High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach.
Isabel SolaresLaura Izquierdo-SanchezMontserrat Morales-ConejoDaniel JericóFrancisco Javier CastelbónKarol Marcela CórdobaAna SampedroCarlos LumbrerasMaría Jesús Moreno-AliagaRafael Enríquez de SalamancaPedro BerraondoAntonio FontanellasPublished in: Biomedicines (2021)
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.
Keyphrases
- type diabetes
- glycemic control
- blood glucose
- insulin resistance
- end stage renal disease
- cancer therapy
- chronic kidney disease
- mental health
- newly diagnosed
- oxidative stress
- metabolic syndrome
- adipose tissue
- ejection fraction
- photodynamic therapy
- risk factors
- high fat diet
- polycystic ovary syndrome
- intensive care unit
- cross sectional
- mesenchymal stem cells
- electronic health record
- bone marrow
- hepatitis b virus
- big data
- weight loss
- depressive symptoms
- endothelial cells
- skeletal muscle
- weight gain
- stress induced