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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 尽管有证据表明，细胞机制和定向反应的孤立？-细胞和隔离？细胞是相同的，胰岛素和胰高血糖素分泌反应在体内常常是不同的。 例如，血浆葡萄糖的增加刺激胰岛素但抑制胰高血糖素分泌，血浆葡萄糖的减少抑制胰岛素但刺激胰高血糖素分泌。 胰岛内胰岛素假说？细胞胰岛素β调节？通过胰岛内微循环的细胞胰高血糖素分泌-将解决这个明显的矛盾。 基于C肽阴性T1 DM患者，无？-细胞，是一个模型的孤立？细胞胰高血糖素分泌，使用血浆胰高血糖素浓度作为主要结果变量，我们计划通过测试四个假设来评估人类胰岛内胰岛素假设的有效性： 9.1. 与非糖尿病个体相比，T1 DM患者在典型（通常为高血糖）临床条件下和正常血糖条件下过夜胰岛素输注后空腹血浆胰高血糖素浓度均升高。 30例T1 DM患者和30例匹配的非糖尿病对照患者将在空腹过夜后采样。 大多数患者也将在整夜空腹后进行采样，整夜胰岛素输注足以产生约90 mg/dL的空腹血糖浓度。 9.2. 混合餐后血浆胰高血糖素浓度在非糖尿病个体中降低，但在T1 DM患者中升高。 25名T1 DM患者（接受基础胰岛素输注）和25名匹配的非糖尿病对照者将在配方混合餐后4小时连续采样。 9.3. 磺酰脲类药物可降低非糖尿病患者的血浆胰高血糖素浓度，但可升高T1 DM患者的血浆胰高血糖素浓度。 25名T1 DM患者（接受基础胰岛素输注）和25名匹配的非糖尿病对照者将在服用格列美脲后4小时连续采样，并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个体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。 在高血糖钳夹期间，将对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患者连续采样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.