Epigallocatechin gallate improves insulin sensitivity in rats experiencing catch-up growth after being small for gestational age by upregulating PDX1 expression

Introduction

Small for gestational age (SGA) refers to newborns who exhibit a weight below the 10th percentile for their gestational age (1,2). The prevalence of SGA follows a geographical pattern, with rates of approximately 10% in developed countries and up to 53% in developing countries of South Asia (1,3). SGA is attributed to various maternal and placental factors, including medical conditions, infections, poor nutrition, substance abuse, and more (1,4).

The majority of SGA infants may accelerate growth in the early life, which is defined as catch-up growth (CUG) (5,6). Despite the fact that most SGA neonates experience CUG, a notable proportion fail to achieve full growth recovery. Even among those who do exhibit CUG, there remains an elevated risk of medical complications (7). Specifically, individuals undergoing CUG are susceptible to developing metabolic disorders such as obesity, abnormal glucose tolerance, dyslipidemia, insulin resistance, and even type 2 diabetes mellitus (8,9). However, the precise underlying mechanism behind these occurrences remains incompletely understood.

The PDX1 gene plays a pivotal role in regulating both the development and homeostasis of the pancreas (10). It not only governs the differentiation of pancreatic progenitor cells into various endocrine cell types but also promotes insulin secretion by facilitating the proliferation and survival of pancreatic β cells (11-13). Knockout studies have demonstrated that PDX1 deficiency results in defective pancreas development, while mutations and deficiencies in PDX1 have been linked to diabetic phenotypes (14-17). Moreover, there is evidence suggesting an association between PDX1 mutations and SGA (18).

Epigallocatechin gallate (EGCG), one of the most abundant catechins found in green tea, is associated with numerous potential health benefits (19). Extensive research has highlighted its antioxidant, anti-inflammatory, and anti-cancer properties, which may contribute to its potential advantages for cardiovascular health, weight management, and cancer prevention (20,21). Consequently, EGCG is commonly consumed as a dietary supplement. Notably, studies have suggested that EGCG can increase thermogenesis (22), promote fat oxidation (23), enhance insulin sensitivity (24), and control lipid metabolism (25). However, the precise mechanism underlying EGCG’s beneficial effects on metabolic health remains incompletely understood, and its potential to improve pancreatic function in individuals experiencing CUG remains uncertain.

To address these questions, we established an SGA rat model and selected SGA rats undergoing CUG. We provided them with either normal water or water containing EGCG to assess EGCG’s effect on their fasting blood sugar levels and insulin sensitivity. Furthermore, we examined the proliferation and survival of insulin-secreting pancreatic cells in these rats, along with the expression of PDX1. We present this article in accordance with the ARRIVE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-357/rc).

Methods

Establishment and treatment of the SGA rat model

Pregnant Sprague Dawley rats were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Pregnant Sprague Dawley rats on the ad libitum diet were utilized to deliver pups for the appropriate for gestational age (AGA) control group. The SGA rat model was established following a previously published protocol (26). In brief, pregnant female rats were housed in a facility with a 12-hour light/dark cycle and provided ad libitum access to water and food. Food restriction commenced on gestational day 10, with rats receiving 50% of the normal diet consumed by those with unrestricted access. Following delivery, all female rats received a normal diet, and the pups were weaned at 21 days of age. From weaned day, fed with normal food and measured body length and weight. SGA pups with a body weight and length not less than −2 standard deviations (SDs) score were categorized as CUG. These pups were randomly divided into two groups: the untreated CUG group and the EGCG-treated CUG (CUG + EGCG) group, each comprising 6 pups. The groups were administered either normal water or water containing 0.25 mg/mL EGCG for a duration of 4 weeks according to a previous method (27). The animal experiments in this study were conducted by the Laboratory Animals-General Code of Animal Welfare of China. Animal experiments were performed under a project license (No. IACUC-20240129-03) granted by institutional ethics board of Zhejiang Chinese Medical University, in compliance with institutional guidelines for the care and use of animals.

