Paradoxical increase in liver ketogenesis during long-term insulin-induced hypoglycemia in diabetic rats

Abstract

It is well established that insulin inhibits liver ketogenesis. However, during insulin-induced hypoglycemia (IIH) the release of counterregulatory hormones could overcome the insulin effect on ketogenesis. To clarify this question the ketogenic activity in livers from alloxan-diabetic rats submitted to long-term IIH was investigated. Moreover, liver glycogenolysis, gluconeogensis, ureagenesis and the production of L-lactate were measured, and its correlation with blood levels of ketone bodies (KB), L-lactate, glucose, urea and ammonia was investigated. For this purpose, overnight fasted alloxan-diabetic rats (DBT group) were compared with control non-diabetic rats (NDBT group). Long-term IIH was obtained with an intraperitoneal injection of Detemir insulin (1 U/kg), and KB, glucose, L-lactate, ammonia and urea were evaluated at 0, 2, 4, 6, 8 or 10 h after insulin injection. Because IIH was well established two hours after insulin injection this time was used for liver perfusion experiments. The administration of Detemir insulin decreased (P < 0.05) blood KB and glucose levels, but there was an increase in the blood L-lactate levels and a rebound increase in blood KB during the glucose recovery phase of IIH. In agreement with these results, the capacity to produce KB from octanoate was increased in the livers of DBT rats. Moreover, the elevated blood L-lactate levels in DBT rats could be attributed to the higher (P < 0.05) glycogenolysis when part of glucose from glycogenolysis enters glycolysis, producing L-lactate. In contrast, except glycerol, gluconeogenesis was negligible in the livers of DBT rats. Therefore, during long-term IIH the higher liver ketogenic capacity of DBT rats increased the risk of hyperketonemia. In addition, in spite of the fact that the insulin injection decreased blood KB, there was a risk of worsening lactic acidosis.

Oral Glutamine Is Superior Than Oral Glucose to Promote Glycemia Recovery in Mice Submitted to Insulin-Induced Hypoglycemia

“…For example, despite the paradigm that insulin inhibits hepatic gluconeogenesis, our previous studies in rats suggest that the counterregulatory mechanisms can surpass the inhibitory effects of insulin on liver gluconeogenesis [7–12]. In agreement with our studies, other investigations demonstrated that the administration of gluconeogenic precursors such as alanine [13], lactate [14], and pyruvate [15] during IIH decreased the risk of hypoglycemia and/or promoted glycemia recovery.…”

“…The decreased glycemia (Figure 2) after insulin injection was more intense and prolonged if compared with previous studies in rats [8–12]. Moreover, it was observed that lactate and glycerol were less effective in promoting glycemia recovery compared with the amino acids glutamine and alanine (Figure 3).…”

“…This animal model that has been used by our research group since 1994 [5] is suitable to investigate the metabolic changes induced by IIH [6–12]. …”

Acute Effects of Different Intensities of Resistance Training on Glycemic Fluctuations in Patients With Type 1 Diabetes Mellitus

“…The glucose muscle uptake continued for 2 hours after exercise, regardless of insulin action. Only a single set, however, improved insulin sensibility for 16 hours post-exercise (Schiavon et al, 2011).…”

“…For example, an increased number of glucose transporters 4 (GLUT4) and its movement toward the plasma membrane of the muscle cell (Cauza et al, 2005;Schiavon, Gazola, Furlan, Barrena, & Bazotte, 2011), increased hexokinase activity (Murias, Kowalchuk, & Paterson, 2010), decreased free fatty acids release (Hansen, Landstad, Gundersen, Torjesen, & Svebak, 2012;Hazley, Ingle, Tsakirides, Carroll, & Nagi, 2010), and an increased blood flow causing greater glucose uptake (Behnke & Delp, 2010). Regarding GLUT4, Bienso et al (2012) suggested the immediate biomarker for glucose transport in response to acute exercise is an AMP-activated protein kinase (AMPK), since its activation is made by changes in intracellular adenosine triphosphate (ATP) and adenosine monophosphate (AMP) ratio, creatine phosphate, and pH, resulting in a GLUT4 cycle increase.…”