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Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS) are chronic disorders characterized by hyperglycemia. Sechium edule (S. edule) has emerged as a complementary option due to its bioactive compounds. A systematic review of preclinical and clinical studies was carried out until 25 May 2025 in the databases PubMed, Scopus, Web of Science, SciELO, and TESIUNAM. The keywords were “diabetes mellitus”, “Sechium edule”, “Squash”, “Chayote”, “hypoglycemic effect”, and “Older adults”. A total of 110 articles were found; 11 met eligibility criteria (six clinical trials and five preclinical trials). Three clinical trials met the requirements for meta-analysis. The mean difference (MD) was calculated, and data were analyzed using RevMan 5.4 software. The meta-analysis showed a statistically significant decrease in serum glucose after three months (MD = −20.56, 95%CI −29.35 to −11.77, p < 0.0001) and six months after intervention (MD = −12.96, 95%CI = −21.90 to −4.02, p = 0.004). Likewise, there was a significant decrease in glycosylated hemoglobin (HbA1c) after three months (MD = −1.12, 95% CI = −1.45, −0.78, p < 0.0001) and after six months of intervention (MD = −0.92, 95% CI = −1.13, −0.25, p = 0.002). Our findings showed that S. edule intake has a statistically significant hypoglycemic effect in older adults with T2DM or MS by decreasing serum glucose and HbA1c levels. However, the magnitude of the decrease is clinically modest, so it cannot be a substitute for pharmacological treatment. For this reason, the intake of S. edule can only be considered as a complement to pharmacological treatment. Full article

Diabetes represents one of the major challenges in preserving health in the 21st century. It has been estimated that in 2050, 853 million subjects will live with diabetes. It was also reported that 3.4 million adults died from diabetes and related comorbidities. Chronic hyperglycemia, if not properly managed, leads to skeletal fragility with fracture risk that augments with age. In type 1 diabetes (T1D), the augmented fracture risk can be partially explained by lower areal bone mineral density (aBMD). Interestingly, in type 2 diabetes (T2D), the risk of fractures increases with normal or elevated aBMD. In this review, the recent updates on diabetes and bone health (2023–2025) are reported, thus describing bone quality and the role of mediators involved in diabetes pathogenesis. Consequently, the role of Vitamin D, Incretins, Glucagon-like peptide-2 (GLP-2), neurotensin, asprosin, irisin, and Thioredoxin-interacting protein (TXNIP) will be described considering the interplay between diabetes and bone health. The importance of monitoring diabetic patients’ bone health is underlined, together with the therapeutic approaches to avoid fractures. Full article

Background/Objectives: Gestational diabetes mellitus (GDM) is a state of hyperglycemia during pregnancy, increasing the risk of birth complications, and subsequent type 2 diabetes mellitus in the mother and offspring. Risk factors such as diet, obesity, and family history have demonstrated strong association with GDM, but no clear pathophysiology has been ascertained. Methods: An analysis was conducted on 38 women with and 296 without GDM, within a case/control study of pre-eclampsia. The genetic variants examined were selected from among a published polygenic risk score of 10 variants (PRS-10). Genetic models were evaluated for each variant by multivariate logistic regression methods adjusted for age, body mass index, and pre-eclampsia. Since the genotypes for three of the PRS-10 were not available, a risk score comprising the total risk alleles among seven of the variants (PRS-7) was evaluated among those with all genotypes available. Results: Multivariate logistic regression showed significant, independent, positive associations between body mass index (BMI) and age. The posited PRS-7 showed a trend (OR 1.56, 95% CI 0.92–2.56, p = 0.070), and sensitivity analysis comprising three variants (PRS-3) was significantly associated with GDM (OR 2.43, 95% CI 1.17–5.06, p = 0.017). In univariate analysis, rs1421085 was associated with GDM (OR 0.50, 95% CI 0.26–0.95, p = 0.034), but not after adjustment for covariates, and paradoxically not for the expected risk allele. None of the other six variants showed an individual association with GDM. The previously published meta-analysis of PRS-10 showed a degree of heterogeneity (p_Q= 0.03) among the three cohorts analyzed, suggesting that variant effects may differ according to the genetic background, which points to the importance of examining the generalizability of any posited polygenic risk scores. Conclusions: In conclusion, we provide additional support for and further refine the results of a previously published polygenic risk score for GDM in an ethically unrelated population. Full article

