In this study the hypothesis that irreversible glucose loss results in an ‘uncoupling’ of the somatotrophic axis (increasing plasma GH levels and decreasing plasma IGF-I) was tested. During periods of negative energy balance the somatotrophic axis respond by increasing plasma GH and decreasing plasma IGF-I levels. In turn, elevated GH repartitions nutrient by increasing lipolysis and protein synthesis, and decreases protein degradation. Irreversible glucose loss was induced using sub-cutaneous injections of phloridizin. Seven non-lactating cows were treated with 8 g/day phloridizin (PHZ) and seven control animals (CTRL, 0 g/day), while being restricted to a diet of 80% maintenance. PHZ treatment increased urinary glucose excretion (P < 0.001), resulting in hypoglycemia (P < 0.001). As a response to this glucose loss, the PHZ treated animals had elevated plasma NEFA (P < 0.005) and BHBA (P < 0.001) levels. Average plasma insulin concentrations were not altered with PHZ treatment (P = 0.059). Plasma GH was not different between the two groups (P > 0.1), whereas plasma IGF-I levels decreased significantly (P < 0.001) with PHZ treatment. The decline in plasma IGF-I concentrations was mirrored by a decrease in the abundance of hepatic IGF-I mRNA (P = 0.005), in addition the abundance of hepatic mRNA for both growth hormone receptors (GHR(tot) and GHR(1A)) was also decreased (P < 0.05). Therefore, the irreversible glucose loss resulted in a partial ‘uncoupling’ of the somatotrophic axis, as no increase in plasma GH levels occurred although plasma IGF-I levels, hepatic IGF-I mRNA declined, and the abundance of liver GH receptor mRNA declined.