Adiponectin is known to be an anti-diabetic adipocytokine. However, the action mechanism by which it produces this effect remains controversial. In the present study, we investigated the long-term central effect of adiponectin on energy homeostasis, peripheral insulin resistance, β-cell function and mass in rats and aimed to determine the mechanism by which its effect was achieved. Intracerebroventricular infusion of adiponectin (50 ng/h) and artificial cerebrospinal fluid (CSF) was conducted by means of an osmotic pump for 4 weeks on nondiabetic rats and 90% pancreatectomised diabetic rats that were both fed 45% energy fat diets. After 4-weeks of treatment, i.c.v. adiponectin improved hypothalamic insulin/leptin signalling in nondiabetic and diabetic rats compared to i.c.v. CSF but it did not change the phosphorylation of AMP kinase (AMPK) in the hypothalamus. Adiponectin infusion decreased epididymal fats, representing visceral fat, by increasing energy expenditure and fat oxidation. During the euglycaemic hyperinsulinaemic clamp, i.c.v. adiponectin improved whole body insulin sensitivity and decreased hepatic glucose output in the hyperinsulinaemic state by attenuating hepatic insulin resistance. Central infusion of adiponectin did not modulate glucose-stimulated insulin secretion during the hyperglycaemic clamp compared to i.c.v. CSF infusion but it enhanced insulin sensitivity at a hyperglycaemic state. Although there were no changes in insulin secretion capacity, central adiponectin increased pancreatic β-cell mass in nondiabetic and diabetic rats as a result of decreasing β-cell death. In conclusion, long-term central infusion of adiponectin enhanced energy homeostasis by increasing energy expenditure via activating hypothalamic leptin and insulin signalling pathways but without potentiating AMPK signalling; it also improved glucose homeostasis by attenuating insulin resistance.

Transient carotid artery occlusion causes ischemia/reperfusion (I/R) injury resulting in neuron and pancreatic β-cell death with consequential post-stroke hyperglycemia, which can lead to diabetes and may accelerate the development of Alzheimer's disease. Antioxidants have been shown to protect against the I/R injury and destruction of neurons. However, it is unknown whether the protection against I/R injury extends to the pancreatic β-cells. Therefore, we investigated whether treatment with ebselen, a glutathione peroxidase mimic, prevents neuronal and β-cell death following I/R in gerbils susceptible to stroke. After 28 days post artery occlusion, there was widespread neuronal cell death in the CA1 of the hippocampus and elevated IL-1β and TNF-α levels. Pretreatment with ebselen prevented the death by 56% and attenuated neurological damage (abnormal eyelid drooping, hair bristling, muscle tone, flexor reflex, posture, and walking patterns). Ischemic gerbils also exhibited impaired glucose tolerance and insulin sensitivity which induced post-stroke hyperglycemia associated with decreased β-cell mass due to increased β-cell apoptosis. Ebselen prevented the increased β-cell apoptosis, possibly by decreasing IL-1β and TNF-α in islets. Ischemia also attenuated hepatic insulin signaling, and expression of GLUT2 and glucokinase, whereas ebselen prevented the attenuation and suppressed gluconeogenesis by decreasing PEPCK expression. In conclusion, antioxidant protection by ebselen attenuated I/R injury of neurons and pancreatic β-cells and prevented subsequent impairment of glucose regulation that could lead to diabetes and Alzheimer's disease.