Hormonal control of ketogenesis. Rapid activation of hepatic ketogenic capacity in fed rats by anti-insulin serum and glucagon.

McGarry, Julie; Wright, P. H.; Foster, Daniel W.

doi:10.1172/jci108038

Cited by 218 publications

(77 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3. The objective here was to treat fasted rats with NA, but to maintain a high plasma FFA level by coinfusion of a triglyceride emulsion (Intralipid) plus heparin, a well established maneuver that promotes intravascular lipolysis (21). In the three groups of animals depicted, the starting ( Ϫ 60 min) plasma FFA concentration ranged from ‫ف‬ 1.2-1.5 mM (Fig.…”

Section: Resultsmentioning

confidence: 99%

Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat.

Stein¹,

Esser²,

Stevenson³

et al. 1996

J. Clin. Invest.

343

271

View full text Add to dashboard Cite

We asked whether the well known starvation-induced impairment of glucose-stimulated insulin secretion (GSIS) seen in isolated rat pancreas preparations also applies in vivo. Accordingly, fed and 18-24-h-fasted rats were subjected to an intravenous glucose challenge followed by a hyperglycemic clamp protocol, during which the plasma-insulin concentration was measured. Surprisingly, the acute (5 min) insulin response was equally robust in the two groups. However, after infusion of the antilipolytic agent, nicotinic acid, to ensure low levels of plasma FFA before the glucose load, GSIS was essentially ablated in fasted rats, but unaffected in fed animals. Maintenance of a high plasma FFA concentration by coadministration of Intralipid plus heparin to nicotinic acid-treated rats (fed or fasted), or further elevation of the endogenous FFA level in nonnicotinic acidtreated fasted animals by infusion of etomoxir (to block hepatic fatty acid oxidation), resulted in supranormal GSIS. The in vivo findings were reproduced in studies with the perfused pancreas from fed and fasted rats in which GSIS was examined in the absence and presence of palmitate. The results establish that in the rat, the high circulating concentration of FFA that accompanies food deprivation is a sine qua non for efficient GSIS when a fast is terminated. They also serve to underscore the powerful interaction between glucose and fatty acids in normal ␤ cell function and raise the possibility that imbalances between the two fuels in vivo could have pathological consequences. ( J. Clin. Invest. 1996. 97:2728-2735.)

show abstract

Section: Resultsmentioning

confidence: 99%

Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat.

Stein¹,

Esser²,

Stevenson³

et al. 1996

J. Clin. Invest.

343

271

View full text Add to dashboard Cite

show abstract

“…Nevertheless, several in vitro studies have shown that glucagon can enhance hepatic ketone body production directly (41,49). In the rat in vivo, McGarry and co-workers (50) have demonstrated that physiologic quantities of glucagon can convert the fed liver to a ketogenic mode. Possibly, a similar key action of glucagon in the human liver could explain, in part, the lack of ketoacidosis after withdrawal of insulin from ketosis-prone diabetics during suppression of glucagon secretion (33).…”

Section: Discussionmentioning

confidence: 99%

Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin.

Gerich¹,

Lorenzi²,

Bier³

et al. 1976

J. Clin. Invest.

194

View full text Add to dashboard Cite

A B S T R A C T To study the individual effects of glucagon and growth hormone on human carbohydrate and lipid metabolism, endogenous secretion of both hormones was simultaneously suppressed with somatostatin and physiologic circulating levels of one or the other hormone were reproduced by exogenous infusion. The interaction of these hormones with insulin was evaluated by performing these studies in juvenile-onset, insulin-deficient diabetic subjects both during infusion of insulin and after its withdrawal.Infusion of glucagon (1 ng/kg min) during suppression of its endogenous secretion with somatostatin produced circulating hormone levels of approximately 200 pg/ml. When glucagon was infused along with insulin, plasma glucose levels rose from 94±8 to 126±+12 mg/100 ml over 1 h (P <0.01); growth hormone, P-hydroxybutyrate, alanine, FFA, and glycerol levels did not change. When insulin was withdrawn, plasma glucose, fi-hydroxybutyrate, FFA, and glycerol all rose to higher levels (P < 0.01) than those observed under similar conditions when somatostatin alone had been infused to suppress glucagon secretion. Thus, under appropriate conditions, physiologic levels of glucagon can stimulate lipolysis and cause hyperketonemia and hyperglycemia in man; insulin antagonizes the lipolytic and ketogenic effects of glucagon more effectively than the hyperglycemic effect. produced circulating hormone levels of approximately 6 ng/ml. When growth hormone was administered along with insulin, no effects were observed. After insulin was withdrawn, plasma P-hydroxybutyrate, glycerol, and FFA all rose to higher levels (P < 0.01) than those observed during infusion of somatostatin alone when growth hormone secretion was suppressed; no difference in plasma glucose, alanine, and glucagon levels was evident. Thus, under appropriate conditions, physiologic levels of growth hormone can augment lipolysis and ketonemia in man, but these actions are ordinarily not apparent in the presence of physiologic levels of insulin. INTRODUCTIONThe physiologic importance of glucagon and growth hormone in human carbohydrate and lipid homeostasis is poorly understood. Administration of pharmacologic amounts of glucagon can augment lipolysis (1-4), ketogenesis (1-4), and glucose production (1-5) in man, but these effects are difficult to interpret because such quantities of glucagon may promote growth hormone (6) and catecholamine (7) release. Moreover, similar results have not been consistently observed in studies using physiologic concentrations of glucagon (3,8,9). Evidence for the participation of growth hormone in human lipid and carbohydrate metabolism is based largely on results obtained after administration of pharmacologic quantities of growth hormone and on observations in hypophysectomized individuals. Growth hormone, when administered in pharmacologic doses, reportedly diminishes glucose utilization (10-15) and promotes lipolysis (10, 16) and ketosis (10, 15, 16) in man, but similar