Hyperinsulinemic-euglycemic clamp

For hyperinsulinemic-euglycemic clamp assays, the animals were subjected to a 12-hour fast and then anesthetized with isoflurane (R510-22-10, Shenzhen RWD Life Science Co., Ltd., Shenzhen, China). Regarding the anesthesia process, an inhalation anesthesia machine (KW-MZJ, Nanjing KEV BASIS Biotechnology Co., Ltd., Nanjing, China) was used with an anesthetic gas of 500–700 mL/min for rats. Space filled up about 1 min with 5% isoflurane concentration, with 2–3 min for the animal was narcosis completely, and the operational maintenance concentration is 1.5–2%. Subsequently, a sterile catheter was inserted into both the tail vein and artery. After a 30-min stabilization period, 0.8 mL of blood was collected, and the catheter in the tail vein was flushed with heparin-containing saline. Next, a 25% glucose solution was infused into the tail artery via the catheter to rapidly increase the blood sugar level to 13.5 mmol/L within 1 min and maintain this level for the subsequent 60 min. Throughout this procedure, blood samples were collected every 5 min during the first 15 min and every 15 min thereafter for a total duration of 60 min. Blood sugar and insulin levels were quantified using a commercial blood sugar meter and a rat insulin enzyme linked immunosorbent assay (ELISA) kit (PI606, Beyotime Biotechnology Co., Ltd., Shanghai, China), following the manufacturer’s instructions.

Homeostatic model assessment of insulin resistance (HOMA-IR) scores was calculated by fasting glucose and fasting insulin according to a previous formula (28): HOMA-IR = fasting glucose (mmol/L) × fasting insulin (µIU/mL)/22.5.

Hematoxylin-eosin (HE) and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining

At the end of the research, animals were euthanized using cervical dislocation in isoflurane-induced deep anesthesia following World Organization for Animal Health (Office International Des Epizooties, OIE) protocols. When rats do not move, breathe, and have pupil dilation, stop dislocation and observe for 2–3 minutes to ensure rats completely dead. Then dissected animals and collected pancreas to perform histopathology experiments and molecular experiments. Cutting each pancreas into 2 equal-sized pieces, one piece was used for frozen section, the other was used for Western blot and quantitative polymerase chain reaction (qPCR). To make frozen sections, immediately embed tissues in OCT (BL1674A, Biosharp Life Sciences Co., Ltd., Beijing, China) and frozen in liquid nitrogen. After fully frozen, using Leica CM1950 cryostat to cut OCT-embedded tissues into frozen sections at 8 µm, mounting sections on adhesive glass slides. Next, slides were fixed 10 minutes at 4 ℃ with cold acetone, followed by rinsing with phosphate-buffered saline (PBS) three times and subsequent blocking with 10% goat serum for 1 hour at room temperature (RT). Subsequently, the sections were incubated with 3% H₂O₂ to blocking endogenous peroxidase for 10 minutes. Using a kit generated by Solarbio (G1120) to analyze histopathological features of pancreas, following manufacturer’s instructions. Using TUNEL assay kit (P-CA-007, Procell, Wuhan Pricella Biotechnology Co., Ltd., Wuhan, China) to detect apoptotic cells, following the manufacturer’s instructions. Finally, the results were observed and imaged using an Axio Imager M2 microscope (Germany). For quantifications, randomly selected TUNEL stained sections from each group, took pictures on three different fields of each section and calculated whole cell numbers, TUNEL positive cell numbers and ratio using Image-Pro Plus 6.0 software. Data presented with average ratio of each section.

qPCR

Total RNA was extracted from the pancreatic tissues of each rat using the Trizol reagent (15596018CN, Invitrogen, Thermo Fisher Scientific, Massachusetts, USA) according to the manufacturer’s instructions. The concentration of RNA was determined using a Nanodrop spectrophotometer (Nanodrop2000, Thermo Fisher), and 2 µg of RNA from each rat was subjected to reverse transcription using the HiScript III All-in-one Reverse Transcription SuperMix (R333-01, Vazyme Biotech Co., Ltd., Nanjing, China). qPCR was performed using the Power SYBR Green PCR Master Mix (A46012, Applied Biosystems, Thermo Fisher) on an ABI 7500 machine (Applied Biosystems). The relative expression of target genes was calculated by the 2^−∆∆Ct method. The following primers were employed: rat PDX1-QF: 5'-CCTTTCCCGAATGGAACCGA-3', rat PDX1-QR: 5'-TTTTCCACGCGTGAGCTTTG-3'; rat 18S-QF: 5'-ACCCGTTGAACCCCATTCGTGA-3', rat 18S-QR: 5'-GCCTCACTAAACCATCCAATCGG-3'.

