Effect of ketone bodies on glucose production and utilization in the miniature pig.

Abstract

As bstract. The effect of ketone bodies on glucose production (Ra) and utilization (Rd) was investigated in the 24-h starved, conscious unrestrained miniature pig. Infusing Na-DL-3-OH-butyrate (Na-DL-f-OHB) and thus shifting the blood pH from 7.40 to 7.56 resulted in a decrease of Ra by 52% and of Rd by 45%, as determined by the isotope dilution technique. Simultaneously, the concentrations of arterial insulin and glucagon were slightly enhanced, whereas the plasma levels of glucose, lactate, pyruvate, alanine, a-amino-N, and free fatty acids (FFA) were all reduced. Infusion ofNa-bicarbonate, which yielded a similar shift in blood pH, did not mimick these effects. Infusion of equimolar amounts of the ketoacid, yielding a blood pH of 7.35, induced similar metabolic alterations with respect to plasma glucose, Ra, Rd, and insulin; however, plasma alanine and a-amino-N increased.Infusing different amounts of Na-DL-3-OHB resulting in plasma steady state levels of ketones from 0.25 to 1.5 mM had similar effects on arterial insulin and glucose kinetics. No dose dependency was observed.Prevention of the Na-DL-3-OHB-induced hypoalaninemia by simultaneous infusion of alanine (1 ttmol/kg X min) did not prevent hypoglycemia.Infusion of Na-DL-l-OHB plus insulin (0.4 mU/kg in plasma glucose and Ra; however, on infusion of somatostatin plus Na-DL-3-OHB, hypoglycemia and the reduced Ra were maintained.In the anaesthetized 24-h starved miniature pig, Na-DL-3-OHB infusion decreased the hepatic exchange for glucose, lactate, and FFA, whereas the exchange for glycerol, alanine, and a-amino-N as well as liver perfusion rate were unaffected. Simultaneously, portal glucagon and insulin as well as hepatic insulin extraction rate were elevated. Leg exchange for glucose, lactate, glycerol, alanine, a-amino-N, and FFA were decreased, while ketone body utilization increased.Repeated infusion of Na-DL-3-OHB at the fourth, fifth, and sixth day of starvation in the conscious, unrestrained mini-pig resulted in a significant drop in urinary nitrogen (N)-excretion. However, this effect was mimicked by infusing equimolar amounts of Na-bicarbonate. In contrast, when only the ketoacid was given, urinary Nexcretion accelerated.To summarize: (a) Ketone bodies decrease endogenous glucose production via an insulin-dependent mechanism; in addition, ketones probably exert a direct inhibitory action on gluconeogenesis. The ketone bodyinduced hypoalaninemia does not contribute to this effect. (b) The counterregulatory response to hypoglycemia is reduced by ketones. (c) As a consequence of the decrease in Ra, glucose utilization declines during ketone infusion.(d) The insulin-stimulated MCR for glucose is not affected by ketones. (e) Ketones in their physiological moiety do not show a protein-sparing effect.

Long-term elevation of β-hydroxybutyrate in dairy cows through infusion: Effects on feed intake, milk production, and metabolism

“…In contrast to a previous study that found increased glucagon concentrations after BHBA infusion in pigs (Müller et al, 1984), in the current study BHBA infusion decreased glucagon concentration in HyperB compared with the control group. Plasma glucose is derived from the feed, glycogen, and by gluconeogenesis, and it is regulated by several hormones, mainly glucagon and insulin.…”

“…This finding is consistent with other reports of decreased plasma glucose concentration associated with elevated BHBA in pregnant sheep Harmeyer 2003, 2004), dogs (Felts et al, 1964;Madison et al, 1964), and pigs (Müller et al, 1984). However, our findings are in contrast to other reports that described a hyperglycemia in rabbits (Mirsky and Broh-Kahn, 1937) induced by ketone bodies infusion.…”

“…The present results of mRNA abundance of key enzymes related to hepatic gluconeogenesis (PC, glucose-6-phosphatase, mitochondrial phosphoenolpyruvate carboxykinase) are in contrast with suggestions from previous studies that indicated an inhibition of gluconeogenesis by elevated plasma BHBA concentration (Müller et al, 1984;Schlumbohm and Harmeyer, 2003). Müller et al (1984) suggested that ketone bodies probably have a direct inhibitory action on gluconeogenesis.…”

“…Information about the reasons for decreased plasma glucose concentration due to the elevated BHBA concentration is limited; hypothetically, insulin plays a role in this effect. Infusion of BHBA increases insulin secretion in pigs (Müller et al, 1984). Madison et al (1964) suggested that pancreatic beta cells respond to the high plasma BHBA concentration with increased insulin secretion in dogs.…”

“…Intravenous BHBA infusion led to decreased plasma concentration of glucose in dogs (Madison et al, 1964), pigs (Müller et al, 1984), and ewes Harmeyer, 2003, 2004). The reason for declined glucose during the infusion of BHBA remains unclear, but those authors suggested that infusion of BHBA induced hypoglycemia through direct or indirect inhibition of gluconeogenesis, or by a change in the insulin concentration in pig and sheep (Müller et al, 1984;Schlumbohm and Harmeyer, 2004). This mechanism has not yet been investigated in dairy cows.…”