Antecedent Adrenaline Attenuates the Responsiveness to But Not the Release of Counterregulatory Hormones during Subsequent Hypoglycemia

Galan, Bastiaan E. de; Rietjens, Saskia J.; Tack, Cees J.; Werf, S.P. van der; Sweep, Fred C.G.J.; Lenders, Jacques W.M.; Smits, Paul

doi:10.1210/jc.2003-030407

Cited by 12 publications

(7 citation statements)

References 40 publications

(41 reference statements)

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“…There is also evidence that recent antecedent epinephrine elevations do not cause HAAF (78). Epinephrine infusions did not reduce the plasma epinephrine (or glucagon) and neurogenic symtom responses to subsequent hypoglycemia in nondiabetic subjects.…”

Section: The Mechanism Of the Shift Of The Glycemic Thresholds For Symentioning

confidence: 92%

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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Section: The Mechanism Of the Shift Of The Glycemic Thresholds For Symentioning

confidence: 92%

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

2005

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“…Ultimate plasma adrenaline concentrations were similar in men and women (7.96 6 0.47 versus 8.31 6 0.58 nmol/L, P = NS), and compatible with those attained under hypoglycemic conditions. 8 Adrenaline infusion caused a dose-dependent increase in heart rate in both men and women, but the increase was significant larger in men (20.3 6 1.4 versus 11.2 6 2.8 bpm, P , 0.01, Fig. 1).…”

Section: Resultsmentioning

confidence: 79%

“…These subjects also participated in a previous study. 8 All subjects were healthy and did not use any medication, except for oral contraceptives that were used by all female participants. The study was performed as a placebo controlled single blind crossover design and was approved by the medical ethics committee of the Radboud University Nijmegen Medical Center.…”

Section: Subjectsmentioning

confidence: 99%

Effect of Sex on the Cardiovascular Response to Adrenaline in Humans

Schouwenberg¹,

Rietjens²,

Smits³

et al. 2006

Journal of Cardiovascular Pharmacology

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Cardiovascular responsiveness to stress conditions differs between men and women. It is not known to what extent this observation is explained by differences in the release of stress hormones like adrenaline, or by differences in the response to adrenaline. Therefore, we quantified the hemodynamic response to infusion of adrenaline (0.04, 0.06, and 0.08 microg x kg(-1) x min(-1) for 20 minutes each) in 8 healthy men and 8 healthy premenopausal women. Arterial plasma adrenaline levels were measured before and after infusion. Heart rate and intra-arterial blood pressure were monitored throughout the experiment. Arterial plasma adrenaline levels increased similarly in both sexes. There was a larger increase in systolic blood pressure in women compared with men (17.6 +/- 2.8 versus 5.1 +/- 3.1 mm Hg, P < 0.01). In contrast, men showed a larger increase in heart rate compared with women (20.3 +/- 1.4 versus 11.2 +/- 2.8 bpm, P < 0.01). In conclusion, these data suggest that the cardiovascular response to adrenaline is predominantly alpha-adrenergic in premenopausal women, and predominantly beta-adrenergic in age-matched men.

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“…Taken together, these data support the notion that repeated adrenergic activation during antecedent bouts of hypoglycaemia plays a fundamental role in suppressing the sympathoadrenal response to subsequent episodes of hypoglycaemia and that β‐adrenergic receptor blockers may be a useful therapeutic strategy to prevent the development of HAAF and improve hypoglycaemia awareness in patients with T1D. In contrast to these findings, de Galan and colleagues reported that prior administration of epinephrine to healthy human subjects did not affect autonomic or neuroglycopenic symptoms, nor did it impair the counterregulatory hormone responses 39 . Differences in the responses to epinephrine infusion between the two studies may be attributed to the amplitude and/or duration of epinephrine exposure, as well as the length of time between the epinephrine infusion and the clamp procedure.…”

Section: Discussionmentioning

confidence: 97%

Carvedilol prevents impairment of the counterregulatory response in recurrently hypoglycaemic diabetic rats

Farhat

Vliet

Gong³

et al. 2021

Endocrino Diabet & Metabol

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Aim It has been suggested that repeated activation of the adrenergic system during antecedent episodes of hypoglycaemia contributes to the development of counterregulatory failure. We previously reported that treatment with carvedilol, a non‐specific β‐blocker, prevented the development of counterregulatory failure and improved hypoglycaemia awareness in recurrently hypoglycaemic non‐diabetic rats. The current study investigated whether carvedilol has similar benefits in diabetic rats. Methods Recurrently hypoglycaemic streptozotocin‐diabetic rats (STZ+RH) were treated with carvedilol for one week prior to undergoing a hypoglycaemic clamp. Hypoglycaemia awareness was evaluated in streptozotocin‐diabetic rats made hypoglycaemia unaware using repeated injections of 2‐deoxyglucose. Results Compared to hypoglycaemia‐naïve STZ‐diabetic controls, exogenous glucose requirements were more than doubled in the STZ+RH animals and this was associated with a 49% reduction in the epinephrine response to hypoglycaemia. Treating STZ+RH animals with carvedilol improved the epinephrine response to hypoglycaemia. Of note, neither recurrent hypoglycaemia nor carvedilol treatment affected the glucagon response in diabetic animals. Additionally, carvedilol treatment improved the feeding response to insulin‐induced hypoglycaemia in diabetic animals made ‘hypoglycaemia unaware’ using repeated injections of 2‐deoxyglucose, suggesting the treatment improved awareness of hypoglycaemia as well. Conclusion Our data suggest that carvedilol may be useful in preventing impairments of the sympathoadrenal response and the development of hypoglycaemia unawareness during recurring episodes of hypoglycaemia in diabetic animals.

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Antecedent Adrenaline Attenuates the Responsiveness to But Not the Release of Counterregulatory Hormones during Subsequent Hypoglycemia

Cited by 12 publications

References 40 publications

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

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

Effect of Sex on the Cardiovascular Response to Adrenaline in Humans

Carvedilol prevents impairment of the counterregulatory response in recurrently hypoglycaemic diabetic rats

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