Rieko Genma

High Incidence of Positive Autoantibodies against Thyroid Peroxidase and Thyroglobulin in Patients with Sarcoidosis

OBJECTIVE Although abnormalities of the humoral immune system, such as increased immunoglobulin production, are known in sarcoidosis, the relationship between sarcoidosis and autoimmune disorders is uncertain. We studied the incidence of thyroid autoantibodies and the prevalence of Hashimoto’s thyroiditis in patients with sarcoidosis.

ABCC8 polymorphism (Ser1369Ala): influence on severe hypoglycemia due to sulfonylureas

AIMS Sulfonylureas are categorized according to their binding sites of the ATP-sensitive K+ channel (K(ATP) channel) complex in pancreatic β-cells. The binding sites are classified as A, B and A + B site (both A and B sites), respectively. The Ser1369Ala variant in the sulfonylurea receptor gene ABCC8 which encodes a subunit of the K(ATP) channel complex has been demonstrated to be associated with the hypoglycemic effect of gliclazide, which binds to the A site. However, the hypoglycemic effect of the Ser1369Ala variant on treatment with A + B binding site sulfonylureas, such as glimepiride or glibenclamide, is still uncertain. MATERIALS & METHODS In a case-control study, 32 patients with Type 2 diabetes admitted to hospital with severe hypoglycemia and 125 consecutive Type 2 diabetic outpatients without severe hypoglycemia were enrolled. We determined the genotypes of the ABCC8 polymorphism (Ser1369Ala) in the patients with or without severe hypoglycemia. All of the patients were taking glimepiride or glibenclamide. RESULTS In the patients treated with glimepiride or glibenclamide, we found no significant differences in the distribution of the Ser1369Ala genotype between patients with or without severe hypoglycemia (p = 0.26). Moreover, the Ala1369 minor allele tended to be less frequent in the hypoglycemic group (31 vs 43%; OR: 1.65; 95% CI: 0.92-2.96; p = 0.09). CONCLUSION Our findings suggest that the Ser1369Ala variant is not a major predictive factor of severe hypoglycemia due to glimepiride or glibenclamide, both of which bind to the A + B site. It is likely that severe hypoglycemia due to A + B binding site sulfonylureas will be mediated by other factors, and not the Ala1369 minor allele.

A cross-sectional study of glucose regulation in young adults with very low birth weight: impact of male gender on hyperglycaemia

Objectives To investigate glucose regulation in young adults with very low birth weight (VLBW; <1500 g) in an Asian population. Design Cross-sectional observational study. Setting A general hospital in Hamamatsu, Japan. Participants 111 young adults (42 men and 69 women; aged 19–30 years) born with VLBW between 1980 and 1990. Participants underwent standard 75 g oral glucose tolerance test (OGTT). Primary and secondary outcome measures The primary outcomes were glucose and insulin levels during OGTT and risk factors for a category of hyperglycaemia defined as follows: diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting glycaemia (IFG) and non-diabetes/IGT/IFG with elevated 1 h glucose levels (>8.6 mmol/l). The secondary outcomes were the pancreatic β cell function (insulinogenic index and homeostasis model of assessment for beta cell (HOMA-β)) and insulin resistance (homeostasis model of assessment for insulin resistance (HOMA-IR)). Results Of 111 young adults with VLBW, 21 subjects (19%) had hyperglycaemia: one had type 2 diabetes, six had IGT, one had IFG and 13 had non-diabetes/IGT/IFG with elevated 1 h glucose levels. In logistic regression analysis, male gender was an independent risk factor associated with hyperglycaemia (OR 3.34, 95% CI 1.08 to 10.3, p=0.036). Male subjects had significantly higher levels of glucose and lower levels of insulin during OGTT than female subjects (p<0.001 for glucose and p=0.005 for insulin by repeated measures analysis of variance). Pancreatic β cell function was lower in men (insulinogenic index: p=0.002; HOMA-β: p=0.001), although no gender difference was found in insulin resistance (HOMA-IR: p=0.477). In male subjects, logistic regression analysis showed that small for gestational age was an independent risk factor associated with hyperglycaemia (OR 33.3, 95% CI 1.67 to 662.6, p=0.022). Conclusions 19% of individuals with VLBW already had hyperglycaemia in young adulthood, and male gender was a significant independent risk factor of hyperglycaemia. In male young adults with VLBW, small for gestational age was associated with hyperglycaemia.

