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Objective The measurement of C-peptide immunoreactivity (CPR) is essential for evaluating the pancreatic β-cell function and selecting appropriate therapeutic agents in patients with diabetes mellitus. The meal tolerance test (MTT) is simple to administer physiological insulin-stimulating test. Previous studies have reported that several CPR-related indices are useful markers for predicting insulin requirement in type 2 diabetes. In the present study, we investigated the serum CPR response during the MTT in hospitalized patients with type 2 diabetes mellitus in order to clarify the clinical utility of the MTT. Methods We performed the MTT using a test meal with timed measurements of the serum CPR level based on the oral glucose tolerance test over 180 minutes and tested the correlation of various CPR-related indices and clinical factors in patients with type 2 diabetes mellitus. Patients The subjects were patients with type 2 diabetes mellitus who had been admitted to our hospital for diabetes management and education. The final study population consisted of 68 patients. Results The fasting CPR level was correlated with the 24-hour urinary CPR excretion and body mass index. The serum CPR level at 120 minutes in the MTT was strongly correlated with the area under the curve of CPR during the MTT. The patients who needed insulin therapy at 6 months after hospitalization showed a significant lower incremental CPR value from 0 to 120 minutes in the MTT than those who did not need insulin therapy. Conclusion The plasma C-peptide levels at 0 and 120 minutes in the MTT provide essential information for the clinical management of patients with type 2 diabetes mellitus.

Aims/Introduction The prevalence of clinical polyneuropathies (ClinPNs) or nerve conduction abnormality (NCA) in the groups stratified by glucose tolerance, individual components of metabolic syndrome (metabolic syndrome [MetS] components: hypertension, dyslipidemia, obesity) and MetS defined by the International Diabetes Federation consensus was investigated in the Japanese general population. Factors associated with ClinPN and NCA were also identified. Materials and Methods A total of 625 examinees of regional medical checkup programs were recruited to this cross‐sectional study. ClinPNs were diagnosed by the Toronto Consensus. NCA was judged by at least one bilateral abnormality of sural nerve action potential amplitude or conduction velocity measured by a point‐of‐care nerve conduction device (DPNCheck). Clinical factors associated with ClinPNs or NCA were examined by multiple logistic regression analysis. Deteriorating factors of sural nerve action potential amplitude or conduction velocity values were also investigated in participants without diabetes (n = 550). Results As for glucose tolerance, ClinPNs or NCA significantly increased only in known diabetes patients compared with other groups. There was no difference between prediabetes and the normal group. The prevalence of ClinPNs and NCA was not significantly related to MetS or MetS’ components, except for frequent NCA in obesity. The factors significantly associated with both NCA and ClinPNs were smoking and known diabetes. In non‐diabetic participants, aging, tall height and hypertension were significant deteriorating factors of nerve conduction functions. Conclusions In Japan, ClinPNs and NCA were increased in known diabetes patients, but did not increase in participants with prediabetes, MetS and MetS’ components. Smoking and known diabetes were factors significantly associated with ClinPNs or NCA. Hypertension might be a modifiable deteriorating factor of nerve function.

T2DM is a common disease progressed over the long duration of life. Because of lacking apparent symptoms and signs in many cases, interrelationship between patient and doctor becomes complicated...

Aims/Introduction As the extensor digitorum brevis muscle is a small muscle in the most distal part of the legs, its atrophy (EDBA) might reflect symmetric polyneuropathy (SPN). We aimed to clarify the EDBA‐related factors and the usefulness of bilateral EDBA detection for diagnosing SPN, especially diabetic SPN (DSPN). Materials and Methods In 1,893 participants from the Japanese general population (investigation I) and 133 established diabetes patients (investigation II), relationships between EDBA and various factors including the traditional sitting style called “seiza’” (kneeling and sitting on one’s heels) were investigated. Analyses were carried out by univariate and multivariate analysis, and SPN or DSPN was diagnosed by the criteria of “Probable DSPN” of the Toronto Consensus. The validity of EDBA detection for diagnosing SPN/DSPN was also evaluated. Results Investigation I: EDBA was more prevalent in women than men (44% vs 20%). Significant EDBA‐related factors were aging and seiza habit regardless of sex. Male‐specific EDBA‐related factors were SPN and known diabetes. In men without seiza habit, EDBA was significantly associated with SPN regardless of diabetes, so EDBA seemed to be a useful sign for diagnosing SPN/DSPN. Investigation II: In men, DSPN was more prevalent in the EDBA group than the non‐EDBA group (71% vs 33%). Sensitivity, specificity, positive predictive value and kappa coefficient of EDBA detection for diagnosing DSPN were 44, 87, 67% and 0.323, showing fair agreement. Conclusions EDBA detection might be a useful method to screen for distal symmetric polyneuropathy, such as DSPN in men, although the exclusion of individuals with seiza habit is necessary to improve accuracy., Extensor digitorum brevis atrophy detection might be a useful method to screen for distal symmetric polyneuropathy, such as diabetic symmetric polyneuropathy in men, although the exclusion of individuals with seiza habit is necessary to improve accuracy.

Aims/Introduction To explore the relationships between periodontitis and microvascular complications as well as glycemic control in type 2 diabetes patients. Materials and Methods This multicenter, hospital-based, cross-sectional study included 620 patients with type 2 diabetes. We compared the prevalence and severity of periodontitis between patients with ≥1 microvascular complication and those without microvascular complications. We also compared the prevalence and severity of periodontitis among patients with different degrees of glycemic control. Results After adjusting for confounding factors, multiple logistic regression analysis showed that the severity of periodontitis was significantly associated with the number of microvascular complications (odds ratio 1.3, 95% confidence interval 1.1–1.6), glycated hemoglobin ≥8.0% (64 mmol/mol; odds ratio 1.6; 95% confidence interval 1.1–2.3), and older age (≥50 years; odds ratio 1.7; 95% confidence interval 1.1–2.6). However, the prevalence of periodontitis was not significantly associated with the number of microvascular complications, but was associated with male sex, high glycated hemoglobin (≥8.0% [64 mmol/mol]), older age (≥40 years), longer duration of diabetes (≥15 years) and fewer teeth (≤25). Furthermore, propensity score matching for age, sex, diabetes duration and glycated hemoglobin showed that the incidence of severe periodontitis was significantly higher among patients with microvascular complications than among those without microvascular complications (P < 0.05). Conclusions The number of microvascular complications is a risk factor for more severe periodontitis in patients with type 2 diabetes, whereas poor glycemic control is a risk factor for increased prevalence and severity of periodontitis.

