L. Lamarche

Bio: L. Lamarche is an academic researcher from Université de Montréal. The author has contributed to research in topics: Catecholamine & Epinephrine. The author has an hindex of 4, co-authored 4 publications receiving 49 citations.

Hepatic denervation reduces adrenal catecholamine secretion during insulin-induced hypoglycemia.

Abstract: The present study was designed to investigate the functional implication of hepatic afferent nerves in controlling adrenal medullary counterregulatory response to insulin-induced hypoglycemia in anesthetized dogs subjected to an acute surgical denervation of the liver. Aortic glucose concentration decreased similarly in the groups of dogs with hepatic denervation (n = 8) and sham denervation (n = 8) reaching a glucose nadir 30 min after insulin injection (0.15 IU/kg i.v.) from a control value of 89.46 +/- 3.15 and 88.91 +/- 2.86 mg/dl to 52.92 +/- 3.27 and 48.80 +/- 4.18 mg/dl (P < 0.05), respectively. The catecholamine output from the adrenal glands in the sham group significantly increased (P < 0.05), reaching a maximum level 45 min after insulin injection from a control value for epinephrine of 86.35 +/- 26.65 ng/min and for norepinephrine of 32.14 +/- 11.68 ng/min to 659.03 +/- 269.39 and 181.21 +/- 63.03 ng/min, respectively. By contrast, however, adrenal catecholamine output increased only slightly in the hepatic-denervated group during insulin-induced hypoglycemia, from 148.37 +/- 95.29 and 52.06 +/- 28.05 ng/min to 210.49 +/- 96.09 and 79.61 +/- 26.11 ng/min for epinephrine and norepinephrine, respectively, the difference being statistically nonsignificant compared with the corresponding preinjection control value. The maximum net response of adrenal epinephrine and norepinephrine output observed in dogs with hepatic denervation was significantly attenuated by approximately 90 and 82% of the values obtained from the sham group, respectively. In a separate series of experiments, aortic immunoreactive insulin and glucagon concentrations were measured and found to be similar between hepatic-denervated and sham-denervated groups after insulin-induced hypoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective hypoglycemia in the liver induces adrenomedullary counterregulatory response

Abstract: The present study was designed to investigate adrenal medullary responses to a selective regional hypoglycemia in the liver of dogs with hepatic cross-perfusion. The liver of recipient dogs (Rc) was perfused with vena caval and aortic blood of donor dogs (Dn) through the portal vein and hepatic artery, respectively. Total hepatic venous blood of Rc was returned to Dn through the left jugular vein. Upon the cross-perfusion, glucose (Glc, 5%) was infused at an average rate of 3.5 +/- 0.2 mg.kg-1.min-1 (n = 12) in Rc to compensate the loss of hepatic Glc delivery into the systemic circulation. Insulin (5.0 IU/kg i.v.) was administered to Dn followed by infusion with an average rate of 0.95 +/- 0.17 IU kg-1.min-1 (n = 6), and this served as the hepatic hypoglycemic group. Saline was similarly administered to Dn, which served as the normoglycemic control group. In the hepatic hypoglycemic group, aortic and vena caval Glc levels in Dn, which represent Glc concentrations entering the liver of Rc, decreased from 129.9 +/- 7.1 and 122.5 +/- 7.8 to 44.6 +/- 6.1 and 38.0 +/- 5.9 mg/dl (P < 0.05) 45 min after insulin administration, respectively. During this regional hepatic hypoglycemia in Rc, the systemic glycemia being kept within a normal range, adrenal epinephrine and norepinephrine output increased from 245.5 +/- 55.8 and 39.1 +/- 9.9 to 618.9 +/- 180.4 and 134.3 +/- 52.7 ng/min (P < 0.05), respectively. By contrast, aortic Glc and insulin levels in Dn of the normoglycemic control group remained unchanged, as did adrenal epinephrine and norepinephrine output in Rc. The results indicate that the regional hepatic hypoglycemia can significantly increase adrenal catecholamine secretion even during systemic (central) normoglycemia. The study suggests that the hepatoadrenal Glc counter-regulatory reflex may be functionally implicated in insulin-induced hypoglycemia.

Evidence against a humoral control mechanism in adrenal catecholamine secretion during insulin-induced hypoglycemia.

Abstract: The present study tested the hypothesis that a humoral control mechanism is involved in the enhanced adrenal catecholamine secretion during insulin-induced hypoglycemia. The experiments were carried out in anesthetized dogs in which neuronal and humoral components were simultaneously determined by measuring catecholamine output from the right innervated and the left acutely denervated adrenal gland, respectively. Different levels of hypoglycemia were induced by intravenous injection of insulin with doses of 0.075 (n = 6), 0.150 (n = 6), and 0.300 IU/kg (n = 6) in three separate groups of dogs. Catecholamine output in the right innervated gland increased dose dependently (P less than 0.05), reaching a maximum level 45 min after insulin administration. By contrast, catecholamine output from the left denervated adrenal gland remained unchanged at all doses tested. In sham-denervated animals (n = 7), catecholamine output from the left adrenal gland increased to a magnitude similar to that observed in the right innervated gland after insulin administration. Plasma glucose concentration significantly decreased in a dose-dependent manner, reaching a nadir 30 min after insulin administration. Maximum decreases in plasma glucose concentration could be strongly correlated with maximum increases in catecholamine output from the right innervated adrenal gland (r = -0.66, n = 18, P = 0.011), but not with those from the left denervated gland (r = -0.32, n = 18, P = 0.455). The present results do not support the functional existence of a humoral mechanism permitting the release of adrenal catecholamines during insulin-induced hypoglycemia.

