(723.3) Renal gluconeogenesis induction by glucagon and insulin receptor deletion in humans

Poster Board Number: E170

Swasti Tiwari (Sanjay Gandhi Postgradulate Institute of Medical Sciences), Rajni Sharma (Sanjay Gandhi Postgradulate Institute of Medical Sciences), Biswajit Sahoo (Sanjay Gandhi Postgradulate Institute of Medical Sciences), Aneesh Srivastava (Sanjay Gandhi Postgradulate Institute of Medical Sciences)

Gluconeogenesis is one of the key processes through which the kidney contributes to glucose homeostasis. Recently, we provided evidence to suggest that early insulin resistance may impair fast-fed regulation of Phosphoenolpyruvate Carboxykinase (PEPCK), rate-limiting enzyme for gluconeogenesis in humans.  To confirm this and to elucidate a link between insulin resistance and fast-fed regulation of PEPCK in the kidneys, we studied primary proximal tubule cells (hPT) and urinary extracellular vesicles (uEVs) from humans. We demonstrate that fasted hPTs had higher PEPCK and insulin receptor substrate-2 (IRS2) mRNA levels than fed cells. The fast-fed regulation was, however, attenuated in insulin receptor knockdown hPTs (IRKO). The insulin receptor knockdown was confirmed by a blunted insulin-induced suppression in PEPCK and PGC1α mRNA and p-IR and p-AKT protein expression in IRKO cells. Exosomes secreted by the wild-type or IRKO hPT showed similar regulation as observed in the respective hPT. Similarly, in human uE, the relative abundance of IRS-2 mRNA (to IRS1) was higher in the fasted state relative to the fed condition. However, the fast-fed difference was absent in subjects with early insulin resistance. These subjects had higher circulating glucagon levels relative to subjects with optimal insulin sensitivity. Furthermore, in hPT cells, glucagon significantly induced PEPCK mRNA, IRS2 mRNA, and gluconeogenesis. Insulin receptor deletion further increased their levels. Together the data suggest that reduced insulin sensitivity and high glucagon in early insulin resistance may impair renal gluconeogenesis via IRS2 regulation.Funding from ICMR-CARE and SGPGI intramural to ST and CSIR to RS.

Work was supported by grants from the Indian Council of Medical Research, Government of India , and Sanjay Gandhi PGI intramural to Swasti Tiwari. Ms. Rajni Sharma was supported by Council of Scientific and Industrial Research, Government of India.