α2-Adrenoceptor Regulation of Blood Glucose Homeostasis

Fagerholm, Veronica; Haaparanta, Merja; Scheinin, Mika

doi:10.1111/j.1742-7843.2011.00699.x

Cited by 115 publications

(90 citation statements)

References 43 publications

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“…Our study population may have differed from those in studies primarily concerning diabetes treatment and this could explain our finding of a lack of increased risk associated with very low HbA 1c levels. The SCOUT patients with obesity and cardiovascular disease might have been at lower risk of hypoglycaemia than other individuals with type 2 diabetes because of, for example, their higher adrenergic tone [27]. It is also possible that the lower glucose levels seen in our study cohort were more likely to have been achieved by improved diet, increased exercise and/or weight loss rather than by increasing use of glucose-lowering medications.…”

Section: Discussionmentioning

confidence: 55%

Relationship between HbA1c levels and risk of cardiovascular adverse outcomes and all-cause mortality in overweight and obese cardiovascular high-risk women and men with type 2 diabetes

et al. 2012

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Aims/hypothesis The optimal HbA 1c concentration for prevention of macrovascular complications and deaths in obese cardiovascular high-risk patients with type 2 diabetes remains to be established and was therefore studied in this post hoc analysis of the Sibutramine Cardiovascular OUTcomes (SCOUT) trial, which enrolled overweight and obese patients with type 2 diabetes and/or cardiovascular disease. Methods HRs for meeting the primary endpoint (nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death) and all-cause mortality were analysed using Cox regression models. Results Of 8,252 patients with type 2 diabetes included in SCOUT, 7,479 had measurements of HbA 1c available at baseline (i.e. study randomisation). Median age was 62 years (range 51-86 years), median BMI was 34.0 kg/m 2 (24.8-65.1 kg/m 2 ) and 44% were women. The median HbA 1c concentration was 7.2% (3.8-15.9%) (55 mmol/l [18-150 mmol/l]) and median diabetes duration was 7 years (0-57 years). For each 1 percentage point HbA 1c increase, the adjusted HR for the primary endpoint was 1.17 (95% CI 1.11, 1.23); no differential sex effect was observed (p00.12 for interaction). In contrast, the risk of all-cause mortality was found to be greater in women than in men: HR 1.22 (1.10, 1.34) vs 1.12 (1.04, 1.20) for each 1 percentage point HbA 1c increase (p 00.02 for interaction). There was no evidence of increased risk associated with HbA 1c ≤6.4% (≤46 mmol/l). Glucose-lowering treatment regimens, diabetes duration or a history of cardiovascular disease did not modify the associations. Diabetologia (2012) 55:2348-2355 DOI 10.1007/s00125-012-2584 Conclusions/interpretation In overweight, cardiovascular high-risk patients with type 2 diabetes, increasing HbA 1c concentrations were associated with increasing risks of cardiovascular adverse outcomes and all-cause mortality.

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Section: Discussionmentioning

confidence: 55%

Relationship between HbA1c levels and risk of cardiovascular adverse outcomes and all-cause mortality in overweight and obese cardiovascular high-risk women and men with type 2 diabetes

et al. 2012

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“…The a 2 -adrenergic receptors are known to play important role in the regulation of the blood glucose homeostasis (Fagerholm et al 2011). a 2 -Adrenergic receptors are present in the central and peripheral nervous system (Bundzikova et al 2009).…”

Section: Introductionmentioning

confidence: 99%

“…The main regulator of the HPA axis is a corticotrophinreleasing hormone (CRH), finally causing a glucocorticoid secretion by the adrenal cortex (Kalantaridou et al 2010). Glucocorticoid usually increases the gluconeogenesis activity, leading to an increase of the blood glucose level (Fagerholm et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Involvement of α2-adrenergic receptor in the regulation of the blood glucose level induced by immobilization stress

