Plasma levels of the orexigenic
hormone,
ghrelin, decrease rapidly on nutrient ingestion and yet are paradoxically elevated in rats with
hyperphagia induced by
streptozotocin-induced diabetes (STZ-DM). In the current work, we investigated the mechanisms underlying the relationships among uncontrolled diabetes, food intake, and plasma
ghrelin concentrations in an effort to clarify whether increased
ghrelin signaling contributes to diabetic
hyperphagia. Whereas food intake did not increase until d 3 after STZ administration, plasma
ghrelin levels were increased by more than 2-fold (P < 0.05) on d 1. As
hyperphagia developed, however, plasma
ghrelin levels declined steadily. Because this reduction of plasma
ghrelin levels was reversed by matching food intake of STZ-DM rats to that of nondiabetic controls, our results demonstrated that the effect of uncontrolled diabetes to increase plasma
ghrelin levels is partially offset by hyperphagic feeding. In addition, we found that although intragastric nutrient infusion rapidly and comparably decreased plasma
ghrelin levels in both groups (by 46-49%; P < 0.05), this effect was short lived in STZ-DM rats relative to nondiabetic controls (60 min vs. 120 min; P < 0.05). We further demonstrated that in rats with STZ-DM, food intake increased by 357% (P < 0.05) in response to intracerebroventricular administration of
ghrelin at a dose that was subthreshold for feeding effects in nondiabetic controls. Collectively, these findings demonstrate that uncontrolled diabetes increases both circulating
ghrelin levels and behavioral sensitivity to
ghrelin. Although plasma
ghrelin levels fall in response to hyperphagic feeding, these findings support the hypothesis that increased
ghrelin signaling contributes to the pathogenesis of diabetic
hyperphagia.