Kaihara Kelly A, Dickson Lorna M, Ellenbroek Johanne H, Orr Caitlin M D, Layden Brian T, Wicksteed Barton
Kovler Diabetes Center, The University of Chicago, Chicago, IL Committee for Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL.
Kovler Diabetes Center, The University of Chicago, Chicago, IL Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL.
Diabetes. 2015 May;64(5):1688-97. doi: 10.2337/db14-1051. Epub 2014 Dec 4.
Diabetes arises from insufficient insulin secretion and failure of the β-cell mass to persist and expand. These deficits can be treated with ligands to Gs-coupled G-protein-coupled receptors that raise β-cell cAMP. Here we studied the therapeutic potential of β-cell cAMP-dependent protein kinase (PKA) activity in restoring glucose control using β-caPKA mice. PKA activity enhanced the acute insulin response (AIR) to glucose, which is a primary determinant of the efficacy of glucose clearance. Enhanced AIR improved peripheral insulin action, leading to more rapid muscle glucose uptake. In the setting of pre-established glucose intolerance caused by diet-induced insulin resistance or streptozotocin-mediated β-cell mass depletion, PKA activation enhanced β-cell secretory function to restore glucose control, primarily through augmentation of the AIR. Enhanced AIR and improved glucose control were maintained through 16 weeks of a high-fat diet and aging to 1 year. Importantly, improved glucose tolerance did not increase the risk for hypoglycemia, nor did it rely upon hyperinsulinemia or β-cell hyperplasia, although PKA activity was protective for β-cell mass. These data highlight that improving β-cell function through the activation of PKA has a large and underappreciated capacity to restore glucose control with minimal risk for adverse side effects.
糖尿病源于胰岛素分泌不足以及β细胞数量无法维持和增加。这些缺陷可以通过与Gs偶联的G蛋白偶联受体的配体来治疗，这些配体可提高β细胞中的环磷酸腺苷（cAMP）水平。在这里，我们使用β-caPKA小鼠研究了β细胞cAMP依赖性蛋白激酶（PKA）活性在恢复血糖控制方面的治疗潜力。PKA活性增强了对葡萄糖的急性胰岛素反应（AIR），而这是葡萄糖清除效率的主要决定因素。增强的AIR改善了外周胰岛素作用，使肌肉对葡萄糖的摄取更快。在由饮食诱导的胰岛素抵抗或链脲佐菌素介导的β细胞数量减少引起的预先存在的葡萄糖不耐受情况下，PKA激活增强了β细胞分泌功能以恢复血糖控制，主要是通过增强AIR来实现的。在高脂饮食16周以及衰老至1岁的过程中，增强的AIR和改善的血糖控制得以维持。重要的是，改善的糖耐量并未增加低血糖风险，也不依赖于高胰岛素血症或β细胞增生，尽管PKA活性对β细胞数量具有保护作用。这些数据表明，通过激活PKA来改善β细胞功能具有巨大且未被充分认识的能力，能够以最小的不良副作用风险恢复血糖控制。
