Desensitization of the inhibitory effect of norepinephrine on insulin secretion from pancreatic islets of exercise-trained rats

Urano, Yuriko; Ueda, Hiroshi; Ogasawara, Jun; Sakurai, Takeshi; Takei, Megumi; Izawa, Tetsuya

doi:10.1016/j.metabol.2004.06.008

Cited by 16 publications

(13 citation statements)

References 46 publications

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“…Chronic exposure of high catecholamine concentrations has been shown to persistently reduce both mRNA and protein expression of ARs (5,12,14) and related G proteins (52), which is also supported in the current study (Fig. 4).…”

Section: Discussionsupporting

confidence: 89%

“…Differences were determined between treatment groups for pre-and posttreatment GSIS studies. AR, ␣ 2C -AR, and G␣ i-2 mRNA concentrations were lower in pancreatic islets from NE-infused fetuses compared with controls, indicating AR desensitization in fetal islets (45,52). No differences were noted for measured ␤-cell regulatory factors; however, the reduction of UCP2 mRNA indicates improved insulin stimulus-secretion coupling in islets from NE fetuses.…”

Section: Discussionmentioning

confidence: 86%

“…Thus, this lower expression of ␣ 2A -AR and ␣ 2C -AR might lead to decreased adrenergic inhibition of insulin secretion (51,55). The decreased expression of G␣ i-2 is also postulated to lower NE inhibitory effects on insulin secretion (52). Therefore, desensitization of both ␣ 2 -ARs and G␣ i-2 contributes to a higher insulin concentration as well as higher insulin responsiveness after the 7-day NE infusion is removed, whereas plasma NE concentrations remain greater than controls.…”

Section: Discussionmentioning

confidence: 98%

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Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep

Chen

Green

Macko

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Chen X, Green AS, Macko AR, Yates DT, Kelly AC, Limesand SW. Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep. Am J Physiol Endocrinol Metab 306: E58 -E64, 2014. First published November 19, 2013 doi:10.1152/ajpendo.00517.2013.-Intrauterine growth-restricted (IUGR) fetuses experience prolonged hypoxemia, hypoglycemia, and elevated norepinephrine (NE) concentrations, resulting in hypoinsulinemia and ␤-cell dysfunction. Previously, we showed that acute adrenergic blockade revealed enhanced insulin secretion responsiveness in the IUGR fetus. To determine whether chronic exposure to NE alone enhances ␤-cell responsiveness afterward, we continuously infused NE into fetal sheep for 7 days and, after terminating the infusion, evaluated glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-induced insulin secretion (GPAIS). During treatment, NE-infused fetuses had greater (P Ͻ 0.05) plasma NE concentrations and exhibited hyperglycemia (P Ͻ 0.01) and hypoinsulinemia (P Ͻ 0.01) compared with controls. GSIS during the NE infusion was also reduced (P Ͻ 0.05) compared with pretreatment values. GSIS and GPAIS were approximately fourfold greater (P Ͻ 0.01) in NE fetuses 3 h after the 7 days that NE infusion was discontinued compared with age-matched controls or pretreatment GSIS and GPAIS values of NE fetuses. In isolated pancreatic islets from NE fetuses, mRNA concentrations of adrenergic receptor isoforms (␣1D, ␣2A, ␣2C, and ␤1), G protein subunit-␣i-2, and uncoupling protein 2 were lower (P Ͻ 0.05) compared with controls, but ␤-cell regulatory genes were not different. Our findings indicate that chronic exposure to elevated NE persistently suppresses insulin secretion. After removal, NE fetuses demonstrated a compensatory enhancement in insulin secretion that was associated with adrenergic desensitization and greater stimulus-secretion coupling in pancreatic islets. adrenergic receptor; ␤-cell; intrauterine growth restriction; uncoupling protein 2; catecholamines SMALL-FOR-GESTATIONAL AGE or intrauterine growth-restricted (IUGR) infants are at greater risk for developing metabolic diseases such as type 2 diabetes mellitus (29,40,54). Impaired insulin secretion is associated with a diabetic phenotype indicating that in utero complications can permanently compromise ␤-cell development and function (27,28). A fetal sheep model with placental insufficiency-induced intruterine growth restriction shares many similarities with human IUGR fetuses, such as asymmetric growth, hypoxemia, hypoglycemia, hypoinsulinemia, and hypercatecholaminemia [epinephrine and norepinephrine (NE)] (4, 16,18,22,23,32,41,47). Furthermore, glucose-stimulated insulin secretion (GSIS) and ␤-cell mass are lower in IUGR sheep fetuses, which also replicate features in human IUGR fetuses (34 -36, 41, 53). Several characteristics of the fetal IUGR environment, including hypoglycemia, hypoxemia, and hypercatecholaminemia, are proposed to ...

