Mechanism of action of adrenomedullin and its receptors in diabetic peripheral neuropathy

doi:10.12092/j.issn.1009-2501.2026.08.015

Abstract

Abstract:

Diabetic Peripheral Neuropathy (DPN) is one of the most disabling chronic complications of diabetes mellitus, and its pathogenesis involves multiple factors such as insulin resistance, oxidative stress, inflammatory response, and neurological injury. Adrenomedullin (AM), as a peptide molecule with a wide range of biological activities, exhibits a complex regulatory role in the development of DPN by binding to its receptors CRLR/RAMPs. In this paper, we systematically reviewed the involvement of AM and its receptor in the pathological process of DPN through multiple mechanisms, such as the regulation of insulin resistance, endothelial dysfunction, lipid metabolism disorders, oxidative stress and inflammatory response. However, the bidirectional regulatory properties of AM at different physiological and pathological stages, and the coexistence of its positive and negative effects may stem from the intertwining of multiple mechanisms and regulatory differences. In this paper, we systematically summarize the molecular mechanisms and therapeutic potential of AM and its receptors in DPN, reveal its potential as a multi-target therapeutic strategy, and provide an important theoretical basis for future precision interventions targeting the AM signaling pathway.

Key words: adrenomedullin, diabetic peripheral neuropathy, insulin resistance, obesity

CLC Number:

Ailin LU, Yongqing WU, Mengrui YUAN, Hongyi LIU. Mechanism of action of adrenomedullin and its receptors in diabetic peripheral neuropathy[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(8): 1144-1152.

