Comparative effects of short-term and long-term insulin-induced hypoglycemia on glucose production in the perfused livers of weaned rats

Abstract

The liver glucose production (LGP) levels of 15-h overnight fasted weaned rats submitted to short-term insulin-induced hypoglycemia (ST-IIH) and long-term IIH (LT-IIH) were compared. Experiments to characterize ST-IIH or LT-IIH that followed an intraperitoneal (ip) injection (1.0 U/kg) of regular (ST-IIH) or insulin detemir (LT-IIH) were performed and glycemia were measured 0 (normoglycemic control), 0.5 h (ST-IIH), 4 h and 6 h (LT-IIH) later. The values of glycemia (mg/dl) were 77.8 ±l 7.2 (normoglycemic control), 26.2 ±l 6.1 (ST IIH 0.5 h), 21.2 ±l 7.6 (LT-IIH 4 h) and 35.3 ±l 14.5 (LT-IIH 6.0). The LGP levels were measured in the rats submitted to ST-IIH (0.5 h) and LT-IIH (4 h or 6 h). The rats that received ip saline were used as the normoglycemic control group (COG). The livers from the COG and IIH groups (ST-IIH or LT-IIH) were perfused in situ with infusion of L-alanine (5 mM), L-glutamine (10 mM), glutamine dipeptide (5 mM), L-lactate (2 mM) or glycerol (2 mM). The ST-IIH rats showed a higher LGP level than COG group following the L-glutamine infusion (p < 0.05), but the LGP levels that were measured following the L-lactate, L-alanine, glutamine dipeptide (5 mM), L-lactate (2 mM) or glycerol infusion remained unchanged. Moreover, if the period of IIH was expanded to 4 h following insulin injection, the LGP levels induced by L-alanine, glutamine dipeptide or glycerol infusion also increased (p < 0.05, LT-IIH vs. COG). However, the LGP from the L-lactate infusion remained unchanged until 6 h after insulin injection. In conclusion, these results suggest that the intensification of liver gluconeogenesis during ST-IIH and LT-IIH in weaned rats is not a synchronous "all or nothing" process; instead, this process integrated in a temporal manner and is specific for each gluconeogenic substrate.

Oral lactate intensifies insulin toxicity during severe insulin-induced hypoglycemia in mice

“…When coupled with results from our previous study (Hartman et al, 2010;Rodrigues et al, 2011), this new concept concerning the role of lactate as a brain fuel (Pellerin, Magistretti, 2012;Proia et al, 2016;Smith et al, 2003), suggests the possibility of using lactate rather than glucose to treat insulin induced hypoglycemia (Chan et al, 2013;De Feyter et al, 2013;Herzog et al, 2013;Oldenbeuving et al, 2014;Rooijackers et al, 2016).…”

“…In this regard, the effects of glucose have previously been compared with those of glutamine, alanine, lactate, and pyruvate (Galende et al, 2009;Hartman et al, 2010;Nunes Santiago et al, 2013;Rodrigues et al, 2011).…”

“…Because glucose inhibits liver gluconeogenesis and does not alleviate hypoglycemia induced by insulin administration (Galende et al, 2009), liver glucose continues to be produced from lactate during periods of hypoglycemia (Hartman et al, 2010;Rodrigues et al, 2011). Moreover, lactate has been proposed as an alternative brain energy fuel (Pellerin, Magistretti, 1994, Wyss et al, 2011.…”