Impaired glucagon response to sympathetic nerve stimulation in the BB diabetic rat: effect of early sympathetic islet neuropathy

Mundinger, Thomas O.; Mei, Qi; Figlewicz, Dianne P.; Lernmark, Åke; Taborsky, Gerald J.

doi:10.1152/ajpendo.00136.2003

Cited by 31 publications

(28 citation statements)

References 51 publications

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“…The regulation of glucagon secretion during hypoglycemia is complex. There are data demonstrating that glucagon secretion during hypoglycemia is in part mediated via ANS mechanisms (31). However, there are also data in humans indicating that additional pathways exist for regulating the response of the hormone during hypoglycemia (18).…”

Section: Discussionmentioning

confidence: 99%

Effects of oral carbohydrate on autonomic nervous system counterregulatory responses during hyperinsulinemic hypoglycemia and euglycemia

Ertl¹,

Mann²,

Richardson³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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The effects of oral carbohydrate on modulating counterregulatory responses in humans remain undecided. This study's specific aim was to determine the effects of oral carbohydrate on autonomic nervous system (ANS) and neuroendocrine responses during hyperinsulinemic hypoglycemia and euglycemia. Nineteen healthy volunteers were studied during paired, single blind experiments. Nine subjects underwent two-step glucose clamps consisting of 60 min of euglycemia (5.0 mmol/l) followed by either 15 g of oral carbohydrate (cal) as orange juice or a noncaloric control (nocal) and subsequent 90 min of clamped hypoglycemia (2.9 mmol/l). Ten other subjects underwent two randomized 150-min hyperinsulinemic-euglycemic clamps with cal or nocal control administered at 60 min. Oral carbohydrate initially blunted (P < 0.05) epinephrine, norepinephrine, cortisol, glucagon, pancreatic polypeptide, muscle sympathetic nerve activity (MSNA), symptom, and systolic blood pressure responses during hypoglycemia. However, by the end of 90 min of hypoglycemia, plasma epinephrine and norepinephrine responses had rebounded and were increased (P < 0.05) compared with control. MSNA and cortisol levels remained suppressed during hypoglycemia (P < 0.05) after cal, whereas pancreatic polypeptide, glucagon, symptom, and blood pressure responses increased similar to control following initial suppression. Oral carbohydrate had no effects on neuroendocrine or ANS responses during hyperinsulinemic euglycemia. These results demonstrate that oral carbohydrate can have differential effects on the time course of ANS and neuroendocrine responses during hypoglycemia. We conclude that gastro-splanchnic-portal sensing of an amount of carbohydrate recommended for use in clinical practice for correction of hypoglycemia can have widespread and significant effects on central nervous system mediated counterregulatory responses in healthy humans.

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Section: Discussionmentioning

confidence: 99%

Effects of oral carbohydrate on autonomic nervous system counterregulatory responses during hyperinsulinemic hypoglycemia and euglycemia

Ertl¹,

Mann²,

Richardson³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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“…was started, in diabetic mice only, 20 min into the stabilisation period to achieve baseline glucose levels similar to those of nondiabetic controls. A baseline blood sample was then drawn from the portal vein for later measurement of plasma glucose, glucagon and adrenaline concentrations, using assay methods described previously [18]. The volume of all portal vein blood samples was fully replaced by a concomitant jugular vein infusion of heparinised donor blood.…”

Section: Methodsmentioning

confidence: 99%

“…Sympathetic nerve fibres within the islet were identified by NPY immunostaining and quantified by tracing each fibre segment within an islet image using a computer (arrows in Fig. 2a) to obtain the cumulative area of NPY-positive nerve fibres (µm 2 /islet), as we have done previously for islet sympathetic nerves of BB and Wistar rats [17,18].…”

Section: Sympathetic Neural Activationmentioning

confidence: 99%

“…Therefore, we looked for an anatomical impairment of the third autonomic input, the islet sympathetic nerves, because preventing the activation of islet sympathetic nerves during IIH markedly impairs the glucagon response, at least in non-diabetic animals [15]. When we analysed the sympathetic nerves of the BB diabetic rat, an animal model with severe autoimmune diabetes [16], we found both an early, selective and marked loss of their islet sympathetic nerve terminals [17] and an impairment of their glucagon response to selective sympathetic nerve stimulation [18]. We named this syndrome early sympathetic islet neuropathy (eSIN) to distinguish it from diabetic autonomic neuropathy.…”