Western blot

50 mg of pancreatic tissues from each rat were homogenized on ice and then centrifuged for 30 minutes at 13,000 rpm at 4 ℃. The resulting supernatants were collected, and the protein concentration was determined using a BCA kit (PA115, TIANGEN Biotech Co., Ltd., Beijing, China). Subsequently, 30 µg of protein from each sample was denatured in a 100 ℃ water bath, loaded onto each well of 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gels, separated by electrophoresis, and transferred onto polyvinylidene fluoride (PVDF) membranes. Following this, the membranes were blocked with 5% non-fat milk at RT and then incubated overnight at 4 ℃ with primary antibody solutions. Afterward, the membranes were washed three times with TBST (TBS + 0.1% Tween 20) and incubated with the secondary antibody solution for 1 hour at RT. Following three additional washes with TBST, the membranes were incubated with the working solution prepared from an ECL kit (P0018S, Beyotime) to develop signals, which were then captured using a ChemiDoc machine (Bio-Rad Laboratories, Inc., California, USA). The intensity of bands was quantified using Image J software (National Institutes of Health, NIH, Maryland, USA). The experiments were repeated three times. The following antibodies were used: anti-PDX1 (20989-1-AP, Proteintech Group, Inc., Chicago, USA), anti-β-actin (20536-1-AP, Proteintech; 1:1,000), horseradish peroxidase (HRP)-conjugated goat anti-rabbit IgG (SA00001-2, Proteintech; 1:3,000).

Cell viability assay

Immortalized pancreatic β cell line MIN6 (ml096595, Dalian Meilun Biotechnology Co., Ltd., Dalian, China) was purchased from Shanghai Enzyme-linked Biotechnology Co., Ltd. (Shanghai, China). Cultured cells in RPMI1640 (ml-CC4960, meilunbio) medium containing 10% fetal bovine serum (FBS, Cytiva Lifesciences, Danaher Corporation, Washington, D.C., USA) and 1× penicillin-streptomycin (15140-148, Gibco, Thermo Fisher) at 37 ℃ in 5% CO₂ conditions.

To establish high glucose (HG)-induced insulin-resistant β cell model, MIN6 cells were seeded into 6-well culture plates and treated with normal glucose (NG; ~10 mM) or HG (~30 mM) over 48 hours according to a previous method (29). Indicated cells were seeded into 96-well plates, following 24 hours of drug exposure to test cytotoxicity by a Cell Counting Kit-8 (CCK-8) kit (C0037, Beyotime).

Flowcytometry

Using 0.25% trypsin (2520056, Gibco) to digest and collect cells of each group, separately. Then counting 1×10⁶ cells suspending in 100 µL PBS for apoptotic assay, stained cell 20 minutes with 5 µL AnnexinV-FITC and 10 µL PI in dark condition. Subsequently, analyzed apoptotic cell ratio by a flowcytometry machine (Novocyte1300, ACEA Biosciences, Agilent Technologies, Inc., California, USA) following manufacturer’s instructions.

Statistical analysis

Statistical analysis and plot generation were conducted using Prism software (v8.0, GraphPad, USA). Data were presented as mean ± SD. Significance between two datasets was calculated using unpaired two-tailed Student’s t-test, while significance among three datasets was assessed using one-way analysis of variance (ANOVA). P value <0.05 was considered statistically significant.

Results

EGCG treatment improved the insulin sensitivity of SGA rats undergoing CUG

To investigate the effect of EGCG on the insulin sensitivity of SGA rats with CUG, we initially assessed the fasting blood glucose levels of rats in the AGA, untreated CUG, and EGCG-treated CUG groups. Our results revealed that untreated CUG rats exhibited significantly higher levels of fasting blood glucose compared to AGA rats. However, this elevation was notably attenuated upon EGCG treatment (Figure 1A). Subsequently, we measured the fasting insulin levels in these rats. ELISA data revealed that untreated CUG rats exhibited lower insulin levels than AGA rats, and EGCG treatment rescued the fasting insulin levels to levels comparable to those in AGA rats (Figure 1B). Consistently, the impaired insulin sensitivity observed in untreated CUG rats was restored by EGCG treatment, as indicated by the HOMA-IR scores (Figure 1C). These findings demonstrate that EGCG treatment can improve impaired insulin sensitivity in CUG rats.

