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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8002016 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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