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Biomedical subjects

N Tonooka

Publications and source records attributed to N Tonooka.

At least 19 recordsLinked to original sources
PubMed2002

High frequency of mutations in the HNF-1alpha gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance.

AIMS/HYPOTHESIS: There is an emerging epidemic of Type II (non-insulin-dependent) diabetes mellitus of youth in Japan and in many other developed countries. The aim of this study was to determine the prevalence of mutations in the hepatocyte nuclear factor (HNF)-1alpha gene (TCF1) in a large group of Japanese patients with early-onset non-Type I (insulin-dependent) diabetes mellitus. Since approximately 20% of Caucasian patients with HNF-1alpha mutations have been shown to be obese or overweight, we also examined the association of genetic variations in TCF1 with body weight in Japanese subjects. METHODS: We examined 203 patients with non-Type 1 diabetes who had been diagnosed before they reached 15 years of age. Ten exons and flanking introns of TCF1 of these patients were directly sequenced for mutations. RESULTS: We found 14 different mutations in 18 patients (8.9%), including one that was found to be de novo. The patients with the mutations had lower BMI (20.1+/-3.0 kg/m(2)) at diagnosis than the patients without them (24.5+/-6.0 kg/m(2)) (p=0.0024). All of the patients with the mutations, except for one, Y120, had normal body weight (BMI<25 kg/m(2)); the frequency of HNF-1alpha mutations in the non-obese patients of this study was 17% (17/101). Patient Y120, who had atypical symptoms of mild obesity and insulin resistance at diagnosis, was found to have inherited an additional mutation in an obesity-related gene. CONCLUSION/INTERPRETATION: A considerable number of non-obese Japanese patients with non-Type 1 diabetes of youth have HNF-1alpha-deficient diabetes. Lack of obesity could well be a characteristic feature of this form of diabetes.

Asian People↗
PubMed2001

Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects.

Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4alpha, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese.

Adolescent↗
PubMed2001

Diabetes mellitus with left transverse sinus thrombosis and right transverse sinus aplasia.

A 67-year-old woman with diabetes mellitus was hospitalized due to a throbbing headache. She appeared neurologically normal, except for meningeal irritation. The cerebrospinal fluid pressure was high. There was increased fluid protein without an increased cell count. Brain CT scan showed no abnormality, however, brain magnetic resonance angiography (MRA) showed complete right transverse sinus stasis and partial left transverse sinus stasis, indicating bilateral transverse sinus thrombosis. At this time thrombin anti-thrombin III complex (TAT) and prothrombin fragment F1+2 (PTF1+2) indicating hypercoagulation had increased. Urokinase, followed by aspirin and ticlopidine hydrochloride were administered. After diet therapy and transient insulin administration, her blood glucose levels improved. By the 22nd day, the headache had disappeared. Subsequently, brain MRA showed left transverse sinus blood flow recovery and complete right transverse sinus stasis, while carotid angiography showed recovered left transverse sinus but right transverse sinus defect. TAT and PTF1+2 levels improved concomitantly with better blood glucose control. We diagnosed this case as left transverse sinus thrombosis because of the hypercoagulable state resulting from diabetes mellitus accompanied by right transverse sinus aplasia.

Aged↗
PubMed1981

Evidence that thyrotropin and prolactin are not secreted by the posterior pituitary of the rat.

After eutopic hypophysectomy of the host, transplants under the renal capsule of three whole pituitaries or of the adenohypophysis alone were capable of maintaining plasma PRL concentration equal to or greater than that of intact controls. The basal plasma TSH levels in rats with these types of heterotopic pituitaries was below that of intact controls but was significantly increased by TRH or chronic antithyroid treatment. Rats with posterior pituitary (intermediate and neural lobe) heterotopic transplants were incapable, under any conditions tested, of raising the plasma PRL or TSH concentration above that seen in hypophysectomized controls without pituitary transplants. In a further experiment, selective extirpation of the anterior or posterior lobe of the eutopic pituitary was performed. Plasma concentrations of TSH and PRL in rats with anterior lobectomy were not significantly different from those of hypophysectomized controls but were significantly higher than those of hypophysectomized controls in rats with posterior lobectomy. These data indicate that only the adenohypophysis secretes physiologically significant quantitites of these two hormones. (Endocrinology 108: 382, 1981)

Animals↗
PubMed1980

Effect of propylthiouracil on nycthemeral and sex related variation of plasma TSH in rats.

Studies of the effect on feedback mechanisms in nycthemeral fluctuation of plasma TSH and of its sex-related variation were carried out on normally fed (Purina) and propylthiouracil (PTU) treated rats. Plasma TSH concentration of purina fed rat was significantly higher in males than in females (M = 96 +/- 14, F = 49 +/- 3 microunits/ml, P less than 0.01). Plasma T4 concentration also showed a high tendency in males compared to females (M = 7.4 +/- 0.5, F = 5.8 +/- 1.0 micrograms/dl, 0.05 less than P less than 0.1) but the statistical difference was not significant. Plasma TSH demonstrated a typical periodicity characterized by a zenith at 1200 hr and a nadir at 1800 hr as in the previous reports. Plasma TSH concentrations rose apparently after the diet was switched to the one containing 0.15% of PTU. On the other hand, plasma T4 concentrations decreased to the very low levels following PTU administration. Concerning to the nycthemeral fluctuation and its sex related variation following PTU administration, nycthemeral fluctuation in male rats disappeared rapidly, whereas it was preserved in female rats. These facts showed that it kept more persistent fluctuation in female rats than in male rats under the high plasma TSH levels. Furthermore, female rats showed higher concentration of plasma TSH after PTU treatment compared to male rats. These results suggest that the nycthemeral fluctuation of plasma TSH was abolished or masked by the feedback mechanism of hypothalamo-pituitary-thyroid axis and there was a sex-related difference.