We measured pain threshold of intra-epidermal nerve terminal (PINT) which is a simple and noninvasive method that can measure pain threshold of A delta fiber by intra-epidermal electrical stimulation. We aimed to investigate normal value, prevalence of abnormality and clinically associated factors to PINT and quantitative vibratory perception threshold (QVT). PINT and QVT were measured by a portable peripheral nerve testing device PNS-7000, and a vibration sensation meter AU 02-B in 656 Japanese regional health checkup examinees (40-75 years old; years old). Glucose tolerance; normal (N), pre-DM, newly diagnosed DM (NDM) and known DM (KDM), and neuropathic findings (pain, paresthesia, numbness in legs and reduced ATRs) were also determined. Relationship between age, glucose tolerance, neuropathic findings and PINT or QVT were investigated by simple and multivariate analyses. In 445 non-DM subjects without neuropathic findings, normal limit value of PINT (mA) was set by quantile regression method, and relationship between prevalence of PINT or QVT abnormalities and clinical factors were examined. As results, PINT was not changed under 70 years old, then somewhat elevated. QVT elevated from 50 years old. PINT was not associated with QVT. PINT was significantly elevated in NDM and KDM. QVT was elevated in diabetes and hypertension. Among the neuropathic findings, PINT was significantly associated with only pain. By multiple regression analyses, significant aggravating factors of PINT were aging and glucose intolerance. Normal values of PINT were > 0.4 (0.5 (70< years old) Prevalence of PINT abnormality were 3%, 4%, 13% and 9% in N, pre-DM, NDM and KDM, respectively. They were significantly increased with the deterioration of glucose tolerance. QVT abnormality was not significantly increased with glucose intolerance. In conclusion, PINT reflects small nerve fiber function, and associates with DM. So, PINT may be a useful for diagnosis and evaluation of small fiber neuropathy. Disclosure H. Sasaki: None. S. Kishimoto: None. K. Ogawa: None. S. Kurisu: None. K. Nanjo: None. Funding Japan Society for the Promotion of Science

Aims/Introduction The adenosine triphosphate (ATP)-sensitive potassium (KATP) channel is a key component of insulin secretion in pancreatic β-cells. Activating mutations in ABCC8 encoding for the sulfonylurea receptor subunit of the KATP channel have been associated with the development of neonatal diabetes mellitus (NDM). The aim was to investigate clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent NDM (PNDM). Materials and Methods The coding regions and conserved splice sites of KCNJ11, ABCC8 and INS were screened for mutations in a 12-year-old girl diagnosed with PNDM. The functional property of the mutant channel identified was examined with patch-clamp experiments in COS-1 cells. We also investigated the difference of effectiveness between two groups of oral sulfonylureas in vitro and in the patient. Results We identified a heterozygous missense mutation (c.3593 C>T, Pro1198Leu) in ABCC8. The mutated residue (P1198) is located within a putative binding site of sulfonylureas, such as tolbutamide or gliclazide. In patch-clamp experiments, the mutant channel was less ATP sensitive than the wild type. Furthermore, the sensitivity to tolbutamide was also reduced in the mutant channel. In addition to the tolbutamide/gliclazide binding site, glibenclamide is thought to also bind to another site. Glibenclamide was more effective than other sulfonylureas in vitro and in the patient. The treatment of the patient was finally able to be switched from insulin injection to oral glibenclamide. Conclusions We identified the Pro1198Leu ABCC8 mutation in a PNDM patient, and clarified the functional and clinical characterization. The present findings provide new information for understanding PNDM.

Aims/Introduction Although arteriosclerotic diseases have been reported to be frequently complicated by diabetes mellitus (DM), a detailed relationship between hyperglycemia and arterial stiffness has not been fully clarified. We investigated the influence of hyperglycemia on arterial stiffness using the cardio-ankle vascular index (CAVI), which is a new method for estimating arterial stiffness. Materials and Methods CAVI values of 52 early-staged DM patients (duration

Risk factors for cardiovascular complications in Japanese patients with diabetes have not been fully elucidated.Our objective was to determine incidence of and risk factors for coronary heart disease (CHD) and stroke in Japanese diabetic patients.We conducted a prospective study at 59 hospitals throughout Japan.Patients included 940 men and 831 women with type 2 diabetes (mean age, 58.2 yr) without a history of cardiovascular complications who were followed for a median of 7.86 yr.This was an observational study.Incidence of CHD and stroke was evaluated.Incidences of CHD and stroke per 1000 person-years were 9.59 and 7.45, respectively, whereas those of myocardial and brain infarctions were 3.84 and 6.29, respectively. Multivariate Cox analysis revealed that the serum log-transformed triglyceride level was a potent and independent predictor of CHD [hazard ratio (HR) = 1.54; 95% confidence interval (CI) = 1.22-1.94 per 1 sd increase), comparable to low-density lipoprotein (LDL) cholesterol (HR = 1.49; 95% CI = 1.25-1.78 per 1 sd increase). Triglycerides and LDL cholesterol linearly and continuously increased CHD risk, and subjects in the top third for both had markedly high risks of CHD, and their effects were possibly additive. However, serum triglycerides worked independently of blood pressure levels. Systolic blood pressure was the only significant predictor for stroke except for age (HR = 1.31; 95% CI = 1.04-1.65, per 1 sd increase).In Japanese patients with type 2 diabetes, the serum triglyceride level was a leading predictor of CHD, comparable to LDL cholesterol. Because the serum triglyceride level is not a leading predictor of CHD in diabetic subjects in Western countries, ethnic group-specific strategies for prevention of diabetic macroangiopathy may be indicated.

