# Neuromodulation using Bioelectronics-enabled therapies to combat insulin resistance and its comorbidities

**Authors:** Yosra Magdi Mekki, Jeongeun Park, Zeinah Alzaareer, Zaeem Hussain, Ayesha Gulzar, Abdelnaser Elzouki, Amparo Güemes, Susu M. Zughaier

PMC · DOI: 10.1007/s40200-026-01876-w · Journal of Diabetes and Metabolic Disorders · 2026-02-13

## TL;DR

This paper explores how neuromodulation, especially vagus nerve stimulation, can help treat insulin resistance and related health issues by targeting metabolic pathways.

## Contribution

The paper highlights the potential of bioelectronics and neuromodulation as novel therapies for insulin resistance and its comorbidities.

## Key findings

- Neuromodulation can target neuroendocrine systems to manage insulin resistance.
- Vagus nerve stimulation reduces inflammation and combats insulin resistance.
- Challenges remain in optimizing therapeutic effects and ethical considerations with closed-loop systems.

## Abstract

Insulin resistance is a complex metabolic disorder that involves multiple molecular pathways to disrupt insulin signaling and is associated with systemic complications.

We searched through the literature using databases such as PubMed and selected relevant published papers related to the topic of this review.

We synthesized this review based on the relevant literature and found that neuromodulation can target neuroendocrine systems responsible for metabolic homeostasis to manage insulin resistance. This involves integrating neural circuit modulation into biological systems. We also found that neuromodulation, particularly vagus nerve stimulation, can reduce inflammation and combat insulin resistance and its associated comorbidities. However, with advancements in closed-loop systems and artificial intelligence, challenges persist in maximizing therapeutic effects, minimizing adverse events, and balancing ethical considerations.

Neuromodulation offers novel treatment options for metabolic disorders. An enhanced understanding of neuro-metabolic reflex in insulin resistance is needed to develop more effective and safer neuromodulation therapy.