Urinary excretion of pyridinoline and deoxypyridinoline measured by immunoassay in hypothyroidism

OBJECTIVE We measured pyridinium cross‐links, markers of bone resorption, by an enzyme‐linked immunosorbent assay (ELISA) in hypothyroid patients to see whether bone resorption was reduced in hypothyroidism and whether it increased with T4 treatment.

Alterations in the enzyme activity and protein contents of protein disulfide isomerase in rat tissues during fasting and refeeding

Protein disulfide isomerase (PDI) is an enzyme that participates in the formation of disulfide bonds. It is also known to be the subunits of some enzymes and the membrane-associated thyroid hormone-binding protein. In this study, we measured the quantitative distribution of PDI protein in rat tissues and examined the relationship between protein level and enzyme activity in PDI during fasting and refeeding. Western blotting with specific anti-PDI antiserum detected the PDI protein band of 55 kd. Among several tissues, liver contained the largest amount of PDI protein, followed by kidney and fat, in which one-third to one-fourth of the hepatic PDI protein existed. The PDI protein band was also detected in heart and muscle. Fasting for 3 days decreased PDI protein levels in rat liver by 40%; control levels were recovered after 3 days of refeeding. The same change was observed in kidney. PDI activity, measured by the scrambled ribonuclease method, did not show the parallel alteration to PDI protein level in liver and kidney. Isomerase activity decreased to 50% of control values during fasting, but did not recover by refeeding. Thyroidal status did not affect either PDI protein level or isomerase activity. These findings show that fasting and refeeding affect PDI protein and enzyme activity, and that PDI protein level does not always reflect PDI activity.

Difference in dominant negative activities between mutant thyroid hormone receptors α1 and β1 with an identical truncation in the extreme carboxyl-terminal tau4 domain

Although different expression patterns of thyroid hormone receptor (TR) alpha1 and beta1 have been reported, no essential distinction has been established in their functions. Unlike the TR beta gene, a mutation in the TR alpha1 gene has never been found in patients with resistance to thyroid hormone (RTH). Previously we found a mutant TR beta with an 11-carboxyl (C)-terminal amino acid truncation (betaF451X) in a girl with severe RTH. BetaF451X is a natural mutant with disruption of the transactivation domain, tau4, and it had very strong dominant negative activities. Based on the fact that the 46 amino acid sequence in the extreme C-terminal region is identical in TR alpha1 and TR beta, except for a C-terminal three amino acid extension of TR alpha1, we constructed a mutant TR alpha1 (alphaF397X) with the identical C-terminal truncation to betaF451X, to study functional differences between TR alpha1 and beta1. Both betaF451X and alphaF397X had negligible T3 binding and transcriptional activities even with 1 microM T3. The dominant negative activities of the mutant TRs were remarkable and T3 response element (TRE)-dependent. Co-expression of betaF451X decreased the CAT activity of either wild-type TR alpha1 or beta1 at 100 nM T3 by approximately 90% on the TRE-pal2 and 70% on DR4. AlphaF397X inhibited the transcriptional activities of both wild-type TR alpha1 and beta1 by approximately 50% on TRE-pal2 and by 60% on DR4. The dominant negative potency of betaF451X was significantly stronger than that of alphaF397X on the TRE-pal2, -DR4 and chicken lysozyme silencer F2, but similar on TRE-myosin heavy chain alpha and malic enzyme. No partiality for the TR subtypes was found in the dominant negative effects of betaF451X and alphaF397X. Co-expression with RXR enhanced the dominant negative effects of alphaF397X, but not of betaF451X. The results indicate that there are different dominant negative properties between alphaF397X and betaF451X, which are TRE-dependent, despite their identical C-terminal truncation. Deletion in the tau4 domain might affect the receptor structures of TR alpha1 and beta1 differently.

