Processes under hypothalamic control, such as thermogenesis, feeding behavior, and pituitary hormone secretion, are disrupted in poorly controlled diabetes, but the underlying mechanisms are poorly understood. Because glial cells regulate neurosecretory neurons through modulation of synaptic inputs and function, we investigated the changes in hypothalamic glia in rats with streptozotocin-induced diabetes mellitus. Hypothalamic glial fibrillary acidic protein (GFAP) levels decreased significantly 6 wk after diabetes onset. This was coincident with decreased GFAP immunoreactive surface area, astrocyte number, and the extension of GFAP immunoreactive processes/astrocyte in the arcuate nucleus. Cell death, analyzed by terminal deoxyuridine 5-triphosphate nick-end labeling and ELISA, increased significantly at 4 wk of diabetes. Proliferation, measured by Western blot for proliferating cell nuclear antigen and immunostaining for phosphorylated histone H-3, decreased in the hypothalamus of diabetic rats throughout the study, becoming significantly reduced by 8 wk. Both proliferation and death affected astroctyes because both phosphorylated histone H-3- and terminal deoxyuridine 5-triphosphate nick-end labeling-labeled cells were GFAP positive. Western blot analysis revealed that postsynaptic density protein 95 and the presynaptic proteins synapsin I and synaptotagmin increased significantly at 8 wk of diabetes, suggesting increased hypothalamic synaptic density. Thus, in poorly controlled diabetic rats, there is a decrease in the number of hypothalamic astrocytes that is correlated with modifications in synaptic proteins and possibly synaptic inputs. These morphological changes in the arcuate nucleus could be involved in neurosecretory and metabolic changes seen in diabetic animals.

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Poorly controlled diabetes is associated with hormonal imbalances, including decreased prolactin production partially due to increased lactotroph apoptosis. In addition to its metabolic actions, ghrelin inhibits apoptosis in several cell types. Thus, we analyzed ghrelin's effects on diabetes-induced pituitary cell death and hormonal changes. Six weeks after onset of diabetes in male Wistar rats (streptozotocin 70 mg/kg), mini-pumps infusing saline or 24 nmol ghrelin/day were implanted (jugular). Rats were killed two weeks later. Ghrelin did not modify body weight or serum glucose, leptin or adiponectin, but increased total ghrelin (p<0.05), IGF-I (p<0.01) and prolactin (p<0.01) levels. Ghrelin decreased cell death, iNOS and active caspase-8 (p<0.05) and increased prolactin (p<0.05), Bcl-2 (p<0.01) and Hsp70 (p<0.05) content in the pituitary. In conclusion, ghrelin prevents diabetes-induced death of lactotrophs, decreasing caspase-8 activation and iNOS content and increasing anti-apoptotic pathways such as pituitary Bcl-2 and Hsp70 and serum IGF-I concentrations.