Figure 1 EGCG improved insulin sensitivity in CUG rats. (A) Fasting blood glucose concentrations in rats with the indicated treatments at different time points. (B) ELISA data showing the fasting blood insulin levels in rats with the indicated treatments at different time points. (C) HOMA-IR results illustrating the insulin sensitivity in rats with the indicated treatments at different time points. Higher values represent lower insulin sensitivity. AGA, appropriate for gestational age; CUG, catch-up growth; EGCG, epigallocatechin gallate; ELISA, enzyme linked immunosorbent assay; HOMA-IR, homeostatic model assessment of insulin resistance.

EGCG protected pancreatic cells from damage and apoptosis

As EGCG elevated the fasting insulin levels of CUG rats, we investigated whether EGCG regulates the survival of pancreatic cells. HE data revealed that the islets of AGA and EGCG-treated CUG rats resembled more secreted protein granules than those of CUG rats (yellow arrow). EGCG protects islets from duct structure reconstructions (black five-pointed star) and islet structural damage (black arrow) (Figure 2A). Furthermore, the apoptosis of islet cells, which was elevated in CUG rats, was attenuated by EGCG treatment (Figure 2B). These observations suggest that EGCG treatment promotes the proliferation and survival of pancreatic cells.

Figure 2 EGCG protected pancreatic cells from damage and apoptosis. (A) HE data showing the structure of pancreatic tissues from the rat with the indicated treatments. The yellow arrows indicate protein granules; black arrow indicates loosed structure; black five-stars indicate ducts. (B) TUNEL data illustrating the apoptosis of islet cells in rats with the indicated treatment. AGA, appropriate for gestational age; CUG, catch-up growth; EGCG, epigallocatechin gallate; HE, hematoxylin and eosin; TUNEL, TdT-mediated dUTP Nick-End Labeling.

EGCG increased the expression of PDX1 influenced cell cycle in CUG pancreatic tissues

To elucidate the mechanism by which EGCG improves pancreatic function in CUG rats, we examined the expression of PDX1, a master regulator of pancreatic exocrine cell differentiation, proliferation, and survival. qPCR and Western blot analysis revealed a significant downregulation of pancreatic PDX1 expression in untreated CUG rats. EGCG treatment substantially increased pancreatic PDX1 levels (P<0.05), restoring them to levels comparable to those in AGA rats (Figure 3A-3C). Remarkably, restored PDX1 expression in EGCG-treated CUG rats correlated with PCNA, CDK4, cyclin D2 upregulation in pancreas (Figure 3B,3C), which indicated cell cycle progression. These findings indicate that EGCG may enhance pancreatic function in CUG rats by elevating PDX1 expression.

Figure 3 EGCG increased the expression of PDX1 influenced cell cycle in CUG pancreatic tissues. (A) qPCR data showing the levels of pancreatic PDX1 mRNA in rats with the indicated treatment. (B) Representative Western blot data and (C) quantifications showing EGCG upregulated PDX1, cyclinD2, CDK4, PCNA protein levels, which down-regulated in CUG tissues. AGA, appropriate for gestational age; CUG, catch-up growth; EGCG, epigallocatechin gallate; qPCR, quantitative polymerase chain reaction.

EGCG protected pancreatic β cell from HG induced damage through regulating PDX1 expression

To further clarify the mechanism under EGCG’s protective effects in pancreatic β cells, we established a HG-induced insulin resistance β cell model, assessed β cell viability and apoptosis rate with or without EGCG treatments. Cell viability assays showed that EGCG significantly elevated cell viability depending on dosage, approximately 10 µM was the optimal drug concentration in the HG damage condition (Figure 4A). Therefore, 10 µM EGCG concentration was used for further in vitro experiments. Furthermore, knocking down PDX1 expression may mitigate EGCG’s protective effects. Cell viability assays demonstrated that EGCG improved HG damaged β cell survival, while PDX1 knocked down eliminated this result (Figure 4B). Apoptotic cell assays also illustrated EGCG’s protective effects reversed by PDX1 knockdown (Figure 4C,4D).

