Insulin-like growth factor-1 activates AMPK to augment mitochondrial function and correct neuronal metabolism in sensory neurons in type 1 diabetes.
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2019-02
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Abstract
Objective
Diabetic sensorimotor polyneuropathy (DSPN) affects approximately half of diabetic patients leading to significant morbidity. There is impaired neurotrophic growth factor signaling, AMP-activated protein kinase (AMPK) activity and mitochondrial function in dorsal root ganglia (DRG) of animal models of type 1 and type 2 diabetes. We hypothesized that sub-optimal insulin-like growth factor 1 (IGF-1) signaling in diabetes drives loss of AMPK activity and mitochondrial function, both contributing to development of DSPN.Methods
Age-matched control Sprague-Dawley rats and streptozotocin (STZ)-induced type 1 diabetic rats with/without IGF-1 therapy were used for in vivo studies. For in vitro studies, DRG neurons from control and STZ-diabetic rats were cultured and treated with/without IGF-1 in the presence or absence of inhibitors or siRNAs.Results
Dysregulation of mRNAs for IGF-1, AMPKα2, ATP5a1 (subunit of ATPase), and PGC-1β occurred in DRG of diabetic vs. control rats. IGF-1 up-regulated mRNA levels of these genes in cultured DRGs from control or diabetic rats. IGF-1 treatment of DRG cultures significantly (P < 0.05) increased phosphorylation of Akt, P70S6K, AMPK and acetyl-CoA carboxylase (ACC). Mitochondrial gene expression and oxygen consumption rate (spare respiratory capacity), ATP production, mtDNA/nDNA ratio and neurite outgrowth were augmented (P < 0.05). AMPK inhibitor, Compound C, or AMPKα1-specific siRNA suppressed IGF-1 elevation of mitochondrial function, mtDNA and neurite outgrowth. Diabetic rats treated with IGF-1 exhibited reversal of thermal hypoalgesia and, in a separate study, reversed the deficit in corneal nerve profiles. In diabetic rats, IGF-1 elevated the levels of AMPK and P70S6K phosphorylation, raised Complex IV-MTCO1 and Complex V-ATP5a protein expression, and restored the enzyme activities of Complex IV and I in the DRG. IGF-1 prevented TCA metabolite build-up in nerve.Conclusions
In DRG neuron cultures IGF-1 signals via AMPK to elevate mitochondrial function and drive axonal outgrowth. We propose that this signaling axis mediates IGF-1-dependent protection from distal dying-back of fibers in diabetic neuropathy.Type
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Aghanoori, Mohamad-Reza, Darrell R Smith, Shiva Shariati-Ievari, Andrew Ajisebutu, Annee Nguyen, Fiona Desmond, Carlos HA Jesus, Xiajun Zhou, et al. (2019). Insulin-like growth factor-1 activates AMPK to augment mitochondrial function and correct neuronal metabolism in sensory neurons in type 1 diabetes. Molecular metabolism, 20. pp. 149–165. 10.1016/j.molmet.2018.11.008 Retrieved from https://hdl.handle.net/10161/33171.
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Annee Nguyen
Annee is a graduate student in Duke's Department of Pharmacology, a joint program with Molecular Cancer Biology. She is excited to identify therapeutic molecules and elucidate therapeutic mechanisms of antitumor efficacy that may also target secondary comorbid conditions, such as pain or neurological deficits. She is passionate about scientific education and communication and hopes to remain in academia with the goal of cultivating the next generation of scientists.
In 2017, Annee graduated from the University of California, San Diego, from Warren College, with a Bachelor of Science in Human Biology (double minoring in Psychology and Theatre) as magna cum laude and as part of the Sigma Chapter of the Phi Beta Kappa Society and obtained a contiguous Master of Science in Biology in 2018, concentrating in Neuropathology and Scientific Communication.
Since 2014, her prior research experience includes working with various preclinical models of peripheral neuropathy (with Dr. Nigel Calcutt and Dr. Christina Sigurdson of UC San Diego’s Department of Pathology), equine and murine models of neuroaxonal dystrophy (with Dr. Carrie Finno of UC Davis’s School of Veterinary Medicine), and CNS tumor preclinical models of recurrent glioblastoma and spine tumors and metastases at Duke University Medical Center with Dr. Rory Goodwin of the Duke Center for Brain and Spine Metastasis and the Department of Neurosurgery. In each lab, she sought to identify therapeutics that could prevent, reverse, or abate the neurodegenerative diseases of focus and explored mechanisms of disease development and therapeutic impact. Throughout her experiences, Annee has continually focused on developing projects driven by clinical impact and focused on taking science from bench to bedside and back.
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