Reduced beta-adrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness.

Korytkowski, Mary T.; Mokáň, Marián; Veneman, Th.F.; Mitrakou, Asimina; Cryer, Philip E.; Gerich, John E.

doi:10.2337/diacare.21.11.1939

Cited by 59 publications

(41 citation statements)

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“…Prior exposure to hypoglycemia has been found to decrease heart rate responsiveness to ␤-adrenergic agonist treatment in subjects with type 1 diabetes, but to increase adrenergic sensitivity when measured this way in nondiabetic healthy subjects (30). In addition, hypoglycemia unawareness has been associated with a decrease in ␤-adrenergic sensitivity (31). Of course, these changes in sensitivity refer to catecholamine responsiveness, whereas, in the current study, we addressed sympathetic neural effects.…”

Section: Discussionmentioning

confidence: 85%

Effect of Acute and Antecedent Hypoglycemia on Sympathetic Neural Activity and Catecholamine Responsiveness in Normal Rats

Sivitz

Herlein

Morgan³

et al. 2001

Diabetes

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Adrenergic responsiveness to acute hypoglycemia is impaired after prior episodes of hypoglycemia. Although circulating epinephrine responses are blunted, associated alterations in adrenal sympathetic nerve activity (SNA) have not been reported. We examined adrenal nerve traffic in normal conscious rats exposed to acute insulin-induced hypoglycemia compared with insulin with (clamped) euglycemia. We also examined adrenal SNA and catecholamine responses to insulin-induced hypoglycemia in normal conscious rats after two antecedent episodes of hypoglycemia (days ؊2 and ؊1) compared with prior episodes of sham treatment. Acute insulin-induced hypoglycemia increased adrenal sympathetic nerve traffic compared with insulin administration with clamped euglycemia (165 ؎ 12 vs. 118 ؎ 21 spikes/s [P < 0.05]; or to 138 ؎ 8 vs. 114 ؎ 10% of baseline [P < 0.05]). In additional experiments, 2 days of antecedent hypoglycemia (days -2 and -1) compared with sham treatment significantly enhanced baseline adrenal SNA measured immediately before subsequent acute hypoglycemia on day 0 (180 ؎ 11 vs. 130 ؎ 12 spikes/s, respectively; P < 0.005) and during subsequent acute hypoglycemia (229 ؎ 17 vs. 171 ؎ 16 spikes/s; P < 0.05). However, antecedent hypoglycemia resulted in a nonsignificant reduction in hypoglycemic responsiveness of adrenal SNA when expressed as percent increase over baseline (127 ؎ 5% vs. 140 ؎ 14% of baseline). Antecedent hypoglycemia, compared with sham treatment, resulted in diminished epinephrine responsiveness to subsequent hypoglycemia. Norepinephrine responses to hypoglycemia were not significantly altered by antecedent hypoglycemia. In summary, prior hypoglycemia in normal rats increased adrenal sympathetic tone, but impaired epinephrine responsiveness to acute hypoglycemia. Hence, these data raise the intriguing possibility that increased sympathetic tone resulting from antecedent hypoglycemia downregulates subsequent epinephrine responsiveness to hypoglycemia. Alternatively, it is possible that the decrease in epinephrine responsiveness after antecedent hypoglycemia could be the result of reduced adrenal sympathetic nerve responsiveness. Diabetes 50:1119 -1125, 2001 I mpaired hypoglycemic counterregulation and hypoglycemia unawareness are well-recognized complications of long-standing diabetes (1,2). Hypoglycemia unawareness has also been observed as a reversible consequence of transient prior hypoglycemic events (3-5) and has been observed even in individuals without diabetes (6). However, the pathophysiology of hypoglycemic counterregulation and hypoglycemia unawareness is still unclear. Although much has been learned of catecholamine and other hormonal responses to hypoglycemia, the role of sympathetic neural activity per se to adrenal and other tissues has received only limited study.Peripheral sympathetic nerve activity (SNA) originating in hypothalamic centers may be important in the counterregulatory response to hypoglycemia. Hoffman et al. (7) found that skeletal muscle SNA in type 1 diabetic and nondia...