Aims/Introduction: We have previously reported that the Pro198Leu missense polymorphism in the glutathione peroxidase 1 (GPx-1) gene was associated with frequent macrovascular disease (MVD). Our goal was to examine whether the GPx-1 genotype is associated with diabetic neuropathy. Materials and Methods: We determined the GPx-1 genotype in 173 Japanese type 2 diabetic patients who received medical interviews, physical examinations, nerve conduction studies, quantitative vibratory perception (QVP), head-up tilt and heart rate variability tests by polymerase chain reaction-restriction fragment-length polymorphism. Diabetic sensorimotor distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathy (DAN) were evaluated separately. DSPN and DAN were defined by two or more abnormalities of neuropathic leg symptoms, diminished Achilles tendon reflexes or impaired QVP in toes, and two autonomic dysfunctions, respectively. The association of the GPx-1 genotype with DSPN, DAN, MVD and other clinical manifestations was analyzed. Results: The prevalence of DSPN, impaired QVP and painful leg cramps in patients having a genotype with Pro/Leu at the codon 198 (Pro/Leu type) was significantly higher than those with Pro/Pro type. As a result of multivariate analyses that contained the GPx-1 genotype as an independent variable, the Pro/Leu type was extracted as a significant risk factor of DSPN, QVP impairment and MVD. The statistical significance did not disappear, even after proteinuria, retinopathy and a history of MVD were introduced as independent variables. In contrast, the GPx-1 genotype was not associated with DAN. Conclusions: The Pro198Leu missense polymorphism of the GPx-1 gene might have a common genetic predisposition to DSPN and MVD. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00127.x, 2011)

Aims/Introduction: In order to diagnose diabetic symmetric polyneuropathy (DSPN) more simply and accurately, we identified symptoms that correlated with neurological functions and existed more frequently in diabetic than non-diabetic subjects. Materials and Methods: The relationships between 10 symptoms (numbness or paresthesia in toe and sole, numbness in hand, pain in foot or hand, coldness in legs, painful leg cramp, dizziness on standing, sweating restricted to face/trunk and frequent constipation/diarrhea) and clinical background, defined as DSPN and cardiovascular autonomic neuropathy (CAN) by the criteria proposed in the statement of the American Diabetes Association, and seven quantitative nerve function data were evaluated in 593 diabetic patients in Wakayama Medical University Hospital (WMUH). Furthermore, the prevalence of various symptoms was examined by three questionnaires: a WMUH survey (999 diabetic outpatients), a Nationwide survey (1524 male diabetic outpatients under a primary-care physician) and a Control survey (501 non-diabetic subjects). Results: Bilateral ‘numbness in toe and sole’, ‘paresthesia in toe and sole’, ‘pain in foot’ and ‘sweating restricted to face/trunk’ were significantly associated with diabetes duration, retinopathy, probable and confirmed DSPN, possible and advanced CAN, and all or six nerve functions. Questionnaire surveys clarified that symptoms that are not rare (>15%) and more frequent in diabetic than non-diabetic subjects were bilateral ‘numbness in toe and sole’, ‘paresthesia in toe and sole’, ‘coldness in legs’, ‘dizziness on standing’ and ‘sweating restricted to face/trunk’. Conclusions: Therefore, bilateral ‘numbness in toe and sole’, ‘paresthesia in toe and sole’ and ‘sweating restricted to face/trunk’ are suitable symptoms useful for the diagnosis of DSPN. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00124.x, 2011)

Some mutations of the insulin gene cause hyperinsulinemia or hyperproinsulinemia. Replacement of biologically important amino acid leads to defective receptor binding, longer half-life and hyperinsulinemia. Three mutant insulins have been identified: (i) insulin Chicago (F49L or PheB25Leu); (ii) insulin Los Angeles (F48S or PheB24Ser); (iii) and insulin Wakayama (V92L or ValA3Leu). Replacement of amino acid is necessary for proinsulin processing results in hyperproinsulinemia. Four types have been identified: (i) proinsulin Providence (H34D); (ii) proinsulin Tokyo (R89H); (iii) proinsulin Kyoto (R89L); and (iv) proinsulin Oxford (R89P). Three of these are processing site mutations. The mutation of proinsulin Providence, in contrast, is thought to cause sorting abnormality. Compared with normal proinsulin, a significant amount of proinsulin Providence enters the constitutive pathway where processing does not occur. These insulin gene mutations with hyper(pro)insulinemia were very rare, showed only mild diabetes or glucose intolerance, and hyper(pro)insulinemia was the key for their diagnosis. However, this situation changed dramatically after the identification of insulin gene mutations as a cause of neonatal diabetes. This class of insulin gene mutations does not show hyper(pro)insulinemia. Mutations at the cysteine residue or creating a new cysteine will disturb the correct disulfide bonding and proper conformation, and finally will lead to misfolded proinsulin accumulation, endoplasmic reticulum stress and apoptosis of pancreatic β-cells. Maturity-onset diabetes of the young (MODY) or an autoantibody-negative type 1-like phenotype has also been reported. Very recently, recessive mutations with reduced insulin biosynthesis have been reported. The importance of insulin gene mutation in the pathogenesis of diabetes will increase a great deal and give us a new understanding of β-cell biology and diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00100.x, 2011).