Figure 4 EGCG protected pancreatic β cell from high glucose induced damage through regulating PDX1 expression. (A) Cell viability data showing EGCG protect pancreatic β cell from HG induced damage, approximately 10 µM is the appropriate concentration for in vitro treatments. (B) Cell viability data elucidating PDX1 knockdown inhibited EGCG protective effect. (C) Representative flowcytometry plots and (D) quantifications of apoptotic cell ratio illustrating PDX1 knock down mitigated EGCG protected effect in pancreatic β cell. EGCG, epigallocatechin gallate; HG, high glucose; NG, normal glucose.

EGCG improved PDX1 expression to regulate pancreatic β cell proliferation

Cell viability assays and apoptotic assays demonstrated that EGCG may enhance pancreatic β cell survival rate by regulating PDX1 expression under insulin resistance damage context. To further elucidate PDX1 expression level and cell cycle changes in response to EGCG treatment, Western blot was used to analyze PDX1, cyclin D2, CDK4 and PCNA expression. Western blot data showed that HG damaged pancreatic β cell proliferation by downregulating PDX1, PCNA, CDK4 and cyclin D2. Meanwhile, EGCG improved proliferation correlated protein levels by increasing PDX1 expression (Figure 5A,5B). These data illustrated that EGCG protects pancreatic β cells from insulin resistance by upregulating PDX1 expression.

Figure 5 EGCG improved PDX1 expression to regulate pancreatic β cell proliferation. (A) Representative Western blot plots and (B) relative quantifications of each protein demonstrating EGCG affects cyclinD2, CDK4, PCNA expression through regulating PDX1. AGA, appropriate for gestational age; EGCG, epigallocatechin gallate; HG, high glucose.

Discussion

The potential health benefit of drinking green tea is widely recognized, attributed to its rich content of bioactive compounds, particularly catechins. Among these, EGCG is the most abundant catechin. Consequently, its functions in various contexts have been intensively investigated. In addition to its well-known functions in other scenarios, our findings reveal the uncharacterized function of EGCG in improving insulin sensitivity in SGA rats undergoing CUG.

SGA poses significant health risks in affected individuals, as even most SGA infants undergo CUG in their first or second year of life (30). However, these individuals still have a high incidence of developing various disorders, particularly metabolic abnormalities. Therefore, the identification of a novel compound that could be used as a drug or dietary supplement holds significant meaning in the prevention and/or treatment of metabolic disorders occurring in individuals experiencing CUG individuals.

Numerous pieces of clinical evidence indicates that EGCG has positive effects on regulation energy metabolism. For instance, low dose of EGCG supplements resulted in elevated metabolic rate (31). However, rarely clinical trials aiming at modulating metabolic disorder in SGA infants, which may due to the high risk of clinical test in newborns.

Our data provide direct evidence that EGCG can improve insulin sensitivity in fasting CUG rats. This effect may be achieved through a mechanism distinct from the one by which EGCG strengthens insulin sensitivity in contexts other than CUG from SGA, as the impact of EGCG on insulin secretion is context-dependent. For instance, EGCG inhibits BCH [β-2-aminobicycle(2.2.1)-heptane-2-carboxylic acid]-stimulated insulin secretion by pancreatic β cells but has no inhibition on glucose-stimulated insulin secretion under high energy conditions (32).

In the CUG rats, EGCG likely facilitates insulin secretion by potentiating the proliferation and survival of β cells. However, EGCG only partially rescues the proliferation and apoptosis in CUG rats, indicating additional mechanisms are involved in mediating the protective effect of EGCG on pancreatic β cells. One possibility is that EGCG also promotes insulin production by enhancing the differentiation of β cells. This hypothesis is supported by the significant increase in the expression of PDX1 induced by EGCG, as PDX1 positively regulates the differentiation, proliferation, and survival of pancreatic exocrine cell types, as mentioned above. Nevertheless, how EGCG regulates PDX1 expression remains unclear. Further investigations are warranted to address these questions.

