Centrally mediated hypoglycemic effect of insulin: apparent involvement of specific insulin receptors (original) (raw)
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Characterization and Regulation of Insulin Receptors in Rat Brain
Journal of Neurochemistry, 1984
An in vitro receptor binding assay, using filtration to separate bound from free [1251]insulin, was developed and used to characterize insulin receptors on membranes isolated from specific areas of rat brain. The kinetic and <equilibrium binding properties of central receptors were similar to those of hepatic receptors. The binding profiles in all tissues were complex and were consistent with binding in multiple steps or to multiple sites. Similar binding properties were found among receptors in olfactory tuberclebulb, cerebral cortex, hippocampus, striatum, hypothalamus, and cerebellum. High affinity [1251]insulin binding sites (K , = 3-11 nM) were distributed evenly between membranes isolated from PI and P, fractions of these brain areas, with the exception of the olfactory tubercle in which binding to P, membranes was
Receptor binding and biological effect of insulin in human adipocytes
Diabetologia, 1977
The binding of 125I-labelled insulin to human adipocytes was studied at 37 ~ C. The precipitability of the 125I-labelled insulin preparation (0.03 nmol/1) in tfichloroacetic acid and the concentration of biologically active insulin (7.5 nmol/1) remained constant in buffer incubated with human adipocytes (100 ~tl cells/ml suspension) for 30-60 minutes at 37 ~ C, whereas more than half of the insulin was inactivated by rat fat cells under the same conditions. A constant level of binding of 125I-labelled insulin (0.03 nmol/1) to human adipocytes was obtained after 45 minutes. The apparent dissociation constant of receptor binding was about 0.2 nmol/1 as compared to about 2 nmol/l for rat adipocytes. Conversion of [U-14C]glucose to lipids was stimulated halfmaximally by about 0.05 nmol/l of insulin (similar to rat adipocytes). Thus, half-maximal stimulation of human adipocytes was obtained with a receptor occupancy of about 20-30 per cent.
Functional Properties of the Subtype of Insulin Receptor Found on Neurons
Journal of Neurochemistry, 1988
In this report, we have examined the structure, regulation, and function of insulin receptors in cultured neurons from fetal chicken brain. The apparent molecular weight of the a-subunit of neuronal insulin receptors, analyzed by photoaffinity labeling and sodium dodecyl sulfate gel electrophoresis under reducing conditions, was 1 15,000. The number of insulin receptors in the cultures increased from day 2 to day 4 during a period of extensive process formation. After 5 days in culture, there were approximately 40,000 high-affinity insulin receptors per neuron. When neurons were photoaffinity labeled at 16°C and then warmed to 37°C for 30 rnin, approximately 40% of the cell-surface receptors were recovered in the intracellular, trypsin-insensitive pool. Chronic exposure of neurons to insulin (100 ng/ml) resulted in a time-dependent loss of neuronal insulin receptors with a maximal decrease of 50% after 24 h. Insulin had no effect on glucose transport, glucose oxidation, or glycogen synthase activity in neurons. ~
Mechanism of action of insulin and insulin analogues
Diabetologia, 1981
A [14C]~glucose tracer infusion method was used to compare the effects of insulin infusion on glucose metabolism with the effects of infusion of three semisynthetic modified insulins and of proinsu= lin. Insulin produced hypoglycaemia in the anaesthetised dog by decreasing hepatic glucose production and increasing peripheral glucose utilisation. Compensatory antihypoglycaemic mechanisms eventually modified these responses. A1, Be9-Diacetyl insulin exerted an hypoglycaemic effect entirely by stimulation of peripheral glucose uptake. A1-B29 crosslinked insulins and proinsulin produced hypoglycaemia almost entirely by decreasing hepatic glucose production and had little effect on tissue uptake. These observations suggest that insulin analogues may have actions in vivo that are qualitatively different from those of native insulin and suggest that certain analogues have a predominant action on the liver. This has important therapeutic implications concerning the development of semisynthetic insulins for clinical use.
The neuronal insulin receptor in its environment
Journal of Neurochemistry
Insulin is known mainly for its effects in peripheral tissues, such as the liver, skeletal muscles and adipose tissue, where the activation of the insulin receptor (IR) has both short-term and long-term effects. Insulin and the IR are also present in the brain, and since there is evidence that neuronal insulin signaling regulates synaptic plasticity and that it is impaired in disease, this pathway might be the key to protection or reversal of symptoms, especially in Alzheimer's disease. However, there are controversies about the importance of the neuronal IR, partly because biophysical data on its activation and signaling are much less complete than for the peripheral IR. This review briefly summarizes the neuronal IR signaling in health and disease, and then focuses on known differences between the neuronal and peripheral IR with regard to alternative splicing and glycosylation, and lack of data with respect to phosphorylation and membrane subdomain localization. Particularities in the neuronal IR itself and its environment may have consequences for downstream signaling and impact synaptic plasticity. Furthermore, establishing the relative importance of insulin signaling through IR or through hybrids with its homolog, the insulin-like growth factor 1 receptor, is crucial for evaluating the consequences of brain IR activation. An improved biophysical understanding of the neuronal IR may help predict the consequences of insulintargeted interventions.
Proceedings of the National Academy of Sciences, 1974
Chronic (5-16 hr) exposure of cultured human lymphocytes to 10 -8 M insulin at 37° in vitro produced a decrease in insulin receptor concentrations unaccounted for by simple occupancy of sites; acute exposure (0-2 hr) was without effect. These results reproduced observations in vivo where chronic hyperinsulinemia (e.g., 10 -8 M insulin in the circulation of obese insulinresistant hyperglycemic mice) is associated with a substantial reduction in the concentration of insulin receptors per cell, while acute hyperinsulinemia in vivo has no effect on receptor concentration. These data suggest a reciprocal relationship between insulin in the extracellular fluid and the concentration of insulin receptors per cell, which is mediated at the target cell itself by intracellular insulin-sensitive regulatory processes and directly affects target-cell sensitivity to hormone.