Nesfatin-1 is a polypeptide derived from the posttranslational processing of the N-terminal fragment of nucleobindin 2 (NUCB2), that was originally identified as an anorexigenic hypothalamic neuropeptide. A number of reports have recently shown that NUCB2/Nesfatin-1 is widely expressed in various peripheral tissues, including those of the gastrointestinal tract where it may participate in various pathophysiological processes. One of its roles may be regulation of energy homeostasis. As a result, Nesfatin-1 may be a novel target for exploring the underlying mechanisms and the treatment of metabolic syndromes.

View full abstract

It is well known that hypothyroidism is associated with anemia. It has also been reported that alcohol consumption may affect thyroid function. Furthermore, hemoglobin levels of drinkers are reportedly higher than those of non-drinkers. However, no published study has investigated the association between thyroid function evaluated with the free thyroxine (FT4) test and anemia while taking drinking status into account. We conducted a cross-sectional study of 843 men aged 30-89 years undergoing general health checks. While no significant associations were noted between FT4 and anemia for total subjects, when the analysis was limited to non-drinkers, a significant association was observed. After adjustment for classical cardiovascular risk factors and thyroid stimulating hormones (TSH), adjusted odds ratio (OR) and 95% confidence interval (CI) for an increment of 1SD (standard deviation) for FT4 (0.17 ng/dL) for anemia were 0.85 (0.67-1.09) for total subjects, 0.59 (0.41-0.85) for non-drinkers, and 1.23 (0.83-1.83) for drinkers. In conclusion, FT4 is inversely associated with anemia for non-drinking but not for drinking men. However, drinking may act as a confounding factor for this association.

View full abstract

Thyroxine (T₄) needs to be converted to 3,5,3’-triiodothyronine (T₃) by iodothyronine deiodinase to exert its biological activity. Recent studies revealed the presence of type 2 iodothyronine deiodinase (D2) in human thyroid tissue, human skeletal muscle and other tissues, suggesting that D2 is involved in maintaining plasma T₃ level in human. Tumor necrosis factor α (TNFα) is an inflammatory cytokine of which production is elevated in patients with nonthyroidal illness. Although several lines of evidence suggest the causal role of TNFα in nonthyroidal illness, detailed nature of the effect of TNFα on D2 remains unclear. In the present study, we identified D2 activity and D2 mRNA in TCO-1 cells, which were derived from human anaplastic thyroid carcinoma, and studied the mechanisms involved in the regulation of D2 expression by TNFα. The characteristics of the deiodinating activity in TCO-1 cells were compatible with those of D2 and Northern analysis demonstrated that D2 mRNA was expressed in TCO-1cells. D2 activity and D2 mRNA expression were rapidly increased by dibutyryl cAMP ((Bu)₂cAMP). TNFα showed an inhibitory effect on (Bu)₂cAMP-stimulated D2 activity in spite of little effect on (Bu)₂cAMP-stimulated D2 mRNA expression. MG132, a proteasome inhibitor abolished TNFα suppression of D2 activity whereas BAY11-7082 or 6-Amino-4-(4-phenoxyphenylethylamino) quinazoline, inhibitors of nuclear factor-κB (NF-κB) failed to attenuate the effect of TNFα on D2 activity. These data suggest that a posttranslational mechanism through proteasomal degradation but not NF-κB activation is involved in the suppression of D2 by TNFα.

View full abstract

Pharmacologic glucocorticoids (GCs) inhibit osteoblast function and induce osteoporosis. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may play a role in osteoporosis as it regulates GC action at a pre-receptor level by converting inactive GC to its active form. Further, 11β-HSD1 was found increasingly expressed in bone with age. In spite of these obervations, its function in senile osteoporosis remains uncertain. In this study we constructed a lentiviral vector overexpressing mouse 11β-HSD1 and then MC3T3-E1 preosteoblast cells were infected by the negative control lentivirus and 11β-HSD1-overexpressing lentivirus, respectively. The mRNA and protein levels of 11β-HSD1 were significantly increased in MC3T3-E1 cells that were infected by 11β-HSD1-overexpressing lentivirus compared to the cells infected by the negative control lentivirus. The osteogenic differentiation of MC3T3-E1 preosteoblast cells was dramatically suppressed by 11β-HSD1 overexpression under the reductase substrate dehydrocorticosterone (DHC). The inhibition effect was similar to the inhibition of osteogenesis by over-dose GCs, including ALP activity, the ultimate calcium nodus formation as well as the expression of the osteogenic genes such as ALP, BSP, OPN and OCN. However, with addition of BVT.2733, a selective inhibitor of 11β-HSD1, all of the above osteogenic repression effects by 11β-HSD1 overexpression were reversed. Furthermore, a GC receptor antagonist RU486 also showed the similar effect, preventing inhibition of osteogenesis by 11β-HSD1 overexpression. These results demonstrated that the specific 11β-HSD1 inhibitor BVT.2733 can reverse the suppression effect towards osteogenic differentiation in 11β-HSD1 overexpressed MC3T3-E1 cells. Inhibition of 11β-HSD1 can be a new therapeutic strategy for senile osteoporosis.