Background/Objectives: Diabetic ketoacidosis (DKA) is a life-threatening emergency resulting in significant morbidity and health care utilization. The most common cause of DKA in the general population is insulin nonadherence, but limited data exists on precipitating factors for DKA in cancer patients. In this study, we characterize the demographic and clinical characteristics of hospitalized patients with DKA at our comprehensive cancer center. Methods: This single-center retrospective study evaluated 91 patients with 94 admissions for DKA at our institution between January 2019 and December 2021. Demographic, clinical, and biochemical data were obtained from a review of the electronic medical record. Patient characteristics were summarized using descriptive statistics for continuous variables and categorical variables. Results: Of the 91 patients, 21% of patients (n = 19) had underlying type 1 diabetes, 49% of patients (n = 45) had type 2 diabetes, and 30% of patients (n = 27) had drug-induced diabetes. A total of 39% (n = 29) had poorly controlled diabetes with HbA1c > 9% (75 mmol/mol). In patients with known type 1 diabetes, the most common provoking factors were inadequate insulin therapy and infection related causes. In patients with known type 2 diabetes or no previous history of diabetes, the most common provoking factors were medications such as immune checkpoint inhibitors, SGLT2 inhibitors and steroids. Conclusions: We characterized the precipitating factors for DKA based on patients’ underlying diabetes status. While insulin non-adherence was the most common cause in patients with known type 1 diabetes, drugs associated with cancer related treatments emerged most common precipitating factor for DKA in cancer patients with underlying type 2 diabetes or drug induced diabetes. A tailored approach with proactive counseling may be helpful in timely recognition and treatment of DKA in cancer patients. Full article

Diabetes, a major global healthcare challenge, is characterized by chronic hyperglycemia and significantly exacerbates the severity of systemic complications. Iron, an essential element ubiquitously present in biological systems, is involved in many biological processes facilitating cell proliferation and growth. However, excessive iron accumulation promotes oxidative damage through the Fenton reaction, thereby increasing the incidence of diabetes and worsening diabetic complications. Notably, ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key mechanism underlying diabetes and diabetic complications. In this review, we provide an update on the current understanding of iron metabolism dysregulation in diabetes risk, and disclose the mechanistic links between iron overload and diabetes evidenced in hereditary hemochromatosis and thalassemia. We particularly highlight iron-mediated oxidative stress as a central nexus impairing glucose metabolism and insulin sensitivity. Furthermore, we discuss the significance of dysmetabolic iron and ferroptosis activation in the progression of diabetes and diabetic complications, as well as the possible application of natural products for iron metabolism regulation and ferroptosis-inhibition-targeted therapeutic strategies to treat diabetes and diabetic complications. Full article