Simultaneous evaluation of medullary secretory functions of normal and acutely denervated adrenals

Abstract: Adrenal medullary secretory function of the right innervated gland was simultaneously compared with that of contralateral acutely denervated gland in anesthetized dogs. During bilateral carotid artery occlusion (BCO), output (in ng/min) from right innervated gland of epinephrine and norepinephrine increased from 86.6 +/- 33.0 and 34.4 +/- 15.1 to 280.8 +/- 86.7 (P less than 0.01, n = 7) and 104.4 +/- 40.6 (P less than 0.01, n = 7), respectively. By contrast, epinephrine output from left denervated gland increased only slightly (P less than 0.05), and norepinephrine did not increase significantly. Net catecholamine output from left denervated gland was markedly attenuated by approximately 90% (P less than 0.01, n = 7) compared with that from right innervated gland. During BCO in the second group of dogs, catecholamine output from sham-denervated left gland increased significantly (P less than 0.01, n = 7) to an extent slightly lower than that observed in right innervated gland. In the third group, intravenous injections of dimethylphenylpiperazinium (5 and 15 micrograms/kg) resulted in a dose-dependent increase (P less than 0.05, n = 7) in catecholamine output from both right innervated and left denervated gland. The results indicate that the present procedure of acute surgical adrenal denervation can eliminate the centrally mediated adrenal response, whereas the medullary secretory response to blood-borne substances remains intact. This model may be a useful tool for studying neuronal and humoral medullary secretory functions in vivo under various experimentally induced stress conditions.

Hypothalamic ATP-sensitive K + Channels Play a Key Role in Sensing Hypoglycemia and Triggering Counterregulatory Epinephrine and Glucagon Responses

Abstract: It has been postulated that specialized glucose-sensing neurons in the ventromedial hypothalamus (VMH) are able to detect falling blood glucose and trigger the release of counterregulatory hormones during hypoglycemia. The molecular mechanisms used by glucose-sensing neurons are uncertain but may involve cell surface ATP-sensitive K + channels (K ATP channels) analogous to those of the pancreatic β-cell. We examined whether the delivery of sulfonylureas directly into the brain to close K ATP channels would modulate counterregulatory hormone responses to either brain glucopenia (using intracerebroventricular 5-thioglucose) or systemic hypoglycemia in awake chronically catheterized rats. The closure of brain K ATP channels by global intracerebroventricular perfusion of sulfonylurea (120 ng/min glibenclamide or 2.7 μg/min tolbutamide) suppressed counterregulatory (epinephrine and glucagon) responses to brain glucopenia and/or systemic hypoglycemia (2.8 mmol/l glucose clamp). Local VMH microinjection of a small dose of glibenclamide (0.1% of the intracerebroventricular dose) also suppressed hormonal responses to systemic hypoglycemia. We conclude that hypothalamic K ATP channel activity plays an important role in modulating the hormonal counterregulatory responses triggered by decreases in blood glucose. Our data suggest that closing of K ATP channels in the VMH (much like the β-cell) impairs defense mechanisms against glucose deprivation and therefore could contribute to defects in glucose counterregulation.

Role of Monosaccharide Transport Proteins in Carbohydrate Assimilation, Distribution, Metabolism, and Homeostasis

Abstract: The facilitated diffusion of glucose, galactose, fructose, urate, myoinositol, and dehydroascorbicacid in mammals is catalyzed by a family of 14 monosaccharide transport proteins called GLUTs. These transporters may be divided into three classes according to sequence similarity and function/substrate specificity. GLUT1 appears to be highly expressed in glycolytically active cells and has been coopted in vitamin C auxotrophs to maintain the redox state of the blood through transport of dehydroascorbate. Several GLUTs are definitive glucose/galactose transporters, GLUT2 and GLUT5 are physiologically important fructose transporters, GLUT9 appears to be a urate transporter while GLUT13 is a proton/myoinositol cotransporter. The physiologic substrates of some GLUTs remain to be established. The GLUTs are expressed in a tissue specific manner where affinity, specificity, and capacity for substrate transport are paramount for tissue function. Although great strides have been made in characterizing GLUT-catalyzed monosaccharide transport and mapping GLUT membrane topography and determinants of substrate specificity, a unifying model for GLUT structure and function remains elusive. The GLUTs play a major role in carbohydrate homeostasis and the redistribution of sugar-derived carbons among the various organ systems. This is accomplished through a multiplicity of GLUT-dependent glucose sensing and effector mechanisms that regulate monosaccharide ingestion, absorption,distribution, cellular transport and metabolism, and recovery/retention. Glucose transport and metabolism have coevolved in mammals to support cerebral glucose utilization.

