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

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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.