Type 2 diabetes (T2D) is a complex metabolic disease characterized by chronic hyperglycemia due to insulin resistance and inadequate insulin secretion. Beyond the classically implicated organs, emerging evidence highlights the gut as a central player in T2D pathophysiology through its interactions with metabolic organs. The gut hosts trillions of microbes and enteroendocrine cells that influence inflammation, energy homeostasis, and hormone regulation. Disruptions in gut homeostasis (dysbiosis and increased permeability) have been linked to obesity, insulin resistance, and β-cell dysfunction, suggesting multifaceted “Gut-X axes” contribute to T2D development. We aimed to comprehensively review the evidence for gut-mediated crosstalk with the pancreas, endocrine system, liver, and kidneys in T2D. Key molecular mechanisms (incretins, bile acids, short-chain fatty acids, endotoxins, etc.) were examined to construct an integrated model of how gut-derived signals modulate metabolic and inflammatory pathways across organs. We also discuss clinical implications of targeting Gut-X axes and identify knowledge gaps and future research directions. A literature search (2015–2025) was conducted in PubMed, Scopus, and Web of Science, following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews). Over 150 high-impact publications (original research and review articles from Nature, Cell, Gut, Diabetologia, Lancet Diabetes & Endocrinology, etc.) were screened. Data on gut microbiota, enteroendocrine hormones, inflammatory mediators, and organ-specific outcomes in T2D were extracted. The GRADE framework was used informally to prioritize high-quality evidence (e.g., human trials and meta-analyses) in formulating conclusions. T2D involves perturbations in multiple Gut-X axes. This review first outlines gut homeostasis and T2D pathogenesis, then dissects each axis: (1) Gut–Pancreas Axis: how incretin hormones (GLP-1 and GIP) and microbial metabolites affect insulin/glucagon secretion and β-cell health; (2) Gut–Endocrine Axis: enteroendocrine signals (e.g., PYY and ghrelin) and neural pathways that link the gut with appetite regulation, adipose tissue, and systemic metabolism; (3) Gut–Liver Axis: the role of microbiota-modified bile acids (FXR/TGR5 pathways) and bacterial endotoxins in non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance; (4) Gut–Kidney Axis: how gut-derived toxins and nutrient handling intersect with diabetic kidney disease and how incretin-based and SGLT2 inhibitor therapies leverage gut–kidney communication. Shared mechanisms (microbial SCFAs improving insulin sensitivity, LPS driving inflammation via TLR4, and aryl hydrocarbon receptor ligands modulating immunity) are synthesized into a unified model. An integrated understanding of Gut-X axes reveals new opportunities for treating and preventing T2D. Modulating the gut microbiome and its metabolites (through diet, pharmaceuticals, or microbiota therapies) can improve glycemic control and ameliorate complications by simultaneously influencing pancreatic islet function, hepatic metabolism, and systemic inflammation. However, translating these insights into clinical practice requires addressing gaps with robust human studies. This review provides a state-of-the-art synthesis for researchers and clinicians, underlining the gut as a nexus for multi-organ metabolic regulation in T2D and a fertile target for next-generation therapies. Full article

Hyperglycemia in early-stage embryogenesis is linked to diabetic embryopathy. High-glucose-concentration-induced accumulation of hexokinase-2 (HK2) may initiate metabolic dysfunction that contributes to diabetic embryopathy, including increased formation of methylglyoxal (MG). In this study, we evaluated changes in HK2 protein levels and embryo dysmorphogenesis in an experimental model of diabetic embryopathy. Rat embryos were cultured with high glucose concentrations, and the effects of glyoxalase 1 (Glo1) inducer, trans-resveratrol and hesperetin (tRES + HESP) were evaluated. Rat embryos, on gestational day 9, were cultured for 48 h in low and high glucose concentrations with or without tRES + HESP. Embryo crown–rump length, somite number, malformation score, concentrations of HK2 and Glo1 protein, rates of glucose consumption, and MG formation were assessed. Under low-glucose conditions, embryos exhibited normal morphogenesis. In contrast, high-glucose conditions led to reduced crown–rump length and somite number, and an increased malformation score. The addition of 10 μM tRES + HESP reversed these high glucose-induced changes by 60%, 49%, and 47%, respectively. Embryos cultured in high glucose showed increases in HK2 concentration (42%), glucose consumption (75%), and MG formation (27%), normalized to embryo volume. These elevated HK2 levels were normalized by treatment with 10 μM tRES + HESP. Thus, high-glucose-induced metabolic dysfunction and embryopathy may both be initiated by HK2 accumulation and may be preventable with tRES + HESP treatment. Full article

Diabetes is increasingly recognized as a chronic inflammatory disease marked by systemic metabolic disturbances, with endothelial dysfunction playing a central role in its complications. Hyperglycemia, a hallmark of diabetes, drives endothelial damage by inducing excessive reactive oxygen species (ROS) production, particularly hydrogen peroxide (H₂O₂). This oxidative stress impairs endothelial cells, which are vital for vascular health, leading to severe complications such as diabetic nephropathy, retinopathy, and coronary artery disease—major causes of morbidity and mortality in diabetic patients. Recent studies have highlighted the therapeutic potential of placenta-derived mesenchymal stem cells (pMSCs), in mitigating these complications. pMSCs exhibit anti-inflammatory, antioxidant, and tissue-repair properties, showing promise in reversing endothelial damage in laboratory settings. To explore their efficacy in a more physiologically relevant context, we used a streptozotocin (STZ)-induced diabetic mouse model, which mimics type 1 diabetes by destroying pancreatic beta cells and causing hyperglycemia. pMSCs were administered via intra-peritoneal injections, and their effects on endothelial injury and tissue damage were assessed. Metabolic tests, including glucose tolerance tests (GTTs) and insulin tolerance tests (ITTs) revealed that pMSCs did not restore metabolic homeostasis or improve glucose regulation. However, histopathological kidney, heart, and eye tissue analyses demonstrated significant protective effects. pMSCs preserved glomerular structure in the kidneys, protected cardiac blood vessels, and maintained retinal integrity, suggesting their potential to address diabetes-related tissue injuries. Although these findings underscore the therapeutic potential of pMSCs for diabetic complications, further research is needed to optimize dosing, elucidate molecular mechanisms, and evaluate long-term safety and efficacy. Combining pMSCs with other therapies may enhance their benefits, paving the way for future clinical applications. Full article