Introduction: We investigated the effect of Ricetrienol, which is an anti-oxidant extracted from rice bran, and α-tocopherol on the adipocytokine abnormalities and fatty liver in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Materials and Methods: A total of 18 OLETF rats were bred using a 30% sucrose solution (the diabetic group; DM), whereas another 18 OLETF rats were bred using ordinary water (the non-diabetic obese group; OB) as drinking water, respectively. After the sucrose-fed rats developed diabetes, all of the rats from the diabetic and obese groups were randomly divided into three groups. Then each group was fed either standard chow (DM-S, OB-S group), 0.05% Ricetrienol-containing chow (DM-R, OB-R group) or 0.05%α-tocopherol-containing chow (DM-A, OB-A group), respectively. After 12 weeks of feeding, all the rats were killed. Plasma insulin, adiponectin, resistin and leptin were assayed by enzyme immunoassay. Histopathological findings of liver tissue were scored according to Brunt and Kleiner’s method, and triglyceride contents of the liver tissue were investigated. Results: Plasma adiponectin was significantly reduced in DM-S compared with OB-S, but it had significantly increased in DM-R and DM-A as opposed to DM-S. Plasma resistin showed a significant increase in DM-S compared with OB-S, but it was significantly reduced in DM-A than in DM-S. Though the triglyceride contents of liver tissue significantly increased in DM-S as opposed to OB-S, they were significantly reduced in DM-R compared with DM-S. Histopathological scores were significantly higher in DM-S than OB-S. Conclusions: The present study shows that Ricetrienol might prevent adipocytokine abnormalities and fatty liver in OLETF diabetic rats. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00090.x, 2011)

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.

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.

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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 (ΔBP) were performed, and the relationships between pruritus and nerve functions were evaluated. RESULTS 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. ΔBP in diabetic subjects with TPUO was significantly impaired compared with that in those without TPUO. Larger ΔBP was identified as a significant risk factor of TPUO independent of other nerve dysfunctions by multiple logistic regression analysis. CONCLUSIONS 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.

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.

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.

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.

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.

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.

Circulating adiponectin (ADP) level in diabetic patients was mainly studied from a viewpoint of insulin action, with little being known about the regulation by pancreatic beta-cell function. We thus investigated the relationship between the serum ADP concentration and pancreatic beta-cell function in non-obese [body mass index (BMI)30 kg/m(2)] diabetic patients. Serum ADP was measured in 239 type 2 diabetic patients, 61 type 1 diabetic patients and 159 non-obese and non-diabetic subjects with enzyme-linked immunosorbent assay. Serum ADP was analyzed separately by gender. In both males and females, the ADP level increased in conjugation with beta-cell dysfunction, estimated by fasting serum C-peptide, and showed marked increase in type 1 diabetic patients. Multivariate analysis in type 2 diabetic patients showed that the fasting serum C-peptide was extracted as an independent and significantly negative modulator for serum ADP in addition to BMI. The ADP level was not associated with the daily dose of injected insulin in the multivariate analysis using insulin treated patients with types 1 and 2 diabetes. These results indicate that pancreatic beta-cell function is one of a significant negative modulator for the circulating ADP level in non-obese diabetic patients and support the presence of an adipoinsular axis.

As a westernized lifestyle becomes widespread in Japan, the number of individuals with obesity, as well as type 2 diabetes, is rapidly increasing. In this investigation, we studied the prevalence of obesity and its association with the development of diabetic macroangiopathy and microangiopathy. The clinical records of 634 patients in our hospital with type 2 diabetes were surveyed. The relationship between obesity and diabetic retinopathy and nephropathy and macroangiopathy (carotid artery intima-media thickness, IMT) was examined using univariate and multivariate analysis. A body mass index (BMI) ≥ 25 kg/m 2 was used as the diagnostic criterion for obesity. The prevalence of obesity at the time of the survey was 35% and a history of obesity was reported in 70% of the survey population. Multiple regression analysis revealed that the maximum BMI was significantly correlated with IMT thickening. The prevalence of nephropathy in previously obese patients was significantly higher than in non-obese patients. The maximum BMI was significantly associated with the development of retinopathy and nephropathy, as shown by logistic regression analysis. This suggests that a history of obesity may be an important risk factor for the development of micro- and macroangiopathy in Japanese with type 2 diabetes.

The discriminating abilities of fasting plasma glucose (FPG) and HbA1c were compared on screening tests for impaired glucose tolerance (IGT) and IGT plus diabetes mellitus by the receiver operating characteristic (ROC) curve analysis. Furthermore, effects of sex, age and BMI were examined on sensitivity and specificity of the optimal cutoff points. This study included 997 subjects who were recruited for 75 g OGTT after the first screening of the Japan Diabetes Prevention Program. According to the 1997 criteria of the American Diabetes Association (ADA), 140 subjects were classified as diabetic and 256 as IGT. The areas under the ROC curves of FPG were significantly larger than those of HbA1c. The optimal cutoff points of FPG were 102 mg/dl for IGT and 105 mg/dl for IGT plus diabetes mellitus. Those of HbA1c were both 5.3%. In screening with FPG, females had significantly lower sensitivity and higher specificity than males, and the specificity for IGT plus diabetes mellitus was the lowest in the obese group. In screening with HbA1c, the specificity was low in the older and the obese groups. We concluded that FPG was superior to HbA1c for screening of IGT and IGT plus diabetes mellitus and the optimal cutoff point of FPG would be 102 mg/dl or greater.