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep

Chen

Green

Macko

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…4G), suggesting that ghrelin activation of Kv channels is mediated by cAMP signaling pathway. It is also known that members of the G␣ i -family are involved in transducing the information of inhibitory hormones and neurotransmitters to cyclic AMP productions (42)(43)(44), voltage-dependent Ca 2ϩ channels (45,46), and insulin exocytosis (29). Whether the ghrelin action could also involve these processes is unknown and definitely requires further studies.…”

Section: Discussionmentioning

confidence: 99%

Ghrelin Uses Gαi2 and Activates Voltage-Dependent K+ Channels to Attenuate Glucose-Induced Ca2+ Signaling and Insulin Release in Islet β-Cells

2007

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Ghrelin reportedly serves as a physiological regulator of insulin release. This study aimed to explore signaling mechanisms for insulinostatic ghrelin action in islet ␤-cells, with special attention to heterotrimeric GTP-binding proteins and K ؉ channels. Plasma insulin and growth hormone (GH) concentrations in rats were measured by enzyme-linked immunosorbent assay (ELISA). Islets were isolated from rats, ghrelin-knockout (Ghr-KO) mice, and wild-type mice by collagenase digestion, and insulin release was determined by ELISA. In rat single ␤-cells, cytosolic Ca 2؉ concentration ([Ca 2؉ ] i ) was measured by fura-2 microfluorometry, and membrane potentials and whole cell currents by patch-clamp technique. In rats, systemic ghrelin administration decreased plasma insulin concentrations, and this effect was blocked by treatment with pertussis toxin (PTX), whereas stimulation of GH release remained unaffected. In rat islets, ghrelin receptor antagonist increased and exogenous ghrelin suppressed glucoseinduced insulin release in a PTX-sensitive manner. Glucose-induced insulin release from islets was greater in Ghr-KO than wild-type mice, and this enhanced secretion was blunted with PTX. Ghrelin PTX sensitively increased voltage-dependent K ؉ (Kv) currents without affecting ATP-sensitive K ؉ channels in rat ␤-cells.

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“…EC 50 is the concentration of the competitor that competes for half the specific binding a-adrenergic receptors are known to have a critical role in regulating neurotransmitter release from the sympathetic nerves and from the adrenergic neurons in the central nervous system [43]. The increased sympathetic activity and the released NE inhibit glucose-stimulated insulin secretion and cyclic adenosine monophosphate (cAMP) contents in rat islets [44][45][46]. When we analysed the a 1 -adrenergic receptor status using [ 3 H]prazosin with phentolamine in the cerebral cortex, we found that a 1 -adrenergic receptor number decreased significantly in 72 h after pancreatectomy as indicated by decreased B max .…”

Section: Discussionmentioning

confidence: 99%

Decreased α1-Adrenergic Receptor Binding in the Cerebral Cortex and Brain Stem during Pancreatic Regeneration in Rats

2006

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The purpose of this study was to investigate the role of brain alpha1-adrenergic receptor binding in the rat model of pancreatic regeneration using 60-70% pancreatectomy. The alpha1-adrenergic receptors kinetics was studied in the cerebral cortex and brain stem of sham operated, 72 h pancreatectomised and 7 days pancreatectomised rats. Scatchard analysis with [3H]prazosin in cerebral cortex and brain stem showed a significant decrease (P < 0.01), (P < 0.05) in maximal binding (Bmax) with a significant decrease (P < 0.001), (P < 0.01) in the Kd in 72 h pancreatectomised rats compared with sham respectively. Competition analysis in cerebral cortex and brain stem showed a shift in affinity during pancreatic regeneration. The sympathetic activity was decreased as indicated by the significantly decreased norepinephrine level in the plasma (P < 0.001), cerebral cortex (P < 0.01) and brain stem (P < 0.001) of 72 h pancreatectomised rats compared to sham. Thus, from our results it is suggested that the central alpha1-adrenergic receptors have a functional role in the pancreatic regeneration mediated through the sympathetic pathway.

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Desensitization of the inhibitory effect of norepinephrine on insulin secretion from pancreatic islets of exercise-trained rats

Cited by 16 publications

References 46 publications

Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep

Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep

Ghrelin Uses Gαi2 and Activates Voltage-Dependent K+ Channels to Attenuate Glucose-Induced Ca2+ Signaling and Insulin Release in Islet β-Cells

Decreased α1-Adrenergic Receptor Binding in the Cerebral Cortex and Brain Stem during Pancreatic Regeneration in Rats

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