Type 2 diabetes is a multifactorial disease characterized by chronic hyperglycemia, insulin resistance, oxidative stress, inflammation, and dyslipidemia, factors that contribute to the development of long-term complications. In this context, the 2-aminobenzothiazole scaffold has emerged as a promising candidate due to its broad spectrum of biological properties. In this study, we performed a multidisciplinary evaluation of benzothiazole derivatives (5a–d, 8a–d, 11a–d, and 12c–d), starting with the in silico prediction of their properties, along with molecular docking against aldose reductase (ALR2) and peroxisome proliferator-activated receptor gamma (PPAR-γ). All compounds complied with the main rules of pharmacological similarity and optimal affinity, highlighting 8d (ΔG = −8.39 kcal/mol for ALR2 and −7.77 kcal/mol for PPAR-γ). Selected compounds from families C and D were synthesized in moderate yields (~60%) and showed low acute oral toxicity (LD₅₀ > 1250 mg/Kg). Compounds 8c and 8d inhibited ALR2 at concentrations below 10 µM. In vivo studies using a streptozotocin-induced diabetic rat model with a high-fat diet revealed that compound 8d produced sustained antihyperglycemic effects and reduced insulin resistance, dyslipidemia, and polydipsia, without inducing hepatotoxicity or displaying intrinsic antioxidant or anti-inflammatory activity. These findings suggest that 8d is a promising candidate for further development in diabetes-related therapeutic strategies. Full article

Background and Clinical Significance: Ischemic optic neuropathies (IONs) are significant causes of vision loss resulting from compromised blood flow to the optic nerve. Diabetes mellitus (DM) exacerbates the risk of IONs through chronic hyperglycemia and associated vascular dysfunction. Recently, semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has been linked to ocular complications, including non-arteritic anterior ischemic optic neuropathy (NAION), potentially due to the rapid glycemic changes or vascular effects. Case Presentation: A 55-year-old female with type 2 DM, hypertension, and hyperlipidemia presented with blurred vision and optic disc edema after four months of semaglutide therapy (Ozempic^®, Sydney, Australia). Initially diagnosed with diabetic papillopathy (DP), her condition progressed to NAION, leading to partial visual recovery with corticosteroid treatment and improved glycemic management. Diagnostic evaluations, including visual field testing, optical coherence tomography, and fluorescein angiography, supported the diagnosis. Conclusions: This case report describes the clinical course of a diabetic patient treated with a semaglutide who developed an ischemic optic event. The timing of symptom onset in relation to the initiation of semaglutide therapy raises the possibility of a causal association between the drug and this rare ocular complication. Close monitoring of ocular health is crucial for patients on GLP-1 receptor agonists, particularly those with pre-existing vascular risk factors. Further research is needed to elucidate the underlying mechanisms and guide clinical practice. Full article

