Objective
We have two objectives for this proposal.
1) We will identify the metabolic defect that results in impaired ammoniagenesis, and hence impaired acid excretion, in mouse models of type 1 diabetes.
2) We will determine if the decreased rates of ammoniagenesis increased the risk of developing ketoacidosis in mouse models of type 1 diabetes.
Background Rationale
SGLT2 inhibitors are a novel drug class that protect patients with type 2 diabetes against adverse heart and kidney outcomes. Unfortunately, they are not approved for use in patients with type 1 diabetes due to an increased risk of euglycemic ketoacidosis, which is a serious complication when acid accumulates in the patient's body. Consequently, patients with type 1 diabetes are deprived of the benefit of these drugs. The current dogma is that patients with type 1 diabetes are predisposed to euglycemic ketoacidosis when there is a change in their insulin dosing. In this proposal, we intend to demonstrate that that there are alternate novel mechanisms that contribute to the unique risk that patients with type 1 diabetes have with this drug.
Description of Project
SGLT2 inhibitors are a novel drug class that protect patients with type 2 diabetes against adverse heart and kidney outcomes. Unfortunately, they are not approved for use in patients with type 1 diabetes due to an increased risk of euglycemic ketoacidosis, which is a serious complication when acid accumulates in the patient's body. Consequently, patients with type 1 diabetes are deprived of the benefit of these drugs. The current dogma is that patients with type 1 diabetes are predisposed to euglycemic ketoacidosis when there is a change in their insulin dosing. Our preliminary data suggest that there may be other contributing factors, specifically that patients with type 1 diabetes have impaired ability of their kidney to excrete acid due to impaired ammoniagenesis, one of the most important mechanisms whereby the kidney removes acid. We and others have shown that ammonia excretion decreases with SGLT2 inhibitors. In this study, we propose to identify why acid handling is impaired in type 1 diabetes using mouse models and demonstrate that this contributes to an increased risk of developing euglycemic ketoacidosis.
Anticipated Outcome
The anticipated outcome is identification of the metabolic defect that causes impaired ammoniagenesis in patients with type 1 diabetes and verification that this alteration contributes to increased risk of euglycemic ketoacidosis. These experiments will then well-position us to identify non-invasive markers of impaired acid-base handling in patients with type 1 diabetes. Going forward, we anticipate that we will be able to risk-stratify patients with type 1 diabetes if they can safely receive an SGLT2 inhibitor. Moreover, there drugs that increase ammoniagenesis and could be explored as therapeutic options to ameliorate this adverse effect.
Relevance to T1D
There have been numerous pharmacologic advances in the past decade which protect patients with type 2 diabetes from serious complications. Unfortunately, none of these agents are being used in type 1 diabetes. Our data suggest that there is an alternate, novel mechanism that may contribute towards the increased risk of euglycemic ketoacidosis in type 1 diabetes, specifically impaired ammoniagenesis (or decreased acid excretion) in type 1 diabetes. We will leverage this information to create a novel risk-stratification method to identify patients with type 1 diabetes who can safely receive SGLT2 inhibitors.