Hepatocyte growth factor inhibits insulin-stimulated glycogen synthesis in primary cultured hepatocytes

Kaibori, Masaki; Kwon, A‐Hon; Teshima, Shigeru; Nakanishi, Hideki; Kitano, Takahiro; Kamiyama, Yasuo; Okumura, Tadayoshi

doi:10.1016/s0168-8278(02)00455-5

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…This overall dose-response relationship is consistent with what is known about the control of hepatic glycogen metabolism by insulin in vivo [16]. Furthermore, the observation of a direct effect of insulin at these concentrations is novel, and is in contrast to other reports using in vitro systems where the effect of insulin on hepatocytes or other liver-derived cell lines was observed only at supra-physiological concentrations [24,25], or sometimes not at all [26].…”

Section: Assay Development For Insulin Analogs and Insulin Receptor Agonistssupporting

confidence: 88%

Probing Hepatic Glucose Metabolism via 13C NMR Spectroscopy in Perfused Livers—Applications to Drug Development

Miller

Cao

2021

Metabolites

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Despite being first published over 40 years ago, the combination of 13C nuclear magnetic resonance spectroscopy (NMR) and the isolated perfused liver preparation remains a unique and relevant approach in investigating the effects of pharmacological interventions on hepatic metabolism. The use of intact, perfused livers maintains many metabolic reactions at their respective rates in vivo, while the use of 13C-labelled substrates in combination with 13C NMR allows for a detailed study of specific pathways, as well as the design of robust assays which can be used to evaluate novel pharmacological agents. In this review article, we share some of the methods used to probe glucose metabolism, and highlight key findings and successes derived from the application of this specialized technique to the area of drug development for diabetes and related metabolic disorders.

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Section: Assay Development For Insulin Analogs and Insulin Receptor Agonistssupporting

confidence: 88%

Probing Hepatic Glucose Metabolism via 13C NMR Spectroscopy in Perfused Livers—Applications to Drug Development

Miller

Cao

2021

Metabolites

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“…In our previous report, we found that HGF stimulated the association of IRS-1 with PI3K in primary cultures of rat hepatocytes [24]. Immunoprecipitation experiments with anti-c-Met and antiPI3Kp85 antibodies revealed that rhHGF-activator stimulated the association of c-Met with tyrosinephosphorylated IRS-1, and then the association of tyrosine-phosphorylated IRS-1 with p85, a regulatory subunit of PI3K (Fig.…”

Section: Effect Of Rhhgf-activator On Hgf Signal Via C-metmentioning

confidence: 64%

Administration of rhHGF-Activator Via Portal Vein Stimulates the Regeneration of Cirrhotic Liver After Partial Hepatectomy in Rats1

Yanagida

Kaibori

Hijikawa

et al. 2006

Journal of Surgical Research

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“…Perfusate insulin concentrations of 100 pM and above were able to block the effects of glucagon to stimulate glycogen breakdown, and consistent with in vivo data [5], the titration of insulin effect on the liver was very steep, transitioning from no effect to maximal effect over only one order of magnitude concentration range (Figures 5A,B). These observations relating to the behavior of insulin are noteworthy as in many in vitro systems, the effect of insulin on hepatocytes or other liver-derived cell lines is observed only at supra-physiological concentrations [27,28], or sometimes not at all [29]. In summary, we were able to use 13 C MRS at UHF to develop a perfused liver model capable of measuring hepatic glycogen synthesis in real time and observing modulation of glycogen synthesis due to known effectors at physiological plausible concentrations.…”

Section: Discussionmentioning

confidence: 96%

13C MRS Studies of the Control of Hepatic Glycogen Metabolism at High Magnetic Fields

et al. 2017

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Introduction: Glycogen is the primary intracellular storage form of carbohydrates. In contrast to most tissues where stored glycogen can only supply the local tissue with energy, hepatic glycogen is mobilized and released into the blood to maintain appropriate circulating glucose levels, and is delivered to other tissues as glucose in response to energetic demands. Insulin and glucagon, two current targets of high interest in the pharmaceutical industry, are well-known glucose-regulating hormones whose primary effect in liver is to modulate glycogen synthesis and breakdown. The purpose of these studies was to develop methods to measure glycogen metabolism in real time non-invasively both in isolated mouse livers, and in non-human primates (NHPs) using 13 C MRS.Methods: Livers were harvested from C57/Bl6 mice and perfused with [1-13 C] Glucose. To demonstrate the ability to measure acute changes in glycogen metabolism ex-vivo, fructose, glucagon, and insulin were administered to the liver ex-vivo. The C1 resonance of glycogen was measured in real time with 13 C MRS using an 11.7T (500 MHz) NMR spectrometer. To demonstrate the translatability of this approach, NHPs (male rhesus monkeys) were studied in a 7 T Philips MRI using a partial volume 1 H/ 13 C imaging coil. NPHs were subjected to a variable IV infusion of [1-13 C] glucose (to maintain blood glucose at 3-4x basal), along with a constant 1 mg/kg/min infusion of fructose. The C1 resonance of glycogen was again measured in real time with 13 C MRS. To demonstrate the ability to measure changes in glycogen metabolism in vivo, animals received a glucagon infusion (1 µg/kg bolus followed by 40 ng/kg/min constant infusion) half way through the study on the second study session.Results: In both perfused mouse livers and in NHPs, hepatic 13 C-glycogen synthesis (i.e., monotonic increases in the 13 C-glycogen NMR signal) was readily detected. In both paradigms, addition of glucagon resulted in cessation of glycogen synthesis and induction of glycogen breakdown. In the perfused liver, inclusion of insulin was able to dose-dependently block the effect of glucagon.Miller et al. C MRS of Hepatic GlycogenConclusion: Hepatic glycogen synthesis, as well as acute hormonally-induced changes thereof, can be measured using 13 C MRS at high magnetic fields both ex-vivo and in vivo. Measurements of this process represent novel, translatable biomarkers of glucagon action, and additionally may be useful for pharmacological targets which modulate glycogen metabolism.

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Hepatocyte growth factor inhibits insulin-stimulated glycogen synthesis in primary cultured hepatocytes

Cited by 4 publications

References 26 publications

Probing Hepatic Glucose Metabolism via 13C NMR Spectroscopy in Perfused Livers—Applications to Drug Development

Probing Hepatic Glucose Metabolism via 13C NMR Spectroscopy in Perfused Livers—Applications to Drug Development

Administration of rhHGF-Activator Via Portal Vein Stimulates the Regeneration of Cirrhotic Liver After Partial Hepatectomy in Rats1

13C MRS Studies of the Control of Hepatic Glycogen Metabolism at High Magnetic Fields

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