Thiamine as Adjunctive Therapy for Diabetic Ketoacidosis

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Abstract Diabetic Ketoacidosis (DKA) is a potentially life-threatening disorder that may also expose patients to overt or sub-clinical morbidity. Even with optimal preventative strategies, a sub-set of patients will inevitably continue to develop DKA. Thiamine is an essential co-factor for several key enzymes of metabolism including pyruvate dehydrogenase (gatekeeper for Krebs Cycle). Insulin biosynthesis is impaired in thiamine deficiency rats and this is likely due to the decreased glucose oxidation. In addition, our preliminary data reveals that patients with moderate to severe DKA have high rates of thiamine deficiency which is associated with higher levels of acidosis. Moreover, we have found that thiamine will increase oxygen consumption in vitro for patients with DKA therefore suggesting a potential functional need regardless of plasma levels. Thiamine deficiency is well known to result in lactic acidosis secondary to impaired aerobic metabolism and is a causal component of neurological and memory disorders, specifically the Wernicke-Korsakoff Syndrome. Moreover, glucose loading has been described as a precipitant of thiamine deficiency and we have demonstrated that metabolic stress can deplete thiamine levels over time. Thus, we hypothesize that the provision of intravenous thiamine to patients with DKA will serve as adjunctive measure to more rapidly reverse acidosis and will improve cellular oxygen consumption potentially with protective effects on beta islet cells of the pancreas. To test this hypothesis, we will perform a prospective, randomized trial providing thiamine (versus placebo) for DKA. Our primary endpoint will be more rapid reversal of acidosis in the thiamine group as compared to the placebo arm. Our secondary outcomes will include determination of whether thiamine will improve cellular oxygen consumption, reduce lactic acidosis, and shorten hospital length of stay. We also include the exploratory aim of determining whether thiamine will preserve beta cell function as estimated through C-peptide measurements. The long-term goal of this line of research is to evaluate thiamine as an adjunctive therapy for DKA. Thiamine is safe, inexpensive, and easily administered – thus, if our hypothesis is proven true and future research proves efficacy, adoption of this adjunctive therapy is feasible and significant.