Abstract: PO0727
Insulin Resistance Is Associated with Decreased Renal Insulin Receptor Beta in Aged D4 Null Mice
Session Information
- Diabetic Kidney Disease: Basic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Liu, Mingda, The Core Laboratory,Nanjing BenQ Medical center,The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Wang, Weiwan, The Core Laboratory,Nanjing BenQ Medical center,The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Wang, Quansheng, Department of Endocrine,Nanjing BenQ Medical center,The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Ren, Zhiyun, The Core Laboratory,Nanjing BenQ Medical center,The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Wang, Xiaoyan, The Core Laboratory,Nanjing BenQ Medical center,The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Background
Insulin resistance is a major concern in metabolic disorders related to diabetes.
Methods
In order to explore the hypothesis that D4 dopamine receptor (D4R) increases insulin sensitivity through its activation of insulin receptor beta (IR-beta), we demonstrated the functional role of D4R in the prevention of insulin resistance by studying Drd4 null (Drd4-/-) mice and wild-type (Drd4+/+) littermates.
Results
We found that Drd4-/- mice ( 14 mos) had increased fasting blood glucose regardless of sex but their urines were negative for glucose and ketones, suggesting that the mice fed normal salt/normal fat diet were pre-diabetic. Serum insulin levels were increased in male Drd4-/- mice but not altered in female Drd4-/- mice after an 8 hr fast indicating that these mice have resistance or insensitivity to endogenous insulin.The aged male and female Drd4-/- mice had similar body weights, fasting serum total and free cholesterols, triglycerides, to their age and sex -matched Drd4+/+ littermates, suggesting that the old Drd4-/- mice were not obese and had no dyslipidemia. Relative to Drd4+/+ littermates (100±7 %，n=6)， Drd4-/- mice had decreased IR-beta（19±4%, n=4）but normal protein expressions of IR-alpha, insulin degrading enzyme, insulin substrate 1, sodium glucose transporter 2 and glucose transporters in renal cortex homogenates, indicating that the decreased protein expression of IR-beta contributed to the insulin resistance in the aged Drd4-/- mice. Drd4-/- mice had decreased phosphorylated IR-beta at Tyr1631&1345, not Tyr972. Renal expression of insulin receptor beta was located in mouse renal glomeruli and tubules and co-localized n the apical membrane with NCC in the distal convoluted tubules in cortex and NKCC2 in the thick ascending limbs of loop of Henle in the outer medulla.D4R and IR-beta were co-immunoprecipitated in immortalized mouse renal distal convoluted tubule cells and the co-immunoprecipitation was increased by D4R agonist and not altered by D4R antagonist.
Conclusion
Our results suggest that disruption of D4R may play an important role in the insulin resistance via interactions with IR-beta in kidney.