Renal Glucose Release after Unilateral Renal Denervation during a Hypoglycemic Clamp in Pigs with an Altered Hypothalamic Pituitary Adrenal Axis after Late-Gestational Dexamethasone Injection

Abstract

Previously, we demonstrated in pigs that renal denervation halves glucose release during hypoglycaemia and that a prenatal dexamethasone injection caused increased ACTH and cortisol concentrations as markers of a heightened hypothalamic pituitary adrenal axis (HPAA) during hypoglycaemia. In this study, we investigated the influence of an altered HPAA on renal glucose release during hypoglycaemia. Pigs whose mothers had received two late-gestational dexamethasone injections were subjected to a 75 min hyperinsulinaemic–hypoglycaemic clamp (<3 mmol/L) after unilateral surgical denervation. Para-aminohippurate (PAH) clearance, inulin, sodium excretion and arterio–venous blood glucose difference were measured every fifteen minutes. The statistical analysis was performed with a Wilcoxon signed-rank test. PAH, inulin, the calculated glomerular filtration rate and plasma flow did not change through renal denervation. Urinary sodium excretion increased significantly (p = 0.019). Side-dependent renal net glucose release (SGN) decreased by 25 ± 23% (p = 0.004). At 25 percent, the SGN decrease was only half of that observed in non-HPAA-altered animals in our prior investigation. The current findings may suggest that specimens with an elevated HPAA undergo long-term adaptations to maintain glucose homeostasis. Nonetheless, the decrease in SGN warrants further investigations and potentially caution in performing renal denervation in certain patient groups, such as diabetics at risk of hypoglycaemia.

Effect of Low-Frequency Renal Nerve Stimulation on Renal Glucose Release during Normoglycemia and a Hypoglycemic Clamp in Pigs

“…Furthermore, we were able to show that a prenatal administration of dexamethasone in late-term pregnant sows induced both elevated baseline levels of ACTH and cortisol in the offspring and heightened the increase in these respective hormones during a hypoglycemic episode [50]. Interestingly, animals from the same litter who underwent a unilateral renal denervation procedure exhibited only a 25% decrease in the renal gluconeogenic response compared to the animals in the above-mentioned study that did not receive a prenatal glucocorticoid administration [51]. This might be indicative of early life adaptive processes that downregulate the share of sympathetic innervation in renal gluconeogenesis in favor of other regulatory mechanisms in order to maintain glucose homeostasis.…”

“…The latter could only be found in a Wilcoxon signed rank exact test that incorporated two distinct time points-the first period of LFS that followed one of non-stimulation during normoglycemia-but not in a linear mixed model. Formerly, we were able to show that unilateral renal denervation decreases SGN compared to the non-ablated kidney, while absolute renal glucose output still remained positive compared to normoglycemia [49], and that this decrease is halved in specimens with an altered hypothalamic-pituitaryadrenal axis (HPAA) due to late-gestational glucocorticoid injections [51]. Despite the very circumscribed results for the effects of LFS on SGN that reached significance, this study can in our estimation still be cautiously regarded as a positive control to our previous investigations of the influence of renal denervation on renal glucose release.…”

“…The choice of the pig animal model was partly based on the fact that our preliminary experiments on HPAA activation and renal denervation were carried out in the same animal model, and thereby ensured comparability [50,51], and furthermore, because the pig animal model is an established model used to carry out studies on metabolic processes, which, due to the similarities of the respective physiological processes, can be approximated to humans. In addition, it is also possible to imitate diabetic metabolic situations [50,51]. The position and shape of the kidneys in pigs also lend themselves to analogies with human anatomy [50,51].…”

“…In addition, it is also possible to imitate diabetic metabolic situations [50,51]. The position and shape of the kidneys in pigs also lend themselves to analogies with human anatomy [50,51].…”

“…Importantly, this current study utilized a somewhat different experimental setup than that of our previous investigations of the influence of sympathetic nerves on renal gluconeogenesis. In our previous studies, we defined hypoglycemia as either below 3 mmol/L [51] or below 2 mmol/L [49], preceded by, respectively, a 24-h food withdrawal prior to the commencement of the intervention. In this study, we decided on a closer approximation to more frequently occurring episodes of mild hypoglycemia.…”