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

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.

α-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study

“…In the AIP context, it attempted to re-establish glucose homeostasis by activating hepatic gluconeogenesis and increasing mitochondrial mass, but it also induced ALAS1 expression [ 12 , 13 , 17 ], thereby exacerbating the porphyrins’ overproduction. In keeping with these findings, we found that the induction of fasting through glucose deprivation halved PBGD enzymatic activity at 50% and sensitized siPBGD cells to upregulate ALAS1, likely via PGC1α, without increasing heme production, similar to what has been reported in AIP rodents and patients exposed to precipitating factors [ 10 , 16 ].…”

“…The binomial association between porphyrins and acute neuropsychiatric attacks has been at the basis of AIP pathogenesis for decades. Still, there are several reports that cast doubt about the exclusive pathogenic role of heme precursors in disease, as AIP patients who accumulate ALA and PBG may not manifest any acute attack throughout their life [ 16 , 22 ]. Thus, other factors may be involved in the pathophysiology of the acute event.…”

“…Treatments were freshly prepared and administered when appropriate. The potential efficacy of α-LA alone and α-LA + Gluc were compared to 0.33 mM glucose (siPBGD + Gluc) [ 16 ].…”

“…Foregoing studies have highlighted that AIP is featured by an impaired glucose metabolism in experimental models to the extent that carbohydrate loading has been proposed as alternative strategy in patients with mild attacks. Moreover, AIP patients showed a higher prevalence of hyperinsulinemia and insulin resistance (IR) compared to control volunteers including family members without HMBS mutations and porphyrin accumulation [ 16 , 17 ], thereby opening new perspectives for the development of novel medical care aiming to improve insulin sensitivity. Consistently, a liver-targeted insulin therapy in AIP mice promoted ALAS1 downregulation and improved glucose metabolism [ 16 ].…”

“…Moreover, AIP patients showed a higher prevalence of hyperinsulinemia and insulin resistance (IR) compared to control volunteers including family members without HMBS mutations and porphyrin accumulation [ 16 , 17 ], thereby opening new perspectives for the development of novel medical care aiming to improve insulin sensitivity. Consistently, a liver-targeted insulin therapy in AIP mice promoted ALAS1 downregulation and improved glucose metabolism [ 16 ]. Therefore, this study aimed to reproduce in vitro a condition that parallels human AIP by silencing PBGD mRNA in human HepG2 hepatoma cells and investigating metabolic alterations occurring at baseline and during a stressful factor (fasting), pointing to an in-depth characterization of glucose metabolism and mitochondrial turnover.…”