| Budget Amount *help |
¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1995: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1994: ¥900,000 (Direct Cost: ¥900,000)
|
|---|
| Research Abstract |
In obese humans as well as obese animals, insulin resistance resultant of hyperinsulinemia is one of the pathogenetic factors which induces hypertension. The present study aims to investigate involvement of brain function in the interaction of hypertension with hyperinsulinemia particularly from a histaminergic point of view, i.e., impaired hypothalamic histamine functions in those pathological symptoms. Results : 1) Diabetic (DM) rats induced by streptozotosin (STZ) increased, food intake and decreasd body weight. Concentration of hypothalamic neuronal histamine decreased under the hyperglycemic and insulin deficient conditions in the DM rats. The reduction of neuronal histamine was resulted from inactivation of histamine synthesizing enzyme, histidine decarboxylase enzyme (HDC). 2) Insulin-induced hypoglycemia, but not insulin per se, activated histamine turnover in the hypothalamus. 3) Neuronal histamine was hrdly detectable in the hypothalamus of the obese Zucker compared with that
… More
in the lean littermates hypothalanus. HDC activity decreased as well in the obese Zucker. These results indicate that blood glucose levels, modulate a turnover rate of hypothalamic neuronal histamine. Consequently, in the obese Zuckers with hyperinsulinemia, but with normoglycemia, some genetic factor other thana metabolic one seems is highly probable to induce dysfunction of the histamine neuron system in the hypothalamus. In fact, we have recently clarified that abnormalities of leptin receptor in the hypothalamus cause to maintain low activity of histaminergic neuron system. 4) Tumor necrosis factor-alpha (TNFalpha), which was predominantly secreted from the adipose tissue and involved in the development of insulin resistance, did not affect activity of histamine neuron while intracerebroventriculer (i.c.v) administration of the cytokine decreased food intake. Interleukin-1beta decreased food intake as well, but the suppressive effect on food intake was regulated by hypothalamic neuronal histamine. 5) According to a in vivo microdialysis study, activation of a hypothalamic histamine system enhanced lipolytic action in the adipose tissue through a sympathetic nervous system. 6) Activation of histamine neuron produced biphasic responses in insulin secretion, i.e., rapid acceleration due to direct stimulation of the increased glucose level and succeeding suppression due to indirect modulation of the hypothalamus. 7) Insulin i.c.v.infusion did not affect electrophysiological activity of efferent adrenal sympathetic nerve. Icv infusion of histamine, but not insulin, increased blood presser level in rats. Taken together, it is not likely that acute change in central insulin level may affect histamine neuronal activity and resultant increase in blood pressuer. The present findings suggest that chronic interaction between hypothalamic histamine, metabolic factor such as glucose concentration, hyperinsulinemia and potent secretion of leption may cause insulin resistance Less
|
