Lifestyle factors including diet and biochemical biomarkers in acute intermittent porphyria: Results from a case-control study in northern Norway

Storjord, Elin; Dahl, Jim André; Landsem, Anne; Ludviksen, Judith Krey; Karlsen, Marlene Blomstereng; Karlsen, Bård Ove; Brekke, Ole-Lars

doi:10.1016/j.ymgme.2018.12.006

Cited by 24 publications

(28 citation statements)

References 42 publications

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“…Of interest, PBGD mutation carriers with hyperinsulinemia report no clinical symptoms related to AIP. Similarly, Storjord et al also found higher serum insulin levels associated with lower biochemical disease activity in their patient cohort [15]. These data suggest that IR and high-serum insulin levels are not a consequence of disease activity, but rather that sustained hyperinsulinemia can protect against acute attacks of porphyria.…”

Section: Discussionmentioning

confidence: 64%

“…However, recent studies have not shown a clear preventive effect. While high carbohydrate intake and the subsequent increase of insulin levels were associated with lower biochemical disease activity in a case-control trial performed in northern Norway [15], prophylactic infusion of dextrose or a carbohydrate-rich diet have yielded inconclusive clinical findings in epidemiological studies in the USA [16].…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…[104][105][106] Finally, subjects with acute intermittent porphyria should avoid the KD as the lack of carbohydrates in is a well-known precipitating factor causing relapse of the condition. 107…”

Section: Increased Serum Uric Acid and Abnormal Lipid Profilementioning

confidence: 99%

Scientific evidence underlying contraindications to the ketogenic diet: An update

et al. 2020

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Summary First identified as a feasible treatment for intractable epilepsy, the ketogenic diet (KD) has recently gained popularity thanks to growing evidence on applications such as weight loss, most importantly, but also NAFLD, cancer, neurologic conditions and chronic pain. As with any treatment, whether pharmacologic or not, the KD might not be an appropriate intervention for every individual, and a number of contraindications have been proposed, now deeply rooted into clinical practice, excluding de facto many patients that could benefit from its use. However, many of these concerns were expressed due to the absence of clinical studies conducted on fragile populations, and an assessment of lately emerged evidence relative to KD safety is currently lacking and much needed. We herein provide a critical revision of the literature behind each safety alert, in order to guide through the treatment options in the case of subjects with an indication to the KD and a borderline safe situation. Based on available evidence, the possible use of this diet as a therapeutic intervention should be assessed on a patient‐to‐patient basis by adequately skilled medical doctors, keeping in mind current recommendations, but reading them through the knowledge of the current state of the art.

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“…The basal characterization of hepatic metabolism in AIP context has been poorly explored, and just one study reported that the hepatic transcriptomic profile was similar between AIP and the congenic wild-type (WT) mice in the absence of the stress-induced attack [ 12 ]. Nonetheless, the characterization of nutritional status of AIP subjects highlighted that the inadequate glucose and carbohydrates consumption of less than 45–60% of the total energy intake was associated with disease severity [ 24 , 25 ]. In addition, sub-clinical OXPHOS defects, resulting in high circulating lactate levels, were found outside of the crisis in AIP patients in clinical remission [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, there may be some discrepancies in gene expression at baseline between transcriptomic findings by Chen et al [ 12 ] and ours, which was mainly due to the limitations of transient PBGD silencing in vitro, which could not fully resemble the features of a stable knockout model. However, the downregulation of glycolysis and the biochemical evaluation of energetic status of siPBGD cells could, in broad terms, mirror the energy failure featuring AIP patients at higher risk of developing symptoms [ 12 , 24 , 25 , 26 ]. Previous evidence has outlined that most of the dysregulated pathways in the liver that may precipitate in the AIP acute attacks are under the transcriptional regulation of PCG1α, a powerful nutrient sensor activated in response to stressful factors [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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Background: Acute intermittent porphyria (AIP) is caused by the haploinsufficiency of porphobilinogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting, and alterations in glucose metabolism, insulin resistance, and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the metabolic pathways in PBGD-silenced hepatocytes and assessed the efficacy of an insulin mimic, α-lipoic acid (α-LA), as a potential therapeutic strategy. Methods: HepG2 cells were transfected with siRNA-targeting PBGD (siPBGD). Cells were cultured with low glucose concentration to mimic fasting and exposed to α-LA alone or with glucose. Results: At baseline, siPBGD cells showed a lower expression of genes involved in glycolysis and mitochondrial dynamics along with reduced total ATP levels. Fasting further unbalanced glycolysis by inducing ATP shortage in siPBGD cells and activated DRP1, which mediates mitochondrial separation. Consistently, siPBGD cells in the fasted state showed the lowest protein levels of Complex IV, which belongs to the oxidative phosphorylation (OXPHOS) machinery. α-LA upregulated glycolysis and prompted ATP synthesis and triglyceride secretion, thus possibly providing energy fuels to siPBGD cells by improving glucose utilization. Finally, siPBGD exposed to α-LA plus glucose raised mitochondrial dynamics, OXPHOS activity, and energy production. Conclusions: α-LA-based therapy may ameliorate glucose metabolism and mitochondrial dysfunctions in siPBGD hepatocytes.

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Lifestyle factors including diet and biochemical biomarkers in acute intermittent porphyria: Results from a case-control study in northern Norway

Cited by 24 publications

References 42 publications

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

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

Scientific evidence underlying contraindications to the ketogenic diet: An update

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

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