ArticlePloS one2018
5-aminolevulinic acid (ALA) deficiency causes impaired glucose tolerance and insulin resistance coincident with an attenuation of mitochondrial function in aged mice.
Article in PloS one, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 39 citations in OpenAlex.
- Trial
- The ketogenic diet is not for everyone: contraindications, side effects, and drug interactions.Annals of medicine · 2026Review
- More than a ring: the emerging role of heme in angiogenesis.Cell communication and signaling : CCS · 2026Review
- Protoporphyrin IX Beyond Conventional Applications: A Review of Emerging Research Directions.Life (Basel, Switzerland) · 2025Review
- From Deficiency to Therapy: Systemic Consequences of ALAS1 Disruption and the Protective Role of 5-ALA.Life (Basel, Switzerland) · 2025Review
- 5-Aminolevulinic Acid (5-ALA) Plays an Important Role in the Function of Innate Immune Cells.Inflammation · 2025Article
- Regulation of the expression of ferrochelatase in a murine model of diabetes mellitus type I.Biochemistry and biophysics reports · 2025Article
- Therapeutic potential of 5-aminolevulinic acid in metabolic disorders: Current insights and future directions.iScience · 2024Review
- Heme deficiency in skeletal muscle exacerbates sarcopenia and impairs autophagy by reducing AMPK signaling.Scientific reports · 2024Article
- Unearthing FLVCR1a: tracing the path to a vital cellular transporter.Cellular and molecular life sciences : CMLS · 2024Review
- Pilot Trial on the Effect of 5-Aminolevulinic Acid on Glucose Tolerance in Patients with Maternally Inherited Diabetes and Deafness.Diabetes therapy : research, treatment and education of diabetes and related disorders · 2023Article
- Antagonism of ALAS1 by the Measles Virus V protein contributes to degradation of the mitochondrial network and promotes interferon response.PLoS pathogens · 2023Article
- Understanding Carbohydrate Metabolism and Insulin Resistance in Acute Intermittent Porphyria.International journal of molecular sciences · 2022Review
- Article
- Evolutionary Trend Analysis of Research on 5-ALA Delivery and Theranostic Applications Based on a Scientometrics Study.Pharmaceutics · 2022Article
- Therapy Follows Diagnosis: Old and New Approaches for the Treatment of Acute Porphyrias, What We Know and What We Should Know.Diagnostics (Basel, Switzerland) · 2022Review
- Assessment of porphyrogenicity of drugs and chemicals in selected hepatic cell culture models through a fluorescence-based screening assay.Pharmacology research & perspectives · 2022Article
- Complex response to physiological and drug-induced hepatic heme demand in monoallelicMolecular genetics and metabolism reports · 2021Article
- Crosstalk between Metabolic Disorders and Immune Cells.International journal of molecular sciences · 2021Review
- An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases.Cancers · 2021Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In vertebrates, the initial step in heme biosynthesis is the production of 5-aminolevulinic acid (ALA) by ALA synthase (ALAS). ALA formation is believed to be the rate-limiting step for cellular heme production. Recently, several cohort studies have demonstrated the potential of ALA as a treatment for individuals with prediabetes and type-2 diabetes mellitus. These studies imply that a mechanism exists by which ALA or heme can control glucose metabolism. The ALAS1 gene encodes a ubiquitously expressed isozyme. Mice heterozygous null for ALAS1 (A1+/-s) experience impaired glucose tolerance (IGT) and insulin resistance (IR) beyond 20-weeks of age (aged A1+/-s). IGT and IR were remedied in aged A1+/-s by the oral administration of ALA for 1 week. However, the positive effect of ALA proved to be reversible and was lost upon termination of ALA administration. In the skeletal muscle of aged A1+/-s an attenuation of mitochondrial function is observed, coinciding with IGT and IR. Oral administration of ALA for 1-week brought about only a partial improvement in mitochondrial activity however, a 6-week period of ALA treatment was sufficient to remedy mitochondrial function. Studies on differentiated C2C12 myocytes indicate that the impairment of glucose metabolism is a cell autonomous effect and that ALA deficiency ultimately leads to heme depletion. This sequela is evidenced by a reduction of glucose uptake in C2C12 cells following the knockdown of ALAS1 or the inhibition of heme biosynthesis by succinylacetone. Our data provide in vivo proof that ALA deficiency attenuates mitochondrial function, and causes IGT and IR in an age-dependent manner. The data reveals an unexpected metabolic link between heme and glucose that is relevant to the pathogenesis of IGT/IR.
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