View full abstract

Nighttime food intake is associated with weight gain and higher HbA1c levels. We experienced night eaters who have no memory of their nocturnal eating in the morning. In this study, the curious night eating behavior was designated as “unremembered nocturnal eating syndrome (UNES)”. We screened 1,169 patients with diabetes for sleep quality and abnormal eating behavior at night using the Pittsburgh Sleep Quality Index questionnaire with an additional question regarding UNES. When abnormal nocturnal eating behavior was noted, detailed clinical information was extracted from interviews with the patients. We identified 9 patients who experienced UNES. They had a higher BMI compared with subjects who reported no such episodes. Among them, 6 patients who consumed food at night without memory 2-5 times per month or more had significantly higher HbA1c levels. Continuous glucose monitoring in a patient with type 1 diabetes revealed an abrupt elevation of glucose levels from midnight when some foods were consumed. Eight of the 9 patients were taking benzodiazepine and/or non-benzodiazepine hypnotic agents when they experienced the episodes. The prevalence of UNES was 0.8% in all subjects and 4% in those taking hypnotic drugs. The ratio of hypnotic drug use in subjects with UNES was significantly higher than for individuals without UNES (89% vs. 17%, p<0.0001). Although UNES seems to be etiologically heterogeneous, hypnotics-induced parasomnia and/or anterograde amnesia may be associated with the behavior. UNES is not rare in diabetic patients on hypnotic medicine and may be a hidden cause of unexpected morning hyperglycemia.

View full abstract

We recently have reported that ghrelin modulates adult hippocampal neurogenesis. However, there is a possibility that the action of ghrelin on hippocampal neurogenesis could be, in part, due to the ability of ghrelin to stimulate the GH/insulin-like growth factor (IGF)-1 axis, where both GH and IGF-1 infusions are known to increase hippocampal neurogenesis. To explore this possibility, we assessed the impact of ghrelin on progenitor cell proliferation and differentiation in the dentate gyrus (DG) of spontaneous dwarf rats (SDRs), a dwarf strain with a mutation of the GH gene resulting in total loss of GH. Double immunohistochemical staining revealed that Ki-67-positive progenitor cells and doublecortin (DCX)-positive neuroblasts in the DG of the SDRs expressed ghrelin receptors. We found that ghrelin treatment in the SDRs significantly increased the number of proliferating cell nuclear antigen- and BrdU-labeled cells in the DG. The number of DCX-labeled cells in the DG of ghrelin-treated SDRs was also significantly increased compared with the vehicle-treated controls. To test whether ghrelin has a direct effect on cognitive performance independently of somatotropic axis, hippocampus-dependent learning and memory were assessed using the Y-maze and novel object recognition (NOR) test in the SDRs. Ghrelin treatment for 4 weeks by subcutaneous osmotic pump significantly increased alternation rates in the Y-maze and exploration time for novel object in the NOR test compared to vehicle-treated controls. Our results indicate that ghrelin-induced adult hippocampal neurogenesis and enhancement of cognitive function are mediated independently of somatotropic axis.

View full abstract

The major contributors to the pathogenesis of type 2 diabetes are impaired insulin action and insulin secretion, including second phase insulin secretion (2^nd ISEC). This study aimed to compare surrogates derived from the mixed meal tolerance test (MTT) with 2^nd ISEC derived from modified low-dose graded glucose infusion (M-LDGGI) in patients with type 2 diabetes. We were subsequently able to decide which surrogate would be performed easily and accurately. Twenty type 2 diabetes patients were enrolled. They received both MTT and M-LDGGI. The standardized MTT meals were provided at 8:00 A.M. and 12:00 P.M. The M-LDGGI was a simplified version of the Polonsky method; only two 80-min stages of glucose infusion (2 and 6 mg/kg/min) were given. The slopes of the insulin to glucose curve during the test were regarded as the 2^nd ISEC. First, we used the area under the insulin curve (AUC_IN) during MTT to quantify the 2^nd ISEC. The best correlated AUC_IN was from 60-240 min. Second, the slopes between any two time points of the plasma insulin to glucose level (SLOPE_I/G) were also assessed. The time period best correlated with 2^nd ISEC was from 0-120 min (SLOPE_0-120). Finally, the insulin-to-glucose ratio (IG_r) of each time point was used to estimate the 2^nd ISEC, and the best correlation was observed at 180 min. In conclusion, estimating 2^nd ISEC surrogates derived from MTT proved to be possible. The most accurate surrogate is the SLOPE_0-120, while IG_r180 is another less precise but more convenient method.

