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Abnormal insulin receptor tyrosine kinase activity in kidney basolateral membranes from non-insulin-dependent
G Grunberger1, K Nagy, D Rempinski
1Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI.
Abstract:
Neonatal rats that receive injections of streptozotocin develop insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM). Insulin resistance precedes development of overt diabetes, and some insulin bioeffects are known to be impaired at the postreceptor level in several target tissues of this rat model. We studied a possible contribution of altered insulin receptor function to the impaired insulin action in these animals. Activity of the insulin-sensitive tyrosine kinase of receptors from kidney cortical basolateral membranes (BLMs) obtained from these nonobese, normoinsulinemic, insulin-resistant rats was examined at the age of 5 weeks (before overt hyperglycemia developed) and at 10 weeks (after NIDDM was fully manifested). In experimental animals, at both 5 and 10 weeks, binding of insulin labeled with iodine 125 to crude kidney BLM was higher than in their control littermates. However, no such difference was found with insulin binding to purified insulin receptors from BLM. The insulin receptor, tyrosine kinase activity (TKA), to an exogenous substrate was higher in diabetic tissue both at basal condition and after insulin stimulation at both 5 and 10 weeks of age. Autophosphorylation of the beta-subunit of the insulin receptor and the proportion of tyrosine-phosphorylated ("active") insulin receptors from BLM was also higher in diabetic rats. There was an age-related increase in the receptor TKA between 5 and 10 weeks in both diabetic and control animals. A 24-hour fast normalized insulin binding and nearly abolished the difference in TKA of the BLM receptors from 5-week-old insulin-resistant rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Neonatal rats with streptozotocin-induced diabetes exhibit enhanced insulin receptor tyrosine kinase activity (TKA) in kidney membranes, indicating altered insulin signaling contributes to insulin resistance before overt hyperglycemia develops.
Area of Science:
- Endocrinology
- Metabolic Disorders
- Molecular Biology
Background:
- Neonatal streptozotocin injection in rats models non-insulin-dependent diabetes mellitus (NIDDM).
- Insulin resistance in this model precedes hyperglycemia, with postreceptor defects implicated.
- Altered insulin receptor function is investigated as a contributor to impaired insulin action.
Purpose of the Study:
- To investigate the role of insulin receptor function in insulin resistance in a rat model of NIDDM.
- To examine insulin receptor tyrosine kinase activity (TKA) in kidney basolateral membranes (BLMs) at different stages of diabetes development.
Main Methods:
- Streptozotocin-induced diabetic and control rats were studied at 5 and 10 weeks of age.
- Insulin binding assays were performed on crude and purified kidney BLMs.
- Insulin receptor TKA, autophosphorylation, and tyrosine-phosphorylation levels were assessed.
Main Results:
- Higher insulin binding to crude BLMs but not purified receptors in diabetic rats.
- Elevated basal and insulin-stimulated insulin receptor TKA in diabetic rat kidney BLMs at both 5 and 10 weeks.
- Increased insulin receptor autophosphorylation and proportion of active receptors in diabetic rats.
- Fasting normalized insulin binding and TKA differences in 5-week-old insulin-resistant rats.
Conclusions:
- Insulin resistance in this NIDDM model is associated with enhanced insulin receptor tyrosine kinase activity.
- Postreceptor alterations in insulin receptor function contribute to impaired insulin action.
- Fasting may partially reverse these receptor-level defects in early insulin resistance.