Antilipolytic activity of insulin and proinsulin on ACTH and cyclic nucleotide-induced lipolysis in the isolated adipose cell of rat

Solomon, Solomon S.; Brush, James S.; Kitabchi, Abbas E.

doi:10.1016/0005-2760(70)90104-9

Cited by 35 publications

(13 citation statements)

References 7 publications

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“…Recent studies in our laboratory (19) on biological properties of beef and pork proinsulin and beef intermediates have extended our findings in regard to antilipolytic properties of these compounds on ACTH-induced lipolysis under isolated fat cells. The half-maximal response doses calculated for the above compounds give the following figures expressed as molar concentration for antilipolytic properties of pork insulin and proinsulin, as well as beef insulin, proinsulin, and intermediates, respectively: 1.4 X 10', 1.3 X 109, 1.7 X 10-1, 2.7 X 10-10, and 3.5 X 10'-.…”

Section: Addendumsupporting

confidence: 69%

The biological and immunological properties of pork and beef insulin, proinsulin, and connecting peptides

Kitabchi¹

1970

J. Clin. Invest.

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A B S T R A C T The recently discovered hormone precursors, pork and beef proinsulins, their respective connecting peptides, and beef proinsulin intermediates have been compared to insulin in their ability to stimulate the conversion of glucose-U-"C to 1"CO2 and lipids in isolated fat cells. The concentrations of beef and pork proinsulins required to achieve the same biological effect were, respectively, 15 and 10 times that of insulin. Beef proinsulin intermediates required only 2.6 times the concentration of insulin for the same effect. Pork and beef connecting peptides in high or low concentrations alone or in combination with proinsulin, insulin, or proinsulin intermediates showed no biological effect on the isolated fat cell system. The insulin-like activity of beef and pork proinsulins on the isolated fat cell system was not abolished with pancreatic trypsin or kallikrein inhibitors. Pork insulin antiserum inhibited the biological activity of pork insulin and proinsulin as well as that of beef insulin or proinsulin. Pork proinsulin antiserum also inhibited the insulin-like activity of both pork insulin and proinsulin. By the radioimmunoassay method, pork insulin antiserum bound only j to j as much proinsulin as insulin. Beef proinsulin intermediates, on the other hand, were found to react with the pork insulin antiserum to an extent nearly equal to that of insulin. These data suggest that (a) proinsulin exhibits its effect on the isolated fat cells independent of its conversion to insulin, (b) connecting peptides have no biological effect under present experimental conditions, and (c) in comparison to insulin, immunological reactivity of proinsulin is greater than its biological activity using our pork insulin antiserum; thus, the This work was presented in part at the Midwestern Section meeting of the American Federation for Clinical Research, October 1969 (1).

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Section: Addendumsupporting

confidence: 69%

The biological and immunological properties of pork and beef insulin, proinsulin, and connecting peptides

Kitabchi¹

1970

J. Clin. Invest.

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“…The production of both components is regulated by physiological concentrations of insulin, although production of the stimulator appears to be more sensitive to the hormone after 5 min of incubation. Although the relationship between the two factors is not yet clear, these results imply the existence of an intrinsic homeostatic mechanism for the regulation ofPDHase by insulin and might perhaps be related to the paradoxical effects of insulin on lipolysis in adipocytes (31,32).…”

Section: Discussionmentioning

confidence: 99%

Putative mediators of insulin action: regulation of pyruvate dehydrogenase and adenylate cyclase activities.

Saltiel¹,

Siegel²,

Jacobs³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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Recent evidence suggests that certain actions of insulin may be mediated by the selective generation of chemically undefined intracellular substances. Incubation of rat liver particulate fraction with low concentrations of insulin enhances the release into the supernatant of a substance that stimulates mitochondrial pyruvate dehydrogenase. Higher concentrations of insulin release less stimulating activity. It is possible to resolve activities that stimulate and inhibit pyruvate dehydrogenase by differential ethanol extraction of the supernatant solutions. The elaboration of both factors is dependent upon the presence of insulin in a dose-dependent manner. Moreover, fractions that contain the pyruvate dehydrogenase-inhibiting activity also inhibit adipocyte basal and hormonally stimulated adenylate cyclase. The production of this adenylate cyclase inhibitory activity is also stimulated by insulin. Cyclase inhibition is virtually abolished when the nonhydrolyzable ATP analog, 5'-adenylyl imidodiphosphate, is included in the assay. These results indicate that the bimodal effects of insulin on certain functions may be ascribed to the generation of at least two distinct chemical substances that show opposing activities, which may operate by regulating phosphorylation reactions.

