Beta oxidation in the brain is required for the effects of non-esterified fatty acids on glucose-induced insulin secretion in rats.

AIMS/HYPOTHESIS: NEFA play a key role in the setting of insulin resistance and hyperinsulinaemia, which are both features of the prediabetic state. In addition to the direct effects on pancreas and peripheral tissues, NEFA have been reported to act via changes in autonomic nervous system activity. The present study was aimed at studying the effects of a local increase in NEFA in the brain on glucose-induced insulin secretion (GIIS) and on insulin action. We hypothesised that cerebral NEFA beta oxidation is a prerequisite for these central effects. METHODS: Male Wistar rats were infused with Intralipid/heparin for 24 h through the carotid artery towards the brain (IL rats), after which we performed the GIIS test, a euglycaemic-hyperinsulinaemic clamp and c-fos immunochemistry. In another series of experiments, Intralipid/heparin infusion was coupled with lateral ventricular infusion of etomoxir, a CPT1 inhibitor, which was initiated 5 days previously. RESULTS: During the infusion period, there were no changes in plasma NEFA, insulin or glucose concentrations. IL rats displayed an increased GIIS compared with control rats (C rats) infused with saline/heparin, and their liver insulin sensitivity was decreased. Furthermore, lipid infusion induced a significant decrease in c-fos-like immunoreactive neurons in medial hypothalamic nuclei, and an increase in lateral hypothalamus. Neuronal activation profile was almost normalised in IL rats infused with etomoxir, and GIIS was strongly decreased, possibly because of the concomitant normalisation of hepatic glucose output. CONCLUSIONS/INTERPRETATION: These results strongly suggest that beta oxidation is required for the central effects of NEFA on GIIS.

Acute 2DG-induced glucoprivation or dexamethasone abolishes 2DG-induced glucoregulatory responses to subsequent glucoprivation.

Behavioral, neuroendocrine, and autonomic responses to glucoprivation are impaired after a glucoprivic episode. A life-threatening manifestation of this effect, known as hypoglycemia-associated autonomic failure (HAAF), occurs in diabetic patients as a result of prior inadvertent hypoglycemia resulting from insulin therapy. Glucocorticoids, which are elevated by glucoprivation, have been implicated in the pathogenesis of HAAF. The goal of the present study was to examine the effect of glucocorticoids on glucoregulatory responses in a rat model of HAAF. 2-deoxy-D-glucose (2DG; 200 mg/kg) was used to induce glucoprivation. Rats were injected with saline, 2DG, or the synthetic glucocorticoid, dexamethasone (DEX; 250 microg/rat) in the morning. Then 6 h later, rats were injected with 2DG, and their feeding and hyperglycemic responses were measured. Both 2DG and DEX in the morning eliminated glucoprivic feeding and hyperglycemic responses in the afternoon test. Epinephrine (0.3 mg/kg) administration in the afternoon elicited marked hyperglycemia in animals given 2DG that morning, demonstrating that glycogen depletion from morning glucoprivation was not responsible for the absence of the hyperglycemic response in the afternoon test. The effects of prior saline or 2DG treatment on subsequent glucoprivic feeding were also examined in adrenalectomized rats in which the source of endogenous glucocorticoids was removed. In these animals, prior glucoprivation did not attenuate 2DG-induced feeding in the afternoon test. These findings demonstrate that a single glucoprivic episode is sufficient to cause impairment in glucoregulatory responses to a second glucoprivic episode in the same day. In addition, these results strongly implicate glucocorticoids in the pathogenesis of HAAF.

Repeated 2-deoxy-D-glucose-induced glucoprivation attenuates Fos expression and glucoregulatory responses during subsequent glucoprivation.

A condition of reduced responsiveness to hypoglycemia, known as hypoglycemia-associated autonomic failure (HAAF), occurs in diabetic patients in the wake of a prior hypoglycemic episode. This condition suggests that hypoglycemia alters central glucose-sensing mechanisms. This experiment examined the effects of repeated 2-deoxy-D-glucose (2DG)-induced glucoprivation on subsequent 2DG-induced feeding and hyperglycemic responses in rats. Fos immunoreactivity (ir) in adrenal medulla and brain sites involved in these responses was also examined. Rats were injected daily for 10 days with 2DG (200 mg/kg) or saline (0.9%) or were handled. On day 11, rats were injected with 2DG (200 mg/kg). After injection, food intake was measured in one group. In another group, food was withheld, and multiple blood samples were collected for glucose determination. In a third group, food was withheld, and rats were killed after 2 h for evaluation of Fos-ir. Prior repeated glucoprivation reduced subsequent feeding and hyperglycemia responses to 2DG to baseline levels. Double-label immunohistochemistry showed that Fos-ir was reduced or abolished in catecholamine cell groups A1, A1/C1, C1, C3, and A6 and in the paraventricular nucleus of the hypothalamus and adrenal medulla. In other brain sites, 2DG-induced Fos-ir was diminished or unaffected by prior glucoprivation. Sites in which Fos-ir was abolished have been implicated previously in glucoprivic control of feeding and adrenal medullary secretion. Therefore, the present findings may identify crucial neuroanatomical sites that are altered by prior glucoprivation and that mediate some of the physiological deficits observed in HAAF.