Yoshikatsu Nakai

Interleukin-6 stimulates the secretion of adrenocorticotropic hormone in conscious, freely-moving rats.

In order to assess the effect of interleukin-6 on the hypothalamo-pituitary-adrenal axis, we administered recombinant human interleukin-6 to conscious, freely-moving rats. The intravenous injection of interleukin-6 significantly increased the plasma level of adrenocorticotropic hormone 30 min after the injection in a dose-related manner. Immunoneutralization of corticotropin-releasing hormone blocked the stimulatory effects of interleukin-6 on adrenocorticotropic hormone secretion. These observations suggest that interleukin-6 stimulates the secretion of adrenocorticotropic hormone through the corticotropin-releasing hormone and is possibly involved in the interaction between the neuroendocrine and immune system.

Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus.

The aim of the present study was to investigate the association of serum adiponectin concentration with regional adiposity and insulin resistance in subjects with type 2 diabetes mellitus. A total of 73 Japanese men with type 2 diabetes (aged 59 +/- 11 years and body mass index [BMI] 23.8 +/- 3.0 kg/m(2), mean +/- SD) were studied. Fasting serum adiponectin and leptin concentrations were determined by radioimmunoassay. Regional adiposity was measured by abdominal computed tomography (CT) at the umbilical level, and insulin resistance was estimated by homeostasis model assessment (HOMA-R). Univariate regression analysis showed that serum adiponectin levels were negatively correlated with subcutaneous and visceral fat areas. With multivariate regression analysis, visceral fat area was a predominant determinant of serum adiponectin levels. In contrast, subcutaneous fat area was strongly associated with serum leptin concentrations. Among subcutaneous and visceral fat areas, BMI, and serum leptin levels, both subcutaneous and visceral fat areas were independently associated with HOMA-R. In another model incorporating serum adiponectin levels, serum adiponectin levels were selected as an independent determinant of HOMA-R instead of visceral fat area. In conclusion, hypoadiponectinemia was associated with visceral fat accumulation rather than subcutaneous fat depot in Japanese men with type 2 diabetes mellitus. Both subcutaneous and visceral fat accumulation contribute to insulin resistance in these subjects, and the contribution of visceral fat may be mediated, in part, by hypoadiponectinemia.

Responses of Plasma Adrenocorticotropic Hormone, Cortisol, and Cytokines during and after Upper Abdominal Surgery

There is currently accumulating evidence for bidirectional communication between the neuroendocrine and immune systems. Various cytokines have been suggested to be involved in the stimulation of stress hormone secretion during the times of infection and inflammation. To assess the possible involvement and pathophysiologic significance of cytokines in the mechanisms responsible for the perioperative stress response of the hypothalamo-pituitary-adrenal axis, we observed the changes of plasma adrenocorticotropic hormone and cortisol levels together with those of plasma endotoxin and cytokine levels. In patients undergoing pancreatoduodenectomy, perioperative stimulation of adrenocorticotropic hormone and cortisol secretion was accompanied by a significant elevation of plasma cytokine levels. Application of epidural block up to the upper thoracic levels failed to suppress this stress response effectively. In patients undergoing unilateral total hip replacement, the response of plasma hormone levels was smaller and briefer with no significant increase of plasma cytokine levels. Application of epidural block up to the lower thoracic levels suppressed this hormonal response almost completely. In patients undergoing pancreatoduodenectomy, a significant elevation of plasma endotoxin level was followed by a gradual but significant elevation of plasma tumor necrosis factor alpha and interleukin-6 levels. It seems likely that the stimulatory effects of these cytokines on the secretion of adrenocorticotropic hormone and cortisol might be involved in the development of the greater and more prolonged stress response of hypothalamo-pituitary-adrenal axis. Our present study suggests that not only neural input from the surgical wound but also stimulation of cytokine production were responsible for the development of the stress response of the hypothalamo-pituitary-adrenal axis during and after upper abdominal surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on ectopic ACTH‐producing tumors. II. Clinical and biochemical features of 30 cases

This report describes the clinical and biochemical features of 30 cases of ectopic ACTH‐producing tumors diagnosed by the detection of ACTH in the tumor tissues. Several uncommon tumors, such as tumors of the esophagus, stomach, and larynx, were included in this series. None of the patients with bronchogenic carcinoma showed signs of classical Cushings syndrome, whereas 7 of the remaining 13 patients with other tumors were Cushingoid in appearance. Adrenocortical hyperfunction was present in 61% at the first examination and developed during the course of the disease in 18% more. In the remaining patients (21%), adrenocortical function remained within normal limits. These results indicate that there exist ectopic ACTH‐producing tumors without clinical and biochemical sequelae of excess hormone. In some of the tumor extracts studied, MSH and CRF‐like activities and serotonin were detected. This suggests that multiple hormone production is not uncommon in ectopic ACTH‐producing tumors.

