Acute effects of GLP-1 on glucose uptake in obese subjects

体外研究表明，GLP-1在脂肪和肌肉中都有轻微的胰岛素样作用。我们在非肥胖(即正常的葡萄糖摄取，因此不抵抗胰岛素的作用)受试者中进行了一项研究(发表于J.Clin。内分泌激素。Metab.，83：2399-2405,1998)静脉注射GLP-1，但不能证明这一现象。我们使用最先进的方法，使用氚葡萄糖来研究葡萄糖的输出和肝脏的摄取。然而，由于受试者还很年轻，胰岛素的作用完全正常，我们可能无法表现出微妙的胰岛素模拟作用。因此，我们在肥胖、非糖尿病(胰岛素抵抗，空腹血糖正常)受试者中启动了一项研究，以了解GLP-1是否会降低胰岛素抵抗。我们在12名体重指数为30的受试者中完成了这项研究。似乎GLP-1在肥胖者中确实具有胰岛素样作用(即增强胰岛素作用)(MS提交)。它似乎也抑制了非酯化脂肪酸的形成--比单独使用胰岛素更有效。这告诉我们，类似GLP-1的化合物，如GLP-1本身或exendin-4，可能不仅对糖尿病有用，而且对糖耐量减低也有用。目前可用于2型糖尿病的治疗方案并不完美。由于胰岛β细胞功能的恶化，绝大多数2型糖尿病患者在生命中的某个阶段需要胰岛素。NumberZ01AG00214-08 LCI项目已经表明，持续的GLP-1治疗改善了啮齿动物的葡萄糖耐量并增加了β细胞更新率。每顿饭前皮下注射GLP-1确实能降低血糖。但在下一次注射之前，血糖水平又会上升。我们希望观察持续皮下注射GLP-1是否能使血糖正常化并维持正常。因此，我们通过Mini-Med泵(一个寻呼机大小的小泵)连续给2型糖尿病患者皮下注射GLP-1 48小时。然后，我们通过评估胰岛素分泌量和胰岛素敏感性来检查葡萄糖稳态。来自5名受试者的数据显示，以这种方式给予的GLP-1可以使血糖正常化。然后，我们将我们的发现扩展到实际的患者。利用因急性中风入院的糖尿病患者以及同时患有糖尿病的患者，我们启动了一个项目，在他们住院的前72小时内静脉注射GLP-1(IRB编号：HRV99-08-13-01)。通过这种方式，我们将能够确定GLP-1是否可以使血糖正常化，不仅是在门诊环境中，而且在压力条件下也是如此。

Research done in vitro has shown that GLP-1 is mildly insulinomimetic in both fat and muscle. We undertook a study in non-obese (i.e. normal glucose uptake and therefore not resistant to insulin's actions ) subjects (published J. Clin. Endocrinol. Metab., 83:2399-2405,1998) with intravenous GLP-1 and could not demonstrate this phenomenon. We used state-of-the-art methodology using tritiated glucose to study glucose output and uptake by the liver. However, as the subjects were young with perfectly normal insulin action we may not have been able to show subtle insulinomimetic actions. We therefore initiated a study in obese, non diabetic (insulin resistant, with normal fasting blood glucose) subjects to see if GLP-1 would decrease resistance to insulin. We finished the study in 12 subjects whose BMI was >30. It does appear that GLP-1 is indeed insulinomimetic (i.e. augments insulin action) in obese people (ms submitted). It also appears to suppress formation of non-esterified fatty acids-more than does insulin alone. This tells us that a GLP-1 like compound, such as GLP-1 itself or exendin-4, might not only be useful in diabetes, but also in glucose intolerance. Treatment options that are presently available for type 2diabetes are less than perfect. The vast majority of type 2diabetic subjects require insulin at some point in their lives because of deteriorating beta cell function. Project NumberZ01AG00214-08 LCI has shown that continuous GLP-1 treatment improves glucose tolerance and increases the rate of beta cell turnover in rodents. GLP-1, given subcutaneously to humans before each meal, does lower blood sugar. But blood sugar levels rise again before the next bolus. We wished to see if GLP-1 given continuously subcutaneously would normalize and maintain a normal blood sugar. We therefore gave GLP-1 continuously subcutaneously, via a Mini-Med pump (a small pump about the size of a beeper) to Type 2 diabetic subjects for 48 hours. We then examined glucose homeostasis by reviewing insulin secretory capacity and insulin sensitivity. Data from 5 subjects showed that GLP-1 given in this manner can normalize blood sugars. We then expanded on our findings to the actual patient. Using diabetic patients who are admitted to hospital with an acute stroke and who are also suffering from diabetes we have initiated a project whereby GLP-1 is given intravenously for the first 72 h of their hospital stay (IRB number: HRV99-08-13-01). In this manner we will be able ascertain if GLP-1 can normalize blood glucose not only in an out-patient setting by also under stressful conditions.