Alpha-adrenergic system in the modulation of pancreatic A and B cell function in normal rats

Filipponi, P; Gregorio, F. Di; Ferrandina, Celestino; Nicoletti, Ildo; Mannarelli, C.; Pippi, Roberto; Santeusanio, Fausto

doi:10.1016/s0168-8227(86)80069-9

Cited by 13 publications

(8 citation statements)

References 35 publications

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“…Stimulatory and inhibitory neurotransmitters and hormones modify the responses of pancreatic β‐cells to metabolized nutrients. Noradrenaline, released by sympathetic efferent nerves innervating the pancreatic islets, and adrenaline, secreted into the blood by the chromaffin cells of the adrenal medulla, inhibit insulin secretion by activating α 2 ‐adrenoceptors on pancreatic β‐cells ( Metz et al ., 1978 ; Nakaki et al ., 1980 ; Filipponi et al ., 1986 ; Angel and Langer, 1988 ). Increased insulin secretion and improved glucose tolerance following α 2 ‐adrenoceptor antagonist administration in healthy animal and human subjects and in subjects with type II diabetes have been demonstrated in most ( Linde and Deckert, 1973 ; Robertson and Porte, 1973 ; Ahrén et al ., 1984 ; Hsu et al ., 1987 ; Kawazu et al ., 1987 ; Langer, 1987 ; Ortiz‐Alonso et al ., 1991 ; Berridge et al ., 1992 ; Berlin et al ., 1994 ; Angel et al ., 1996 ; Abdel‐Zaher et al ., 2001 ), but not all studies ( Östenson et al ., 1988 ; John et al ., 1990 ; Karhuvaara et al ., 1990 ; Hiyoshi et al ., 1995 ; Natali et al ., 1998 ).…”

Section: Introductionmentioning

confidence: 99%

α_2A‐Adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice

Fagerholm

Scheinin

Haaparanta

2008

British J Pharmacology

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Background and purpose: The imidazoline-type a 2 -adrenoceptor antagonists (±)-efaroxan and phentolamine increase insulin secretion and reduce blood glucose levels. It is not known whether they act by antagonizing pancreatic b-cell a 2 -adrenoceptors or by a 2 -adrenoceptor-independent mechanisms. Many imidazolines inhibit the pancreatic b-cell K ATP channel, which is the molecular target of sulphonylurea drugs used in the treatment of type II diabetes. To investigate the mechanisms of action of (±)-efaroxan and phentolamine, a 2A -adrenoceptor knockout (a 2A -KO) mice were used. Experimental approach: Effects of ( ± )-efaroxan, 5 mg kg À1 , and phentolamine, 1 mg kg À1 , on blood glucose and insulin levels were compared with those of the non-imidazoline a 2 -adrenoceptor antagonist [8aR,12aS,13aS]-5,8,8a,9,10,11, 12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphonyl) , 1 mg kg À1 , and the sulphonylurea glibenclamide, in a 2A -KO and control (wild type (WT)) mice. Key results: In fed WT mice, ( ± )-efaroxan, phentolamine and RS79948-197 reduced blood glucose and increased insulin levels. Fasting abolished these effects. In fed a 2A -KO mice, (±)-efaroxan, phentolamine and RS79948-197 did not alter blood glucose or insulin levels, and in fasted a 2A -KO mice, blood glucose levels were increased. Glibenclamide, at a dose only moderately efficacious in WT mice (5 mg kg À1 ), caused severe hyperinsulinaemia and hypoglycaemia in a 2A -KO mice. This was mimicked in WT mice by co-administration of RS79948-197 with glibenclamide. Conclusions and implications: These results suggest that (±)-efaroxan and phentolamine increase insulin secretion by inhibition of b-cell a 2A -adrenoceptors, and demonstrate a critical role for a 2A -adrenoceptors in limiting sulphonylurea-induced hyperinsulinaemia and hypoglycaemia.

