Abstract Sprague-Dawley male rats (n=21) weighing 175 ± 10 g, after one week of control diet feeding, were assigned to one of two treatments for another week: a) control diet group (CD) which was fed a diet consisting of 65% carbohydrate (n=10), and b) low carbohydrate diet group (LCD) which was fed an isocaloric diet consisting of 5% carbohydrate (n=11). Rats were killed by decapitation under pentobarbital anesthesia after a 12 hour fast. Brain tissue and mixed arteriovenous blood were collected. Body weight, weight gain and food intake were unaffected by diet (159.2 ± 9.8 g vs 158.5 ± 7.5 g, 52.5 g vs 51.0 g, and 14.3 ± 1.7 g vs 14.5 ± 1.8 g for CD and LCD, respectively. Hypothalamic and plasma B-Endorphin (B-EP) were significantly elevated in the LCD compared to the CD (376.7 ± 17.5 pmol/g vs 153.0 ± 14.7 pmol/g, and 8.7 ± 1.2 pg/ml vs 4.7± 1.4 pg/ml, p< 0.05). Plasma glucose decreased in the LCD group almost to hypoglycemic levels compared to the CD group (63.5 ± 3.6 mg/dl vs 81.9 ± 3.4 mg/dl, p < 0.05). Significant negative correlations were obtained between plasma glucose concentration and hypothalamic (r = −0.77, p< 0.05) and plasma B-EP (r = −0.60 p < 0.05). Plasma insulin declined in the LCD compared to the CD (16.5 ± 2.4 uIU/ml vs 32.8 ± 2.8 uIU/ml, p < 0.05). Plasma glucagon was elevated in the LCD group compared to the CD group (309.4 ± 19.8 pg/ml vs 145.0 ± 13.3 pg/ml, p < 0.05). The data suggest that dietary carbohydrate restriction can result in low plasma glucose and may be a stimulus for a significant rise of both central and peripheral B-EP. These results support the notion that glucose homeostasis could be regulated, at least in part, by B-EP mechanisms which appear to occur independent of insulin stimulation.