Meanwhile, it is worth noting that our conclusion is based on a food restriction-based animal model and a HG induced insulin resistance pancreatic β cell model. Given the diverse causes of SGA, it remains undetermined whether EGCG has a similar effect on CUG recovered from SGA resulting from other factors. Additionally, immortalized pancreatic β cell line exists abnormal proliferation rate, it is unable to display physiological β cell response. Also, the optimal EGCG concentration may need to be determined to achieve the best therapeutic effect. Most importantly, the efficacy of EGCG should be verified in clinical trials before being widely applied to combat metabolic disorders in SGA-affected individuals.

Conclusions

In summary, our findings reveal that EGCG could improve insulin sensitivity in CUG rats recovered from SGA, possibly by elevating PDX1 expression. These observations expand our understanding of the function of EGCG and underscore its therapeutic potential as both a drug and a beneficial dietary supplement.

Acknowledgments

We would like to thank the associate editor and the reviewers for their useful feedback for improving the paper.

Footnote

Reporting Checklist: The authors have completed the ARRIVE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-357/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-357/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-357/prf

Funding: This research was funded by the Medical and Health Science and Technology Project of Zhejiang Province (No. 2022KY703), and the Zhejiang Province Traditional Chinese Medicine Science and Technology Project (No. 2024ZL363).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-357/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Animal experiments were performed under a project license (No. IACUC-20240129-03) granted by institutional ethics board of Zhejiang Chinese Medical University, in compliance with institutional guidelines for the care and use of animals.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Osuchukwu OO, Reed DJ. Small for Gestational Age (Archived). 2024 Aug 11. Treasure Island (FL): StatPearls Publishing; 2025.
2. DeVore GR, Polanco B, Lee W, et al. Maternal rest improves growth in small-for-gestational-age fetuses (<10th percentile). Am J Obstet Gynecol 2025;232:118.e1-12. [Crossref] [PubMed]
3. Lee AC, Katz J, Blencowe H, et al. National and regional estimates of term and preterm babies born small for gestational age in 138 low-income and middle-income countries in 2010. Lancet Glob Health 2013;1:e26-36. [Crossref] [PubMed]
4. Finken MJJ, van der Steen M, Smeets CCJ, et al. Children Born Small for Gestational Age: Differential Diagnosis, Molecular Genetic Evaluation, and Implications. Endocr Rev 2018;39:851-94. [Crossref] [PubMed]
5. Cooke R, Goulet O, Huysentruyt K, et al. Catch-Up Growth in Infants and Young Children With Faltering Growth: Expert Opinion to Guide General Clinicians. J Pediatr Gastroenterol Nutr 2023;77:7-15. [Crossref] [PubMed]
6. Li Y, Wen J, Jiang Q, et al. Different Catch-Up Growth Patterns in Very Preterm and Small for Gestational Age Infants. Clin Pediatr (Phila) 2025;64:780-90. [Crossref] [PubMed]
7. Vizzari G, Morniroli D, Tiraferri V, et al. Postnatal growth of small for gestational age late preterm infants: determinants of catch-up growth. Pediatr Res 2023;94:365-70. [Crossref] [PubMed]
8. Jain S, Alshaikh BN, Elmrayed S, et al. Short- and longer-term growth and development of fat mass in preterm infants. Semin Fetal Neonatal Med 2025;30:101636. [Crossref] [PubMed]
9. Brouwer ECJ, Floyd WN, Jensen ET, et al. Risk of Obesity and Unhealthy Central Adiposity in Adolescents Born Preterm With Very Low Birthweight Compared to Term-Born Peers. Child Obes 2024;20:485-93. [Crossref] [PubMed]
10. Ebrahim N, Shakirova K, Dashinimaev E. PDX1 is the cornerstone of pancreatic β-cell functions and identity. Front Mol Biosci 2022;9:1091757. [Crossref] [PubMed]