Regulation of glucose homeostasis in humans with denervated livers.

Abstract: The liver plays a major role in regulating glucose metabolism, and since its function is influenced by sympathetic/ parasympathetic innervation, we used liver graft as a model of denervation to study the role of CNS in modulating hepatic glucose metabolism in humans. 22 liver transplant subjects were randomly studied by means of the hyperglycemic/ hyperinsulinemic (study 1), hyperglycemic/isoinsulinemic (study 2), euglycemic/hyperinsulinemic (study 3) as well as insulin-induced hypoglycemic (study 4) clamp, combined with bolus-continuous infusion of [3-3H]glucose and indirect calorimetry to determine the effect of different glycemic/insulinemic levels on endogenous glucose production and on peripheral glucose uptake. In addition, postabsorptive glucose homeostasis was cross-sectionally related to the transplant age (range = 40 d-35 mo) in 4 subgroups of patients 2, 6, 15, and 28 mo after transplantation. 22 subjects with chronic uveitis (CU) undergoing a similar immunosuppressive therapy and 35 normal healthy subjects served as controls. The results showed that successful transplantation was associated with fasting glucose concentration and endogenous glucose production in the lower physiological range within a few weeks after transplantation, and this pattern was maintained throughout the 28-mo follow-up period. Fasting glucose (4. 55+/-0.06 vs. 4.75+/-0.06 mM; P = 0.038) and endogenous glucose production (11.3+/-0.4 vs. 12.9+/-0.5 micromol/[kg.min]; P = 0.029) were lower when compared to CU and normal patients. At different combinations of glycemic/insulinemic levels, liver transplant (LTx) patients showed a comparable inhibition of endogenous glucose production. In contrast, in hypoglycemia, after a temporary fall endogenous glucose production rose to values comparable to those of the basal condition in CU and normal subjects (83+/-5 and 92+/-5% of basal), but it did not in LTx subjects (66+/-7%; P < 0.05 vs. CU and normal subjects). Fasting insulin and C-peptide levels were increased up to 6 mo after transplantation, indicating insulin resistance partially induced by prednisone. In addition, greater C-peptide but similar insulin levels during the hyperglycemic clamp (study 1) suggested an increased hepatic insulin clearance in LTx as compared to normal subjects. Fasting glucagon concentration was higher 6 mo after transplantation and thereafter. During euglycemia/hyperinsulinemia (study 3), the insulin-induced glucagon suppression detectable in CU and normal subjects was lacking in LTx subjects; furthermore, the counterregulatory response during hypoglycemia was blunted. In summary, liver transplant subjects have normal postabsorptive glucose metabolism, and glucose and insulin challenge elicit normal response at both hepatic and peripheral sites. Nevertheless, (a) minimal alteration of endogenous glucose production, (b) increased concentration of insulin and glucagon, and (c) defective counterregulation during hypoglycemia may reflect an alteration of the liver-CNS-islet circuit which is due to denervation of the transplanted graft.

Portal vein afferents are critical for the sympathoadrenal response to hypoglycemia.

Abstract: We sought to elucidate the role of the portal vein afferents in the sympathetic response to hypoglycemia. Laparotomy was performed on 27 male Wistar rats. Portal veins were painted with either 90% phenol (denervation group [PDN]) or 0.9% saline solution (sham-operated group [SHAM]). Rats were chronically cannulated in the carotid artery (sampling), jugular vein (infusion), and portal vein (infusion). After a recovery period of 5 days, animals were exposed to a hyperinsulinemic-hypoglycemic clamp, with glucose infused either portally (POR) or peripherally (PER). In all animals, systemic hypoglycemia (2.48+/-0.09 mmol/l) was induced via jugular vein insulin infusion (50 mU x kg(-1) x min(-1)). Arterial plasma catecholamines were assessed at basal (-30 and 0 min) and during sustained hypoglycemia (60, 75, 90, and 105 min). By design, portal vein glucose concentrations were significantly elevated during POR versus PER (4.4+/-0.14 vs. 2.5+/-0.07 mmol/l; P<0.01, respectively) for both PDN and SHAM. There were no significant differences in arterial glucose or insulin concentration between the four experimental conditions at any point in time. When portal glycemia and systemic glycemia fell concomitantly (SHAM-PER), epinephrine increased 12-fold above basal (3.75+/-0.34 and 44.56+/-6.1 nmol/l; P<0.001). However, maintenance of portal normoglycemia (SHAM-POR) caused a 50% suppression of the epinephrine response, despite cerebral hypoglycemia (22.2+/-3.1 nmol/l, P<0.001). Portal denervation resulted in a significant blunting of the sympathoadrenal response to whole-body hypoglycemia (PDN-PER 27.6+/-3.8 nmol/l vs. SHAM-PER; P<0.002). In contrast to the sham experiments, there was no further suppression in arterial epinephrine concentrations observed during PDN-POR versus PDN-PER (P = 0.8). These findings indicate that portal vein afferent innervation is critical for hypoglycemic detection and normal sympathoadrenal counterregulation.