Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia

Abstract

Matveyenko AV, Bohland MA, Saberi M, Donovan CM. Portal vein hypoglycemia is essential for full induction of hypoglycemiaassociated autonomic failure with slow-onset hypoglycemia. Am J Physiol Endocrinol Metab 293: E857-E864, 2007. First published July 17, 2007; doi:10.1152/ajpendo.00283.2007.-Antecedent hypoglycemia leads to impaired counterregulation and hypoglycemic unawareness. To ascertain whether antecedent portal vein hypoglycemia impairs portal vein glucose sensing, thereby inducing counterregulatory failure, we compared the effects of antecedent hypoglycemia, with and without normalization of portal vein glycemia, upon the counterregulatory response to subsequent hypoglycemia. Male Wistar rats were chronically cannulated in the carotid artery (sampling), jugular vein (glucose and insulin infusion), and mesenteric vein (glucose infusion). On day 1, the following three distinct antecedent protocols were employed: 1) HYPO-HYPO: systemic hypoglycemia (2.52 Ϯ 0.11 mM); 2) HYPO-EUG: systemic hypoglycemia (2.70 Ϯ 0.03 mM) with normalization of portal vein glycemia (portal vein glucose ϭ 5.86 Ϯ 0.10 mM); and 3) EUG-EUG: systemic euglycemia (6.33 Ϯ 0.31 mM). On day 2, all groups underwent a hyperinsulinemic-hypoglycemic clamp in which the fall in glycemia was controlled so as to reach the nadir (2.34 Ϯ 0.04 mM) by minute 75. Counterregulatory hormone responses were measured at basal (Ϫ30 and 0) and during hypoglycemia (60 -105 min). Compared with EUG-EUG, antecedent hypoglycemia (HYPO-HYPO) significantly blunted the peak epinephrine (10.44 Ϯ 1.35 vs. 15.75 Ϯ 1.33 nM: P ϭ 0.01) and glucagon (341 Ϯ 16 vs. 597 Ϯ 82 pg/ml: P ϭ 0.03) responses to next-day hypoglycemia. Normalization of portal glycemia during systemic hypoglycemia on day 1 (HYPO-EUG) prevented blunting of the peak epinephrine (15.59 Ϯ 1.43 vs. 15.75 Ϯ 1.33 nM: P ϭ 0.94) and glucagon (523 Ϯ 169 vs. 597 Ϯ 82 pg/ml: P ϭ 0.66) responses to day 2 hypoglycemia. Consistent with hormonal responses, the glucose infusion rate during day 2 hypoglycemia was substantially elevated in HYPO-HYPO (74 Ϯ 12 vs. 49 Ϯ 4 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ; P ϭ 0.03) but not HYPO-EUG (39 Ϯ 7 vs. 49 Ϯ 4 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 : P ϭ 0.36). Antecedent hypoglycemia local to the portal vein is required for the full induction of hypoglycemiaassociated counterregulatory failure with slow-onset hypoglycemia. glucose sensor; sympathoadrenal; counterregulation INTENSIVE INSULIN REPLACEMENT therapy has proven to be an effective tool in the reduction of mean plasma glycemia and subsequent prevention of microvascular and macrovascular complications in patients with type 1 diabetes (T1DM) and late-stage type 2 diabetes (14, 34). However, intensive glucose management is associated with increased frequency of iatrogenic hypoglycemia (14), which results in increased morbidity and has been described as the major obstacle in the management of the disease (6). In diabetes, hypoglycemia results from imperfect insulin replacement combined with an impaired sympathoadrenal response, absent glucagon secretion, a...

Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis

“…Of note, altered neural feedback from the hepatoportal region to the brain has been previously shown to alter counterregulatory hormone secretion in the setting of hypoglycemia, albeit under very different experimental conditions. Elegant studies by Donovan and colleagues (24)(25)(26)(27) showed that denervation of the mesenteric region in the rat can alter the counterregulatory responses to insulin-induced hypoglycemia. This effect was only observed, however, when the fall in plasma glucose was slow (i.e., ~0.5 mg/dl/min), whereas disruption of neural input was of no consequence when the fall of the plasma glucose level was rapid (~1.3 mg/dl/min).…”

Hepatic Nervous System and Neurobiology of the Liver

“…This mechanism appears to be critical for the initiation of food intake, rather than the termination of feeding upon its inhibition (104). However, in hypoglycemic conditions the vagal branch does not appear to trigger feeding except in slow-onset hypoglycemia (56). Rapid-onset hypoglycemia is detected by the brain but, not by the liver (19, 86).…”

The role of the autonomic nervous liver innervation in the control of energy metabolism

“…Hypoglycemia detection is not mediated by vagal afferents [99,100], but does involve the capsaicin-sensitive primary spinal afferent nerves [101]. It has also been suggested that portal vein glucose sensors only play a key role in the response to slow-onset hypoglycemia [102], but that the primary place of detection shifts to other loci such as the brain when hypoglycemia develops rapidly [103,104].…”