Pancreatic Islets Exhibit Dysregulated Adaptation of Insulin Secretion after Chronic Epinephrine Exposure.

Rui Li,Sean W Limesand,Huichai Huang,Xiaochuan Chen

doi:10.3390/cimb43010020

Rui Li, Sean W Limesand + Show 2 more

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https://doi.org/10.3390/cimb43010020

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Abstract

Chronic adrenergic stimulation is the dominant factor in impairment of the β-cell function. Sustained adrenergic exposure generates dysregulated insulin secretion in fetal sheep. Similar results have been shown in Min6 under the elevated epinephrine condition, but impairments after adrenergic removal are still unknown and a high rate of proliferation in Min6 has been ignored. Therefore, we incubated primary rats’ islets with half maximal inhibitory concentrations of epinephrine for three days, then determined their insulin secretion responsiveness and related signals two days after removal of adrenaline via radioimmunoassay and qPCR. Insulin secretion was not different between the exposure group (1.07 ± 0.04 ng/islet/h) and control (1.23 ± 0.17 ng/islet/h), but total islet insulin content after treatment (5.46 ± 0.87 ng/islet/h) was higher than control (3.17 ± 0.22 ng/islet/h, p < 0.05), and the fractional insulin release was 36% (p < 0.05) lower after the treatment. Meanwhile, the mRNA expression of Gαs, Gαz and Gβ1-2 decreased by 42.8% 19.4% and 24.8%, respectively (p < 0.05). Uncoupling protein 2 (Ucp2), sulphonylurea receptor 1 (Sur1) and superoxide dismutase 2 (Sod2) were significantly reduced (38.5%, 23.8% and 53.8%, p < 0.05). Chronic adrenergic exposure could impair insulin responsiveness in primary pancreatic islets. Decreased G proteins and Sur1 expression affect the regulation of insulin secretion. In conclusion, the sustained under-expression of Ucp2 and Sod2 may further change the function of β-cell, which helps to understand the long-term adrenergic adaptation of pancreatic β-cell.

Highlights

Placental insufficiency induced intrauterine growth restriction (IUGR) is commonly associated with long-term increased catecholamines as well as impaired insulin secretion in the fetus [1]
Even though the β-cell adaptations could develop in fetuses with elevated norepinephrine concentrations, whether these impairments of β-cell function are directly caused by sustained exposure to chronic adrenergic stimulation is unknown
Total islet insulin content after chronic epinephrine treatment (5.46 ± 0.87 ng/islet/h) was 1.7-fold more than control (3.17 ± 0.22 ng/islet/h, p < 0.05, Figure 3b) and insulin release as a fraction of islet insulin content was lower in the epinephrine group (0.23 ± 0.024, p < 0.05) than in control (0.36 ± 0.043, Figure 3c)

Summary

Introduction

Placental insufficiency induced intrauterine growth restriction (IUGR) is commonly associated with long-term increased catecholamines as well as impaired insulin secretion in the fetus [1]. It has been shown that chronically elevated plasma norepinephrine concentrations during the final trimester continually inhibits insulin secretion in IUGR sheep fetuses [2,3]. Various G proteins are closely associated with adrenergic receptors to mediate insulin secretion in β-cell. Insulin granules’ exocytosis is mediated by a core machinery of membrane-associated soluble Nethylmaleimide-sensitive factor attachment protein receptors (SNAREs), in which this heterotrimeric complex is composed by syntaxin, Snap and Vamp proteins. Another adrenergic inhibition of insulin release is associated with Gβγ (derived from Gi and/or Go) and Gαz, resulting in prevention of the exocytosis of SNAREs [7]. In β-cell, oxidative damages are known to markedly impair glucose-stimulated insulin secretion [11]

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