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

Isabel Solares,Francisco Javier Castelbón,Antonio Fontanellas,Rafael Enríquez De Salamanca,Daniel Jericó,Pedro Berraondo,Montserrat Morales-Conejo,Laura Izquierdo-Sánchez,Carlos Lumbreras,Karol Marcela Córdoba,María Jesús Moreno-Aliaga,Ana Sampedro

doi:10.3390/biomedicines9030255

Abstract

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.

Highlights

Acute intermittent porphyria (AIP, MIM 176000) is an autosomal dominant metabolic disease caused by a partial deficiency of the hepatic porphobilinogen deaminase (PBGD, EC 4.3.1.8), the third enzyme of the heme synthesis pathway [1,2,3]
Forty-four Spanish patients with acute intermittent porphyria (AIP) and 55 control volunteers (CV) matched by age, gender, and BMI were enrolled in an observational case-control study in order to estimate the homeostasis model assessment of insulin resistance (HOMA-IR) index
A high prevalence of hyperinsulinemia and IR was observed in Spanish patients carrying a mutation in the PBGD gene who had either stable or asymptomatic disease (AIP-ASHE)

Summary

Introduction

Acute intermittent porphyria (AIP, MIM 176000) is an autosomal dominant metabolic disease caused by a partial deficiency of the hepatic porphobilinogen deaminase (PBGD, EC 4.3.1.8), the third enzyme of the heme synthesis pathway [1,2,3]. Acute attacks are associated with the high accumulation of porphyrin precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG), when hepatic heme synthesis is up-regulated by endogenous or exogenous factors, such as fasting, hormonal fluctuations during the menstrual cycle, infection, stress, smoking, alcohol, or exposure to porphyrinogenic drugs. All these factors strongly induce the transcription of the first and rate-limiting enzyme in the heme synthesis pathway, ALA Synthase 1 (ALAS1, EC 2.3.1.37) in hepatocytes [1,6,7,8]. Fasting, acting through the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPARα) and the PPAR-gamma coactivator-1 alpha (PGC-1α), can induce a direct transcriptional up-regulation of hepatic ALAS1 [10,11]

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