Researchers examine nerve regeneration with improved corneal nerve fiber density with semaglutide for monogenic obesity

(Image Credit: AdobeStock/Fernanda)

Reviewed by Hoda Gad, MSc, BSc

Monogenic obesity is a rare and severe disease, most often resulting from MC4R mutations that disrupt the neuronal pathways in the hypothalamus and prefrontal cortex. Following 6 months of treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, researchers observed that 2 siblings with monogenic obesity had nerve regeneration and positive changes in the corneal nerves.¹ First author Hoda Gad, MSc, BSc, of the Department of Research at Weill Cornell Medicine - Qatar in Doha, reported the findings in Frontiers in Endocrinology.

According to the researchers, patients with monogenic obesity present with impaired satiety and hyperphagia in early childhood with severe early-onset obesity due to dysregulation of the central leptin-melanocortin neuronal pathways.^2,3

Changes in lifestyle

They explained that changes in lifestyle in patients with MC4R mutations have shown minimal benefit,^4-6 and that even bariatric surgery provided limited long-term benefit.^7-9 However, the use of GLP-1 receptor agonists can achieve beneficial changes in weight, blood pressure, lipids with a decrease in reactive oxygen species, and inflammation, which researchers say could impact neurons.¹⁰

Specifically, they found that GLP-1R–mediated extracellular signal-regulated kinase signaling in diabetic rodents protected large motor fiber function and small fiber structure by a mechanism independent of glycemic control.¹¹ The researchersreported corneal nerve regeneration after bariatric surgery¹² with once-weekly dosing with the GLP-1 agonist exenatide¹³ in 14 patients with type 2 diabetes semaglutide or dulaglutide improved nerve area and sural nerve amplitude.¹⁴

In this case report, Gad and colleagues performed corneal confocal microscopy to assess for evidence of nerve regeneration after treatment with semaglutide in 2 siblings with an MC4R gene mutation: a 10-year-old boy (weight, 100.3 kg; body mass index [BMI], 39.7 kg/m2) and his 8-year-old sister (weight, 58.6 kg; BMI, 32.2 kg/m2).

Their respective baseline hemoglobin A1C (HbA1C) values were 5.8% and 5.6%, total cholesterol was 4.4 and 3.4 mmol/L, low-density lipoprotein was 2.3 and 2 mmol/L, high-density lipoprotein was 2.1 and 1 mmol/L, and triglycerides were 1 and 1.4 mmol/L. Both children exhibited intense hyperphagia, impaired satiety, and severe, early-onset obesity.

Results of semaglutide therapy

Corneal confocal microscopy showed corneal small fiber degeneration in both siblings. “We also showed that 6 months of treatment with semaglutide was associated with small nerve fiber regeneration but with no major effect on weight, HbA1C, and lipids, which argues for alternate mechanisms beyond an improvement in weight and glycemia as a basis for nerve regeneration in these 2 children with MC4R gene mutations,” the researchers reported.

Hypothesis for nerve regeneration without other changes

Obesity is a risk factor for small fiber neuropathy,^15,16 and the researchers had previously reported that nerve regeneration occurred and weight and metabolic parameters improved after bariatric surgery.^17,18 In addition, GLP-1 receptor agonists reduce weight and improve many neuropathic risk factors, including hyperglycemia, blood pressure, and hyperlipidemia.¹⁹

Previous case reports on the use of the daily GLP-1 agonist liraglutide have shown reduced weight and improved glycemia.^20-22 However, the researchers’ recent cohort study showed that liraglutide had no major impact on weight or HbA1C in obese children.²³

Gad and colleagues explained that it is noteworthy that GLP-1 therapies activate SIRT1,^24,25 which may be associated with the nerve regeneration seen in the patients under discussion, independent of weight and glycemia changes.

Additionally, GLP-1 receptors are expressed in the dorsal root ganglion and peripheral nerves,^26-29 and GLP-1 treatment led to intraepidermal nerve fiber regeneration without weight or glucose changes in an animal model of type 1 diabetes mellitus.¹¹ Further, adults with type 2 diabetes mellitus treated with once-weekly exenatide and pioglitazone had small nerve fiber regeneration, despite an increase in weight.¹³

Conclusion

“We believe our study provides novel insights into the complications associated with MC4R gene mutation, as evidenced by subclinical neurodegeneration,” the authors concluded. “Furthermore, we show nerve regeneration after treatment with semaglutide, without an improvement in weight or glycemia, indicating an independent effect of GLP-1 therapy, which merits further study.”

References:

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