2型糖尿病における東洋医学の証と西洋医学的な臨床指標との関連性を明確にするために, 2型糖尿病患者の陰陽証あるいは虚実証の頻度ならびに各証とインスリン抵抗性 (IR) との関連性を検討した。65名の2型糖尿病患者 [男性27名 (平均年齢60.9±12.0歳), 女性38名 (64.9±8.4歳)] を陰陽証あるいは虚実証単独で分類した場合の頻度は, 陰証30.8%, 中間証32.3%, 陽証36.9%あるいは虚証30.8%, 中間証33.8%, 実証35.4%であった。また, 陰陽・虚実証を併用した分類における頻度は陽実証26.2%, 中間中間証21.5%, 陰虚証18.5%, 陽虚証10.8%, 中間実証7.7%, 陽中間証6.2%, 陰中間証6.2%, 中間虚証3.1%であった。一方, インスリン療法を除く2型糖尿病患者についてIRの指標である空腹時血漿インスリン値 (fasting plasma insulin level: F-IRI) と Homeostasis Model Assessment によるインスリン抵抗性指標 (HOMA-IR) を検討すると, F-IRIは実証群が虚証群 (p=0.044) に比し, 陽実証群が陰虚証群 (p=0.033) に比し有意な高値, HOMA-IRは陽実証群が陰虚証群に比し有意な (p=0.017) 高値であった。以上より2型糖尿病患者では陽証と陰証, 実証と虚証が同程度存在することが確認された。さらに, 陽証や実証を呈する2型糖尿病患者ではIRとの関連性を有することが示唆された。

We report a 60-year-old woman with neurosarcoidosis. She was referred to our hospital for examination of the cause of pain in left Th4-6 dermatome. Chest X-ray and computed tomography (CT) revealed bilateral hilar and mediastinal lymphadenopathy, and her serum angiotensin converting enzyme (ACE) level was elevated. Histological finding of mediastinal lymph nodes consisted with sarcoidosis. Therefore, her pain was thought to be spinal root pain caused by neurosarcoidosis. With the administration of prednisolone, her symptom and bilateral hilar lymphadenopathy disappeared, and serum ACE level became normal. It is important to pay attention to neurosarcoidosis when patients show unknown spinal root symptom, although it is rare.

Diabetes mellitus with the mitochondrial DNA 3243(A-G) mutation is reported to represent 0.5-2.8% of the general diabetic population. Since the characterization of diabetes with the mutation is still incomplete, we undertook a nation-wide case-finding study of genetically defined patients using questionnaires in Japan. One hundred and thirteen Japanese diabetic patients with the mutation were registered and analyzed. The patients had a high prevalence of maternal inheritance of diabetes and deafness, short and thin stature, and showed an early middle-aged onset of diabetes and deafness. Eighty-six percent of the patients required insulin therapy due to the progressive insulin secretory defect. Glucose intolerance of the mothers was associated with an early middle-aged onset of diabetes, reduction in the insulin secretory capacity, early requirement of insulin therapy, and increases in the daily insulin dose. The heteroplasmic concentrations of the 3243 mutation in leukocytes were low and declined with aging. The patients had advanced microvascular complications, and mitochondria-related complications such as cardiomyopathy, cardiac conductance disorders, neuromuscular symptoms, neuropsychiatric disturbance, and macular pattern dystrophy. Thus, this study has revealed that: (1) diabetes mellitus with the 3243 mutation is a subtype of diabetes mellitus with mitochondria-related complications; and (2) insulin secretory ability is more severely impaired in the patients whose mothers were glucose intolerance.

Postural tachycardia syndrome is defined as the development of orthostatic symptoms without orthostatic hypotension. We report a 28-year-old female patient with postural tachycardia syndrome who exhibited palpitation, lowgrade fever and weight loss. Evaluation of autonomic nervous system functions showed that cardiovagal function was normal. Sweat response to acetylcholine was decreased. Excessive blood pressure elevation was seen in phase IV of the Valsalva maneuver. Pathophysiologic factors in this case were considered to be α adrenergic denervation and β adrenergic hyperresponsiveness. It is important that this syndrome be widely recognized and properly diagnosed.(Internal Medicine 40: 1032-1036, 2001)

The recent development of molecular biology enables us to identify three abnormal insulins (insulin Chicago, insulin LosAngeles and insulin Wakayama). In Japan, three pedigrees in which affected individuals secrete [LeuA3] insulin (insulin Wakayama) have been identified. In each family, hyperinsulinemia associated with an abnormally elevated insulin to C-peptide molar ratio was demonstrated to occur in an autosomal dominant pattern of inheritance. In accordance with in vivo observations, semisynthetic [LeuA3] insulin demonstrated reduced in vitro receptor binding and biological activity relative to the human standard. The development of diabetes mellitus in affected family members was not uniform, was influenced by aging, and was different among families. Patients with impaired glucose tolerance demonstrated reduced insulin secretory reserve. Some of these features are thought to resemble the nature of noninsulin dependent diabetes mellitus (NIDDM).Therefore, insulin Wakayama may be an useful model for the study of the development of NIDDM.

The preventive effects of combined or separate treatment for 10 weeks with an aldose reductase inhibitor, epalrestat (50 mg/kg/day), and a vasodilator, cilostazol (30 mg/kg/day), on nerve conduction deficits and morphometric alterations were examined in streptozotocin-induced diabetic rats. The average motor nerve conduction velocities (MNCV) in the tail nerve of the untreated diabetic (DM) group, the group treated with epalrestat (ES), the group treated with cilostazol (CZ), the group with both agents together (ES&CZ), and the normal control group were 34.7, 37.7, 39.3, 39.0 and 42.1 m/s, respectively. All treatments partially but significantly prevented a reduction in MNCV. The MNCV in the ES&CZ group was almost the same as in the CZ group. In a morphometric study of the sural nerve, the DM group showed a reduction in the average diameter of myelinated fiber and in occupancy (percentage of the fascicular area occupied by myelinated fibers), and a shift in the diameter–frequency histogram to smaller diameters. Only the CZ group showed evidence of a partial but significant preventive effect on the decrease in occupancy. In the CS and ES&CZ groups, there was a significant tendency away from the shift of histograms to smaller diameters. The ES&CZ group did not show any fewer morphometric changes than the CZ group. Thus, there was no synergism between the effects of epalrestat and cilostazol on the development of experimental diabetic neuropathy. This finding may provide a useful clue to the mechanisms of action of ES and CZ in diabetic neuropathy.

