Mahmoud Nassar,Ajay Chaudhuri,Husam Ghanim,Paresh Dandona

Abstract Type 1 diabetes (T1D) is a chronic autoimmune condition that destroys insulinproducing beta cells in the pancreas,leading to insulin deficiency and hyperglycemia.The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels.However,this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells.Recent research has explored the potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) as a novel intervention to modify the disease course and delay the onset of T1D.GLP-1RAs are medications initially developed for treating type 2 diabetes.They exert their effects by enhancing glucose-dependent insulin secretion,suppressing glucagon secretion,and slowing gastric emptying.Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D.This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D,possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells.This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification,which should open new avenues for preventing and treating T1D,improving the quality of life and long-term outcomes for individuals at risk of T1D.

Key Words: Type 1 diabetes;Semaglutide;Glucagon-like peptide-1 receptor agonists;Insulin therapy;Autoimmune response;Βlood glucose monitoring;Β-cell preservation;Early screening;Teplizumab;Randomized controlled trials

lNTRODUCTlON

Type 1 diabetes (T1D) is a chronic disease that has long posed therapeutic challenges.This ailment,rooted in the autoimmune destruction of pancreatic β-cells by T-cells,results in a severe decline of β-cell activity and an eventual complete lack of insulin[1-3].The only treatment for this disease is intensive insulin therapy,which requires multiple daily injections or continuous subcutaneous insulin infusion with frequent monitoring of blood glucose.Despite advances in closed-loop hybrid pumps and continuous glucose monitoring devices,75% of subjects with T1D maintain an A1c above 7%.Moreover,there is a significant disease burden and emotional burden associated with the diagnosis and management of T1D.Even with modern medical breakthroughs,many T1D sufferers still grapple with maintaining optimal blood sugar levels.Intensive insulin therapies,though advantageous,can sometimes lead to hypoglycemia,presenting a therapeutic conundrum[4,5].

THE POTENTlAL OF GLUCAGON-LlKE PEPTlDE-1 RECEPTOR AGONlSTS

Researchers observed promising results in a study examining the potential benefits of Glucagon-like peptide-1 receptor agonists (GLP-1RAs) for T1D patients with positive C-peptide levels.Our recent exploration,as published in the New England Journal of Medicine,sheds light on a hopeful path.We delved into the impact of semaglutide,a GLP-1RA,within three months on ten newly diagnosed T1D patients.These individuals began with an average glycated hemoglobin of 11.7% ± 2.1% and a fasting C-peptide of 0.65% ± 0.33% ng/mL,all undergoing standard insulin treatments[6].Introducing semaglutide and dietary modifications led to the discontinuation of prandial insulin for all participants within a quarter year.Impressively,by half a year,seven had ceased using basal insulin.A year later,the average glycated hemoglobin decreased to 5.7% ± 0.4%,while the fasting C-peptide surged to an average of 1.05 ± 0.40 ng/mL.Continuous glucose assessments revealed an 89% ± 3% time-in-range[6].

The study entailed a retrospective analysis of 11 normal-weight T1D patients treated with GLP-1RA in conjunction with insulin.Notable findings included a significant reduction in HbA1c levels from 10.74% ± 0.96% to 7.4% ± 0.58% after 12 ± 1 wk of GLP-1RA therapy.Additionally,there was a noteworthy decline in total insulin dose by 64% and a minor weight reduction.Importantly,C-peptide concentrations,indicative of endogenous insulin production,surged significantly,enhancing pancreatic beta-cell function.Remarkably,50% of the study participants achieved freedom from insulin therapy while on GLP-1RA therapy over the study duration[7].

In the Adjunct One Treat-To-Target Randomized Trial,the addition of liraglutide to insulin therapy in T1D was assessed over 52 wk in 1398 adults.Participants were administered liraglutide (at concentrations of 1.8,1.2,or 0.6 mg) or a placebo in conjunction with insulin.The study found that HbA1c levels reduced by 0.34%-0.54% from an initial 8.2%,insulin doses diminished more with liraglutide compared to the placebo,and there was a notable weight reduction in the liraglutide cohorts.However,liraglutide recipients experienced elevated rates of symptomatic hypoglycemia,and the 1.8 mg liraglutide group saw a significant rise in hyperglycemia with ketosis.Consequently,despite its benefits,the increased adverse events suggest caution in the broader clinical application of liraglutide for T1D[8].

lMMUNOTHERAPY: A SPECTRUM OF OUTCOMES

Various immunotherapies,including Teplizumab,Otelixizumab,and Abatacept,have displayed promise but are not without complications.For example,Otelixizumab users have reported headaches,fevers,and rashes,typical reactions to anti-CD3 antibodies[9,10].Teplizumab has been linked to skin issues,leukopenia,respiratory infections,and lymphopenia[11-13].Most issues with Abatacept were related to the infusion process[14,15].

THE DEΒATE ON SCREENlNG

The question of T1D risk screening remains contentious,especially for those without familial ties to the condition.A study by Ziegleretal[5] in Bavaria showcased the viability of screening children during standard pediatric appointments,pinpointing 280 children with multiple autoantibodies,43 of whom later developed T1D[5,16].The means of early identification and action are clear.Yet,the financial and emotional tolls of screening warrant consideration.Nevertheless,research indicates that psychosocial screenings can pinpoint vulnerable families[17].Moreover,regions with a high prevalence of diabetic ketoacidosis could economically justify presymptomatic T1D screenings[18,19].The timing and approach to screening are debated,focusing on the balance between cost and comprehensive detection[18,20,21].

CONCLUSlON

Our findings suggest that early T1D screening,combined with interventions such as GLP-1RA,could significantly impede the progression of the disease,especially in high-risk obese individuals.Pediatric professionals should exercise heightened caution with patients prone to T1D due to genetic or autoimmune factors.As we venture further into this realm,the prospect of an enhanced quality of life for T1D patients becomes increasingly tangible.

FOOTNOTES

Author contributions:All authors have contributed equally to this work;All authors have read and approved the final manuscript.

Conflict-of-interest statement:All the authors report no relevant conflicts of interest for this article.

Open-Access:This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is non-commercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

Country/Territory of origin:United States

ORClD number:Mahmoud Nassar 0000-0002-5401-9562.

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