Pathogenic Factors Responsible for Glucose Intolerance in Patients With NIDDM

To define the pathogenic factors responsible for glucose intolerance in NIDDM, we estimated insulin secretory capacity, SI, and SG in 11 healthy, nondiabetic subjects and 9 NIDDM patients who had no SI impairment. All subjects studied were nonobese and normotensive. Each underwent a 75-g OGTT and a modified FSIGT: glucose was administered (300 mg/kg body weight), and insulin was infused (20 mU/kg over 5 min) from 20 to 25 min after the administration of glucose. SI and SG were estimated by Bergmans minimal-model method. The insulin response to oral glucose was significantly lower in NIDDM patients than in normal control subjects. First-phase insulin secretion expressed as the integrated area of plasma insulin above the basal level during the first 20 min was much smaller in NIDDM subjects (214 ±112 pM · min) than in control subjects (4643 ± 885 pM · min, P < 0.01). S, was not statistically different in normal control subjects (1.27 ± 0.18 × 10−4 min−1 · pM−1) versus diabetic patients (1.62 ± 0.33 × 10−4 min−1 · pM−1). However, SG was significantly lower in diabetic subjects (1.11 ± 0.17 × 10−2 min−1) than in control subjects (2.35 ± 0.26 × 10−2 min−1 P < 0.01). These results suggest that impaired insulin secretion and decreased SG are the factors responsible for glucose intolerance of Japanese NIDDM patients with normal insulin sensitivity. Because SI and SG are the factors responsible for glucose intolerance of NIDDM patients with insulin resistance, it is conceivable that decreased SG is common in NIDDM patients regardless of their SI index.

Presence of immunoreactive beta-endorphin in normal human plasma: a concomitant release of beta-endorphin with adrenocorticotropin after metyrapone administration.

To elucidate whether or not beta-endorphin exists in plasma of normal subjects, plasma extracts obtained before and after metyrapone administration were subjected to gel exclusion chromatography, and fractions obtained were assayed by a sensitive radioimmunoassay for beta-endorphin. The basal plasma level of beta-endorphin was 5.8 +/- 1.1 pg/ml (mean +/- SE, n = 5), which rose significantly to the level of 48.9 +/- 3.8 pg/ml after a single oral dose (30 mg/kg of body wt) of metyrapone administration (P less than 0.001). Plasma ACTH levels also increased from the mean basal level of 73 +/- 4 pg/ml to 269 +/- 41 pg/ml after metyrapone administration. These results indicate that beta-endorphin, distinct from beta-lipotropin, exists in normal human plasma and that it is released from the pituitary concomitantly with ACTH.

Impaired β-cell function and insulin sensitivity in Japanese subjects with normal glucose tolerance

The development of type 2 diabetes mellitus is characterized by both impaired beta-cell function and increasing insulin resistance. To clarify the roles of them in developing type 2 diabetes, we evaluated insulin resistance by HOMA-IR and insulin secretion by HOMA beta-cell in 453 Japanese subjects whose fasting plasma glucose (FPG) and HbA(1c) levels were within normal range. HOMA beta-cell was found to decrease in the over 30 years groups, while HOMA-IR increased with body mass index (BMI). To analyze the reserve capacity of insulin secretion and insulin sensitivity, the 67 of them, who underwent a standard oral glucose tolerance test and were diagnosed with normal glucose tolerance (NGT), were divided into four degrees of BMI age-adjusted to 50 years. They were compared for insulinogenic index and ISI composite proposed by Matsuda and DeFronzo across the range of BMI. ISI composite was significantly less in the highest BMI group, while insulin secretion did not increase in the higher BMI groups. The subjects with higher BMI had remarkably lower insulinogenic indices than those with lower BMI. These data suggest that insulin secretory reserve is insufficient to compensate for increased insulin resistance in Japanese people with NGT at about 50 years of age.

Presence of immunoreactive β-lipotropin and β-endorphin in human placenta

Abstract Utilizing a sensitive radioimmunoassay capable of detecting both β-lipotropin (β-LPH) and β-endorphin (β-EP), we demonstrated the existence of immunoreactive β-LPH and β-EP in extracts of human placentas. Gel chromatographic studies revealed that total β-EP immunoreactivity consists of two fractions with elution positions compatible with β-LPH and β-EP, respectively, and a fraction of larger molecular weight. All three fractions showed parallel curves with the standard curve of β-EP in radioimmunoassay. Our observations suggests that β-EP, β-LPH and possibly their precursor exist in human placenta.

Effect of β-endorphin on pulsatile luteinizing hormone release in conscious castrated rats

Abstract The effect of intraventricular administration of β-endorphin on pulsatile LH release in castrated conscious rats was studied. The administration of 1 μg of β-endorphin into the lateral ventricle inhibited pulsatile discharge of LH secretion. Intravenous administration of naloxone blocked the suppressive effect of β-endorphin on LH release. These results suggest a possible role of β-endorphin, in addition to Met 5 -enkephalin, in the control of LH release in male rats.

Effects of interleukins on plasma arginine vasopressin and oxytocin levels in conscious, freely moving rats

To elucidate whether interleukins are involved in vasopressin or oxytocin release during cytokine-related stressful conditions, we examined the effects of human interleukin-1 beta and interleukin-6 on plasma vasopressin and oxytocin levels in rats. Interleukin-1 beta administrated intravenously stimulated both the vasopressin and oxytocin secretion in dose-dependent manners. Neither hormone release was observed following interleukin-6 administration. Pretreatment with aspirin significantly attenuated the effects of interleukin-1 beta on both the vasopressin and oxytocin levels. SC-19220, a prostaglandin E2 receptor antagonist, did not affect the interleukin-1 beta-induced increase of plasma oxytocin levels, but almost completely abolished its effect on plasma vasopressin levels. These results suggest that under certain stressful conditions which accompany the stimulation of cytokine production, interleukin-1 is involved in the increase of plasma vasopressin and oxytocin levels and, moreover, different kinds of prostaglandins are suggested to participate in these interleukin-1-induced hormone release.