55歳,女性. 2002年7月進行型小細胞肺癌の診断のもとに,全身化学療法を行い, partial response (PR)を得た.しかし平成15年1月多発性脳転移にて再燃再入院した.全脳照射,メソトレキセート(MTX)の髄空内投与を行ったところ,汎血球減少をきたした.その原因として,全脳照射, MTXの髄腔内投与, disseminated intravascular coagulation (DIC)の関与等も想定されたが,骨髄所見より血球貪食症候群が原因と診断した.二次性の血球貪食症候群としては,感染症・悪性腫瘍・自己免疫等が報告されているが,悪性腫瘍,なかでも肺癌に伴うものは少ないため報告する.

We studied the ability of cilostazol (CL), an antithrombotic and vasodilating agent, to prevent functional, structural and biochemical abnormalities including delayed motor nerve conduction velocity (MNCV), morphological changes in myelinated fibers, and decreased Na + -K + -ATPase activity in the peripheral nerves of rats with streptozotocin (STZ)-induced diabetes. Cilostazol treatment (30 mg/kg/day p.o.) for 10 weeks significantly prevented the delay in MNCV in the tail nerve, and morphometric analysis of the sural nerves revealed that this dose of cilostazol had a significant effect on reduction of average size of myelinated fibers. In untreated diabetic rats, cyclic AMP content and Na + -K + -ATPase activity of peripheral nerve were each significantly less than in normal control rats. Cilostazol (30 mg/kg/day) prevented reduction of Na + -K + -ATPase activity. Decrease in cyclic AMP content was completely prevented with both doses of cilostazol (30 and 10 mg/kg/day). These findings suggest that cilostazol may have beneficial effects in the treatment of diabetic neuropathy, possibly via improvement of nerve Na + -K + -ATPase activity and cyclic AMP content. Cilostazol may thus be a potent drug for the clinical treatment of diabetic neuropathy.

Islet amyloid polypeptide (IAPP/Amylin) is a novel peptide which was extracted from islet amyloid deposits in patients with non-insulin-dependent diabetes mellitus (NIDDM). However, its pattern of secretions and plasma concentrations under various conditions has not yet been made clear enough. In this study, we examined IAPP secretion from islet beta-cells in vitro using cultured islet cells of neonatal rat pancreas and plasma IAPP responses under various conditions in vivo in normal control subjects and patients with glucose intolerance. Our data revealed that (1) IAPP is co-secreted with insulin from islet cells of the rat pancreas by glucose and non-glucose stimuli; (2) fasting plasma IAPP levels in normal control subjects are 24.9 +/- 2.0 pg/ml and the molar ratio of IAPP/insulin is approximately 1/7; (3) fasting IAPP levels are high in obese patients and low in insulin-dependent diabetic patients, and the molar ratio of IAPP/C-peptide in NIDDM patients is lower than that in normal control subjects, suggesting the basal hyposecretion of IAPP relative to insulin in NIDDM; and (4) the obese patients who had a hyperresponsiveness of insulin relative to C-peptide had the hyperresponsiveness of IAPP relative to C-peptide during an oral glucose load, suggesting that IAPP may have some physiological effect in glucose metabolism.

Fasting plasma islet amyloid polypeptide concentrations and their responses to an oral glucose load were determined in non-diabetic control subjects and patients with abnormal glucose tolerance in relation to the responses of insulin or C-peptide. Plasma islet amyloid polypeptide was measured by radioimmunoassay. In the non-diabetic control subjects, fasting plasma islet amyloid polypeptide was 6.4 +/- 0.5 fmol/ml (mean +/- SEM) and was about 1/7 less in molar basis than in insulin. The fasting islet amyloid polypeptide level rose in obese patients and fell in patients with Type 1 (insulin-dependent) diabetes mellitus. In non-obese patients with impaired glucose tolerance and Type 2 (non-insulin-dependent) diabetic patients without insulin therapy, the level was equal to that of the control subjects, but a low concentration of islet amyloid polypeptide relative to insulin or C-peptide was observed in the non-obese Type 2 diabetic group. The patterns of plasma islet amyloid polypeptide responses after oral glucose were similar to those of insulin or C-peptide. However, compared to non-obese patients, a hyper-response of islet amyloid polypeptide relative to C-peptide was noted in obese patients who had a hyper-response of insulin relative to C-peptide. This study suggests that basal hypo-secretion of islet amyloid polypeptide relative to insulin exists in non-obese Type 2 diabetes and that circulating islet amyloid polypeptide may act physiologically with insulin to modulate the glucose metabolism.

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.

In long-term diabetes mellitus, thickening of basement membrane in capillaries and small vessels is a characteristic lesion and plays an important role in the progression of diabetic microangiopathy. We have developed a sandwich enzyme immunoassay for human serum type IV collagen peptide with monoclonal antibodies. Previous studies suggested that collagen levels reflect the activity of fibrogenesis in basement membrane. Serum type IV collagen levels were measured in 137 non-insulin-dependent diabetic patients (aged 50–75 yr) with or without clinical signs of retinopathy, nephropathy, and/or neuropathy and 110 healthy subjects (aged 50–75 yr) without serological abnormality. Serum concentrations of type IV collagen were significantly higher (P < 0.01) in diabetic patients (mean ± SE 124.1 ± 4.1 ng/ml) than in healthy subjects (73.9 ± 2.2 ng/ml) and were increased with the prevalence or incidence of diabetic complications. In the patients with diabetic microangiopathy, serum type IV collagen levels became higher as clinical signs worsened. Especially in the patients with diabetic nephropathy, serum type IV collagen levels became higher with elevation of blood urea nitrogen, serum creatinine, and serum β2-microglobulin but not urinary excretion of β2- microglobulin and N-acetyl-β-glucosaminidase. These observations indicated that elevation of serum type IV collagen in diabetic nephropathy was related to glomerular filtration dysfunction rather than renal tubular dysfunction. However, the antigen, which can be detected by our assay system, did not exist in urine specimens of healthy subjects, and an intimate relationship was not observed between serum type IV collagen level and serum creatinine level. These results implied that the serum type IV collagen level reflects its increased synthetic activity in basement membrane rather than its reduced clearance rate. The concentration of serum type IV collagen peptide seems to be a useful, noninvasive, reproducible marker for assessment of the activity or progression of diabetic microangiopathy and for evaluation of therapeutic effects.

