Regulation of hepatic glucose output by glucose in vivo

Müller, Manfred J.; Moring, J.; Seitz, Hans

doi:10.1016/0026-0495(88)90029-7

Cited by 27 publications

(14 citation statements)

References 17 publications

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“…Measurements of glucose kinetics in diabetic humans have showed that R a and R d can both be chronically stimulated (Meyer et al, 1998), and the infusion of exogenous glucose has been used to test the limits of mammalian plasticity for glucose fluxes. In miniature pigs, exogenous glucose causes a dramatic suppression of endogenous R a and a large increase in R d (Muller et al, 1988). The same response has been reported in dogs and humans receiving an oral load of glucose (Abumrad et al, 1982;Ferrannini et al, 1985;Jackson et al, 1986;Kelley et al, 1988), but the capacity of fish to modulate glucose fluxes has never been tested with an exogenous supply.…”

Section: Introductionsupporting

confidence: 53%

“…2). Such a total inhibition of endogenous R a is characteristic of the mammalian response to exogenous glucose (Abumrad et al, 1982;Ferrannini et al, 1985;Jackson et al, 1986;Kelley et al, 1988;Muller et al, 1988), but was unexpected in trout. The liver can only produce glucose in two ways: glycogenolysis and gluconeogenesis.…”

Section: Suppression Of Hepatic Glucose Productionmentioning

confidence: 93%

“…8). For comparison, a 2 h infusion of exogenous glucose at only once the normal rate of hepatic production in miniature pigs caused a 20% increase in glycemia (Muller et al, 1988). Even though the glucose challenge imposed on the pigs was a lot weaker (half the infusion rate for half the time) and took place in a 37°C endotherm with high basal metabolic rate instead of a 13°C ectotherm, these mammals with good glucoregulatory capacity were unable to avoid hyperglycemia.…”

Section: Capacity For Glucoregulationmentioning

confidence: 99%

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Pushing the limits of glucose kinetics: how rainbow trout cope with a carbohydrate overload

Choi

Weber

2015

Journal of Experimental Biology

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Rainbow trout are generally considered to be poor glucoregulators. To evaluate this, exogenous glucose was administered to chronically hyperglycemic fish at twice the endogenous rate of hepatic production, and their ability to modulate glucose fluxes was tested. Our goals were to determine: (1) whether hyperglycemic fish maintain higher glucose fluxes than normal; (2) whether they can lower hepatic production (R a glucose) or stimulate disposal (R d glucose) to cope with a carbohydrate overload; and (3) an estimate of the relative importance of glucose as an oxidative fuel. Results show that hyperglycemic trout sustain elevated baseline R a and R d glucose of 10.6±0.1 µmol kg −1 min −1 (or 30% above normal). If 50% of R d glucose was oxidized as in mammals, glucose could account for 36 to 100% of metabolic rate when exogenous glucose is supplied. In response to exogenous glucose, rainbow trout can completely suppress hepatic glucose production and increase disposal 2.6-fold, even with chronically elevated baseline fluxes. Such large changes in fluxes limit the increase in blood glucose to 2.5-fold and are probably mediated by the effects of insulin on glucose transporters 2 and 4 and on key enzymes of carbohydrate metabolism. Without this strong and rapid modulation of glucose kinetics, glycemia would rise four times faster to reach dangerous levels, exceeding 100 mmol l −1. Such responses are typical of mammals, but rather unexpected for an ectotherm. The impressive plasticity of glucose kinetics demonstrated here suggests that trout have a much better glucoregulatory capacity than is usually portrayed in the literature.

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Section: Introductionsupporting

confidence: 53%

Section: Suppression Of Hepatic Glucose Productionmentioning

confidence: 93%

Section: Capacity For Glucoregulationmentioning

confidence: 99%

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Pushing the limits of glucose kinetics: how rainbow trout cope with a carbohydrate overload

Choi

Weber

2015

Journal of Experimental Biology

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“…Net hepatic glucose output in control dogs, in which euglycemia was maintained, remained essentially unchanged (6,7). Similarly, in the miniature pig, a gradual rise in plasma glucose from 4.0 to 8.5 mmol/l with insulin and glucagon maintained at basal concentrations resulted in suppression of tracer-determined endogenous glucose production (EndoR a ) by 59% (8).…”

Section: Autoregulation In Response To Hyperglycemiamentioning

confidence: 87%

Autoregulation of hepatic glucose production

Moore

Connolly

Cherrington

1998

European Journal of Endocrinology

104

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In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is dif®cult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause signi®cant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60±90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia.A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (#2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role. European Journal of Endocrinology 138 240±248

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“…Thus, the control strength of glucagon is profound, with a dynamic range of approximately 5 mg/kg/min over the physiologic range of plasma glucagon concentrations (Figure 1 and refs. [21][22][23][24][25][26]. Not only is the liver very sensitive to changes in plasma glucagon, it also responds rapidly, with a half-maximal activation time of only 8 minutes (27).…”

Section: Metabolic Credentialsmentioning

confidence: 99%

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

2012

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The hormone glucagon has long been dismissed as a minor contributor to metabolic disease. Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence: (a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency; (b) hyperglucagonemia is present in every form of poorly controlled diabetes; (c) the glucagon suppressors leptin and somatostatin suppress all catabolic manifestations of diabetes during total insulin deficiency; (d) total β cell destruction in glucagon receptor-null mice does not cause diabetes; and (e) perfusion of normal pancreas with anti-insulin serum causes marked hyperglucagonemia. From this and other evidence, we conclude that glucose-responsive β cells normally regulate juxtaposed α cells and that without intraislet insulin, unregulated α cells hypersecrete glucagon, which directly causes the symptoms of diabetes. This indicates that glucagon suppression or inactivation may provide therapeutic advantages over insulin monotherapy.Conflict of interest: Alan D.

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Regulation of hepatic glucose output by glucose in vivo

Cited by 27 publications

References 17 publications

Pushing the limits of glucose kinetics: how rainbow trout cope with a carbohydrate overload

Pushing the limits of glucose kinetics: how rainbow trout cope with a carbohydrate overload

Autoregulation of hepatic glucose production

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

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