AGING AND CENTRAL IL-1B CONTROL OF GLUCOSE HOMEOSTASIS

长期以来，葡萄糖代谢受损与衰老有关。无论原因如何，专家预测，41.5%的65-74岁的人在其一生中将经历非胰岛素依赖型糖尿病（NIDDM）的葡萄糖耐量受损。NIDDM和涉及葡萄糖代谢失调的其他病理状况在老年人中更为普遍，给数百万人带来了巨大的经济负担和难以言表的痛苦。尽管许多研究人员研究了这个问题，但仍然有许多未回答的问题，特别是关于衰老过程中胰岛素的刺激和分泌。最近，细胞因子，如白细胞介素-1 β（IL-1 β），已被证明会影响胰岛素分泌。我们已经证明，尽管血浆葡萄糖水平显著升高，但中枢注射IL-1 β可抑制胰岛素分泌。这一点，再加上人类和大鼠衰老过程中IL-1水平发生变化的事实，使我们提出，与年轻大鼠相比，老年大鼠大脑中IL-1 β水平的改变可能是胰岛素分泌失调的原因。为了验证这一假设，我们打算确定大鼠大脑中IL-1 β水平是否存在年龄依赖性变化。将在禁食24小时的成年（5个月）和老龄（29个月）雄性Fischer 344（F344）大鼠中进行研究，以测定口服葡萄糖负荷后不同时间的血糖、胰岛素、胰高血糖素、IL-1 β的血浆水平和IL-1 β的中枢水平。接下来，我们将通过测定大鼠侧脑室注射（i. c. v.）IL-1 β感染。这项研究将导致更好地了解在衰老过程中观察到的葡萄糖代谢的变化，并可能为这个问题提供更有效的治疗方法。

Impaired glucose metabolism has long been associated with aging. Regardless of the cause, experts predict that 41.5% of people 65-74 years of age will experience impaired glucose tolerance of non-insulin dependent diabetes mellitus (NIDDM) in their lifetime. NIDDM and other pathological conditions involving disregulation of glucose metabolism that are more prevalent in the elderly present an enormous financial burden and untold suffering to millions. Despite the effects of numerous investigators studying this problem, there are still many unanswered questions, especially in regard to insulin stimulation and secretion during aging. Recently cytokines, such as interleukin-1beta (IL-1beta), have been shown to affect insulin secretion. We have shown that central injection of IL-1beta causes an inhibition of insulin secretion in spite of significantly elevated plasma glucose levels. This, coupled with the fact that levels of IL-1 changes during aging in humans and rats, lead us to propose that altered levels of IL-1 beta within the brain of old rats compared to young rats may be responsible for a disregulation of insulin secretion. To test this hypothesis, we intend to determine if there are age-dependent changes in IL-1beta levels in the rat brain. Studies will be undertaken in 24 hour fasted young-adult (5 month) and old (29 month) male Fischer 344 (F344) rats to determine the plasma levels of glucose, insulin, glucagon, IL-1beta, and central levels of IL-1beta at various times after an oral glucose load. Next, we will determine if there are age-dependent changes in the inhibition of insulin secretion produced by centrally injected rat recombinant IL-1beta (rrIL-1beta) by measuring the plasma levels of glucose, insulin, glucagon, and IL-1beta after intracerebroventricular (i.c.v.) Infection of IL-1beta. This research will lead to a better understanding of the alternations in glucose metabolism observed during aging and, possibly, to more effective treatments for this problem.