Figures/Tables 4

References 55

1	Sun J, Wang Y, Zhang X, et al. Prevalence of peripheral neuropathy in patients with diabe-tes: A systematic review and meta-analysis[J]. Prim Care Diabetes, 2020, 14 (5): 435- 444. doi: 10.1016/j.pcd.2019.12.005
2	王秀阁, 倪青, 庞国明. 糖尿病周围神经病变病证结合诊疗指南[J]. 中医杂志, 2021, 62 (18): 1648- 1656. doi: 10.13288/j.11-2166/r.2021.18.017
3	McLatchie LM, Fraser NJ, Main MJ, et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor[J]. Nature, 1998, 393 (6683): 333- 339. doi: 10.1038/30666
4	Dong Y, Ruano SH, Mishra A, et al. Adrenomedullin and its receptors are expressed in mouse pancreatic β-cells and suppresses insulin synthesis and secretion[J]. Plos one, 2022, 17 (3): e0265890. doi: 10.1371/journal.pone.0265890
5	Wu J, Hu H, Li X. Spinal neuron-glial crosstalk and ion channel dysregulation in diabetic neuropathic pain[J]. Front Immunol, 2025, 16, 1480534. doi: 10.3389/fimmu.2025.1480534
6	Martinez A, Weaver C, López J, et al. Regulation of insulin secretion and blood glucose metabolism by adrenomedullin[J]. Endocrinology, 1996, 137 (6): 2626- 2632. doi: 10.1210/en.137.6.2626
7	Sekine N, Takano K, Kimata-Hayashi N, et al. Adrenomedullin inhibits insulin exocytosis via pertussis toxin-sensitive G protein-coupled mechanism[J]. Am J Phy End Metab, 2006, 291 (1): E9- E14. doi: 10.1152/ajpendo.00213.2005
8	Asfari M, Janjic D, Meda P, et al. Establishment of 2-mercaptoethanol-dependent differentiated insulin-secreting cell lines[J]. Endocrinology, 1992, 130 (1): 167- 178. doi: 10.1210/endo.130.1.1370150
9	Mulder H, Ahrén B, Karlsson S, et al. Adrenomedullin: localization in the gastrointestinal tract and effects on insulin secretion[J]. Reg Pep, 1996, 62 (2/3): 107- 112. doi: 10.1016/0167-0115(96)00005-5
10	Khoo S, Griffen SC, Xia Y, et al. Regulation of insulin gene transcription by ERK1 and ERK2 in pancreatic β cells[J]. J Biol Chem, 2003, 278 (35): 32969- 32977. doi: 10.1074/jbc.M301198200
11	Liu J, Liu Z. Muscle insulin resistance and the inflamed microvasculature: fire from within[J]. Int J Mol Sci, 2019, 20 (3): 562. doi: 10.3390/ijms20030562
12	Jahn LA, Hartline L, Liu Z, et al. Metformin improves skeletal muscle microvascular insulin resistance in metabolic syndrome[J]. Am J Phy End Metab, 2022, 322 (2): E173- E180.
13	Guilherme A, Rowland LA, Wang H, et al. The adipocyte supersystem of insulin and cAMP signaling[J]. Trend Cell Biol, 2023, 33 (4): 340- 354. doi: 10.1016/j.tcb.2022.07.009
14	Cho H, Lai CC, Bonnavion R, et al. Endothelial insulin resistance induced by adrenomedullin mediates obesity-associated diabetes[J]. Science, 2025, 387 (6734): 674- 682. doi: 10.1126/science.adr4731
15	Blackwood SJ, Tischer D, van de Ven MPF, et al. Elevated heart rate and decreased muscle endothelial nitric oxide synthase in early development of insulin resistance[J]. Am J Phy End Metab, 2024, 327 (2): E172- E182. doi: 10.1152/ajpendo.00148.2024
16	应巧, 张伟, 泮瑛瑛, 等. 胆石症合并2型糖尿病患者脂肪组织中肾上腺髓质素2、补体因子H表达与ir的相关性研究[J]. 中国卫生检验杂志, 2022, 32 (12): 1461- 1464.
17	Wu RL, Chen N, Chen Y, et al. Visceral adiposity as an independent risk factor for diabetic peripheral neuropathy in type 2 diabetes mellitus: a retrospective study[J]. J Diab Res, 2024, 2024 (1): 9912907. doi: 10.1155/2024/9912907
18	Andersen ST, Witte DR, Dalsgaard EM, et al. Risk factors for incident diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes followed for 13 years: ADDITION-Denmark[J]. Diab Care, 2018, 41 (5): 1068- 1075. doi: 10.2337/dc17-2062
19	陈恕凤, 鲁向锋, 王来元, 等. 肾上腺髓质素基因多态与中国人血脂水平的关系[J]. 中国分子心脏病学杂志, 2016, 10 (1): 1589- 1592. doi: 10.16563/j.cnki.1671-6272.2016.10.008
20	Koyama T, Kuriyama N, Uehara R. Midregional proadrenomedullin can reflect the accumulation of visceral adipose tissue—A key to explaining the obesity paradox[J]. Int J Env Res Pub Heal, 2020, 17 (11): 3968. doi: 10.3390/ijerph17113968
21	Fukai N, Yoshimoto T, Sugiyama T, et al. Concomitant expression of adrenomedullin and its receptor components in rat adipose tissues[J]. Am J Phy End Metab, 2005, 288 (1): E56- E62.
22	Dai HB, Wang HY, Wang FZ, et al. Adrenomedullin ameliorates palmitic acid-induced insulin resistance through PI3K/Akt pathway in adipocytes[J]. Acta Diabet, 2022, 59 (5): 661- 673. doi: 10.1007/s00592-021-01840-5
23	Dai HB, Wang FZ, Kang Y, et al. Adrenomedullin attenuates inflammation in white adipose tissue of obese rats through receptor‐mediated PKA pathway[J]. Obesity, 2021, 29 (1): 86- 97. doi: 10.1002/oby.23012
24	Newton BW, Cologna SM, Moya C, et al. Proteomic analysis of 3T3-L1 adipocyte mitochondria during differentiation and enlargement[J]. J Prot Res, 2011, 10 (10): 4692- 4702. doi: 10.1021/pr200491h
25	Dong Y, Vipin VA, Blesson CS, et al. Impact of adrenomedullin on mitochondrial respiratory capacity in human adipocyte[J]. Sci Rep, 2023, 13 (1): 9578. doi: 10.1038/s41598-023-36622-2
26	Ang L, Mizokami-Stout K, Eid SA, et al. The conundrum of diabetic neuropathies—past, present, and future[J]. J Diab Compl, 2022, 36 (11): 108334. doi: 10.1016/j.jdiacomp.2022.108334
