AIM 8: MAINTENANCE OF THE POSTABSORPTIVE PLASMA GLUCOSE CONCENTRATION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。当血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)低血糖方面发挥着关键作用。胰高血糖素在维持吸收后血糖浓度在生理范围内的作用尚不明确。目前流行的观点认为，胰岛素的降糖作用和胰高血糖素的升糖作用相互作用，使人体吸收后的血糖浓度维持在生理范围内(人体为70~110 mg/dL)。然而，正如所附议定书中详细说明的那样，许多似乎支持这一观点的证据，包括我们自己的，都可以有其他解释。因此，我们计划重新审视这一问题-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-使用胰岛钳技术，注射生长抑素(奥曲肽)单独抑制内源性胰岛素和胰高血糖素(和生长激素)的分泌，与胰岛素替代，与胰高血糖素替代。我们计划首先批判性地评估胰岛钳夹技术的组件，然后用它来检验我们的假设。在目标8.1中，我们将确定在健康人类的胰岛钳夹期间用于基础替代的激素剂量(从文献、我们的经验和我们的假设中)的血药浓度(如果有的话)。然后，在目标8.2中，我们希望确认单独使用生长抑素(这里使用生长抑素类似物奥曲肽)和使用胰岛素替代治疗的升糖反应，并通过替代胰高血糖素和胰岛素加胰高血糖素来进一步检验我们的假设。虽然流行的观点可能是正确的，但我们认为另一种观点，即吸收后血糖浓度仅由胰岛素维持在生理范围内是合理的，因此，这一问题需要更多的人类确凿证据。

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.