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Section: Discussionmentioning

confidence: 85%

Effect of Acute and Antecedent Hypoglycemia on Sympathetic Neural Activity and Catecholamine Responsiveness in Normal Rats

Sivitz

Herlein

Morgan³

et al. 2001

Diabetes

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“…Alternatively, a low ACE activity could enhance substrate mobilisation by interference with hormonal counterregulation, e.g. the response of [28,33] or sensitivity to [34,35] catecholamines that constitute the primary hormonal defence against hypoglycaemia in Type 1 diabetes when the glucagon response is lost.…”

Section: Discussionmentioning

confidence: 99%

Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

et al. 2003

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Aims/hypothesis. We have previously shown a strong relationship between high angiotensin-converting enzyme (ACE) activity, presence of the deletion (D) allele of the ACE gene and recall of severe hypoglycaemic events in patients with Type 1 diabetes. This study was carried out to assess this relationship prospectively. Methods. We followed 171 adult outpatients with Type 1 diabetes in a one-year observational study with the recording of severe hypoglycaemia. Participants were characterised by serum ACE activity and ACE genotype and not treated with ACE inhibitors or angiotensin II receptor antagonists.Results. There was a positive relationship between serum ACE activity and rate of severe hypoglycaemia with a 2.7 times higher rate in the fourth quartile of ACE activity compared to the first quartile (p=0.0007). A similar relationship was observed for the subset of episodes with coma (2.9 times higher rate in fourth quartile compared to first quartile; p=0.048). The impact of serum ACE activity was most pronounced in C-peptide negative subjects (4.2 times higher rate in fourth quartile compared to first quartile; p=0.003), and in this subgroup carriers of the D allele of the ACE gene had higher rates of severe hypoglycaemia compared to the group homozygous for the insertion (I) allele. In a multiple regression analysis high serum ACE activity and impaired awareness of hypoglycaemia were identified as the only significant predictors of severe hypoglycemia. To avoid progression of these frequent episodes into severe hypoglycaemia patients rely on maintenance of performance capacity [3] until hypoglycaemic symptoms are recognised and self-treated or until the next pre-scheduled meal is ingested.Risk of severe hypoglycaemia is a major limiting factor for the achievement of good metabolic control [4] rendering prediction of individual risk of severe hypoglycaemia increasingly important. Loss of hypoglycaemic warning symptoms and blunted hormonal counterregulatory response are the most important known predictors of severe hypoglycaemia [4,5]. However, even patients at high risk according to these paFollowing the Diabetes Control and Complications Trial [1] a growing demand for strict glycaemic control has emerged to avoid late diabetic complications in Type 1 diabetes. As a consequence the majority of patients with Type 1 diabetes experience mild hypoglycaemia on a regular basis and recent studies applying continuous glucose monitoring indicate that pa-

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“…On the other hand, there is some evidence that reduced ␤-adrenergic sensitivity might contribute to the pathogenesis of hypoglycemia unawareness (23)(24)(25)(26). That evidence includes reduced cardiac chronotropic sensitivity to the nonselective ␤-adrenergic agonist isoproterenol in patients with type 1 diabetes and hypoglycemia unawareness (23,24) and reversal of both reduced ␤-adrenergic sensitivity and unawareness following a period of scrupulous avoidance of iatrogenic hypoglycemia (25). Fritsche et al (26) assessed the impact of recent antecedent hypoglycemia on cardiac chronotropic sensitivity to isoproterenol.…”

Section: Haaf In Diabetesmentioning

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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Reduced beta-adrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness.

Abstract: We conclude that subjects with type 1 diabetes and hypoglycemia unawareness have reduced beta-adrenergic sensitivity, which may contribute to their impaired adrenergic warning symptoms during hypoglycemia.

Cited by 59 publications

References 0 publications

Effect of Acute and Antecedent Hypoglycemia on Sympathetic Neural Activity and Catecholamine Responsiveness in Normal Rats

Effect of Acute and Antecedent Hypoglycemia on Sympathetic Neural Activity and Catecholamine Responsiveness in Normal Rats

Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

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

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