Chemical induction of the unfolded protein response in the liver increases glucose production and is activated during insulin-induced hypoglycaemia in rats.

J C Gonzales, C L Gentile, K T Pfaffenbach, Y Wei, D Wang, M J Pagliassotti

Index: Diabetologia 51 , 1920-9, (2008)

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Abstract

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) can regulate insulin secretion, insulin action and in vitro hepatocyte glucose release. The aims of this study were to determine whether chemical agents that induce ER stress regulate glucose production in vivo and to identify a physiological setting in which this may be important.A pancreatic clamp test was performed in anaesthetised rats, and insulin and glucagon were replaced at basal levels. [6,6-(2)H(2)]Glucose was infused in the absence (CON, n = 10) or presence of ER stress-inducing agents, namely, tunicamycin (Tun, n = 10) or thapsigargin (Thap, n = 10).Arterial insulin, glucagon, corticosterone and NEFA concentrations were constant throughout experiments and not different among groups. After 1 h, the glucose concentration was significantly increased in Tun and Thap rats (1.5 +/- 0.2 and 2.1 +/- 0.3 mmol/l, respectively; mean +/- SD), but did not change in CON rats. Glucose production increased (p < 0.05) by 11.0 +/- 1.6 and 13.2 +/- 2.2 micromol kg(-1) min(-1) in Tun and Thap rats, respectively, but did not change in CON rats. When glucose was infused in a fourth group (HYPER) to match the increase in glucose observed in the Tun and Thap rats, glucose production decreased by approximately 22 micromol kg(-1) min(-1). Liver phosphorylase activity was increased and glycogen decreased in the Tun and Thap groups compared with the CON and HYPER groups. Given that glucose deprivation induces ER stress in cells, we hypothesised that hypoglycaemia, a condition that elicits increased glucose production, would activate the UPR in the liver. Three hour hyperinsulinaemic (5 mU kg(-1) min(-1)) -euglycaemic (EUG, approximately 7.2 mmol/l, n = 6) or -hypoglycaemic (HYPO, approximately 2.8 mmol/l, n = 6) clamps were performed in conscious rats. Several biochemical markers of the UPR were significantly increased in the liver, but not in kidney or pancreas, in HYPO vs EUG rats.Based on our findings that the chemical induction of the UPR increased glucose production and that prolonged hypoglycaemia activated the UPR in the liver, we propose that the UPR in the liver may contribute to the regulation of glucose production during prolonged hypoglycaemia.