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High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach

Acute porphyria attacks are associated with the strong up-regulation of hepatic heme synthesis and over-production of neurotoxic heme precursors. First-line therapy is based on carbohydrate loading. However, altered glucose homeostasis could affect its efficacy. Our first aim was to investigate the...

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Autores principales: Solares, Isabel, Izquierdo-Sánchez, Laura, Morales-Conejo, Montserrat, Jericó, Daniel, Castelbón, Francisco Javier, Córdoba, Karol Marcela, Sampedro, Ana, Lumbreras, Carlos, Moreno-Aliaga, María Jesús, Enríquez de Salamanca, Rafael, Berraondo, Pedro, Fontanellas, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002016/
https://www.ncbi.nlm.nih.gov/pubmed/33807619
http://dx.doi.org/10.3390/biomedicines9030255
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author Solares, Isabel
Izquierdo-Sánchez, Laura
Morales-Conejo, Montserrat
Jericó, Daniel
Castelbón, Francisco Javier
Córdoba, Karol Marcela
Sampedro, Ana
Lumbreras, Carlos
Moreno-Aliaga, María Jesús
Enríquez de Salamanca, Rafael
Berraondo, Pedro
Fontanellas, Antonio
author_facet Solares, Isabel
Izquierdo-Sánchez, Laura
Morales-Conejo, Montserrat
Jericó, Daniel
Castelbón, Francisco Javier
Córdoba, Karol Marcela
Sampedro, Ana
Lumbreras, Carlos
Moreno-Aliaga, María Jesús
Enríquez de Salamanca, Rafael
Berraondo, Pedro
Fontanellas, Antonio
author_sort Solares, Isabel
collection PubMed
description Acute porphyria attacks are associated with the strong up-regulation of hepatic heme synthesis and over-production of neurotoxic heme precursors. First-line therapy is based on carbohydrate loading. However, altered glucose homeostasis could affect its efficacy. Our first aim was to investigate the prevalence of insulin resistance (IR) in an observational case-control study including 44 Spanish patients with acute intermittent porphyria (AIP) and 55 age-, gender- and BMI-matched control volunteers. Eight patients (18.2%) and one control (2.3%, p = 0.01) showed a high HOMA-IR index (cut-off ≥ 3.4). Patients with IR and hyperinsulinemia showed clinically stable disease. Thus, the second aim was to evaluate the effect of the co-administration of glucose and a fast-acting or new liver-targeted insulin (the fusion protein of insulin and apolipoprotein A-I, Ins-ApoAI) in AIP mice. The combination of glucose and the Ins-ApoAI promoted partial but sustained protection against hepatic heme synthesis up-regulation compared with glucose alone or co-injected with fast-acting insulin. In a prevention study, Ins-ApoAI improved symptoms associated with a phenobarbital-induced attack but maintained high porphyrin precursor excretion, probably due to the induction of hepatic mitochondrial biogenesis mediated by apolipoprotein A-I. In conclusion, a high prevalence of IR and hyperinsulinemia was observed in patients with AIP. The experimental data provide proof-of-concept for liver-targeted insulin as a way of enhancing glucose therapy for AIP.
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spelling pubmed-80020162021-03-28 High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach Solares, Isabel Izquierdo-Sánchez, Laura Morales-Conejo, Montserrat Jericó, Daniel Castelbón, Francisco Javier Córdoba, Karol Marcela Sampedro, Ana Lumbreras, Carlos Moreno-Aliaga, María Jesús Enríquez de Salamanca, Rafael Berraondo, Pedro Fontanellas, Antonio Biomedicines Article Acute porphyria attacks are associated with the strong up-regulation of hepatic heme synthesis and over-production of neurotoxic heme precursors. First-line therapy is based on carbohydrate loading. However, altered glucose homeostasis could affect its efficacy. Our first aim was to investigate the prevalence of insulin resistance (IR) in an observational case-control study including 44 Spanish patients with acute intermittent porphyria (AIP) and 55 age-, gender- and BMI-matched control volunteers. Eight patients (18.2%) and one control (2.3%, p = 0.01) showed a high HOMA-IR index (cut-off ≥ 3.4). Patients with IR and hyperinsulinemia showed clinically stable disease. Thus, the second aim was to evaluate the effect of the co-administration of glucose and a fast-acting or new liver-targeted insulin (the fusion protein of insulin and apolipoprotein A-I, Ins-ApoAI) in AIP mice. The combination of glucose and the Ins-ApoAI promoted partial but sustained protection against hepatic heme synthesis up-regulation compared with glucose alone or co-injected with fast-acting insulin. In a prevention study, Ins-ApoAI improved symptoms associated with a phenobarbital-induced attack but maintained high porphyrin precursor excretion, probably due to the induction of hepatic mitochondrial biogenesis mediated by apolipoprotein A-I. In conclusion, a high prevalence of IR and hyperinsulinemia was observed in patients with AIP. The experimental data provide proof-of-concept for liver-targeted insulin as a way of enhancing glucose therapy for AIP. MDPI 2021-03-05 /pmc/articles/PMC8002016/ /pubmed/33807619 http://dx.doi.org/10.3390/biomedicines9030255 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Solares, Isabel
Izquierdo-Sánchez, Laura
Morales-Conejo, Montserrat
Jericó, Daniel
Castelbón, Francisco Javier
Córdoba, Karol Marcela
Sampedro, Ana
Lumbreras, Carlos
Moreno-Aliaga, María Jesús
Enríquez de Salamanca, Rafael
Berraondo, Pedro
Fontanellas, Antonio
High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach
title High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach
title_full High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach
title_fullStr High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach
title_full_unstemmed High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach
title_short High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach
title_sort high prevalence of insulin resistance in asymptomatic patients with acute intermittent porphyria and liver-targeted insulin as a novel therapeutic approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002016/
https://www.ncbi.nlm.nih.gov/pubmed/33807619
http://dx.doi.org/10.3390/biomedicines9030255
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