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REGULATION OF HEPATOCELLULAR INSULIN RECEPTORS BY INSULIN AND DEXAMETHASONE: RELATION TO THE REGULATION OF BASAL AND INSULIN-DEPENDENT GLYCOGENESIS.

W.E.Fleig, G.NUther-Fleig, S.Steudter, D.Enderle, H.Ditschuneit. Department of Internal Medicine, Klinikum der Universit~t Ulm, Ulm, Fed. Rep. of Germany.

Regulation by insulin and dexamethasone of insulin binding (Diabetes 33:285) and basal and insulin-stimulated glycogen synthesis from 14C-glucose, net glycogen deposition and glycogen synthase activation was studied in adult rat hepatocytes in serum-free culture (Biochim. Bio- phys. Acta 805:165). Insulin receptor number was increased in a dose-dependent fashion by dexamethasone (+40%) added to the medium between 24 and 48 h of culture, and reduced by insu- lin (-45%), while ligand a f f in i t y of receptors was unaltered. Insulin-induced down-regulation of insulin receptors was not affected by dexamethasone. Changes in insulin receptor numbers were reflected by similar changes in the sensit iv i ty to insulin of glycogenesis from glucose and net glycogen deposition. Increases and reductions of the responsiveness of these para- meters and of glycogen synthase I act iv i ty to insulin caused by both hormones were inversely related to cel lular glycogen contents. Hormonal effects on the basal act iv i ty of the glyco- genic pathway were different from the action on insulin responsiveness. The response of gly- cogenesis to a "physiological" step in ambient glucose concentration (5 to 10 mM) was small compared to the acute action of insulin. We conclude that 1) glucocorticoidsincreaseinsulin receptors without affecting insulin-induced down-regulation, 2) changes by insulin and dexa- methasone of the hepatocellular sensi t iv i ty to insulin with respect to glycogen metabolism are directly related to alterations in the concentration of insulin receptors, 3) changes in the responsiveness to insulin of the glycogenic parameters are mediated by postbinding events, 4) cellular glycogen content may represent one of the determinants of responsiveness, 5) ba- sal and insulin-dependent glycogenesis are regulated independently, 6) insulin rather than ambient glucose concentration is the prime stimulator of hepatic glycogen synthesis.

106

COMPLEMENT ACTIVATION IN PRIMARY BILIARY CIRRHOSIS CPBC): INCREASED HEPATIC SYNTHESIS ANO LACK OF INFLUENCE OF PENICILLAMINE

A.Floreani, P.Marson', M.Chiaramonte, M.Salvagnini, P.F.Gambarz ,V.Malatesta e M~Zagolin, R.Naccarato Cattedra di Gastroenterologia and ~Cattedra di Reuma- tologia, Istituto di Medicine Interne, Universit~ di Padova [Italy)

Sixteen patients with PBC in early or late stages of the disease CII=4; III=9; IV=3) without signs of hepatic decompensation were studied. The mean age was 52 yrs [range 38-63 yrsl~ 7/16 were treated with Penicillamlne C600 mg/day) for over e year. The control subjects included: 19 patients with rheumatoid arthritis iRA) not treated with slow-acting drugs and I? healthy controls matched for age and sex. Total haemolytic activity [CH50), C~, CA, Factor B and C 3 breakdown product, C3d Caccordlng to Perrin et al.) were determined in all subjects. RESULTS AND COMMENTS: No differences were found between Penicillamine treated and non treated patients. No correlation was found between levels of complement components or catabolic pro-

ducts and cholestasis degree. Table summarizes our main findings: Controls (N.17) PBC (N.16) RA (N.19)

CH50 CMtSE) 55.4±2.1 87.0±4.3 ~ 63.1±2.6 ~ C_ (MtSE) 135.9±7.1 164.7±7.7 ~ 136.2±5.6 C~ (M±SEI 24,1±1.8 24.1±2,0 22.0±1.3 F~ctor B CM±SE) 37.3±2.8 49.3±2.7 ~ 49.8±3.8 ~

12.1±O.I 17.6±I.4.x 15.2±1.1 ~ C~d CMtSE} J significantly different from controls (p<0.05 or lower) • signiflcantly different from RA Cp~0.05 or lower)

The increased levels of C3d observed both in RA and PBC ere consistent with a complement hypercatabolism. However, very high levels of C 3 have been observed in PBC (but not in RA). This can be interpreted as an increased hepatic synthesis of C 3 in PBC similar to that observed for other proteins synthesized by hepatocytee in this disorder. Penicillamine does

not seem to influence complement hypercatabolism.

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