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

• Published in: PloS one 2018-01, Vol.13 (1), p.e0189593-e0189593
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 5-Aminolevulinate Synthetase - genetics; 5-Aminolevulinate Synthetase - metabolism; Acids; Age; Aminolevulinic Acid; Animals; Attenuation; Biochemistry; Biology and Life Sciences; Biosynthesis; Blood Glucose - metabolism; Cellular manufacture; Development and progression; Diabetes; Diabetes mellitus; Genetic aspects; Glucagon - metabolism; Gluconeogenesis - genetics; Glucose; Glucose Intolerance; Glucose metabolism; Glucose tolerance; Heme; Homeostasis; Insulin; Insulin - metabolism; Insulin Resistance; Levulinic Acids - metabolism; Medicine; Medicine and Health Sciences; Metabolism; Mice; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Muscles; Musculoskeletal system; Myocytes; Oral administration; Pathogenesis; Pharmaceuticals; Physiological aspects; Risk factors; Rodents; Signal Transduction; Skeletal muscle; Trends; Type 2 diabetes; University faculty; Vertebrates
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0189593

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.