title: Deletion of the insulin receptor in the proximal tubule promotes hyperglycemia.
abstract: Nearly all renal tubular epithelial cells express insulin receptor. The insulin receptor in the distal tubule appears to modulate BP, but the role of the insulin receptor in the proximal tubule is unknown. Here, we selectively knocked out the insulin receptor from the proximal tubules of mice. Western blotting confirmed a two- to three-fold reduction in renal cortical homogenate insulin receptor-β among knockout mice compared with wild-type littermates. Young knockout mice exhibited a mildly diabetic phenotype, evidenced by higher fasting plasma glucose levels than wild-type mice. Assessments by hyperinsulinemic-euglycemic clamp and a glucose tolerance test revealed no differences in insulin sensitivity or overt pancreatic function, respectively. Renal cortical mRNA expression and enzyme activity of glucose-6-phosphatase, which catalyzes the final step of glucose production, were significantly higher in knockout mice. Taken together, these results support a role for insulin receptor in the proximal tubule in the modulation of systemic glucose levels. Downregulation of the insulin receptor in the proximal tubule, which occurs in insulin-resistant states, may promote hyperglycemia through enhanced gluconeogenesis.
authors.affiliation: Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. tiwari_pgi@yahoo.com
authors.forename: Swasti
authors.initials: S
authors.lastname: Tiwari
authors.forename: Ravi Shankar
authors.initials: RS
authors.lastname: Singh
authors.forename: Lijun
authors.initials: L
authors.lastname: Li
authors.forename: Susanna
authors.initials: S
authors.lastname: Tsukerman
authors.forename: Madan
authors.initials: M
authors.lastname: Godbole
authors.forename: Gaurav
authors.initials: G
authors.lastname: Pandey
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Ecelbarger
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000235:genetics*; D015153:Blotting, Western; D017353:Gene Deletion; D005951:Glucose Tolerance Test; D005952:Glucose-6-Phosphatase / Q000378:metabolism*; D006943:Hyperglycemia / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D011972:Receptor, Insulin; D005952:Glucose-6-Phosphatase