AIM 8: MAINTENANCE OF THE POSTABSORPTIVE PLASMA GLUCOSE CONCENTRATION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。当血浆葡萄糖浓度低于生理范围时，胰高血糖素的增加与胰岛素的减少在预防和纠正临床（即症状性）低血糖中起着关键作用。胰高血糖素在生理范围内维持吸收后血浆葡萄糖浓度的作用尚不明确。普遍的观点认为，吸收后血浆葡萄糖浓度维持在生理范围内（人70 ~ 110 mg/dL）是胰岛素的降血糖作用和胰高血糖素的升血糖作用的相互作用。然而，正如所附议定书中的细节，许多看似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，我们计划通过测试胰高血糖素不支持健康人吸收后血浆葡萄糖浓度的假设来重新检查这个问题，使用胰岛钳技术，单独注射生长抑素（奥曲肽）来抑制内源性胰岛素和胰高血糖素（和生长激素）的分泌，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技术的组成部分，然后用它来检验我们的假设。在Aim 8.1中，我们将确定降血糖效应（如果有的话），以及在健康人胰岛钳夹期间选择（从文献、从我们的经验和根据我们的假设）基础替代激素剂量的血浆浓度。然后，在Aim 8.2中，我们希望确认生长抑素（这里使用生长抑素类似物奥曲肽）单独和胰岛素替代的血糖反应，并通过替换胰高血糖素和胰岛素加胰高血糖素进一步验证我们的假设。虽然流行的观点可能是正确的，但我们认为，仅靠胰岛素就能将吸收后血浆葡萄糖浓度维持在生理范围内的另一种观点是合理的，因此，这一问题需要在人类中得到更明确的证据。

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.