11. Oliver-Krasinski JM, Kasner MT, Yang J, et al. The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice. J Clin Invest 2009;119:1888-98. [Crossref] [PubMed]
12. Gao T, McKenna B, Li C, et al. Pdx1 maintains β cell identity and function by repressing an α cell program. Cell Metab 2014;19:259-71. [Crossref] [PubMed]
13. Barco VS, Gallego FQ, Miranda CA, et al. Hyperglycemia influences the cell proliferation and death of the rat endocrine pancreas in the neonatal period. Life Sci 2024;351:122854. [Crossref] [PubMed]
14. Ahlgren U, Jonsson J, Jonsson L, et al. beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev 1998;12:1763-8. [Crossref] [PubMed]
15. Abreu GM. PDX1-MODY: A rare missense mutation as a cause of monogenic diabetes. Eur J Med Genet 2021;64:104194. [Crossref] [PubMed]
16. Bastidas-Ponce A, Roscioni SS, Burtscher I, et al. Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells. Mol Metab 2017;6:524-34. [Crossref] [PubMed]
17. Wang X, Sterr M. Point mutations in the PDX1 transactivation domain impair human β-cell development and function. Mol Metab 2019;24:80-97. [Crossref] [PubMed]
18. Nicolino M, Claiborn KC, Senée V, et al. A novel hypomorphic PDX1 mutation responsible for permanent neonatal diabetes with subclinical exocrine deficiency. Diabetes 2010;59:733-40. [Crossref] [PubMed]
19. Nagle DG, Ferreira D, Zhou YD. Epigallocatechin-3-gallate (EGCG): chemical and biomedical perspectives. Phytochemistry 2006;67:1849-55. [Crossref] [PubMed]
20. Eng QY, Thanikachalam PV, Ramamurthy S. Molecular understanding of Epigallocatechin gallate (EGCG) in cardiovascular and metabolic diseases. J Ethnopharmacol 2018;210:296-310. [Crossref] [PubMed]
21. Chakrawarti L, Agrawal R, Dang S, et al. Therapeutic effects of EGCG: a patent review. Expert Opin Ther Pat 2016;26:907-16. [Crossref] [PubMed]
22. Lee MS, Shin Y, Jung S, et al. Effects of epigallocatechin-3-gallate on thermogenesis and mitochondrial biogenesis in brown adipose tissues of diet-induced obese mice. Food Nutr Res 2017;61:1325307. [Crossref] [PubMed]
23. Hodgson AB, Randell RK, Jeukendrup AE. The effect of green tea extract on fat oxidation at rest and during exercise: evidence of efficacy and proposed mechanisms. Adv Nutr 2013;4:129-40.
24. Liu CY, Huang CJ, Huang LH, et al. Effects of green tea extract on insulin resistance and glucagon-like peptide 1 in patients with type 2 diabetes and lipid abnormalities: a randomized, double-blinded, and placebo-controlled trial. PLoS One 2014;9:e91163. [Crossref] [PubMed]
25. Raederstorff DG, Schlachter MF, Elste V, et al. Effect of EGCG on lipid absorption and plasma lipid levels in rats. J Nutr Biochem 2003;14:326-32. [Crossref] [PubMed]
26. Desai M, Han G, Li T, et al. Programmed Epigenetic DNA Methylation-Mediated Reduced Neuroprogenitor Cell Proliferation and Differentiation in Small-for-Gestational-Age Offspring. Neuroscience 2019;412:60-71. [Crossref] [PubMed]
27. Xu P, Yan F, Zhao Y, et al. Green Tea Polyphenol EGCG Attenuates MDSCs-mediated Immunosuppression through Canonical and Non-Canonical Pathways in a 4T1 Murine Breast Cancer Model. Nutrients 2020;12:1042. [Crossref] [PubMed]
28. Niu HS, Ku PM, Niu CS, et al. Development of PPAR-agonist GW0742 as antidiabetic drug: study in animals. Drug Des Devel Ther 2015;9:5625-32. [Crossref] [PubMed]
29. Song Z, Wang H, Zhu L, et al. Curcumin improves high glucose-induced INS-1 cell insulin resistance via activation of insulin signaling. Food Funct 2015;6:461-9. [Crossref] [PubMed]
30. Su YY, Chen CJ, Chen MH, et al. Long-term effects on growth in preterm and small for gestational age infants: A national birth cohort study. Pediatr Neonatol 2025;66:168-75. [Crossref] [PubMed]
31. Kapoor MP, Sugita M, Fukuzawa Y, et al. Physiological effects of epigallocatechin-3-gallate (EGCG) on energy expenditure for prospective fat oxidation in humans: A systematic review and meta-analysis. J Nutr Biochem 2017;43:1-10. [Crossref] [PubMed]
32. Li C, Allen A, Kwagh J, et al. Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase. J Biol Chem 2006;281:10214-21. [Crossref] [PubMed]