Sepsis initiates two primary metabolic responses: insulin resistance in insulin-responsive tissues and suppression of mitochondrial adenosine triphosphate (ATP) production. These mechanisms underpin the hypermetabolic and hypometabolic phases of sepsis. The hypermetabolic phase features a heightened metabolic rate, rapid immune activation, and increased glucose supply and consumption. In contrast, the hypometabolic phase involves a reduction in metabolic rate and physiological activity across multiple organs, mirroring hibernation-like states.During sepsis, the immune system receives priority access to available glucose, prompting insulin resistance that minimises glucose utilisation by less essential tissues. Concurrently, mitochondrial ATP production via oxidative phosphorylation (OXPHOS) is deprioritised, with the immune system relying on anaerobic glycolysis for ATP generation. This suppression of OXPHOS is only a temporary measure; mitochondrial ATP production must resume for complete recovery. Persistent suppression of mitochondrial ATP production can culminate in critical ATP deficits and cell death.This review examines glucose and insulin metabolism in sepsis, concluding that administering high-dose insulin alongside mild hyperglycaemia and intravenous thiamine—a pyruvate dehydrogenase kinase (PDK) inhibitor—may help restore physiological mitochondrial ATP production during a crucial window in the sepsis process, potentially improving survival outcomes.