Sepsis is usually described as a dysregulated host response to infection associated with severe organ dysfunction and failure. It is responsible for more than 11 million deaths annually. Despite considerable research, the understanding of this disorder remains elusive, and treatment has been limited to supportive care. It is proposed that the cause of the “dysregulation” is a deficiency of intracellular glucose to provide ongoing fuel for the immune response and/or a deficiency of glucose and/or thiamine to provide fuel for mitochondrial production of adenosine triphosphate (ATP). The plausible reason for this deficiency is that during sepsis, the immune system receives priority access to available glucose because of its high acute requirements, prompting insulin resistance that minimizes glucose utilization by less essential tissues. Concurrently, mitochondrial ATP production via oxidative phosphorylation is deprioritized, with the immune system relying on anaerobic glycolysis for ATP generation. This suppression of oxidative phosphorylation is only intended to be a temporary measure as mitochondrial ATP production must be resumed for complete recovery. Persistent suppression culminates in critical ATP deficits and cell death. It is also proposed that administering high-dose insulin alongside mild hyperglycemia and intravenous thiamine—a pyruvate dehydrogenase kinase inhibitor—may help restore physiological mitochondrial ATP production when administered within a critical window during the sepsis process, potentially improving survival outcomes. A recent experiment demonstrated that mice with sepsis achieved superior survival from combined glucose and thiamine compared to those on antibiotics, indicating the potential for combined thiamine, glucose, and high-dose insulin therapy in sepsis. If replicated in human studies, these findings could advance understanding of sepsis pathophysiology and provide a basis for a novel therapeutic strategy involving thiamine, glucose, and high-dose insulin.