Studies on naturally occurring and man-made mutations in the insulin gene have provided new insights into insulin biosynthesis, action, and metabolism. Ten families have been identified in which one or more members have single-point mutations in their insulin genes that result in amino acid substitutions within the proinsulin molecule. Six of these cause the secretion of biologically defective insulin molecules due to changes within the A or B chains. Replacing A3-Val with Leu, B24-Phe with Ser, or B25-Phe with Leu results in molecules that have essentially normal immunoreactivity but greatly reduced insulin-receptor-binding potency. Individuals with these mutations have a syndrome of mild diabetes or glucose intolerance, which is inherited in an autosomal-dominant mode and is associated with hyperinsulinemia and altered insulin-C-peptide ratios. Although affected individuals are heterozygous and coexpress both normal and abnormal molecules, the elevated circulating insulin consists mainly of the biologically defective form, which accumulates because it fails to be rapidly metabolized via receptor-mediated endocytosis. Four additional families have mutations that are associated with relatively asymptomatic hyperproinsulinemia. A point mutation affecting proinsulin occurs in 3 of the 4 families, leading to replacement of Arg-65 by His, which prevents recognition of the C-peptide-A-chain dibasic cleavage site by the appropriate (β-cell processing protease and results in the circulation of a type II proinsulin intermediate form (des 64, 65 HPI). Members of a fourth family with hyperproinsulinemia have a substitution of B10-His with Asp, resulting in a proinsulin that exhibitsmarkedly altered subcellular sorting behavior. A significant proportion of the newly synthesized Asp-10 proinsulin is secreted in an unprocessed form via an unregulated or constitutive secretory pathway. This syndrome has been modeled in transgenic mice by introduction of this abnormal gene into the germ line, resulting in its expression at high levels along with the normal mouse insulin genes in the β-cells. These animals have not only reproduced the hyperproinsulinemia syndrome, thus allowing us to examine its mechanism in considerable detail, but have also provided opportunities to examine other aspects of insulin-gene expression. Various molecular expression techniques are now available that allow normal or mutated insulin genes to be expressed via transfection of DNA in cultured cells, injections of in vitro-generated mRNA into Xenopus oocytes, or translation of mRNA in reticulocyte cell-free systems so that their altered properties can be assessed. Application of these and other molecular biological techniques to the expression of naturally occurring mutant proinsulins and others made in the laboratory has provided new forms of insulin for therapy of diabetes and a deeper understanding of the mechanisms of biosynthesis, intracellular sorting, processing, and secretion of insulin under normal and abnormal conditions.

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.

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

We report a sporadic case of Albright’s hereditary osteodystrophy (AHO)-like syndrome with several endocrinopathies. A 37-yr-old woman had an appearance of AHO but did not have renal PTH resistance. Her case was complicated by non-insulin-dependent diabetes mellitus with severe insulin resistance, central diabetes insipidus, and hyposecretion of GH. Most patients with AHO are found in a family of pseudohypoparathyroidism type-Ia and have a heterozygous mutation that inactivates the α-subunit of Gs (Gsα), the stimulatory regulator of adenylyl cyclase. Some sporadic cases occur in which patients with phenotype similar to AHO have a deletion of chromosome 2q37. However, in this patient, both the Gsα gene structure and the biological activity were normal. In addition, chromosome analysis revealed a normal pattern with no visible deletion of chromosome 2q37. Our findings suggest that one or more other factors may be involved in the pathogenesis of AHO-related disease.

To test an endotracheal placement procedure for malignant esophagorespiratory fistula when endoesophageal placement is inapplicable. We report on patients with malignant esophagorespiratory fistula to which endoesophageal approaches were complicated with a complete obstruction of the hypopharynx, a collapsible tracheobronchus, or a previously placed endoesophageal stents. Gore-Tex membrane-covered Z-stents were deployed in the trachea using a coaxial introducer system in three patients. A Dumon tube was deployed in the bronchus over the bronchofiberscope in one patient. All fistula were completely sealed by the endotracheal or endobronchial stenting. Symptomatic and clinical improvements were immediate obtained. Endotracheal or endobronchial covered stent placement is thought to be an effective alternative method for sealing esophagorespiratory fistula.

Our aim was to obtain information to help in the early detection of impaired nerve function and to assess the severity of diabetic symmetric polyneuropathy (DPN). Various somatic and autonomic nerve functions in 40 diabetics and 20 age-matched healthy volunteers were evaluated using six objective examinations: nerve conduction study, quantitative vibratory perception threshold, heart rate variability, Valsalva test, head-up tilt and quantitative sudomotor axonal reflex test (QSART). The diabetics were divided into three groups according to the severity of their microangiopathy. The nerve function data and level of impairment were compared between a healthy control and three diabetic groups. The relationships between nerve function data and clinical background were also examined using multivariate analysis. Results were as follows: (1) all nerve dysfunctions seemed to develop parallel to the progression of microangiopathy, (2) reduced nerve conduction velocity and elevated vibratory perception thresholds in the feet might be early detectable signs of DPN, (3) vasomotor and sudomotor sympathetic functions and cardiovagal functions seemed to deteriorate with the appearance of microangiopathy, (4) lowered compound muscle action potential seemed to appear at the advanced microangiopathic condition, (5) hypohydrosis was closely related to diabetic foot ulcers. In conclusion, nerve dysfunction in diabetics might generally progress with microangiopathy from somatic sensory nerve dysfunction to autonomic nerve dysfunction and then to somatic motor nerve dysfunction. Sympathetic sudomotor dysfunction might be a sensitive predictor of diabetic foot ulcer.

