Human serum contains, in addition to the "classical" 7.5-kDa insulin-like growth factors (IGFs) I and II, small amounts of larger IGF-II. A 10-kDa IGF-II was isolated by gel filtration, inmunoaffinity chromatography, and reversed-phase HPLC. Upon amino acid sequence determination, a substitution of Cys-Gly-Asp for Ser-33 was found as well as a COOH-terminal extension of 21 residues (E peptide). These sequence differences suggest that 10-kDa IGF-H is a precursor of a variant IGF-II. Since the substitution is not located at a known intron/exon hinge region, the finding of this variant IGF-II is evidence for the presence of more than one gene for IGF-II.
1. Adenylate cyclase in fat-cell ghosts from streptozotocin-diabetic rats is 34% lower than in normal rats. Relative to the basal activity, maximal stimulation by epinephrine and isoproterenol is 10-fold in normal and 14-fold in diabetic fat cells, whereas maximal stimulation by fluoride is 7-fold in both states.2. The sensitivity of adenylate cyclase to epinephrine and isoproterenol is increased in fat-cell ghosts from diabetic rats : the concentrations of these catecholamines required for half-maximal activation of adenylate cyclase is three times lower in diabetic than in normal cells. In contrast, half-maximal stimulation by fluoride occurs at the same concentration in both states.3. Epinephrine-induced activation of cyclic-AMP-dependent protein kinase and of lipolysis correlate with the activation of adenylate cyclase. The epinephrine concentration required for halfmaximal activation of cyclic-AMP-dependent protein kinase and of lipolysis is three times lower in diabetic than in normal cells.in fat-cell homogenates and fat-cell ghosts from diabetic rats. Phosphodiesterase is, therefore, unlikely to be involved in the mechanism causing the 'hypersensitivity phenomenon'.5. The sensitivity of adenylate cyclase to adrenocorticotropin is increased 1 0-fold in fat-cell ghosts from diabetic rats. However, no correlation between adrenocorticotropin-stimulated adenylate cyclase activity and lipolysis is observed. Concentrations required to elicit the first measurable activation of adenylate cyclase stimulate glycerol production maximally. Stimulation of glycerol production starts at 1 00-fold lower concentrations than stimulation of adenylate cyclase.6. Insulin treatment of diabetic rats for 24 h reduces the response of adenylate cyclase to both epinephrine and adrenocorticotropin as compared with saline-treated diabetic animals.It is concluded that the increased sensitivity of adenylate cyclase to epinephrine in diabetic fat-cells is responsible for the enhanced lipolytic sensitivity to this hormone. Increased sensitivity of adenylate cyclase may be due to a change in the binding affinity of the hormone receptor or to altered properties of the coupling mechanism between the receptor and the catalytic subunit of adenylate cyclase.
Cyclic AMP phosphodiesterase activity is increased 55Adipose tissue from streptozotocin-diabetic rats is 5 -10-times more sensitive to the lipolytic action of epinephrine, but not to that of adrenocorticotropin, glucagon and dibutyryl adenosine 3',5'-monophosphate than adipose tissue from normal rats [l] . 'Lipolytic hypersensitivity' to epinephrine is reversible by insulin treatment [ 11. These findings are in accord with the recent observation that the cyclic AMP/protein kinase system of diabetic adipose tissue displays increased sensitivity to activation by epinephrine, but not to activation by adrenocorticotropin [2]. Altogether Abbreoiution. Cyclic AMP, adenosine 3',5'-monophosphate. Enzymes. Adenylate cyclase (EC 4.6.1.1); cyclic AMP phosphodiesterase (EC 3.1.4.17); phosphocreatine ...
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