View full abstract

Central diabetes insipidus (CDI) is associated with arginine vasopressin (AVP) deficiency with resultant polyuria and polydipsia. Intranasal desmopressin provides physiological replacement but oral formulations are preferred for their ease of administration. This study aimed to demonstrate the efficacy and safety of desmopressin orally disintegrating tablet (ODT) in the treatment of Japanese patients with CDI, and confirm that antidiuresis is maintained on switching from intranasal desmopressin to desmopressin ODT. A total of 20 patients aged 6–75 years with CDI were included in this 4-week multicenter, open-label study. Following observation, patients switched from intranasal desmopressin to desmopressin ODT with titration to optimal dose over ≤5 days at the study site. Following three consecutive doses with stable patient fluid balance, patients were discharged with visits at Weeks 2 and 4. Following titration from intranasal desmopressin to ODT, the mean 24-hour urine volume was unchanged, indicating similar antidiuresis with both formulations. The proportion of patients with endpoint measurements (urine osmolality, 24-hour urine volume, hourly diuresis rate and urine-specific gravity) within normal range at Days 1–2 (intranasal desmopressin) and Week 4 (desmopressin ODT) was similar. The mean daily dose ratio of intranasal desmopressin to desmopressin ODT (Week 4) was 1:24 but a wide range was observed across individuals to maintain adequate antidiuretic effect. Hyponatraemia was generally mild and managed by dose titration. Desmopressin ODT achieved sufficient antidiuretic control compared to intranasal therapy and was well tolerated over long-term treatment. The wide range of intranasal:ODT dose ratios underline the importance of individual titration.

View full abstract

Iodine is an essential nutrient for thyroid hormone synthesis, and iodine deficiency especially in pregnant and lactating women results in serious damage to their infants. To characterize iodine nutrition throughout gestation by using a food frequency questionnaire (FFQ) and urinary iodine concentration (UIC) measurement, and to establish appropriate gestational age-specific reference ranges for serum TSH and FT₄ in thyroid autoantibody (ThAb) negative euthyroid Japanese women, a total number of 563 pregnant women including 422 subjects with negative ThAbs, 105 postpartum women and their 297 newborn infants were included in the study. Dietary iodine intake (DII) was evaluated by FFQ. Serum TSH, FT₄ and UIC were sequentially determined in the three trimesters of pregnancy and at the 31st postpartum day. The overall median UICs throughout pregnancy and in the postpartum period were 224.0 and 135.0μg/L, respectively, suggesting sufficient iodine nutrition. The median DII was 842.4μg/day in pregnant women. The median UIC in the first trimester (215.9μg/L) significantly decreased in the second trimester (136.0μg/L). The prevalence of pregnant women with a UIC below 150μg/L was 31.6% and that in lactating women with a UIC below 100μg/L was 33.3%. The pattern of gestational change in serum TSH and FT₄ was comparable to that in iodine-sufficient areas. A substantial percentage of women might be at risk for iodine deficiency if there is a restriction of iodine-rich foods. However, iodine supplementation for pregnant women must be carefully balanced against the risk of iodine excess particularly in Japan. Further research in larger samples is needed.

View full abstract

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder, where insulin resistance might be involved in the development of endocrine and metabolic abnormalities. Insulin resistance (IR) is connected with disturbances in switching between lipid and carbohydrate oxidation in response to insulin, called “metabolic inflexibility”. The aim of the present study was to estimate the whole-body insulin sensitivity, lipid and carbohydrate oxidation, metabolic flexibility in lean and obese PCOS women. The study group consisted of 92 women with PCOS, 40 lean (BMI<25 kg/m²) and 52 overweight or obesity (BMI>25 kg/m²), and 30 healthy normally menstruating women (14 lean and 16 overweight/obese) with normal glucose tolerance. Hyperinsulinemic euglycemic clamp and indirect calorimetry were performed. An increase in respiratory exchange ratio in response to insulin was used as a measure of metabolic flexibility. Both the presence of PCOS (P<0.001) and obesity (P=0.005) were independently characterized by lower insulin sensitivity. PCOS (P=0.002) and obesity (P=0.001) independently predisposed to the lower non-oxidative glucose metabolism. Obese women had lower glucose oxidation (P=0.005) and higher lipid oxidation (P<0.001) in insulin-stimulated conditions in comparison to lean subject whereas PCOS had no effect on these parameters (P=0.29 and P=0.43; respectively). Metabolic flexibility was impaired in the obese (P=0.001) but it was not influenced by the presence of PCOS (P=0.78). Our data indicate that PCOS women have normal metabolic flexibility, which could suggest a distinct pathophysiological mechanism for insulin resistance in this group.

View full abstract