We evaluated the prevalence and risk factors for erectile dysfunction (ED) and interest in ED treatment among Japanese men being treated for type 2 diabetes mellitus. Patients (40-79 years; n=1118) completed the 5-item version of the International Index of Erectile Function (IIEF-5), and questions related to interest in ED pharmacotherapy, subjective symptoms of diabetes, and general quality of life. A separate survey completed by physicians examined the relationships between age, diabetic treatments (insulin or oral), symptoms of diabetes (poor glycemic control, microangiopathy), complications of diabetes (hypertension, ischemic heart disease, cerebrovascular disease), and ED. The prevalence of ED in patients with diabetes was 90%, a rate double that of non-diabetic individuals. Multivariate analyses revealed that age, insulin therapy, microangiopathy, hypertension, history of cerebrovascular or cardiovascular disease, leg dysesthesia, dysuria, insomnia, and anorexia all represented significant risk factors for ED. Half of all respondents were interested (29%) or would consider pharmacotherapy for ED (21%). These findings suggest that ED is a significant problem in Japanese men with diabetes, and that specific risk factors increase the prevalence of ED. Furthermore, the survey results expose national attitudes toward treatment of ED.

Atherosclerosis in type 2 diabetic patients has been linked to increased oxidative stress. Glutathione peroxidase-1 (GPx-1) plays an important role in the antioxidant defense of the vascular wall. To assess the association between variants in the GPx-1 gene and atherosclerosis, we screened the gene in 184 Japanese type 2 diabetic patients and identified four polymorphisms (−602A/G, +2C/T, Ala5/Ala6, and Pro198Leu). Among these polymorphisms, −602G, +2T, Ala6, and 198Leu were in strong linkage disequilibrium with each other. The patients were divided into two groups on the basis of the codon 198 polymorphism, Pro/Pro (n = 151) and Pro/Leu (n = 33), to analyze clinical characteristics. The mean intima-media thickness (IMT) of common carotid arteries (P = 0.0028) and the prevalence of cardiovascular disease (P = 0.035) and peripheral vascular disease (P = 0.027) were significantly higher in the Pro/Leu group than in the Pro/Pro group. In vitro functional analyses indicated that the combination of polymorphisms (Ala6/198Leu) of the GPx-1 gene had a 40% decrease in enzyme activity, and the combination of polymorphisms (−602G/+2T) had a 25% decrease in transcriptional activity. These results suggest that functional variants in the GPx-1 gene are associated with increased IMT of carotid arteries and risk of cardiovascular and peripheral vascular diseases in type 2 diabetic patients.

Oxidative stress and the gene expression at the transcriptional level of antioxidant enzymes were investigated in two models of diabetes in mice. We used KKAy mice as a model of obese insulin-resistant diabetes, and streptozotocin-induced diabetic mice (STZ mice) as a model of insulin-deficient diabetes. C57BL mice and saline-injected ICR mice were used as the respective non-diabetic controls. To assess oxidative damage, plasma malonedialdehyde (MDA), urine 8-isoprostane and 8-hydroxy deoxyguanosine (8-OHdG) were measured. The mRNA expression of antioxidant enzymes, superoxide dismutase 1 (SOD-1) and glutathione peroxidase 1 (GPx-1) in the kidney and heart were quantified using a real-time polymerase chain reaction. The KKAy mice demonstrated moderate hyperglycemia and hyperlipidemia, and the STZ mice showed severe hyperglycemia and hypolipidemia. The KKAy mice, but not the STZ mice, showed elevated plasma MDA relative to the non-diabetic controls. Urine 8-isoprostane and 8-OHdG in both diabetic mouse groups increased significantly. The urine oxidative stress markers in the severely hyperglycemic STZ mice were higher than those in the moderately hyperglycemic KKAy mice. Although GPx-1 and SOD-1 showed elevated mRNA expression in the KKAy mice in the kidney and heart, in the STZ mice they did not increase compared to the controls. The compensatory up-regulation of the mRNA expression of antioxidant enzymes may be impaired in the insulin-deficient severely hyperglycemic state.

Several studies suggest that inflammation plays an important role in the pathogenesis of diabetes mellitus, as well as atherosclerosis, and acute-phase reactants have been proposed as monitors for the ongoing process of these diseases. We studied the clinical significance of serum high-sensitivity C-reactive protein (hs-CRP) in relation to chronic diabetic complications using 114 Japanese patients with Type 2 diabetes mellitus. The hs-CRP values were normalized by logarithmic transformation for statistical analysis. Retinopathy and hypertension were extracted as significant modulators for the hs-CRP value in the diabetic patients, in addition to previously known factors, age, and body mass index (BMI), by multivariate analysis. The hs-CRP level in normotensive diabetic patients without retinopathy was not significantly different from that of normal control participants after adjustment for age and BMI. The hs-CRP value was significantly high in the patients with hypertension, despite the existence or absence of diabetes. On the other hand, the hs-CRP level of the diabetic patients complicated with retinopathy was low especially in those with hypertension. The frequency of patients having an hs-CRP value above 1.0 mg/l who are thought to be at risk for cardiovascular diseases was also high in the patients complicated with hypertension and low in the diabetic patients with retinopathy. These results indicate that the presence or absence of hypertension and retinopathy should be taken into consideration for the interpretation of the serum hs-CRP in diabetic patients.