et al. 2014

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The blood glucose profiles were characterized after mice were forced into immobilization stress with various exposure durations. The blood glucose level was significantly enhanced by immobilization stress for 30 min or 1 h, respectively. On the other hand, the blood glucose level was not affected in the groups which were forced into immobilization stress for 2 or 4 h. We further examined the effect of yohimbine (an α2-adrenergic receptor antagonist) administered systemically or centrally in the immobilization stress model. Mice were pretreated intraperitoneally (i.p.; from 0.5 to 5 mg/kg), intracerebroventricularly (i.c.v.; from 1 to 10 µg/5 µl), or intrathecally (i.t.; from 1 to 10 µg/5 µl) with yohimbine for 10 min and then, forced into immobilization stress for 30 min. The blood glucose level was measured right after immobilization stress. We found that up-regulation of the blood glucose level induced by immobilization stress was abolished by i.p. pretreatment with yohimbine. And the immobilization stress-induced blood glucose level was not inhibited by i.c.v. or i.t. pretreatment with yohimbine at a lower dose (1 µg/5 µl). However, immobilization stress-induced blood glucose level was significantly inhibited by i.c.v. or i.t. pretreatment with yohimbine at higher doses (5 and 10 µg/5 µl). In addition, the i.p. (5 mg/kg), i.c.v. (10 µg/5 µl), or i.t. (10 µg/5 µl) pretreatment with yohimbine reduced hypothalamic glucose transporter 4 expression. The involvement of α2-adrenergic receptor in regulation of immobilization stress- induced blood glucose level was further confirmed by the i.p, i.c.v, or i.t pretreatment with idazoxan, another specific α2-adrenergic receptor antagonist. Finally, i.p., i.c.v., or i.t. pretreatment with yohimbine attenuated the blood glucose level in D-glucose-fed model. We suggest that α2-adrenergic receptors located at the peripheral, the brain and the spinal cord play important roles in the up-regulation of the blood glucose level in immobilization stress.

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“…Together with results from animal studies [4,5], this evidence for a contribution of α 2A -adrenoceptors on beta cells to the development and pathophysiology of type 2 diabetes led to speculation that α 2Α -antagonists could be useful as a treatment tailored to a genetically defined patient subgroup [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of antihyperglycaemic action of efaroxan in mice: time for reappraisal of α2A-adrenergic antagonism in the treatment of type 2 diabetes?

Lehner

Stadlbauer

Adorjan³

et al. 2012

Diabetologia

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Aims/hypothesis Inspired by recent speculation about the potential utility of α 2A -antagonism in the treatment of type 2 diabetes, the study examined the contribution of α 2 -antagonism vs other mechanisms to the antihyperglycaemic activity of the imidazoline (±)-efaroxan. Methods Effects of the racemate and its pure enantiomers on isolated pancreatic islets and beta cells in vitro, as well as on hyperglycaemia in vivo, were investigated in a comparative manner in mice. Results In isolated perifused islets, the two enantiomers of efaroxan were equally potent in counteracting inhibition of insulin release by the ATP-dependent K + (K ATP ) channelopener diazoxide but (+)-efaroxan, the presumptive carrier of α 2 -antagonistic activity, was by far superior in counteracting inhibition of insulin release by the α 2 -agonist UK14,304. In vivo, (+)-efaroxan improved oral glucose tolerance at 100-fold lower doses than (−)-efaroxan and, in parallel with observations made in vitro, was more effective in counteracting UK14,304-induced than diazoxide-induced hyperglycaemia. The antihyperglycaemic activity of much higher doses of (−)-efaroxan was associated with an opposing pattern (i.e. with stronger counteraction of diazoxide-induced than UK14,304-induced hyperglycaemia), which implicates a different mechanism of action. Conclusions/interpretation The antihyperglycaemic potency of (±)-efaroxan in mice is almost entirely due to α 2 -antagonism, but high doses can also lower blood glucose via another mechanism. Our findings call for reappraisal of the possible clinical utility of α 2A -antagonistic compounds in recently identified subpopulations of patients in which a congenitally higher level of α 2A -adrenergic activation contributes to the development and pathophysiology of type 2 diabetes.

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α2-Adrenoceptor Regulation of Blood Glucose Homeostasis

Cited by 115 publications

References 43 publications

Relationship between HbA1c levels and risk of cardiovascular adverse outcomes and all-cause mortality in overweight and obese cardiovascular high-risk women and men with type 2 diabetes

Relationship between HbA1c levels and risk of cardiovascular adverse outcomes and all-cause mortality in overweight and obese cardiovascular high-risk women and men with type 2 diabetes

Involvement of α2-adrenergic receptor in the regulation of the blood glucose level induced by immobilization stress

Mechanisms of antihyperglycaemic action of efaroxan in mice: time for reappraisal of α2A-adrenergic antagonism in the treatment of type 2 diabetes?

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