title: 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.
authors.affiliation: Department of Physiological Sciences, State University of Maringá , Maringá, PR, 87020-900, Brazil.
authors.forename: Fabiana P M
authors.initials: FP
authors.lastname: Schiavon
authors.forename: Vilma A F G
authors.initials: VA
authors.lastname: Gazola
authors.forename: Maria M D P
authors.initials: MM
authors.lastname: Furlan
authors.forename: Helenton C
authors.initials: HC
authors.lastname: Barrena
authors.forename: Roberto B
authors.initials: RB
authors.lastname: Bazotte
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D007003:Hypoglycemia / Q000139:chemically induced*; D007328:Insulin / Q000009:adverse effects*; D007657:Ketone Bodies / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats
chemical_list: D007328:Insulin; D007657:Ketone Bodies