RT Journal Article
T1 High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach
A1 Solares, Isabel
A1 Izquierdo Sánchez, Laura
A1 Morales Conejo, Montserrat
A1 Jericó, Daniel
A1 Castelbón, Francisco Javier
A1 Córdoba, Karol Marcela
A1 Sampedro, Ana
A1 Lumbreras Bermejo, Carlos Juan
A1 Moreno Aliaga, María Jesús
A1 Enríquez de Salamanca, Rafael
A1 Berraondo, Pedro
A1 Fontanellas, Antonio
AB 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.
PB MDPI
SN 2227-9059
YR 2021
FD 2021
LK https://hdl.handle.net/20.500.14352/7391
UL https://hdl.handle.net/20.500.14352/7391
LA eng
NO This research was supported in part by grants from Spanish Institute of Health Carlos III (FIS) cofunded by European Union (ERDF/ESF, “A way to make Europe”/”Investing in your future” [grant numbers PI15/01951, PI18/00860 and PI19/01128], the Spanish Fundación Mutua Madrileña de Investigación Médica, the Spanish Fundación Eugenio Rodríguez Pascual, the CaixaImpulse program, CIBERobn and the Spanish Fundación FEDER para la investigación de enfermedades raras. The financial sponsors had no role in the analysis or the development of conclusions. The investigators are solely responsible for the content and the decision to submit the manuscript for publication.
NO Unión Europea
NO Instituto Español de Salud Carlos III
NO Fundación La Caixa
NO CIBERobn
NO Fundación FEDER para la investigación de enfermedades raras
NO Fundación Eugenio Rodríguez Pascual
NO Fundación Mutua Madrileña de Investigación Médica
DS Docta Complutense
RD 12 abr 2025