AIM 9: TYPE 1 DIABETES: A MODEL OF ISOLATED ALPHA-CELL GLUCAGON SECRETION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 尽管有证据表明分离的？-细胞和分离的？-细胞的细胞机制和定向反应是相同的，但在体内胰岛素和胰升糖素的分泌反应往往是不同的。例如，血糖升高会刺激胰岛素但抑制胰高血糖素的分泌，血糖的降低会抑制胰岛素但刺激胰高血糖素的分泌。胰岛内胰岛素假说--细胞胰岛素通过胰岛内微循环相互调节？-细胞胰升糖素分泌--将解决这一明显的矛盾。基于C肽阴性的无β细胞的T1 DM患者是孤立的胰升糖素分泌模型的假设，以血浆胰高血糖素浓度作为主要结果变量，我们计划通过检验四个假说来评估人类胰岛内胰岛素假说的有效性： 9.1.与非糖尿病患者相比，与非糖尿病患者相比，无论是在典型的、通常是高血糖的临床条件下，还是在胰岛素输注隔夜后的正常血糖条件下，T1 DM患者的空腹血浆胰高血糖素浓度都会升高。30名T1糖尿病患者和30名匹配的非糖尿病对照组将在隔夜禁食后进行抽样。大多数患者还将在隔夜禁食后接受采样，隔夜胰岛素输注足以产生~90 mg/dL的空腹血糖浓度。 9.2.在混合餐后，非糖尿病患者的血浆胰高血糖素浓度降低，而T1糖尿病患者的血浆胰高血糖素浓度升高。25名T1糖尿病患者(接受基础胰岛素输注)和25名匹配的非糖尿病对照组将在配方混合餐后连续采样4小时。 9.3.给予磺脲类药物可降低非糖尿病患者的血浆胰高血糖素浓度，但增加T1 DM患者的血浆胰高血糖素浓度。25例T1 DM患者(接受基础胰岛素输注)和25例匹配的非糖尿病对照组在服用格列美脲后连续采样4小时，同时输注葡萄糖以维持血糖水平-90 mg/dL。 9.4。高血糖降低非糖尿病患者的血浆胰高血糖素浓度，但增加T1 DM患者的血浆胰高血糖素浓度。25例T1 DM患者(接受基础胰岛素输注)和25例匹配的非糖尿病对照组将在高血糖钳夹期间连续采样2小时。

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. Despite evidence that the cellular mechanisms and the directional responses of isolated ?-cells and isolated ?-cells are the same, insulin and glucagon secretory responses are often divergent in vivo. For example, increments in plasma glucose stimulate insulin but suppress glucagon secretion, and decrements in plasma glucose suppress insulin but stimulate glucagon secretion. The intraislet insulin hypothesis - ?-cell insulin reciprocally regulates ?-cell glucagon secretion via the intra-islet microcirculation - would resolve this apparent contradiction. Based on the premise that patients with C-peptide negative T1DM, who have no ?-cells, are a model of isolated ?-cell glucagon secretion, using the plasma glucagon concentration as the primary outcome variable we plan to assess the validity of the intraislet insulin hypothesis in humans by testing four hypotheses: 9.1. Patients with T1DM, compared with nondiabetic individuals, have elevated fasting plasma glucagon concentrations both under typical, often hyperglycemic, clinical conditions and under euglycemic conditions after overnight insulin infusion. Thirty patients with T1DM and 30 matched nondiabetic controls will be sampled after an overnight fast. Most of the patients will also be sampled after an overnight fast with overnight insulin infusions sufficient to produce fasting plasma glucose concentrations of ~90 mg/dL. 9.2. After a mixed meal plasma glucagon concentrations decrease in nondiabetic individuals but increase in patients with T1DM. Twenty-five patients with T1DM (receiving basal insulin infusions) and 25 matched nondiabetic controls will be sampled serially for four hours after a formula mixed meal. 9.3. Administration of a sulfonylurea decreases plasma glucagon concentrations in nondiabetic individuals but increases plasma glucagon concentrations in patients with T1DM. Twenty-five patients with T1DM (receiving basal insulin infusions) and 25 matched nondiabetic controls will be sampled serially for four hours after ingestion of glimepiride with with glucose infused to maintain plasma glucose levels ?90 mg/dL. 9.4. Hyperglycemia decreases plasma glucagon concentrations in nondiabetic individuals but increases plasma glucagon concentration in patients with T1DM. Twenty-five patients with T1DM (receiving basal insulin infusions) and 25 matched nondiabetic controls will be sampled serially for two hours during hyperglycemic clamps.