27	Elafros MA, Reynolds EL, Callaghan BC. Obesity-related neuropathy: the new epidemic[J]. Curr Opin Neurol, 2024, 37 (5): 467- 477. doi: 10.1097/WCO.0000000000001292
28	Kopp KO, Li Y, Glotfelty EJ, et al. Incretin-based multi-agonist peptides are neuroprotective and anti-inflammatory in Cellular models of Neurodegeneration[J]. Biomolecules, 2024, 14 (7): 872. doi: 10.3390/biom14070872
29	Zhang IX, Raghavan M, Satin LS. The endoplasmic reticulum and calcium homeostasis in pancreatic beta cells[J]. Endocrinology, 2020, 161 (2): bqz028. doi: 10.1210/endocr/bqz028
30	Ghosh R, Colon-Negron K, Papa FR. Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes[J]. Mol Metab, 2019, 27, S60- S68. doi: 10.1016/j.molmet.2019.06.012
31	Suetomi R, Ohta Y, Akiyama M, et al. Adrenomedullin has a cytoprotective role against endoplasmic reticulum stress for pancreatic β‐cells in autocrine and paracrine manners[J]. J Diab Invest, 2020, 11 (4): 823- 833. doi: 10.1111/jdi.13218
32	El‐Saka MH, Barhoma RA, Ibrahim RR, et al. Potential effect of adrenomedullin on metabolic and endocrinal dysfunctions in the experimentally induced polycystic ovary: targeting implication of endoplasmic reticulum stress[J]. J Biochem Mol Toxicol, 2021, 35 (5): e22725. doi: 10.1002/jbt.22725
33	Shimosawa T, Ogihara T, Matsui H, et al. Deficiency of adrenomedullin induces insulin resistance by increasing oxidative stress[J]. Hypertension, 2003, 41 (5): 1080- 1085. doi: 10.1161/01.HYP.0000066846.46422.2C
34	Baum P, Toyka KV, Blüher M, et al. Inflammatory mechanisms in the pathophysiology of diabetic peripheral neuropathy (DN)—new aspects[J]. Int J Mol Sci, 2021, 22 (19): 10835. doi: 10.3390/ijms221910835
35	Wang D, Ruan L, Hong Y, et al. Involvement of PKA-dependent upregulation of nNOS–CGRP in adrenomedullin-initiated mechanistic pathway underlying CFA- induced response in rats[J]. Exp Neurol, 2013, 239, 111- 119. doi: 10.1016/j.expneurol.2012.10.006
36	Hong Y, Liu Y, Chabot JG, et al. Upregulation of adrenomedullin in the spinal cord and dorsal root ganglia in the early phase of CFA-induced inflammation in rats[J]. Pain, 2009, 146 (1/2): 105- 113. doi: 10.1016/j.pain.2009.07.015
37	Zeng X, Lin M Y, Wang D, et al. Involvement of adrenomedullin in spinal glial activation following chronic administration of morphine in rats[J]. Eur J Pain, 2014, 18 (9): 1323- 1332. doi: 10.1002/j.1532-2149.2014.493.x
38	Chen Y, Zhang Y, Huo Y, et al. Adrenomedullin mediates tumor necrosis factor-α-induced responses in dorsal root ganglia in rats[J]. Brain Res, 2016, 1644, 183- 191. doi: 10.1016/j.brainres.2016.05.021
39	周萍. 肾上腺髓质素在CFA炎性痛中的作用及胶质细胞参与机制 [D]. 福州: 福建师范大学, 2019.
40	郑思如. 肾上腺髓质素参与高糖及炎症诱导胶质细胞活动的作用与机制 [D]. 福州: 福建师范大学, 2020.
41	Huang H, Wang M, Hong Y. Intrathecal AMinistration of adrenomedullin induces mechanical allodynia and neurochemical changes in spinal cord and DRG[J]. Neurosci Lett, 2019, 690, 196- 201. doi: 10.1016/j.neulet.2018.10.037
42	李盼盼. 肾上腺髓质素参与糖尿病神经病理性疼痛的作用及机制 [D]. 福州: 福建师范大学, 2020.
43	赵天. 肾上腺髓质素(AM)参与大鼠糖尿病神经病理性疼痛的作用及细胞学机制 [D]. 福州: 福建师范大学, 2019.
44	李朋. 肾上腺髓质素活化的星形胶质细胞在疼痛中的作用及机制 [D]. 福州: 福建师范大学, 2019.
45	卢秋华. 肾上腺髓质素参与SNL诱导的大鼠神经病理性疼痛作用及机制 [D]. 福州: 福建师范大学, 2019.
46	薛雅平. 肾上腺髓质素(AM)在神经病理性疼痛中的作用及其机制 [D]. 福州: 福建师范大学, 2017.
47	王凯. 外周肾上腺髓质素在神经病理性疼痛中的作用 [D]. 福州: 福建师范大学, 2018.
48	陈雅娟. 肾上腺髓质素介导肿瘤坏死因子-α 诱导大鼠背根神经节细胞改变[D]. 福州: 福建师范大学, 2016.
49	Özçelik F, Hacimustafaoğlu F, Tanoğlu A. Modulatory effect of resveratrol and melatonin on natural killer cell activity and adrenomedullin in diabetic rats[J]. Turk J Med Sci, 2022, 52 (1): 258- 267. doi: 10.3906/sag-2104-380
50	Hu W, Zhou P, Rao T, et al. Adrenomedullin attenuates interleukin-1β-induced inflammation and apoptosis in rat Leydig cells via inhibition of NF-κB signaling pathway[J]. Exp Cell Res, 2015, 339 (2): 220- 230. doi: 10.1016/j.yexcr.2015.10.024
51	Wang SM, Yang WL. irculating hormone adrenomedullin and its binding protein protect neural cells from hypoxia-induced apoptosis[J]. Biochi Biophy Acta, 2009, 1790 (5): 361- 367. doi: 10.1016/j.bbagen.2009.03.012
52	Wang D, Zeng J, Li Q, et al. Contribution of adrenomedullin to the switch of G protein‐coupled μ‐opioid receptors from Gi to Gs in the spinal dorsal horn following chronic morphine exposure in rats[J]. Brit J Pharmacol, 2016, 173 (7): 1196- 1207. doi: 10.1111/bph.13419
53	Iring A, Jin YJ, Albarrán-Juárez J, et al. Shear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure[J]. J Clin Invest, 2019, 129 (7): 2775- 2791. doi: 10.1172/JCI123825
54	Zirimwabagabo JO, Jailani ABA, Avgoustou P, et al. Discovery of a first-in-class small molecule antagonist against the adrenomedullin-2 receptor: structure–activity relationships and optimization[J]. J Med Chem, 2021, 64 (6): 3299- 3319. doi: 10.1021/acs.jmedchem.0c02191
55	Ou X, Wang Z, Yu D, et al. VEGF-loaded ROS-responsive nanodots improve the structure and function of sciatic nerve lesions in type II diabetic peripheral neuropathy[J]. Biomaterials, 2025, 315, 122906. doi: 10.1016/j.biomaterials.2024.122906

