glycogen and Acute-Phase-Reaction

Three procedures were used to stimulate hepatocyte proliferation in the rat without reducing liver mass, resulting in a supplementary growth which differs from the regenerative growth observed after loss of liver mass by hepatectomy or toxic necrosis. They were: (a) the ingestion of cyproterone, a cytochrome P450 inducing drug (b) the injection of an irritant which provokes glycogenesis and synthesis of acute-phase proteins (c) the injection of albumin-bound bilirubin leading to elimination of glucuronated bilirubin in bile. This ensuing supplementary growth was studied in the rat under several conditions of hepatic proliferation: 1. In normal adult rats, in which hepatocyte proliferation is very low, the effect on proliferation was either weak or undetectable. 2. In suckling rats, with a rapid body and liver growth, all the stimulants provoked a synchronized wave of proliferation with a steep increase of the percentage of S-phase hepatocytes from 4.5% in controls to 15-30% in treated rats. This increase was followed by a compensatory period of low proliferation during which a treatment with a second stimulant was much less effective. 3. In 2/3 hepatectomized adult rats, the proliferation induced by cyproterone was higher than the spontaneous regenerative proliferation alone and additional to it during all of the regenerative process. The proliferation induced by acute inflammation was competitive with the synchronous spontaneous proliferation during the early period of synchronized proliferation following surgery, suggesting that both are similar acute responses. Differently, during the late period of lower and unsynchronized regenerative proliferation, the proliferation provoked by acute inflammation was additional to the spontaneous one. A stimulation of proliferation by injection of the albumin-bilirubin complex was observed during the late period after 2/3 hepatectomy. The highest level of stimulation occurred when the liver growth and the hepatocyte proliferation were already high. This suggests that these stimulants are not complete mitogenic stimuli and need cofactors which are present during the spontaneous growth or, alternatively, that the effect of stimulants is opposed by an inhibitory mechanism present in the adult rat.

Topics: Acute-Phase Reaction; Age Factors; Alanine Transaminase; Albumins; Androgen Antagonists; Animals; Animals, Suckling; Bilirubin; Caseins; Cell Division; Chelating Agents; Chemical and Drug Induced Liver Injury; Cyproterone; Energy Metabolism; Glycogen; Hepatectomy; Hepatocytes; Liver; Liver Diseases; Liver Regeneration; Male; Organ Size; Rats; Rats, Wistar

Type 2 diabetes is a polygenic disease characterized by defects in both insulin secretion and insulin action. We have previously reported that isolated insulin resistance in muscle by a tissue-specific insulin receptor knockout (MIRKO mouse) is not sufficient to alter glucose homeostasis, whereas beta-cell-specific insulin receptor knockout (betaIRKO) mice manifest severe progressive glucose intolerance due to loss of glucose-stimulated acute-phase insulin release. To explore the interaction between insulin resistance in muscle and altered insulin secretion, we created a double tissue-specific insulin receptor knockout in these tissues. Surprisingly, betaIRKO-MIRKO mice show an improvement rather than a deterioration of glucose tolerance when compared to betaIRKO mice. This is due to improved glucose-stimulated acute insulin release and redistribution of substrates with increased glucose uptake in adipose tissue and liver in vivo, without a significant decrease in muscle glucose uptake. Thus, insulin resistance in muscle leads to improved glucose-stimulated first-phase insulin secretion from beta-cells and shunting of substrates to nonmuscle tissues, collectively leading to improved glucose tolerance. These data suggest that muscle, either via changes in substrate availability or by acting as an endocrine tissue, communicates with and regulates insulin sensitivity in other tissues.

Topics: Acute-Phase Reaction; Animals; Blood Glucose; Deoxyglucose; Diabetes Mellitus, Type 2; Fasting; Glucose; Glucose Tolerance Test; Glycogen; Injections, Intraperitoneal; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Lipid Metabolism; Mice; Mice, Knockout; Muscle, Skeletal; Receptor, Insulin; Reference Values

The effect of recombinant human hepatocyte growth factor (h-rHGF), a potent mitogen for hepatocytes, was investigated in primary cultures of human hepatocytes. Here, we describe a series of experiments to investigate the kinetics of its mitogenic action, as well as its metabolic effects on cultured human hepatocytes. The h-rHGF is a potent signal for initiating DNA synthesis in human hepatocytes, with maximal stimulatory effects at 10 ng/mL (0.1 pmol/L). The kinetics of DNA synthesis showed a lag of about 48 to 72 hours, followed by a maximum at 96 hours. At least 48 hours of continuous exposure to h-rHGF are required to initiate DNA synthesis in quiescent human hepatocytes. Cell cycle analysis by flow cytometry showed that most of quiescent 2c cells have left G0/G1 and entered the cell cycle (S and G2/M phases) by 96 hours of continuous exposure to h-rHGF. When compared with other growth factors, h-rHGF was a much more potent mitogen. The effects of 10 ng/mL (0.1 pmol/L) h-rHGF on DNA synthesis were only achieved by 1.5 pmol/L epidermal growth factor (EGF), 0.1 mumol/L insulin, or 1 mumol/L glucagon. It is noteworthy that the effect of h-rHGF was potentiated by glucagon but not by insulin or EGF. The stimulatory effect of HGF on DNA synthesis was gradually inhibited by h-rHGF transforming growth factor beta (TGF-beta) in the range 1 to 10 ng/ml. The HGF also influenced the expression of other hepatic genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute-Phase Reaction; Adult; Aged; Blood Proteins; Cell Division; Cells, Cultured; DNA; Dose-Response Relationship, Drug; Female; Glycogen; Growth Substances; Hepatocyte Growth Factor; Hormones; Humans; Kinetics; Liver; Male; Middle Aged; Recombinant Proteins