Eid Assaad, Bodin Sophie, Ferrier Bernard, Delage Hélène, Boghossian Michelle, Martin Mireille, Baverel Gabriel, Conjard Agnès
Laboratoire de Physiopathologie Métabolique et Rénale, INSERM UMR 499, Faculté de Médecine R.T.H. Laennec, rue G. Paradin, 69372 Lyon Cedex 08, France.
J Am Soc Nephrol. 2006 Feb;17(2):398-405. doi: 10.1681/ASN.2005070742. Epub 2006 Jan 5.
Recent studies indicate that renal gluconeogenesis is substantially stimulated in patients with type 2 diabetes, but the mechanism that is responsible for such stimulation remains unknown. Therefore, this study tested the hypothesis that renal gluconeogenesis is intrinsically elevated in the Zucker diabetic fatty rat, which is considered to be an excellent model of type 2 diabetes. For this, isolated renal proximal tubules from diabetic rats and from their lean nondiabetic littermates were incubated in the presence of physiologic gluconeogenic precursors. Although there was no increase in substrate removal and despite a reduced cellular ATP level, a marked stimulation of gluconeogenesis was observed in diabetic relative to nondiabetic rats, with near-physiologic concentrations of lactate (38%), glutamine (51%) and glycerol (66%). This stimulation was caused by a change in the fate of the substrate carbon skeletons resulting from an increase in the activities and mRNA levels of the key gluconeogenic enzymes that are common to lactate, glutamine, and glycerol metabolism, i.e., mainly of phosphoenolpyruvate carboxykinase and, to a lesser extent, of glucose-6-phosphatase and fructose-1,6-bisphosphatase. Experimental evidence suggests that glucocorticoids and cAMP were two factors that were responsible for the long-term stimulation of renal gluconeogenesis observed in the diabetic rats. These data provide the first demonstration in an animal model that renal gluconeogenesis is upregulated by a long-term mechanism during type 2 diabetes. Together with the increased renal mass (38%) observed, they lend support to the view so far based only on in vivo studies performed in humans that renal gluconeogenesis may be stimulated by and crucially contribute to the hyperglycemia of type 2 diabetes.
最近的研究表明，2型糖尿病患者的肾糖异生受到显著刺激，但其刺激机制尚不清楚。因此，本研究检验了一个假设，即在被认为是2型糖尿病优秀模型的Zucker糖尿病脂肪大鼠中，肾糖异生本质上是升高的。为此，将糖尿病大鼠及其瘦的非糖尿病同窝仔鼠的离体肾近端小管在生理糖异生前体存在的情况下进行孵育。尽管底物清除没有增加，且细胞ATP水平降低，但与非糖尿病大鼠相比，糖尿病大鼠的糖异生受到显著刺激，乳酸（38%）、谷氨酰胺（51%）和甘油（66%）的浓度接近生理水平。这种刺激是由于底物碳骨架的命运发生了变化，这是由乳酸、谷氨酰胺和甘油代谢共有的关键糖异生酶的活性和mRNA水平增加所致，即主要是磷酸烯醇式丙酮酸羧激酶，其次是葡萄糖-6-磷酸酶和果糖-1,6-二磷酸酶。实验证据表明，糖皮质激素和环磷酸腺苷是导致糖尿病大鼠肾糖异生长期刺激的两个因素。这些数据首次在动物模型中证明，2型糖尿病期间肾糖异生通过长期机制上调。连同观察到的肾质量增加（38%），它们支持了迄今为止仅基于在人类中进行的体内研究得出的观点，即肾糖异生可能受到2型糖尿病高血糖的刺激并对其起关键作用。