## Full-text entities

- **Genes:** GCG (glucagon) [NCBI Gene 2641] {aka GLP-1, GLP1, GLP2, GRPP}, Th (tyrosine hydroxylase) [NCBI Gene 21823], Pnpla3 (patatin-like phospholipase domain containing 3) [NCBI Gene 116939] {aka Adpn}, GLP1R (glucagon like peptide 1 receptor) [NCBI Gene 2740] {aka GLP-1, GLP-1-R, GLP-1R}, Adipoq (adiponectin, C1Q and collagen domain containing) [NCBI Gene 11450] {aka 30kDa, APN, Acdc, Acrp30, Ad, Adid}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, IARS1 (isoleucyl-tRNA synthetase 1) [NCBI Gene 3376] {aka GRIDHH, IARS, ILERS, ILRS, IRS, PRO0785}, Il1b (interleukin 1 beta) [NCBI Gene 16176] {aka IL-1beta, Il-1b}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, FOXK1 (forkhead box K1) [NCBI Gene 221937] {aka FOXK1L}, SHBG (sex hormone binding globulin) [NCBI Gene 6462] {aka ABP, SBP, TEBG}, IRS1 (insulin receptor substrate 1) [NCBI Gene 3667] {aka HIRS-1}, MSTN (myostatin) [NCBI Gene 2660] {aka GDF8, MSLHP}, INSR (insulin receptor) [NCBI Gene 3643] {aka CD220, HHF5}, Lep (leptin) [NCBI Gene 16846] {aka ob, obese}, Gcg (glucagon) [NCBI Gene 14526] {aka GLP-1, Glu, PPG}, Retn (resistin) [NCBI Gene 57264] {aka ADSF, Fizz3, Rstn, Xcp4}, SLC2A4 (solute carrier family 2 member 4) [NCBI Gene 6517] {aka GLUT4}, FOXO1 (forkhead box O1) [NCBI Gene 2308] {aka FKH1, FKHR, FOXO1A}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, Agrp (agouti related neuropeptide) [NCBI Gene 11604] {aka Agrt, Art}, PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 5295] {aka AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, OGT (O-linked N-acetylglucosamine (GlcNAc) transferase) [NCBI Gene 8473] {aka HINCUT-1, HRNT1, MRX106, O-GLCNAC, OGT1, XLID106}, PTK2B (protein tyrosine kinase 2 beta) [NCBI Gene 2185] {aka CADTK, CAKB, FADK2, FAK2, PKB, PTK}, Pomc (pro-opiomelanocortin-alpha) [NCBI Gene 18976] {aka ACTH, BE, Beta-LPH, Clip, Gamma-LPH, Npp}, Cck (cholecystokinin) [NCBI Gene 12424], Ghrl (ghrelin) [NCBI Gene 58991] {aka 2210006E23Rik, Ghr, MTLRP, MTLRPAP, m46}, Mc4r (melanocortin 4 receptor) [NCBI Gene 17202] {aka Mc4-r, Pkcp}, CHRNA7 (cholinergic receptor nicotinic alpha 7 subunit) [NCBI Gene 1139] {aka CHRNA7-2, NACHRA7, a7nAChR, nAChR7}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}
- **Diseases:** liver cirrhosis (MESH:D008103), anxiety (MESH:D001007), chronic kidney disease (MESH:D051436), cancer (MESH:D009369), lactic acidosis (MESH:D000140), resistant (MESH:D060467), diabetes (MESH:D003920), pain (MESH:D010146), pancreatic cancer (MESH:D010190), voice alteration (MESH:D014832), inflammation (MESH:D007249), hepatic dysfunction (MESH:D008107), GERD (MESH:D005764), hyperglycemia (MESH:D006943), metabolic syndrome (MESH:D024821), hematoma (MESH:D006406), cirrhosis (MESH:D005355), vomiting (MESH:D014839), metabolic (MESH:D008659), seizure (MESH:D012640), neurological disorders (MESH:D009461), metabolic dysregulations (MESH:D021081), hypoglycemic (MESH:C000721848), gastroparesis (MESH:D018589), overweight (MESH:D050177), diarrhea (MESH:D003967), weight gain (MESH:D015430), MAFLD (MESH:D005234), DIO (MESH:D009765), nausea (MESH:D009325), cough (MESH:D003371), IR (MESH:D007333), CVD (MESH:D002318), infections (MESH:D007239), hypoglycemia (MESH:D007003), AF (MESH:D001281), gastrointestinal complications (MESH:D005767), Hyperinsulinemia (MESH:D006946), diabetic complications (MESH:D048909), death (MESH:D003643), hyperglycemic (MESH:D006944), PCOS (MESH:D011085), hypertension (MESH:D006973), atherosclerosis (MESH:D050197), rheumatoid arthritis (MESH:D001172), epilepsy (MESH:D004827), autonomic neuropathy (MESH:D009422), glucose allostasis (MESH:D018149), bloating (MESH:C535647), paresthesia (MESH:D010292), appetite suppression (MESH:D001068), type 1 diabetes (MESH:D003922), type 2 diabetes (MESH:D003924), IBD (MESH:D015212), acid (MESH:D011015), hoarseness (MESH:D006685), depression (MESH:D003866), breast cancer (MESH:D001943), HF (MESH:D006333)
- **Chemicals:** triacylglycerol (MESH:D014280), phosphatidylinositol 4,5-bisphosphate (MESH:D019269), oxygen (MESH:D010100), nitric oxide (MESH:D009569), ceramide (MESH:D002518), Poly(3,4-ethylenedioxythiophene (MESH:C121383), blood glucose (MESH:D001786), GTS-21 (MESH:C088936), norepinephrine (MESH:D009638), Testosterone (MESH:D013739), acetyl coenzyme A (MESH:D000105), free fatty acids (MESH:D005230), acetylcholine (MESH:D000109), PEDOT: PSS (MESH:C533756), metformin (MESH:D008687), carbohydrates (MESH:D002241), fatty acid (MESH:D005227), BEM (-), glucose (MESH:D005947), reactive oxygen species (MESH:D017382), dopamine (MESH:D004298), diacylglycerol (MESH:D004075), lipid (MESH:D008055), thiazolidinediones (MESH:D045162)
- **Species:** Canis lupus familiaris (dog, subspecies) [taxon 9615], Mus musculus (house mouse, species) [taxon 10090], Sus scrofa (pig, species) [taxon 9823], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116]

## Full text

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## Figures

5 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12905043/full.md

## References

9 references — full list in the complete paper: https://tomesphere.com/paper/PMC12905043/full.md

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Source: https://tomesphere.com/paper/PMC12905043