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Avances en terapia insulínica en la diabetes mellitus tipo 1: Aciertos y desaciertos Translated title: Advances in insulin-therapy in type 1 diabetes mellitus: Success and failures

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      Abstract

      La historia del desarrollo del tratamiento farmacológico de la diabetes tuvo un capítulo esencial en el descubrimiento de la insulina y su introducción como terapia de la diabetes tipo 1. El conocimiento de sus complicaciones trajo consigo la necesidad de una terapia más sofisticada. Desde entonces, las preparaciones de insulina y las estrategias terapéuticas han ido desarrollándose inicialmente a expensas del origen de la insulina, y posteriormente con la incorporación de sustancias que modificaban su absorción. Ya en la década de los 90 surgieron entonces los análogos de la insulina, con una especial capacidad de cambio en su farmacocinética. Más adelante se introdujeron nuevas formas de liberación, que son, las bombas de infusión continua, los aerosoles y todo esto apoyado por nuevos sistemas de monitorización de la glucosa. En la última década el trasplante de islotes y la terapia génica con la obtención de células ß a partir de células madres pluripotenciales, aumentan las expectativas en este campo. Todos estos elementos confirman el interminable camino en la búsqueda de terapéuticas eficaces en el tratamiento de la diabetes mellitus tipo 1. Con este trabajo nos proponemos exponer los principales avances en materia de terapia insulínica y reflexionar sobre aciertos y desaciertos en su introducción.

      Translated abstract

      History of development of pharmacological treatment of diabetes had an essential chapter in descovery of insulin and its introduction as therapy of Type 1 diabetes. Knowledge of its complications, lead to the need of a more sophisticated therapy. Since then, insulin preparations and therapeutical strategies has been initially developing at the expense of insulin origin, and then with incorporation of substances modifying its absorption. As long as in 1990, emerged insulin analogues with an special change ability in its pharmacokinetics. Then, new ways of release were introduced, e.g. continuous infusion pumps, aerosols, and all this supported by new systems of glucose monitoring. In the pas decade, islet transplant and gen therapy with obtention of ß cells from pluripotential stem cells, increase expectation in this field. All these elements confirm the endless path in the search of efficaceous therapeutics in treatment of Type 1 diabetes mellitus. Aim of this paper is to expose main advances on the subject of insulin therapy and to think over sucess and failures in its introduction.

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      Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use.

      In recent years, analogs of human insulin have been engineered with the aim of improving therapy for people with diabetes. To ensure that the safety profile of the human hormone is not compromised by the molecular modifications, the toxico-pharmacological properties of insulin analogs should be carefully monitored. In this study, we compared the insulin and IGF-I receptor binding properties and metabolic and mitogenic potencies of insulin aspart (B28Asp human insulin), insulin lispro (B28Lys,B29Pro human insulin), insulin glargine (A21Gly,B31Arg,B32Arg human insulin), insulin detemir (NN304) [B29Lys(epsilon-tetradecanoyl), desB30 human insulin], and reference insulin analogs. Receptor affinities were measured using purified human receptors, insulin receptor dissociation rates were determined using Chinese hamster ovary cells overexpressing the human insulin receptor, metabolic potencies were evaluated using primary mouse adipocytes, and mitogenic potencies were determined in human osteosarcoma cells. Metabolic potencies correlated well with insulin receptor affinities. Mitogenic potencies in general correlated better with IGF-I receptor affinities than with insulin receptor off-rates. The 2 rapid-acting insulin analogs aspart and lispro resembled human insulin on all parameters, except for a slightly elevated IGF-I receptor affinity of lispro. In contrast, the 2 long-acting insulin analogs, glargine and detemir, differed significantly from human insulin. The combination of the B31B32diArg and A21Gly substitutions provided insulin glargine with a 6- to 8-fold increased IGF-I receptor affinity and mitogenic potency compared with human insulin. The attachment of a fatty acid chain to LysB29 provided insulin detemir with reduced receptor affinities and metabolic and mitogenic potencies but did not change the balance between mitogenic and metabolic potencies. The safety implications of the increased growth-stimulating potential of insulin glargine are unclear. The reduced in vitro potency of insulin detemir might explain why this analog is not as effective on a molar basis as human insulin in humans.
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        Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154.

        Reported effects of anti-CD154 treatment on autoimmunity, alloreactivity, and inflammatory events mediated by macrophages and endothelial cells indicated that it might be an ideal agent for the prevention of intrahepatic islet allograft failure. This hypothesis was tested in MHC-mismatched rhesus monkeys. Transplantation of an adequate number of viable islets resulted in engraftment and insulin independence in six of six recipients treated with anti-CD154 (hu5c8) induction plus monthly maintenance therapy (post-operative day >125, >246, >266, >405, >419, >476). Anti-CD154 (hu5c8) displayed no inhibitory effect on islet cell function. For monkeys followed for >100 days, continued improvement in graft function, as determined by first phase insulin release in response to intravenous glucose, was observed after the first 100 days post-transplant. No evidence of toxicity or infectious complications has been observed. All recipients treated with anti-CD154 became specifically nonresponsive to donor cells in mixed lymphocyte reactions. Furthermore, three monkeys are now off therapy (>113, >67, and >54 days off anti-CD154), with continued insulin independence and donor-specific mixed lymphocyte reaction hyporeactivity. In striking contrast to all previously tested strategies, transplantation of an adequate number of functional islets under the cover of anti-CD154 (hu5c8) monotherapy consistently allows for allogeneic islet engraftment and long-term insulin independence in this highly relevant preclinical model.
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          Insulin analogues and their potential in the management of diabetes mellitus.

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            Author and article information

            Affiliations
            [1 ] Instituto Nacional de Endocrinología Cuba
            Contributors
            Role: ND
            Role: ND
            Journal
            end
            Revista Cubana de Endocrinología
            Rev Cubana Endocrinol
            Editorial Ciencias Médicas (Ciudad de la Habana )
            1561-2953
            April 2007
            : 18
            : 1
            : 0
            S1561-29532007000100007

            http://creativecommons.org/licenses/by/4.0/

            Product
            Product Information: SciELO Cuba
            Categories
            ENDOCRINOLOGY & METABOLISM

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