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Section: Introductionmentioning

confidence: 99%

α_2A‐Adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice

Fagerholm

Scheinin

Haaparanta

2008

British J Pharmacology

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“…Also, studies had shown that in diabetic condition a 2A receptors are more activated which brought out the insulin inhibition and in turn hyperglycemia (5). Rat islet cell membrane is equipped with a 2A -adrenoceptors (6) which are linked to adenylate cyclase inhibits insulin secretion. b 3 adrenoceptors stimulation also results in enhanced insulin secretion (7).…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic regulation of glucose‐induced insulin secretion through dopamine D2 receptors in the pancreatic islets in vitro

2006

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The stimulatory effect of dopamine through dopamine D2 receptor on glucose-induced insulin secretion was studied in the pancreatic islets in vitro. Dopamine significantly stimulated insulin secretion at a concentration of 10-8 M in the presence of high glucose (20 mM). The higher concentrations of dopamine (10(-7)-10(-4)) inhibited glucose-induced insulin secretion in the presence of both 4 mM and 20 mM glucose. Stimulatory and inhibitory effect of dopamine on glucose-induced insulin secretion was reverted by the addition of dopamine D2 receptor antagonists such as butaclamol and sulpiride. Norepinephrine (NE) at 10(-4) M concentration inhibited the dopamine uptake as well as its stimulatory effect at 10(-8) M concentration on glucose induced insulin secretion. Our results suggest that dopamine exerts a differential effect on glucose-induced insulin secretion through dopamine D2 receptor and it is essential for the regulation of glucose-induced insulin secretion by pancreatic islets.

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“…Regulation of these paracrine effects through cell specific ARs remains unknown. Several studies on glucagon secretion demonstrated activation by b-AR agonists (27,28). However, it has also been suggested that a 2 -AR activation stimulates or inhibits stimulated glucagon secretion (29 -32).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of insulin secretion via distinct signaling pathways in alpha2-adrenoceptor knockout mice

Peterhoff

Sieg²,

Brede³

et al. 2003

European Journal of Endocrinology

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Objective: Adrenaline inhibits insulin secretion through activation of a 2 -adrenoceptors (ARs). These receptors are linked to pertussis toxin-sensitive G proteins. Agonist binding leads to inhibition of adenylyl cyclase, inhibition of Ca 2þ channels and activation of K þ channels. Recently, three distinct subtypes of a 2 -AR were described, a 2A -AR, a 2B -AR and a 2C -AR. At present, it is unknown which of these a 2 -AR subtype(s) may regulate insulin secretion. We used mice deficient in a 2 -ARs to analyze the coupling and role of individual a 2 -AR subtypes in insulin-secreting b cells. Methods: The inhibitory effect of adrenaline on insulin secretion was measured in freshly isolated and cultured wild type (wt) and a 2 -AR knockout (KO) mouse islets in order to examine the receptor subtypes which mediate adrenaline-induced inhibition of insulin secretion. Adenylyl cyclase activity was measured in isolated cultured islets. Membrane potential was measured using the amphotericin B permeabilized patch clamp method in isolated and cultured single islet cells. Results: In wt, a 2A -and a 2C -AR KO mouse islets, adrenaline, 1 mmol/l, inhibited secretion by 83, 80 and 100% respectively. In contrast, in a 2A/2C -AR double KO mouse islets, adrenaline had no effect on stimulated secretion indicating that both a 2A -AR and a 2C -AR, but not a 2B -AR, are functionally expressed in mouse islets. Surprisingly, glucose (16.7 mmol/l)-induced secretion in the presence of 1 mmol/l forskolin was greatly impaired in a 2A -AR KO islets. However, when cAMP levels were increased further by the combination of forskolin (5 mmol/l) and 3-isobutyl-1-methylxanthine (100 mmol/l), secretion was stimulated 2.7-fold (8.5-fold in wt islets). Adrenaline lowered the concentration of cAMP in wt and a 2C -AR KO mouse islets by 74%. Adrenaline also hyperpolarized wt and a 2C -AR KO b cells. In contrast, adrenaline did not inhibit adenylyl cyclase in islets of a 2A -AR KO mice, nor did it hyperpolarize a 2A -AR KO b cells. Conclusion: Adrenaline inhibits insulin release through a 2A -and a 2C -ARs via distinct intracellular signaling pathways.

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Alpha-adrenergic system in the modulation of pancreatic A and B cell function in normal rats

Cited by 13 publications

References 35 publications

α_2A‐Adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice

α_2A‐Adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice

Dopaminergic regulation of glucose‐induced insulin secretion through dopamine D2 receptors in the pancreatic islets in vitro

Inhibition of insulin secretion via distinct signaling pathways in alpha2-adrenoceptor knockout mice

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Alpha-adrenergic system in the modulation of pancreatic A and B cell function in normal rats

Cited by 13 publications

References 35 publications

α2A‐Adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice

α2A‐Adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice

Dopaminergic regulation of glucose‐induced insulin secretion through dopamine D2 receptors in the pancreatic islets in vitro

Inhibition of insulin secretion via distinct signaling pathways in alpha2-adrenoceptor knockout mice

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α_2A‐Adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice

α_2A‐Adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice