Incretin Effects and Serum Levels in Genetic Diabetes and Type 1 Diabetes

Pagrindinės aplinkybės: Inkretinai, žarnyne gaminami peptidiniai hormonai, atlieka didžiulį vaidmenį gliukozės apykaitoje: didina insulino sekreciją, mažina gliukagono gamybą ir kontroliuoja sotumo jausmą [1]. Ši inkretinų ir gliukozės reguliacijos sąveika pabrėžia potencialias diabeto valdymo galimybes, sudaro pagrindą tam, kaip inkretinų taikomą gydymą būtų galima pritakyti prie unikalių poreikių, atsirandančių dėl skirtingų diabetų daromos įtakos asmens sveikatai [2]. Kadangi konkrečiam diabeto tipui būdinga individuali patofiziologija, galima tikėtis skirtingo pačių inkretinų ir vaistų poveikio. Sergant 2 tipo diabetu (T2D) inkretinų analogai aktyviai naudojami insulino sekrecijai didinti, nes beta ląstelės vis dar yra gyvos ir gamina insuliną [3]. Sergant 1 tipo diabetu (T1D) autoimuninis beta ląstelių sunaikinimas lemia priklausomybę gydant egzogeniniu insulinu, todėl inkretinai negali tiesiogiai didinti insulino sekrecijos, bet gali būti naudingi sotumo kontrolei ir svorio reguliavimui. Sergant monogeniniu diabetu (MD), vieno geno mutacija turi įtakos insulino gamybai ir (arba) sekrecijai, todėl inkretinų, kaip vaistų, nauda priklauso nuo konkretaus geno defekto [4]. Inkretinų ir inkretinų pagrindu taikomų gydymo metodų poveikis specifiškai neonatalinio tipo diabetui (NDM) ir/arba jaunų suagusiųjų diabeto tipui (MODY) nėra išsamiai ištirti ir reikalauja daugiau tyrimų [5]. Tikslas: atlikti sisteminę duomenų analizę apie inkretinų hormonų kiekį serume ir poveikį gliukozės apykaitai asmenims, sergantiems T1D, MODY ir NDM. Uždaviniai:

1. Apžvelgti ir apibendrinti fiziologinę inkretinų funkciją.
2. Sistemiškai apžvelgti inkretinų koncentracijos atsaką į gliukozės toleravimo testą (OGTT) ir jų poveikį gliukozės apykaitai asmenims, sergantiems T1D.
3. Sistemiškai apžvelgti inkretinų koncentracijos atsaką į OGTT ir jų poveikį gliukozės apykaitai asmenims, sergantiems NDM.
4. Supažindinti su monogeniniais diabeto tipais, apžvelgti inkretinų lygių atsaką į OGTT ir jų poveikį gliukozės apykaitai asmenims, sergantiems MODY tipo diabetu.

Background: Incretins, gut-derived peptide hormones play a huge role in glucose metabolism; causing increase in insulin secretion, decrease in glucagon production and control of satiety [1]. This interplay between incretins and glucose regulation underscores the potential opportunity in diabetes management, it lays the groundwork on how incretin-based treatments can be customized to fit the unique needs that arise from the different ways diabetes impacts an individual's health [2]. As specific type of diabetes owns individual pathophysiology, different effects of incretin by themselves and as medications could be expected. In Type 2 Diabetes (T2D) incretin analogues are used strongly as a therapy to increase insulin secretion, owning to the fact that beta cells are still alive and producing insulin [3] .Whereas, in Type 1 Diabetes (T1D) autoimmune destruction of beta cells determines the dependency on treatment with exogenous insulin, therefore, incretins could not directly cause increase of insulin, but could benefit in satiety control and weight management. In monogenic diabetes (MD), single gene mutations affect insulin production and/or secretion, therefore, the utility of incretins as medications depend on specific gene defect [4]. The effects of incretin and incretin-based therapies specifically for neonatal diabetes mellitus (NDM) or maturity onset diabetes of the young (MODY) hasn't been extensively studied or detailed [5].

Aim: To perform a systematic data analysis on incretin hormone levels in serum and effects on glucose metabolism in individuals with T1D, MODY, and NDM. Objectives:

1. To review and summarize the physiological function of incretins.
2. Systematically review incretin levels response to oral glucose tolerance test (OGTT) and their effect on glucose metabolism in individuals with T1D.
3. Systemically review incretin levels response to OGTT and their effect on glucose metabolism in NDM patients.
4. To introduce monogenic types of diabetes, review incretin levels' response to OGTT and their effects on glucose metabolism in individuals with MODY type of diabetes.

Methodology: The methodology is firstly to choose and select appropriate and furthermore reject unnecessary information providing articles from medical databases such as PubMed, Clinical Key, ScienceDirect etc. Eleven articles concerning T1D were selected. Meanwhile, a total of four articles were chosen for NDM. Finally, six articles were picked to assess the impact of incretins on MODY diabetes. The systematic reviews were reported with PRISMA set.

Results: This systematic review aimed to analyze incretin hormone levels and their effects on glucose metabolism in individuals with T1D, NDM and MODY. In T1D, research showed a reduced incretin effect despite similar postprandial GLP-1 and GIP levels compared to healthy controls. Patients with residual beta cell function, indicated by detectable C-peptide, had lower GLP-1 levels than C-peptide-negative individuals, suggesting a link between residual beta cell function and GLP-1 secretion. The impaired incretin effect in T1D seems primarily linked to defective insulin secretion rather than altered hormone levels. For NDM, research suggested that KATP channel mutations, such as those linked to KCNJ11-PNDM, do not significantly impact incretin secretion. However, individuals with RFX6 mutations showed markedly reduced GLP-1 and GIP levels. The combination of GLP-1 receptor agonists and sulfonylureas (SU) provided promising benefits in glycemic management for patients with KCNJ11-related NDM. In MODY, HNF1A-diabetes (MODY 3) exhibited a reduced incretin effect despite normal GLP-1 and GIP secretion, while GCK-diabetes (MODY 2) maintained a normal incretin effect. GLP-1 receptor agonists and DPP-4 inhibitors showed potential in improving beta cell function and glucose metabolism in MODY subtypes.

Conclusion: 1. This review emphasizes the extensive physiological roles of incretins, showing their profound effects on metabolism, particularly glucose homeostasis, and extending to cardiovascular, digestive, and bone health. 2. In T1D, incretin levels are commonly reduced, yet some patients maintain residual secretion, especially GLP-1, from functional intestinal L-cells. This complexity in T1D's pathogenesis suggests that measuring incretin levels could inform more tailored therapeutic strategies.3. Studies on NDM indicate that serum incretin levels do not increase post-meal, despite enhanced insulin secretion after tailored treatments. This points to a possible role of incretin signalling disruption in NDM's pathogenesis, requiring further investigation to clarify incretins' specific functions.4. The diversity of MODY and scant targeted research allow only limited insights into GCK and HNF1A diabetes. GCK- MODY patients have incretin levels similar to healthy individuals, indicating normal incretin and beta-cell responsiveness. Conversely, individuals with HNF1A-MODY experience diminished incretin effects and insulin secretion, highlighting the need for customized diagnostic and therapeutic approaches.