Background/Objectives: Overnutrition increases comorbidities such as gestational diabetes during pregnancy that can have detrimental consequences for both parent and progeny. We previously reported that high-fat (HF) diet and late-gestation diabetes (DM) incite mitochondrial dysfunction, oxidative stress, and cardiometabolic disease in first generation (F1) rat offspring, partially through epigenomic and transcriptomic programming. Primordial germ cells, which become the second generation (F2), are also exposed, which could incite generational risk. This study aimed to determine whether the F2 transcriptome already has genomic variation at the preimplantation embryo stage, and whether variations normalize, persist or compound in the third generation (F3). Methods: F0 female rats were fed a control or HF diet, then DM was induced in HF-fed dams on gestational day (GD)14, exposing F1 offspring and F2 primordial germ cells to hyperlipidemia, hyperglycemia and fetal hyperinsulinemia during the last third of pregnancy. F1 pups were reared by healthy dams and bred to produce F2 embryos (F2e) and F2 pups. F2 offspring were bred to produce F3 embryos (F3e). Embryos were assessed by a novel grading method, live cell imaging, and single-cell RNA sequencing. Results: Embryo grades were not different, but HF+DM F2e had more cells while F3e had fewer cells and overall fewer embryos. HF+DM F2e had similar mitochondria quantity but a downregulation of genes involved in lipid metabolism and more oxidative stress, consistent with mitochondrial dysfunction. They also had an upregulation of chromatin-remodeling genes. The predicted developmental effect is accelerated embryo aging and epigenetic drift. In contrast, HF+DM F3e had an adaptive stress response leading to increased mitochondria quantity and an upregulation of genes involved in mitochondrial respiration, metabolism, and genomic repair that led to a predicted developmental effect of delayed embryo maturation. Conclusions: Although pathways vary, both generations have metabolically linked differentially expressed genes that influence cell fate and developmental pathways. In conclusion, HF+DM pregnancy can program the early embryonic transcriptome for three generations, despite an intergenerational healthy diet. Full article

Background/Objectives: Gestational diabetes mellitus (GDM) complicates approximately 14% of pregnancies worldwide, its prevalence rising with increasing maternal age and obesity. While maternal hyperglycemia is traditionally associated with fetal overgrowth and large-for-gestational-age (LGA) neonates, emerging evidence indicates that GDM may also contribute to small-for-gestational-age (SGA) outcomes. Methods: A comprehensive literature search was conducted using multiple databases, including PubMed, Web of Science, and ScienceDirect, to identify studies related to gestational diabetes mellitus, fetal growth outcomes such as small for gestational age and large for gestational age, and associated pathophysiological mechanisms. Results: This narrative review explores the mechanisms by which GDM influences fetal growth, emphasizing the dual risk of excessive and restricted intrauterine growth. Fetal macrosomia typically results from chronic maternal hyperglycemia, leading to increased transplacental glucose delivery and fetal hyperinsulinemia. In contrast, SGA outcomes are a consequence of vascular and endothelial dysfunction, placental insufficiency, or excessively restrictive glycemic control that limit the availability of nutrients. Both extremes of fetal growth carry a myriad of significant perinatal and long-term metabolic risks. Conclusions: Understanding the diverse pathways through which GDM affects fetal growth is essential for developing individualized clinical strategies. Full article

Background: The prevalence of type 2 diabetes (T2D) is on the rise, and insulin resistance (IR) is one of the key risk factors for developing T2D. This paper seeks to identify risk factors for IR in women with normal menstrual cycles (NM) and early menopausal women (EM). Methods: EM women between 30 and 50 years old were compared with an NM control group. Four machine learning (ML) methods were trained using comprehensive physiological and lifestyle data to estimate a homeostasis model for insulin resistance (HOMA-IR dependent variable). Traditional multiple linear regression (MLR) was used as a benchmark for comparison. Results: A total of 948 participants were enrolled (NM: 410, EM: 538). On average, ML outperformed MLR, identifying the six key risk factors in the EM group (from most to least important) as waist–hip ratio (WHR), triglyceride (TG), glutamic-pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), HDL-Cholesterol (HDL-C), and lactic dehydrogenase (LDH). Rankings differed in the NM group, with WHR identified as the leading risk factor, followed by C-reactive protein (CRP), HDL-C, total bilirubin (TBIL), diastolic blood pressure (DBP), and white blood cell count (WBC). Conclusions: Using ML, we found that WHR and HDL-C are the common denominators in both EM and NM women, with additional correlations with TG, liver enzymes and LDH for EM women. These results clearly indicate the importance of estrogen protection, suppressing less important factors (TG, liver enzyme, and LDH), and only the stronger inflammatory markers become important (CRP, TBIL, and WBC). Once estrogen’s protection disappears, the suppression of CRP, TBIL, and WBC would become weaker. Since these 3 features are significantly correlated with body weight, for women under 50, reducing body weight is the most important factor in preventing hyperglycemia. Full article

