SLC30A8 gene locus were genotyped in Japanese type 2 diabetic patients (n = 405) and in nondiabetic control subjects (n = 340) using the TaqMan genotyping assay system.
The G allele of rs7923837 was associated with type 2 diabetes [odds ratio 1.66, 95% confidence interval (CI) 1.28-2.15; P = 0.00014], following the same tendency as in the French population of the previous report. Heterozygous and homozygous carriers of the risk allele had odds ratios of 1.57 (95% CI 1.15-2.16; P = 0.0050) and 3.16 (95% CI 1.40-7.16; P = 0.0038) relative to noncarriers. Although the G allele was a major allele (66.5%) in the French population, it was a minor allele (23.8%) in Japanese. The G allele of rs1111875 was also associated with type 2 diabetes (odds ratio 1.42, 95% CI 1.13-1.78; P = 0.0024). Heterozygous and homozygous carriers of the risk allele had odds ratios of 1.31 (95% CI 0.97-1.77; P = 0.0810) and 2.40 (95% CI 1.34-4.32; P = 0.0028) relative to noncarriers. A significant association with type 2 diabetes was not observed for rs13266634.
Polymorphisms in the IDE-KIF11-HHEX gene locus are associated with susceptibility to type 2 diabetes across the boundary of race.
[show abstract][hide abstract] ABSTRACT: We investigated the preventive effects of ferulic acid (FA) and alpha-tocopherol (AT) on the progression of diabetic nephropathy. Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as type 2 diabetes and non-diabetes models, respectively. Two-thirds of the OLETF rats were fed 0.2% FA-containing or 0.5% AT-containing chow. Diabetic nephropathy was assessed based on urinary protein excretion and pathological changes which were scored based on the percentages of extracellular matrix area in the glomerular area. Furthermore, renal messenger RNA (mRNA) expression of intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and transforming growth factor-beta1 (TGF-beta1) was quantified by real-time polymerase chain reaction. After 12 weeks of FA- or AT-supplementation, urinary protein in untreated-OLETF group was significantly higher than that in LETO group, thus FA-supplementation significantly decreased urinary protein excretion. Pathological scores in FA-supplemented group were significantly lower than those in untreated OLETF group. Supplementation with either FA or AT significantly prevented the elevation of TGF-beta1 mRNA expression caused by diabetes. Treatment with neither FA nor AT had a significant effect on COX-2 or ICAM-1 mRNA expressions. We have demonstrated the preventative effects of FA on diabetic nephropathy via suppression of TGF-beta1 upregulation, furthermore FA may be more potent than AT.
Diabetes research and clinical practice 02/2008; 79(1):11-7. · 2.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: Transcription factor 7-like 2 (TCF7L2) has been shown to be associated with type 2 diabetes mellitus in multiple ethnic groups. Regarding the Asian population, Horikoshi et al. (Diabetologia 50:747-751, 2007) and Hayashi et al. (Diabetologia 50:980-984, 2007) reported that single nucleotide polymorphisms (SNPs) in TCF7L2 were associated with type 2 diabetes in the Japanese population, while contradictory results were reported for Han Chinese populations. The aim of this study was to investigate the associations of the TCF7L2 gene with type 2 diabetes using a relatively large sample size: 2,214 Japanese individuals with type 2 diabetes and 1,873 normal controls. The minor alleles of rs7903146, rs11196205, and rs12255372 showed significant associations with type 2 diabetes (OR=1.48, P=2.7 x 10(-4); OR=1.39, P=4.6 x 10(-4); OR=1.70, P=9.8 x 10(-5), respectively) in the combined sample sets. However, neither rs11196218 nor rs290487 showed a significant association. These results indicate that TCF7L2 is an important susceptibility gene for type 2 diabetes in the Japanese population.
Journal of Human Genetics 02/2008; 53(2):174-80. · 2.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: This report describes a 37-year-old man with tumor-induced osteomalacia (TIO). The patient had hypophosphatemia and elevated fibroblast growth factor 23 (FGF23) in the peripheral blood. Magnetic resonance imaging detected an abnormal mass in the left greater trochanter. Venous sampling revealed a significantly higher level of FGF23 in the left common iliac vein (proximal to the tumor), verifying that the tumor is responsible for TIO. The serum level of FGF23 decreased and symptoms improved after removal of the tumor. The combined diagnostic procedures of MRI and venous sampling for FGF23 effectively detected the tumor responsible for TIO.
Internal Medicine 02/2008; 47(10):957-61. · 0.97 Impact Factor