[1]	Mei CHENG, Zhaohui FANG, Jindong ZHAO, Fengxia SHENG, Mengnan MA. Liraglutide combined with metformin on glycolipid metabolism level and intima-media thickness in overweight/obese patients with type 2 diabetes mellitus [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(5): 623-630.
[2]	Yongjiu JI, Suli ZHOU, Siqi YANG, Yingzhou TU, Chenqi JIANG, Bingyuan ZHANG, Changmao ZHU, Qi ZHANG, Chun YANG, Suwan HU. Median effective dose of oliceridine as an adjunct to propofol sedation in patients with preclinical obesity undergoing same-visit bidirectional endoscopy [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(4): 493-499.
[3]	ZHANG Mengli, WU Fangfang, TAN Zhien, OU Min, LIU Lingjie, LU Na, QIAO Liya, YANG Xiaonan. Effects of branched-chain and aromatic amino acids on type 2 diabetes mellitus and the progress [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2025, 30(4): 526-532.
[4]	WANG Xin, WANG Yifan, SHANG Muhong, LIU Yuyan, CHEN Guangliang. Di'ao Xinxuekang activates IRS-1/PI3K/Akt signal pathway to improve insulin resistance in nonalcoholic fatty hepatitis mice [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2024, 29(2): 121-129.
[5]	GUO Yixun, GUAN Xiaoyin, WANG Bo, WEI Yingda, ZHANG Yan, LIN Jianhua. Research progress on pathogenesis and potential therapeutic target of sarcopenia obesity [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(3): 341-346.
[6]	ZHAO Shifeng, SONG Xiangming, YAO Jianping. Tirzepatide: A new glucagon-like peptide-1 receptor/glucose-dependent insulinotropic peptide receptor dual agonist [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(2): 220-227.
[7]	MA Yitong, MA Jianhong, GAO Yating, LIU Chang. Pathogenic mechanism and research progress of adipocytokines in endometrial cancer [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(11): 1315-1320.
[8]	YANG Li, BAI Huhu, HE Shasha, JIN Yue, LIU Chengsong. Tyrosine phosphorylation of TRPM3 ion channel mediates diabetes-induced heat hyperalgesia [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(9): 971-976.
[9]	QUAN Haiyan, JIANG Xing, HE Lu. Recent progress of mitophagy in hepatic insulin resistance [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(2): 198-204.
[10]	QUAN Haiyan, LIU Yuhuan, YANG Li, YANG Fang, QIN Xuping. Improvement of CGRP on vascular endothelial cells insulin resistance via activation of cAMP/PPARγ/eNOS pathway [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(6): 615-622.
[11]	DING Fan, LI Wenxiong, ZHANG Jiali, ZHANG Yan. Research progress on pathology mechanism and treatment target for diabetic sarcopenia [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(12): 1428-1433.
[12]	ZHENG Li, MO Juanfen, WU Jiayuan, GUO Li, BAO Yi. Study on the anti-hyperlipidemia mechanisms and signaling pathways of traditional Chinese medicine Polygonum cuspidatum based on network pharmacology [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(10): 1107-1119.
[13]	YUAN Lijialong, QIN Xuping. ATP synthase beta subunit function and disease [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(4): 464-470.
[14]	ZHOU Xiahui, WANG Qinglai, ZHU Xuemei, PAN Rongrong, PAN Shenglian, ZHU Fanghui, WANG Ding, LUO Xiaohong. Effects of angelica sinensis polysaccharide on TLR4/MyD88/NF-κB pathway in rats with diabetic neuropathy [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(12): 1340-1347.
[15]	SONG Meiqing. Effect of metformin on bone mineral density, insulin resistance and cytokines in type 2 diabetes mellitus patients with primary hypertension [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22(6): 694-698.