Wednesday, April 2, 2025
4/2/2025
On the regulation of hepatic glucose metabolism during insulin-induced hypoglycemia - Project Summary Iatrogenic hypoglycemia is recognized as a primary barrier to the safe, effective management of blood glucose in people with type 1 diabetes (T1D). In previous experiments in the dog, we observed that C-peptide infusion augmented glucagon secretion and hepatic glucose production during insulin-induced hypoglycemia. The proposed experiments will determine the translational impact of this finding in patients with and without T1D. We will also use the canine model to further explore the mechanistic basis of this protective effect. Specific Aim #1 is to determine, in healthy control subjects, the effect of C-peptide co-infusion with insulin on endogenous glucose production (EGP) and counterregulatory hormone levels during hypoglycemia. This will be addressed by studying a single group of healthy subjects two times. In both studies, hypoglycemia will be induced with an intravenous (IV) infusion of insulin. During one study, C-peptide will be infused during the hypoglycemic period, and in the other study, saline will be infused. EGP is our primary variable, with secondary analyses including counterregulatory hormones and metabolic substrates. Specific Aim #2 is to determine, in T1D patients, the effect of C-peptide co-infusion with insulin on EGP and counterregulatory hormone levels during hypoglycemia. The research plan for this Aim is very similar to that of Aim #1, with the main exception being that we will study T1D patients instead of healthy controls (e.g., two hypoglycemic clamp studies where C-peptide is administered during one study and saline during the other). In addition, the glycemic levels of these T1D patients will be monitored for 10 days prior to this visit to ensure that they do not experience hypoglycemia which could confound the data for the metabolic studies. Similar to Aim #1, EGP is our primary outcome variable, with secondary analyses including hormone and substrate levels. Specific Aim #3 is to determine, in T1D patients, the impact of C-peptide infusion on glucoregulatory responses to a mixed meal challenge. For this Aim, we will work with the same T1D subjects we did for Aim #2. Subjects will undergo two visits. During both visits they will undergo a mixed meal tolerance test (MMTT). During one MMTT we will infuse C-peptide and during the other we will infuse saline as we monitor the glucoregulatory responses to the oral glucose challenge. The primary variable will be glucose responses to the MMTT, while secondary analyses will include hormone and substrate levels. Specific Aim #4 is to determine, in canines, the role of hyperglucagonemia in the increased HGP that occurs when C-peptide is co-infused with insulin during insulin-induced hypoglycemia. Experiments for this aim will be done at Vanderbilt and utilize the canine model to more closely examine the role that glucagon plays in the C- peptide induced enhancement in hypoglycemic counterregulation. For this Aim, we will use somatostatin to regulate pancreatic hormone levels during C-peptide infusion, thereby allowing us to determine their function.
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