Section: Introductionmentioning

confidence: 99%

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Loss of islet sympathetic nerves and impairment of glucagon secretion in the NOD mouse: relationship to invasive insulitis

et al. 2009

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Aims/hypothesis We hypothesised that non-obese diabetic mice (NOD) mice have an autoimmune-mediated loss of islet sympathetic nerves and an impairment of sympathetically mediated glucagon responses. We aimed: (1) to determine whether diabetic NOD mice have an early impairment of the glucagon response to insulin-induced hypoglycaemia (IIH) and a coincident loss of islet sympathetic nerves; (2) to determine whether invasive insulitis is required for this nerve loss; and (3) to determine whether sympathetically mediated glucagon responses are also impaired. Methods We measured glucagon responses to both IIH and tyramine in anaesthetised mice. We used immunohistochemistry to quantify islet sympathetic nerves and invasive insulitis. Results The glucagon response to IIH was markedly impaired in NOD mice after only 3 weeks of diabetes (change, −70%). Sympathetic nerve area within the islet was also markedly reduced at this time (change, −66%). This islet nerve loss was proportional to the degree of invasive insulitis. More importantly, blocking the infiltration prevented the nerve loss. Mice with autoimmune diabetes had an impaired glucagon response to sympathetic nerve activation, whereas those with non-autoimmune diabetes did not. Conclusions/interpretation The invasive insulitis seen in diabetic NOD mice causes early sympathetic islet neuropathy. Further studies are needed to confirm that early sympathetic islet neuropathy is responsible for the impaired glucagon response to tyramine.

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“…While acknowledging that loss of the glucagon response to hypoglycemia in insulin-deficient diabetes cannot be attributed to classical diabetic autonomic neuropathy, Mei and colleagues (42,43) have suggested that it might be the result of an early sympathetic neuropathy that is limited to the pancreatic islets and unique to autoimmune diabetes. That suggestion is based on their finding of a reduced marker of sympathetic nerve terminals (vesicular monoamine transporter 2) in the islets of BB, but not streptozotocin-induced, diabetic rats (42) and reduced glucagon (46) and supported by data from studies of the perfused rat pancreas (47)(48)(49), rat islets (50), and rats in vivo (51), the intraislet insulin hypothesis posits that a decrease in ␤-cell insulin secretion, and thus a decrease in intraislet insulin and a decrease in tonic intraislet ␣-cell inhibition by insulin, is normally a signal for increased glucagon secretion in response to hypoglycemia.…”

Section: The Mechanism Of the Loss Of The Glucagon Response To Hypoglmentioning

confidence: 99%

Mechanisms of Hypoglycemia-Associated Autonomic Failure and Its Component Syndromes in Diabetes

2005

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Iatrogenic hypoglycemia is a problem for people with diabetes. It causes recurrent morbidity, and sometimes death, as well as a vicious cycle of recurrent hypoglycemia, precluding maintenance of euglycemia over a lifetime of diabetes. Improved therapeutic approaches that will minimize both hypo-and hyperglycemia will be based on insight into the pathophysiology of glucoregulation, specifically glucose counterregulation, in insulin-deficient (type 1 and advanced type 2) diabetes. In such patients, hypoglycemia is the result of the interplay of relative or absolute therapeutic insulin excess and compromised physiological (the syndrome of defective glucose counterregulation) and behavioral (the syndrome of hypoglycemia unawareness) defenses against falling plasma glucose concentrations. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing epinephrine responses to a given level of subsequent hypoglycemia in the setting of absent decrements in insulin and absent increments in glucagon) and hypoglycemia unawareness (by reducing sympathoadrenal and the resulting neurogenic symptom responses to a given level of subsequent hypoglycemia) and thus a vicious cycle of recurrent hypoglycemia. The clinical impact of HAAF is well established in type 1 diabetes; it also affects those with advanced type 2 diabetes. It is now known to be largely reversible, by as little as 2-3 weeks of scrupulous avoidance of hypoglycemia, in most affected patients. However, the mechanisms of HAAF and its component syndromes are largely unknown. Loss of the glucagon secretory response, a key feature of defective glucose counterregulation, is plausibly explained by insulin deficiency, specifically loss of the decrement in intraislet insulin that normally signals glucagon secretion as glucose levels fall. Reduced neurogenic symptoms, a key feature of hypoglycemia unawareness, are largely the result of reduced sympathetic neural responses to falling glucose levels. The mechanism by which hypoglycemia shifts the glycemic thresholds for sympathoadrenal activation to lower plasma glucose concentrations, the key feature of both components of HAAF, is not known. It does not appear to be the result of the release of a systemic mediator (e.g., cortisol, epinephrine) during antecedent hypoglycemia or of increased blood-to-brain glucose transport (although increased transport of alternative fuels is conceivable). It is likely the result of alterations of brain metabolism. Although there is an array of clues, the specific alteration remains to be identified. While the research focus has been largely on the hypothalamus, hypoglycemia is now known to activate widespread brain regions, including the medial prefrontal cortex. The possibility that HAAF could be the result of posthypoglycemic brain glycogen supercompensation has also been raised. Finally, there appear to be diverse causes of HAAF. In addition to recent antecedent ...

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Impaired glucagon response to sympathetic nerve stimulation in the BB diabetic rat: effect of early sympathetic islet neuropathy

Cited by 31 publications

References 51 publications

Effects of oral carbohydrate on autonomic nervous system counterregulatory responses during hyperinsulinemic hypoglycemia and euglycemia

Effects of oral carbohydrate on autonomic nervous system counterregulatory responses during hyperinsulinemic hypoglycemia and euglycemia

Loss of islet sympathetic nerves and impairment of glucagon secretion in the NOD mouse: relationship to invasive insulitis

Mechanisms of Hypoglycemia-Associated Autonomic Failure and Its Component Syndromes in Diabetes

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