Study summary · research use only
Administration of AICAR, an AMPK Activator, Prevents and Reverses Diabetic Polyneuropathy (DPN) by Regulating Mitophagy
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study in mouse models of type 1 and type 2 diabetes (T1D and T2D) examined the exercise mimetic AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) for diabetic peripheral neuropathy (DPN). AICAR treatment was associated with prevention or reversal of experimental DPN in both models. In high-fat diet (HFD)-fed mice, AICAR increased the ratio of phosphorylated to total AMPK in dorsal root ganglion (DRG) neurons by 3-fold (HFD vs HFD+AICAR; p < 0.001), along with increases in DRP1, phosphorylated ULK1 at Serine-555, and LC3-II by 2-fold. Mitochondria from HFD-fed DRG neurons showed decreased ADP-stimulated state 3 respiration (120 ± 20 nmol O2/min vs 220 ± 20 nmol O2/min in control diet mice; p < 0.001), which increased with AICAR treatment (240 ± 30 nmol O2/min).
Abstract
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes in both Type 1 (T1D) and Type 2 (T2D). While there are no specific medications to prevent or treat DPN, certain strategies can help halt its progression. In T1D, maintaining tight glycemic control through insulin therapy can effectively prevent or delay the onset of DPN. However, in T2D, overall glucose control may only have a moderate impact on DPN, although exercise is clearly beneficial. Unfortunately, optimal exercise may not be feasible for many patients with DPN because of neuropathic foot pain and poor balance. Exercise has several favorable effects on health parameters, including body weight, glycemic control, lipid profile, and blood pressure. We investigated the impact of an exercise mimetic, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on DPN. AICAR treatment prevented or reversed experimental DPN in mouse models of both T2D and T1D. AICAR in high-fat diet (HFD-fed) mice increased the phosphorylation of AMPK in DRG neuronal extracts, and the ratio of phosphorylated AMPK to total AMPK increased by 3-fold (HFD vs. HFD+AICAR; p < 0.001). Phospho AMP increased the levels of dynamin-related protein 1 (DRP1, a mitochondrial fission marker), increased phosphorylated autophagy activating kinase 1 (ULK1) at Serine-555, and increased microtubule-associated protein light chain 3-II (LC3-II, a marker for autophagosome assembly) by 2-fold. Mitochondria isolated from DRG neurons of HFD-fed had a decrease in ADP-stimulated state 3 respiration (120 ± 20 nmol O2/min in HFD vs. 220 ± 20 nmol O2/min in control diet (CD); p < 0.001. Mitochondria isolated from HFD+AICAR-treated mice had increased state 3 respiration (240 ± 30 nmol O2/min in HFD+AICAR). However, AICAR's protection in DPN in T2D mice was also mediated by its effects on insulin sensitivity, glucose metabolism, and lipid metabolism. Drugs that enhance AMPK phosphorylation may be beneficial in the treatment of DPN.
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