Animals↗
PubMed1979

Studies on the effect of neonatal hypermetabolism on hypothalamo-pituitary-thyroid axis in adult rats.

Neonatal rats which had received a daily injection of 50 microgram of 2,4-dinitrophenol (DNP) or 30 microgram of L-thyroxine (T 4) for 7 days beginning on the day of birth were compared as to the late effect of the hypothalamo-pituitary-thyroid axis with the neo saline control. Neo DNP rats and neo T 4 rats revealed the retardation of growth compared with neo saline rats. The plasma level of TSH in both groups presented its low response following TRH administration. Furthermore, plasma TSH levels following the challenge of PTU were depressed in both neo DNP and neo T 4 rats compared with neo saline control rats. A small dose of T 4 injection, however, did not bring any difference on plasma TSH levels between neo T 4 and neo saline control rats while neo DNP rats showed a little blunted response of pituitary compared with neo T 4 and neo saline rats. Pituitary contents of TSH in neo T 4 rats decreased, but not in neo DNP rats. These results suggest that neonatal hypermetabolism causes the hypofunction of pituitary-thyroid axis through adult life and that the alteration of hypothalamus may be more obvious in neo T 4 rats than in neo DNP rats.

Animals↗
PubMed1979

Potentiation by indomethacin of TRH-induced TSH secretion in the rat.

We have studied the effect of two inhibitors of prostaglandin synthesis on the basal and TRH-stimulated plasma TSH levels in the rat. Animals were injected sc daily with indomethacin 3 mg/0.5 ml) or aspirin (16--30 mg/0.5 ml) for 3 days. The plasma T4 and T3 were consistently lower in the indomethacin or aspirin groups than in the controls, while the basal TSH levels did not change. Indomethacin treatment significantly potentiated the TSH response to synthetic TRH (20 ng. iv) in intact and thyroidectomized rats. The pituitary TSH content was markedly increased by indomethacin, while hypothalamic TRH content did not change. In contrast, aspirin inhibited the TSH response to TRH in intact rats, when pituitary TSH content decreased significantly. No potentiation by aspirin of TRH-stimulated TSH response in the thyroidectomized rats was observed. The increased sensitivity of plasma TSH response to exogenous TRH in the indomethacin group is presumably due to higher pituitary TSH content than in the controls. The action of indomethacin appears to be mediated, at least in part, at the pituitary level. In addition, there is a dissociation between the action of indomethacin and the action of aspirin in the TSH response to TRH.

Animals↗
PubMed1979

Comparison of the effects of deafferentation and ablation of medial basal hypothalamus on thyrotropin and prolactin secretion.

To further delineate the interrelationships of neural control of TSH and prolactin secretion, medial basal hypothalamic deafferentation (MBHD) or medial basal hypothalamic ablation (MBHA) were performed in euthyroid or hypothyroid male rats. MBHD produced a prompt and significant fall in plasma TSH but no change in plasma prolactin. MBHA produced a more marked fall in plasma TSH and a 6-fold rise in plasma prolactin within 3 days postoperatively. Plasma TSH remained at a low level postoperatively, but plasma prolactin gradually declined from its peak 3-5 days postoperatively to approximately the initial basal levels 2 weeks postoperatively. MBHA did not appreciably impair the ability of TRH to stimulate TSH secretion or of perphenazine to stimulate prolactin secretion. Where the same experiments were performed in both euthyroid and hypothyroid rats, there was no qualitative difference between the two, although basal plasma TSH was higher and prolactin lower in the hypothyroid than in the euthyroid animals. Our data support the concept that the medial basal hypothalamus is important in stimulating TSH and inhibiting prolactin secretion. Dormant inhibitory influences on prolactin secretion, but not stimulatory influences on TSH secretion, may be aroused after hypothalamic ablation.

Animals↗
PubMed1978

Evidence that control of fetal thyrotropin secretion is independent of both the fetal and maternal hypothalamus.

Propylthiouracil (PTU) administered to pregnant rats from day 18-21 of gestation caused a significant increase in maternal and fetal thyroid weight and plasma TSH. Fetal encephalectomy on day 18 did not significantly affect basal or PTU-stimulated pituitary-thyroid function. Destruction of the basal hypothalamus in the mother on day 13 or 16 markedly reduced maternal plasma TSH and thyroxine and prevented a PTU-induced increase in thyroid size, but did not affect fetal pituitary-thyroid function. Plasma PRL, was undetectable in both intact and encephalectomized fetuses at 21 days but was increased greater than 6-fold to approximately 2 microgram/ml in the mothers by maternal hypothalamic destruction. We conclude that fetal pituitary-thyroid function in the rat is not dependent on either fetal or maternal hypothalamic TRH.

Animals↗
PubMed1978

Lymphoid thyroiditis following immunization with group A streptococcal vaccine.

Severe lymphoid thyroiditis and associated hypothyroidism occurred in all of 7 male and 4 female F(7) derivatives (seventh generation) of rats immunized in each generation against Group A streptococci. This evidence of thyroiditis produced by immunization against a nonthyroidal antigen suggests that some cases of Hashimoto's thyroiditis in humans may result from nonspecific immune responses.

Animals↗