AIM 8: MAINTENANCE OF THE POSTABSORPTIVE PLASMA GLUCOSE CONCENTRATION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。胰高血糖素的增加，与胰岛素的减少一致，在预防以及纠正临床（即，当血浆葡萄糖浓度低于生理范围时，会出现症状性低血糖。胰高血糖素在维持吸收后血糖浓度在生理范围内的作用不太明确。普遍观点认为，通过胰岛素的降糖作用和胰高血糖素的升糖作用的相互作用，吸收后血糖浓度维持在生理范围内（人体为70 - 110 mg/dL）。然而，正如所附方案中的详细说明，许多似乎支持这一观点的证据，包括我们自己的证据，都可以有不同的解释。因此，我们计划重新研究这个问题-通过测试胰高血糖素不支持健康人吸收后血糖浓度的假设-使用胰岛钳夹技术，生长抑素（奥曲肽）输注单独抑制内源性胰岛素和胰高血糖素（和生长激素）分泌，胰岛素替代，胰高血糖素替代。我们计划首先严格评估胰岛钳夹技术的组成部分，然后用它来测试我们的假设。在目标8.1中，我们将确定健康人胰岛钳夹期间基础替代所选激素剂量的血糖效应（如有）和血浆浓度（根据文献、我们的经验和我们的假设）。然后，在目标8.2中，我们希望证实生长抑素（此处与生长抑素类似物奥曲肽）单独和与胰岛素替代的血糖反应，并通过替代胰高血糖素和胰岛素+胰高血糖素进一步验证我们的假设。虽然普遍的观点可能是正确的，但我们认为另一种观点，即仅通过胰岛素将吸收后血糖浓度维持在生理范围内是合理的，因此，该问题需要在人体中获得更明确的证据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Increments in glucagon, in concert with decrements in insulin, play a key role in the prevention, as well as the correction, of clinical (i.e., symptomatic) hypoglycemia when plasma glucose concetration fall below the physiological range. The role of glucagon in maintenance of the postabsorptive plasma glucose concentration within the physiological range is less clear-cut. The prevalent view is that the postabsorptive plasma glucose concentration is maintained within the physiological range (70 to 110 mg/dL in humans) by the interplay of the glucose-lowering action of insulin and the glucose-raising action of glucagon. However, as detailes in the attached protocol, much of the evidence that seemingly supports that view, including our own, is open to alternative interpretations. Therfore, we plan to re-examine this issue - by testing the hypothesis that glucagon does not support the postabsorptive plasma glucose concentration in healthy humans - using the islet clamp technique, somatostatin (octreotide) infusion to suppress endogenous insulin and glucagon (and growth hormone) secretion alone, with insulin replacement, with glucagon replacement. We plan to first critically assess the components of the islet clamp technique and then to use it to test our hypothesis. In Aim 8.1 we will determine the glycemic effects, if any, and the plasma concentrations of the hormone doses selected (from the literature, from our experience and in view of our hypothesis) for basal replacement during islet clamps in healthy humans. Then, in Aim 8.2, we expect to confirm the glycemic responses to somastatin (here with the somatostatin analogue octreotide) alone and with insulin replacement and test our hypothesis further by also replacing glucagon and insulin plus glucagon. While the prevalent view may be correct, we believe that the alternative view that the postabsorptive plasma glucose concentration is maintained within the physiological range by insulin alone is plausible and, therefore, that this issue needs more definitive evidence in humans.