Background: Ramulus Mori (Sangzhi) Alkaloids (SZ-A) are natural hypoglycemic compounds known to enhance insulin secretion. Given the emerging role of the gut microbiota in regulating β-cell function, in this study, we aimed to investigate whether SZ-A exert their beneficial effects through modulating the gut microbiota and its metabolites. Methods: A diabetic mouse model was established using a high-fat diet and streptozotocin, followed by 20 weeks of SZ-A treatment. Gut microbiota and metabolites were profiled via 16S rRNA sequencing and liquid chromatography–mass spectrometry, respectively. Spearman’s correlation analysis was used to explore associations between gut microbiota and metabolites. Single-cell RNA sequencing (scRNA-seq) was used to assess gene expression and signaling pathway changes in β cells. Results: Our results demonstrate that SZ-A alleviated hyperglycemia and increased islet numbers in T2DM mice. SZ-A treatment also reshaped the gut microbiota, notably enriching quantities of Lactobacillus and norank_f__Eubacterium_coprostanoligenes_group, which may contribute to increasing levels of 2-methoxyestradiol (2-ME), a bioactive metabolite. Moreover, scRNA-seq revealed an increased proportion of COMT⁺ cells in the islets, suggesting that 2-ME may also be synthesized within the islets. In vitro, 2-ME suppressed HIF-1α signaling and promoted insulin secretion, indicating that 2-ME may act as a crucial mediator of the beneficial effects of SZ-A. Conclusions: SZ-A improve β-cell function by increasing 2-ME levels via gut microbiota modulation and islet production, ultimately suppressing HIF-1α signaling and restoring β-cell homeostasis. Full article

Type 2 diabetes mellitus (T2DM) is a multifactorial disorder defined by insulin resistance, β-cell dysfunction, and chronic hyperglycemia. Although peripheral mechanisms have been extensively studied, increasing evidence implicates the gastrointestinal tract in disease onset. Insights from bariatric surgery, gut hormone signaling, and incretin-based therapies suggest that the gut contributes actively beyond nutrient absorption. Yet, a cohesive framework integrating these observations remains absent, leaving a critical gap in our understanding of T2DM’s upstream pathophysiology. This work builds upon the anti-incretin theory, which posits that nutrient-stimulated neurohormonal signals—termed “anti-incretins”—arise from the proximal intestine to counteract incretin effects and regulate glycemic homeostasis. The excess of anti-incretin signals, perhaps stimulated by macronutrient composition or chemical additives of modern diets, disrupts this balance and may cause insulin resistance and β-cell depletion, leading to T2D. We hypothesize that the neuroendocrine signals produced by cholecystokinin (CCK)-I and secretin-S cells, both located in the proximal intestine, function as endogenous anti-incretins. In this context, we hypothesize a novel model centered on the chronic overstimulation of I and S cells by high-fat, high glycemic index modern diets. This drives what we term “amplified digestion”—a state marked by heightened vagal and hormonal stimulation of biliary and pancreatic secretions, increased enzymatic and bile acid activity, and alterations in bile acid composition. This condition leads to an extended breakdown of carbohydrates, lipids, and proteins into absorbable units, thereby promoting excessive nutrient absorption and ultimately contributing to insulin resistance and progressive β-cell failure. Multiple lines of clinical, surgical, and experimental evidence converge to support our model, rooted in the physiology of digestion and absorption. Western dietary patterns appear to induce an over-digestive adaptation—marked by excessive vagal and hormonal stimulation of biliary and pancreatic secretion—which amplifies digestive signaling. This heightened state correlates with increased nutrient absorption, insulin resistance, and β-cell dysfunction. Interventions that disrupt this maladaptive signaling—such as truncal vagotomy combined with duodenal bypass—may offer novel, physiology-based strategies for T2DM treatment. This hypothesis outlines a potential upstream contributor to insulin resistance and T2DM, grounded in digestive tract-derived neurohormonal dysregulation. This gut-centered model may provide insight into early, potentially reversible stages of the disease and identify a conceptual therapeutic target. Nonetheless, both the hypothesis and the accompanying surgical strategy—truncal vagotomy combined with proximal intestinal bypass—remain highly exploratory and require systematic validation through mechanistic and clinical studies. Further investigation is warranted to clarify the molecular regulation of I and S enteroendocrine cells, including the genetic and epigenetic factors that may drive hypersecretion. While speculative, interventions—surgical or pharmacologic—designed to modulate these digestive signals could represent a future avenue for research into T2DM prevention or remission, pending rigorous evidence. Full article