Final height and cardiometabolic outcomes in young adults with very low birth weight (<1500 g).

Objective Individuals with very low birth weight (VLBW; <1500 g) are known to be predisposed to both short final height and cardiometabolic disorders. However, associations between final height and cardiometabolic outcomes including glucose metabolism in VLBW individuals in young adulthood are not fully investigated. Methods We investigated glucose metabolism and other cardiometabolic outcomes such as lipid profiles, blood pressure, renal function, urinary albumin, and thyroid function in young adults with VLBW born between 1980 and 1990. Short stature was defined as a final height <10th percentile. Glucose intolerance [diabetes, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG)] was determined using 75-g oral glucose tolerance tests. Associations between final height and cardiometabolic outcomes were examined using logistic or multiple linear regression. Results A total of 628 VLBW individuals were screened and 111 young adults with VLBW (19–30 years) participated in the study. Of the participants, 40 subjects (36%) had short stature with a final height <10th percentile. Eight subjects (7.2%) had glucose intolerance (1, diabetes; 6, IGT; 1, IFG). Short stature was correlated with glucose intolerance (odds ratio 11.1; 95% CI 1.92, 99.7; P = 0.006). Final height was inversely associated with the homeostatic model assessment (HOMA) of insulin resistance, HOMA-β, insulinogenic index, and total/LDL-cholesterol. The associations of final height with insulin sensitivity and lipid profiles remained after adjustment for target height and age at puberty onset. Conclusions Shorter final height was associated with less favorable metabolic profiles in young adults with VLBW, and may be partly mediated by reduced insulin sensitivity. These associations were independent of target height or age at puberty onset.

Glycaemia and autistic traits in very low birth weight infants in adulthood

It is well established that low birth weight is associated with ype 2 diabetes and cardiovascular disease later in life [1]. In ddition to these cardiometabolic disorders, emerging evidence uggests that low birth weight is a risk factor for autism-spectrum isorder (ASD), characterized by neurodevelopmental impairents affecting social interactions and communication, and a estricted range of behaviours and interests [2]. While ASD has een considered a disorder of childhood, recent studies have hown that it can be a serious disorder in adulthood as well [3]. To ate, however, associations between glucose levels and autistic raits in low birth weight infants as adults have remained unclear. n our present exploratory analyses, the aim was to evaluate the elationship between glucose levels and autistic traits in very ow birth weight (VLBW < 1500 g) infants in young adulthood. Participants were recruited from a longitudinal cohort of LBW individuals born between 1980 and 1990 [4,5]. Standard 5-g oral glucose tolerance tests (OGTTs) were performed in hese subjects as young adults (aged 19–30 years). To evaluate heir autistic traits, the autism-spectrum quotient (AQ), a wellalidated self-reported questionnaire of autistic traits for adults, as adopted [6]. The AQ consists of 50 items, scored 0 or 1 nd grouped into five different domains: social skills; attentionwitching; attention to detail; communication; and imagination. he maximum total score is 50, and higher scores indicate more utistic traits. A clinical cutoff value for distinguishing individals with clinically significant levels of autistic traits is set at a otal score ≥ 32. The study was approved by our institutional review board, and ll participants gave their written informed consent to participate n the study. From the original birth cohort, 85 subjects who completed he AQ were included in the analyses [age: 25.0 ± 2.73 years mean ± SD); women: n = 53 (62.4%)]. Mean birth weight as 1159 ± 248 g, and mean gestational age was 29.9 ± 3.2 eeks. The education levels of the responders were: univerity/college, n = 26 (30.6%); high school, n = 53 (62.4%); and unior high school, n = 6 (7.1%). Glucose metabolism outcomes ere: fasting plasma glucose (FPG) 5.02 ± 0.44 mmol/L; fasting lasma insulin 6.58 ± 4.56 U/mL; and HbA1c 5.40 ± 0.31% 35.5 ± 3.4 mmol/mol). The homoeostasis model of assessment