Insulin action on the liver in vivo.

  title={Insulin action on the liver in vivo.},
  author={Alan D. Cherrington and Mary Courtney Moore and Dana K. Sindelar and Dale S. Edgerton},
  journal={Biochemical Society transactions},
  volume={35 Pt 5},
Insulin has a potent inhibitory effect on hepatic glucose production by direct action at hepatic receptors. The hormone also inhibits glucose production by suppressing both lipolysis in the fat cell and secretion of glucagon by the alpha-cell. Neural sensing of insulin levels appears to participate in control of hepatic glucose production in rodents, but a role for brain insulin sensing has not been documented in dogs or humans. The primary effect of insulin on the liver is its direct action. 

Figures from this paper

Current strategies for the inhibition of hepatic glucose production in type 2 diabetes.

Currently available therapeutics which target insulin resistance in the liver are focused on and other hepatic targets are being considered which may lead to alternative strategies for the treatment of diabetes.

Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs.

It is demonstrated that the canine brain senses physiologic elevations in plasma insulin, and that this in turn regulates genetic events in the liver, and this input augments hepatic glucose uptake and glycogen synthesis, reducing NHGO without altering EGP.

Unraveling the Regulation of Hepatic Metabolism by Insulin

Physiology of glucose homeostasis and insulin therapy in type 1 and type 2 diabetes.

  • E. Ferrannini
  • Medicine, Biology
    Endocrinology and metabolism clinics of North America
  • 2012

Resolving the Paradox of Hepatic Insulin Resistance

Basal Insulin: Beyond Glycemia

Understanding the cellular and molecular mechanisms underlying the effects of insulin and how these translate into clinical consequences beyond glycemia will assist primary care physicians in the care of their patients with diabetes and metabolic syndrome.

Molecular Characterization of Insulin-Mediated Suppression of Hepatic Glucose Production In Vivo

In response to acute physiologic hyperinsulinemia, HGP is suppressed primarily through modulation of glycogen metabolism and a transient reduction in net GNG flux occurs and is explained by increased glycolysis resulting from increased F2,6P2 and decreased fat oxidation, supporting the concept that PEPCK has poor control strength over the gluconeogenic pathway in vivo.

Leptin and the central nervous system control of glucose metabolism.

This review highlights growing evidence that leptin action in the central nervous system plays a key role in both body fat stores and blood glucose levels and raises interesting new possibilities for the treatment of diabetes and related disorders.

Deconstructing the Role of PKC Epsilon in Glucose Homeostasis

The hypothalamus bridges the gap between physiology and biochemistry in high-fat diet-induced hepatic insulin resistance

The results of a recent study indicate that hypothalamic insulin resistance via p70 S6 kinase 1 (S6K1) activation induced by a high-fat diet may explain this discrepancy between physiological and biochemical observations.

Hypothalamic insulin signaling is required for inhibition of glucose production

The results reveal a new site of action of insulin on glucose production and suggest that hypothalamic insulin resistance can contribute to hyperglycemia in type 2 diabetes mellitus.

Insulin's direct effects on the liver dominate the control of hepatic glucose production.

It is demonstrated that the direct effects of insulin dominate the acute regulation of HGP in the normal dog and sensitivity of the liver was not enhanced by increased insulin delivery to the head.

Free Fatty Acid as a Link in the Regulation of Hepatic Glucose Output by Peripheral Insulin

The data suggest, but do not prove, that insulin acts to suppress HGO as follows: Insulin slowly traverses the capillary endothelium in adipose tissue; elevated insulin in adipOSE tissue interstdtium inhibits lipolysis, thus decreasing FFA levels; and decreased FFAs act as a signal to the liver to suppress endogenous glucose production.

The Role of Fatty Acids in Mediating the Effects of Peripheral Insulin on Hepatic Glucose Production in the Conscious Dog

The results indicate that peripheral insulin's ability to regulate hepatic glucose production is partially linked to its inhibition of lipolysis, and when plasma NEFA levels were prevented from falling during a selective arterial hyperinsulinemia, ∼55% of insulin%s inhibition of net hepatatic glucose output (NHGO) was eliminated.

Effect of glucagon on glucose production during insulin deficiency in the dog.

It can be concluded that the effect of relative hyperglucagonemia on GP is short-lived and basal glucagon worsens the hyperglycemia pursuant on the induction of insulin deficiency both by triggering an initial overproduction of glucose and by maintaining the basal production rate thereafter.

Direct and Indirect Effects of Insulin to Inhibit Hepatic Glucose Output in Obese Subjects

In a group of insulin-resistant obese subjects, glucose-clamp studies were performed at peripheral insulin levels of 35 ± 3 μU/ml; glucose disposal did not increase, whereas HGO was suppressed by 82%, suggesting that insulin can suppress HGO through indirect extrahepatic actions.

A Comparison of the Effects of Selective Increases in Peripheral or Portal insulin on Hepatic Glucose Production in the Conscious Dog

An increment in portal insulin had a rapid inhibitory effect on NHGO, caused by the suppression of glycogenolysis, while an equal increment in arterial insulin produced an equally potent but slower effect that resulted from a small increase in hepatic sinusoidal insulin, from a suppression of gluconeogenic precursor uptake by the liver, and from a redirection of glycogensolytic carbon to lactate rather than glucose.

Hypothalamic KATP channels control hepatic glucose production

It is shown that activation of ATP-sensitive potassium (KATP) channels in the mediobasal hypothalamus is sufficient to lower blood glucose levels through inhibition of hepatic gluconeogenesis, and that any alteration within this central nervous system/liver circuit can contribute to diabetic hyperglycaemia.

Basal hepatic glucose production is regulated by the portal vein insulin concentration.

It is indicated that after an overnight fast, basal HGP (glycogenolysis) is highly sensitive to the hepatic sinusoidal insulin level and net hepatic glucose output (NHGO) increased significantly, indicating that the liver responds rapidly to a selective decrease in portal vein insulin by markedly increasing HGP as a result of increased glycogenolyses.

Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.

When suprabasal insulin levels in the physiological postprandial range are provided to moderately hyperglycemic depancreatized dogs, suppression of GP appears to be more dependent on peripheral than portal insulin concentrations and may be mainly mediated by limitation of the flow of precursors and energy substrates for gluconeogenesis and by the suppressive effect of insulin on glucagon secretion.