show abstract

“…The peak in hepatic carnitine soon after birth indicated that the rise was most likely a postnatal rather than an antenatal event. This increase coincides with a greater functional capacity to oxidize fatty acids and produce ketones (4,27). The amount of hepatic carnitine is not rate limiting for fatty acid oxidation.…”

Section: Discussionmentioning

confidence: 99%

“…The amount of hepatic carnitine is not rate limiting for fatty acid oxidation. However, the striking increase in carnitine constitutes an indicator, and a possible promoter, of the heightened fatty acid oxidation in newborns (4,(27)(28)(29). The postnatal fall in carnitine was due to decreasing SCAC esters in piglets, whereas that in rodents was due to a decline in the free fraction (4).…”

Section: Discussionmentioning

confidence: 99%

Enterohepatic Distribution of Carnitine in Developing Piglets: Relation to Glucagon and Insulin

et al. 1992

Pediatr Res

View full text Add to dashboard Cite

ABSTRACT. ~Xarnitine plays a crucial role in the perinatal transition from carbohydrate to lipid-derived energy. To examine the potential contribution of assimilated dietary carnitine to the elevated hepatic concentrations in newborns, we measured carnitine concentrations in sow milk, jejunum, and liver, and in vitro jejunal carnitine transport in piglets aged 1-36 d. Hepatic and sow milk total carnitine concentrations peaked soon after birth and declined with age ( p = 0.035 and 0.026, respectively).Although jejunal total carnitine concentrations remained stable, jejunal carnitine flux was higher at 2 d of age than in older piglets. To examine the possible signals that regulate hepatic carnitine, portal enteroinsular hormones were measured by RIA. Portal glucagon ( p = 0.0006), insulin ( p = 0.0001), and g1ucagon:insulin ratio ( p = 0.037) were related to age. Portal glucagon was highest in newborns and during weaning, whereas insulin increased progressively with age; the portal g1ucagon:insulin ratio, like hepatic carnitine, peaked soon after birth and fell with age. A multiple regression analysis indicated a positive association between glucagon and hepatic carnitine and a negative one between insulin and hepatic carnitine (R = 0.802, p = 0.001). An overall pattern of elevated dietary carnitine levels and increased small intestinal absorption and hepatic accumulation of carnitine is noted in early development. The finding of a similar pattern in glucagon-to-insulin ratio suggests that both hormones may participate in the regulation of enterohepatic carnitine distribution in newborns. (Pediatr Res 32: 312-316,1992) Abbreviations PEG, polyethylene glycol SCAC, short-chain acylcarnitine ANOVA, analysis of variance NB, newborn group S, suckling group W, weaning group FW, fully weaned group plays a critical role in the metabolic transition from carbohydrate to lipid-derived energy (2, 3) because hepatic glycogen stores become rapidly depleted and endogenous gluconeogenesis is inadequate in the first 24 h of life (4, 5). As such, carnitine insufficiency has been shown to impair lipid utilization in premature newborns (6, 7). The human newborn is especially susceptible to develop carnitine insufficiency because of low levels in premature infants (8), inadequate dietary intake of carnitine (9), and insufficient endogenous synthesis (10).One marker of the switch from glucose to lipid utilization in the newborn is the increase in hepatic carnitine concentrations compared with the fetus (4). In newborn rats, the Cfold rise in hepatic carnitine has been shown to coincide with enhanced ketone production. Although the origin of hepatic carnitine in newborns has not been fully established, because endogenous synthesis is limited, dietary sources appear to be important. Human and rat milk carnitine concentrations peaked in the first few days after parturition (4, 1 1). In 5-d-old rats, the contribution of milk carnitine to heart (41%) and liver (49%) carnitine stores was substantial (12). We hypothesized that intestinal a...

show abstract

Hormonal control of ketogenesis. Rapid activation of hepatic ketogenic capacity in fed rats by anti-insulin serum and glucagon.

Cited by 218 publications

References 38 publications

Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat.

Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat.

Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin.

Enterohepatic Distribution of Carnitine in Developing Piglets: Relation to Glucagon and Insulin

Contact Info

Product

Resources

About