Muzumdar Radhika, Ma Xiaohui, Atzmon Gil, Vuguin Patricia, Yang Xiaoman, Barzilai Nir
Division of Pediatric Endocrinology, Children's Hospital at Montefiore, Institute for Aging Research and Diabetes Research and Training Center, and the Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
Diabetes. 2004 Feb;53(2):441-6. doi: 10.2337/diabetes.53.2.441.
While the incidence of diabetes increases with age, a decrease in beta-cell function independent of age-related insulin resistance has not been conclusively determined. We studied insulin secretion (by hyperglycemic clamp) in 3-, 9-, and 20-month-old chronically catheterized, awake, Sprague Dawley (SD) rats (n = 78). Insulin action was modulated in a group of old rats by caloric restriction (CR) or by surgical removal of visceral fat (VF-). During the first 2 h of the clamp (11 mmol/l glucose), insulin secretion and insulin resistance (S(i hyper clamp)) demonstrated the characteristic hyperbolic relationship. However, after hyperglycemia for an additional 2 h, the ability to maintain insulin secretion, commensurate with the degree of insulin resistance, was decreased in all aging rats (P < 0.05). Increasing plasma glucose levels to 18 mmol/l glucose, after clamp at 11 mmol/l, increased insulin secretion by approximately threefold in young rats, but failed to induce similar magnitude of response in the aging rats ( approximately 50%). However, elevation of plasma free fatty acid (FFA) levels by twofold (by intralipid infusion during 11 mmol/l glucose clamp) resulted in a robust, approximate twofold response in both young and old rats. Thus, prolonged stimulation by hyperglycemia unveiled a functional defect in insulin secretion with aging. This age-related defect is independent of insulin action and is specific to glucose and not FFAs. We suggest that prolonged hyperglycemic stimulation can be a tool to identify functional defects in insulin secretion, particularly in the context of the hyperbolic relationship with insulin action, in elderly subjects or those at risk for type 2 diabetes.
虽然糖尿病的发病率随年龄增长而增加，但与年龄相关的胰岛素抵抗无关的β细胞功能下降尚未得到最终确定。我们研究了3个月、9个月和20个月大的慢性插管、清醒的斯普拉格-道利（SD）大鼠（n = 78）的胰岛素分泌（通过高血糖钳夹法）。通过热量限制（CR）或手术切除内脏脂肪（VF-）对一组老年大鼠的胰岛素作用进行调节。在钳夹的最初2小时（血糖浓度为11 mmol/l），胰岛素分泌和胰岛素抵抗（S(i hyper clamp)）呈现出典型的双曲线关系。然而，在高血糖状态持续额外2小时后，所有衰老大鼠中与胰岛素抵抗程度相称的维持胰岛素分泌的能力均下降（P < 0.05）。在钳夹至11 mmol/l后将血浆葡萄糖水平升高至18 mmol/l，年轻大鼠的胰岛素分泌增加约三倍，但衰老大鼠未能诱导出类似程度的反应（约50%）。然而，将血浆游离脂肪酸（FFA）水平提高两倍（在11 mmol/l葡萄糖钳夹期间通过输注脂肪乳剂）在年轻和老年大鼠中均导致了强烈的、约两倍的反应。因此，高血糖的长期刺激揭示了衰老过程中胰岛素分泌的功能缺陷。这种与年龄相关的缺陷与胰岛素作用无关，且特定于葡萄糖而非FFA。我们认为，长期高血糖刺激可以作为一种工具，用于识别老年受试者或2型糖尿病高危人群中胰岛素分泌的功能缺陷，特别是在与胰岛素作用的双曲线关系背景下。
