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5-aminolevulinic acid (ALA) deficiency causes impaired glucose tolerance and insulin resistance coincident with an attenuation of mitochondrial function in aged mice (2018)

KELLY, VINCENT; Saitoh, Shinichi; Okano, Satoshi; Nohara, Hidekazu; Nakano, Hiroshi; Sh...

5-aminolevulinic acid (ALA) deficiency causes impaired glucose tolerance and insulin resistance coincident with an attenuation of mitochondrial function in aged mice (2018)

KELLY, VINCENT; Saitoh, Shinichi; Okano, Satoshi; Nohara, Hidekazu; Nakano, Hiroshi; Shirasawa, Nobuyuki; Naito, Akira; Yamamoto, Masayuki; Kelly, Vincent P.; Takahashi, Kiwamu; Tanaka, Tohru; Nakajima, Motowo; Nakajima, Osamu

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 admin...