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Long-term activation of PKA in -cells provides sustained improvement to glucose control, insulin sensitivity and body weight

机译：PKA中的长期活化 - 细胞可持续改进葡萄糖对照，胰岛素敏感性和体重

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Type 2 diabetes is associated with obesity, insulin resistance and -cell failure. Therapeutic aims are to reduce adiposity, improve insulin sensitivity and enhance -cell function. However, it has been proposed that chronically increasing insulin release leads to -cell exhaustion and failure. We previously developed mice to have increased activity of the cAMP-dependent protein kinase (PKA), specifically in -cells (-caPKA mice). -caPKA mice have enhanced acute phase insulin release, which is the primary determinant of the efficacy of glucose clearance. Here these mice were used to determine the sustainability of enhanced insulin secretion, and to characterize peripheral effects of enhanced -cell function. Increased PKA activity was induced by tamoxifen administration at 10weeks of age. Male mice were aged to 12months of age and female mice to 16months. Glucose control in both male and female -caPKA mice was significantly improved relative to littermate controls with ad libitum feeding, upon refeeding after fasting, and in glucose tolerance tests. In female mice insulin release was both greater and more rapid than in controls. Female mice were more insulin sensitive than controls. Male and female -caPKA mice had lower body weights than controls. DEXA analysis of male mice revealed that this was due to reduced adiposity and not due to changes in lean body mass. This study indicates that targeting -cells to enhance insulin release is sustainable, maintains insulin sensitivity and reduces body weight. These data identify -cell PKA activity as a novel target for obesity therapies.
机译：2型糖尿病与肥胖，胰岛素抵抗和核损失有关。治疗目标是降低肥胖，改善胰岛素敏感性和增强 - 细胞功能。然而，已经提出了长期增加的胰岛素释放导致 - 细胞耗尽和失效。我们以前发育了小鼠，以增加营养依赖性蛋白激酶（PKA）的活性，特别是在-Cells（-capka小鼠）中。 -capka小鼠具有增强的急性相胰岛素释放，这是葡萄糖间隙效果的主要决定因素。在这里，这些小鼠用于确定增强胰岛素分泌的可持续性，并表征增强型电池功能的外周效应。通过Tamoxifen给药在10周的年龄诱导PKA活性增加。雄性小鼠年龄在12个月和女性小鼠中为16个月。在禁食后改善后，相对于具有AD Libitum饲养的凋落物对凋落物对照，血糖对照，在禁食后和葡萄糖耐量试验中，显着改善了血糖对照。在雌性小鼠胰岛素中，胰岛素释放均比对照均更快速。雌性小鼠比对照更敏感胰岛素。男性和女性-capka小鼠的体重低于对照。雄性小鼠的Dexa分析显示，这是由于脂肪性降低而不是由于瘦体重的变化。本研究表明，靶向 - 诱导胰岛素释放是可持续的，保持胰岛素敏感性并降低体重。这些数据识别-Cell PKA活性作为肥胖疗法的新靶。

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