Starvation-Induced Ketone Body Production in the Conscious Unrestrained Miniature Pig

Müller, Manfred J.; Paschen, U.; Seitz, Hans

doi:10.1093/jn/112.7.1379

Cited by 21 publications

(14 citation statements)

References 25 publications

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“…3). Infusion of Na-DL-13-OHB (15 gmol/kg X min) led to a drop in blood glucose, R. (-50%), and Rd (-45%). The effects were statistically significant at the beginning of the infusion period, and alterations were observed for up to 135 min perfusion time.…”

Section: Methodsmentioning

confidence: 96%

“…14 male castrated miniature pigs (specific pathogen free, 28-32 kg body wt, 12-mo-old) were purchased (Versuchsgut Domane Relliehausen, Gottingen, Federal Republic of Germany) about 4 wk before the experiments were started. The pigs were held under controlled conditions and kept on a standard chow diet as described previously (15,16).…”

Section: Methodsmentioning

confidence: 99%

“…Simultaneously urine was collected in refrigerated containers and cumulative nitrogen excretion (sum of urea plus NW) was measured as described (15,16).…”

Section: Methodsmentioning

confidence: 99%

“…The methods for the determination ofstandard clinical and laboratory parameters, of glucose, lactate, pyruvate, glycerol, alanine, a-amino-N, free fatty acids (FFA), ofthe hormones insulin and glucagon, of pH, p02, and PCO2 as well as of the specific activity of glucose have been described in detail previously (15,16,18,19 -(pVdc/dt), where c is the concentration of glucose, V represents the glucose distribution volume (calculated from the initial decline in the specific activity of glucose after the primed injection of the tracer), and p is the pool fraction (0.65 according to [21]). Polynomial curves were fitted to the SA and plasma concentrations of glucose vs. time curves and a smoothing tricubic spline algorithm was used for this purpose on a TR 440 Telefunken computer.…”

Section: Methodsmentioning

confidence: 99%

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

Müller¹,

Paschen²,

Seitz³

1984

J. Clin. Invest.

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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.

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Section: Methodsmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

“…Simultaneously urine was collected in refrigerated containers and cumulative nitrogen excretion (sum of urea plus NW) was measured as described (15,16).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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

Müller¹,

Paschen²,

Seitz³

1984

J. Clin. Invest.

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“…As ketone bodies are the result of partial free fatty acid oxidation, no differences in fatty acid oxidation would be expected between pig breeds at the hepatic level. In vivo, early studies with starved miniature pigs (Müller et al, 1982) suggested that mild ketosis encountered was modulated by insulin and glucagon. Indeed, similarly to the present experiment, where glucagon stimulated and insulin inhibited BHB production, it has been reported that ketone bodies synthesis in hepatocytes from 60 kg BW pigs are sensitive to long-term regulation by insulin, glucagon and dexamethasone (Fernández-Fígares et al, 2004), while short-term glucagon addition has been shown to have no effect on ketogenesis in pig hepatocytes (Pégorier et al, 1982).…”

Section: Bhb Synthesismentioning

confidence: 99%

Metabolic differences in hepatocytes of obese and lean pigs

González-Valero

Rodríguez-López

Lachica

et al. 2014

Animal

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There are important differences in terms of metabolic activity, energy utilization and capacity of protein and fat deposition when Iberian and modern pigs are compared. Primary culture of hepatocytes was used to evaluate hepatic function and sensitivity to hormones between breeds without the interference of circulating blood factors. Hepatocytes were isolated from pure Iberian (n = 10) and Landrace (n = 8) pigs of similar BW (24.5 ± 12.1 and 32.9 ± 6.1 kg BW, respectively), by collagenase perfusion. Monolayers were established in medium containing fetal bovine serum for 1 day and switched to serum-free medium for the remainder of the culture period. Hepatocytes were maintained in William's E supplemented with β-mercaptoethanol (0.1 mM), glutamine (2 mM), antibiotics (gentamicin, penicillin, streptomycin and amphotericin B), dimethyl sulfoxide (1 µg/ml), dexamethasone (10 −8 M), insulin (0.173 and 17.3 nM) and glucagon (0.287, 2.87 and 28.7 nM) for 24 to 48 h. Gluconeogenesis (GNG), glycogen degradation, triglycerides (TG) content and esterification, β-hydroxybutyrate (BHB) synthesis, IGF-1 synthesis, albumin and urea synthesis were determined. Iberian pigs had greater capacity of GNG than Landrace (24%, P < 0.05), although no difference in glycogen degradation was found (P > 0.10). TG content and esterification tended to be lower in hepatocytes from Iberian compared with Landrace pigs (12% and 31%, respectively; 0.10 < P < 0.05). Furthermore, addition of free fatty acids (CLA or linoleic acid, 0.2 mM) increased TG content (64%, P < 0.001) although no difference between fatty acids was found. When free fatty acids were compared, a trend toward increased esterification (41%, P = 0.078) was found for CLA. Although glucagon stimulated and insulin inhibited BHB synthesis, no difference between breeds was found (P > 0.10). IGF-1 synthesis was diminished in hepatocytes from Iberian compared with Landrace pigs (16%, P < 0.05). On the contrary, rate of albumin synthesis was greater in Iberian compared with Landrace pigs (58%, P < 0.05). Finally, the capacity of urea synthesis was lower in hepatocytes of Iberian compared with Landrace pigs (37%, P < 0.05). When ammonia was added to the media, urea concentration increased (648%, 1108% and 2791% when 0 mM was compared with 2.5, 5 and 10 mM, respectively). Urea synthesis increased on increasing ammonia content (55% and 325% when 0 mM was compared with 5 and 10 mM, respectively; P < 0.0001). In conclusion, the genetic background accounts for important differences in protein and energy metabolism pathways found in primary culture of hepatocytes from lean and obese pigs.Keywords: hepatocytes, metabolism, pig ImplicationsSeveral studies have shown the existence of numerous dissimilarities in metabolic activity between Iberian and modern pig breeds that might be explained by genotypic differences. Primary hepatocyte cultures are a valuable tool to study specific metabolic liver functions, without the interference of changing levels of metabolites and hormones found in vivo. These...

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