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“…6), perhaps with different potencies, may explain the apparent resolution of stimulatory and inhibitory activities (7). Biphasic responses of target enzymes to these substances may account for the paradoxical effects of insulin on lipolysis (17), adenylate cyclase (18), and cAMP PDE (19). Aside from apparent differences in charge and solubility (7), no differences in the size or chemical sensitivities of these two substances were detected.…”

Section: Discussionmentioning

confidence: 99%

Insulin stimulates the generation from hepatic plasma membranes of modulators derived from an inositol glycolipid.

Saltiel¹,

Cuatrecasas²

1986

Proc. Natl. Acad. Sci. U.S.A.

237

122

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Insulin binding to plasma membrane receptors results in the generation of substances that acutely mimic the actions of the hormone on certain target enzymes. Two such substances, which modulate the activity of the high-affinity cAMP phosphodiesterase (EC 3.1.4.17), have been purified from hepatic plasma membranes. The two have similar properties and activities but can be resolved by ion-exchange chromatography and high-voltage electrophoresis. They exhibit a net negative charge, even at pH 1.9, and an apparent molecular weight of approximately 1400. The generation of these substances from membranes by insulin can be reproduced by addition of a phosphatidylinositol-specific phospholipase C purified from Staphylococcus aureus. This enzyme is known to selectively hydrolyze phosphatidylinositol and release from membranes several proteins that are covalently linked to phosphatidylinositol by a glycan anchor. Both enzyme-modulating substances appear to be generated by the phosphodiesterase cleavage of a phosphatidylinositol-containing glycolipid precursor that has been characterized by thin-layer chromatography. Some of the chemical properties of these substances have been examined. They appear to be related complex carbohydrate-phosphate substances containing glucosamine and inositol. These findings suggest that insulin may activate a selective phospholipase activity that hydrolyzes a membrane phospholipid, releasing a carbohydrate-containing molecule that regulates cAMP phosphodiesterase and perhaps other insulin-sensitive enzymes.The molecular events involved in the biological actions of insulin remain poorly understood. Several studies have suggested that, subsequent to the interaction of insulin with its receptor, one or more chemical mediators are generated that alter the activities of certain insulin-sensitive enzymes (1). The production of these substances has been detected in insulin-treated cells (2, 3). They can also be generated from membrane fractions in response to insulin (4-7), suggesting that all of the necessary components for this process are located in the plasma membrane.In this communication we report the purification and identification of two related carbohydrate-phosphate substances that are generated from liver plasma membranes in response to insulin. These substances modulate the activity of the high-affinity cAMP phosphodiesterase (PDE; EC 3.1.4.17) and may be responsible for the regulation of this enzyme by insulin. EXPERIMENTAL PROCEDURESMaterials. All reagents were from Sigma, with the exception of collagenase (Millipore); Generation of cAMP PDE Modulators by Insulin. These were generated from bovine liver particulate fractions by previously described methods (6)(7)(8) with modification. The particulate fraction (8) was prepared from 100 g of bovine liver and suspended in 500 ml of 50 mM ammonium bicarbonate, pH 7.4 (buffer A), at a final concentration of 2-4 mg of protein per ml. This solution was incubated with 10 nM insulin for 10 min at 370C and acidified to pH 4.0 with formi...

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Antilipolytic activity of insulin and proinsulin on ACTH and cyclic nucleotide-induced lipolysis in the isolated adipose cell of rat

Cited by 35 publications

References 7 publications

The biological and immunological properties of pork and beef insulin, proinsulin, and connecting peptides

The biological and immunological properties of pork and beef insulin, proinsulin, and connecting peptides

Putative mediators of insulin action: regulation of pyruvate dehydrogenase and adenylate cyclase activities.

Insulin stimulates the generation from hepatic plasma membranes of modulators derived from an inositol glycolipid.

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