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Dysregulation of Insulin receptor expression affects proximal tubule gluconeogenesis
Author(s) -
Pandey Gaurav,
Mandhani Anil,
Srivastava Anssesh,
Ecelbarger Carolyn,
Agnihotri Kripa S,
Gaikwad Anil,
Tiwari Swasti
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.740.24
Subject(s) - phosphoenolpyruvate carboxykinase , medicine , endocrinology , gluconeogenesis , insulin , receptor , insulin receptor , kidney , renal cortex , chemistry , biology , enzyme , insulin resistance , metabolism , biochemistry
Reduced insulin receptor protein levels have been reported in the kidney cortex from diabetic human and animals. We have recently reported that targeted deletion of insulin receptor (IR) from proximal tubules (PT) resulted in hyperglycemia in non‐obese mice. To understand the mechanism, we studied human proximal tubule cells (hPTC) and C57bl/c mice fed with high fat diet (HFD, 60% fat for 20 weeks). Immunoblotting revealed a significantly lower expression of IR and blunted rise in p‐AKT levels in the kidney cortex of HFD mice in response to acute insulin (2 unit/kg body weight, i.p) relative to normal chow diet (NCD) n=8/group, p<0.04). Moreover, we found significantly higher transcript levels of phosphoenolpyruvate carboxykinase (PEPCK, rate‐limiting gluconeogenic enzyme) in the kidney cortex from HFD, relative to mice on NCD, (n=8, p<0.05). The higher level of PEPCK in HFD was confirmed by immnoblotting. However, no significant difference was observed in G6Pase and FBPase enzyme transcript levels in the renal cortex of HFD relative to NCD. Furthermore, an in vitro study using primary human PT cells (hPTC) showed insulin's inhibitory effect on cAMP/DEXA –induced gluconeogenesis in these cells. In addition, transcript levels of gluconeogenic enzymes G6Pase and PEPCK were significantly increased in cAMP/DEXA‐stimulated hPTC cells (n=5, p=0.05). However, these effects of insulin on cAMP/DEXA–induced gluconeogenesis and gluconeogenic enzyme induction were blunted in IR silenced hPTC (n=3, p<0.05). Taken together the above data indicate a direct role of insulin receptor in PT‐gluconeogenesis regulation. Thus reduced insulin sensitivity of the proximal tubule could, itself, contribute to hyperglycemia via elevated gluconeogenesis. (BT/HRD/35/02/17/2008) Support or Funding Information The work was supported by the Department of Biotechnology, government of India, Ramalingaswami grant (BT/HRD/35/02/17/2008 to S.T). G.P. was supported by Research Fellowship from University Grant Commission.