Brain metastases (BrM) from colorectal cancer (CRC) are rare but carry dismal prognosis. Emerging genomic analyses have identified insulin receptor substrate 2 (IRS2) amplification as a recurrent event in CRC BrM, suggesting a role in brain tropism and metabolic adaptation. To systematically evaluate clinical, molecular, and preclinical evidence implicating IRS2 in the pathogenesis and therapeutic targeting of CRC brain metastases. We systematically searched PubMed, Embase, Web of Science, and Scopus (inception-Nov 2025) for studies reporting on IRS2 expression, amplification, or perturbation in CRC with emphasis on brain metastases. Human tissue studies, large genomic datasets, and preclinical models (in vivo/in vitro/ex vivo) were included. Data extraction followed PRISMA 2020 guidelines. Among 312 unique records screened, 6 met inclusion criteria (1 large-scale clinical-genomic cohort, 2 preclinical mechanistic studies, 1 therapeutic evaluation, and 2 grey-literature conference reports). The pivotal Neuro-Oncology 2025 study (Greenberg et al.) demonstrated IRS2 amplification in 7.6% of CRC BrM vs 2.9% of non-brain metastases (p < 0.0001) and confirmed protein overexpression by immunohistochemistry. Functional assays revealed that IRS2 overexpression promotes β-catenin activation, oxidative phosphorylation, and CRC survival in brain-like conditions, while silencing reduces intracranial tumor growth and prolongs survival in mice. Treatment with the dual IRS1/2 degrader NT219 + 5-fluorouracil suppressed CRC BrM growth in vivo. IRS2 amplification represents a recurrent but non-universal molecular alteration enriched in a subset of colorectal cancer brain metastases, with mechanistic links to β-catenin signaling and mitochondrial metabolism. Preclinical inhibition of IRS2/IRS1-2 demonstrates translational promise, positioning IRS2 as a context-dependent vulnerability and potential therapeutic target in selected CRC brain-metastatic tumors.

The murine Irs1 knockout model, generated by the spontaneous Irs1S57X mutation in homozygosity, exhibits high embryonic lethality, limiting studies of adult hematopoiesis.

Insulin resistance is a hallmark of type 2 diabetes (T2DM) and can increase the risk of cognitive impairment, including Alzheimer's disease. Nuciferine, an alkaloid derived from lotus leaves, shows neuroprotective effects. This study investigated nuciferine's protective role in T2DM-induced cognitive impairment (T2DM-CI) and its mechanisms. Mouse models were created using high-fat diets and streptozotocin, along with high glucose-induced HT-22 cells. Nuciferine reduced blood glucose, improved cognitive function, and mitigated glial cell activation, neuron and synapse loss in T2DM mice. It enhanced insulin signaling by increasing protein levels of IR, IRS1, and IGF-1R, reversing PI3K and AKT phosphorylation, inhibiting GSK3β activity, and reducing hyperphosphorylated Tau in HT-22 cells and T2DM mice. mRNA levels of these molecules matched their protein levels. Further studies revealed that nuciferine directly interacts with IR, knocking out IR abolished its effects on the PI3K/AKT pathway. Thus, nuciferine activates the PI3K/AKT pathway via IR, improving insulin resistance and slowing T2DM-CI progression.

The Editors-in-Chief have retracted this article. Concerns were raised regarding Fig. 4a , which appears to have areas of overlap with Fig. 4b . The Editors-in-Chief therefore no longer have confidence in the reliability of the data reported in the article. Author Jianqin Yuan has stated on behalf of all authors that they agree to this retraction. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Endothelial NPR-C promotes insulin resistance via Caveolin-1-mediated insulin transcytosis.

Metabolic syndrome (MetS) is a composite cardiometabolic condition defined by visceral obesity, dyslipidemia, hypertension, and insulin resistance, and it promotes the worldwide prevalence of type 2 diabetes and atherosclerotic cardiovascular disease. Nucleic-acid aptamers have developed as programmable recognition ligands that integrate antibody-like specificity with chemical synthesis, modular functionalization, low batch variability, and usually a low immunogenicity. Their translational significance in MetS is not solely in target binding, but in the capacity to establish disease-relevant affinity, stability, and tissue selectivity by advanced SELEX, counter-selection, chemical expansion, truncation, and post-SELEX maturation. Aptamers can function as pathway modulators by inhibiting ligand-receptor interactions, retaining biased receptor conformations, or concentrating therapeutic agents in metabolically compromised tissues. This provides them particularly appealing for targets characterized by receptor recycling, cell-state identification, or inflammatory interactions, rather than by a singular static biomarker. They can serve as sensitive biosensing components in aptasensors for glucose, insulin, glycated proteins, lipids, and inflammatory markers, offering more detailed metabolic phenotyping than single-analyte assays. Recent studies on insulin receptor, PCSK9, adipocyte-, and hepatocyte-targeting aptamers illustrate how aptamers may support both disease-modifying therapy and point-of-care diagnostics in obesity, insulin resistance, MASLD, and dyslipidemia. Nevertheless, matrix-aware validation, serum stability, pharmacokinetic optimization, and proof of superiority over well-known biologics and clinical tests are still necessary for effective translation. Aptamer engineering offers a versatile and mechanistically adaptable framework for precision diagnostics along with targeted intervention in Metabolic syndrome. If these challenges be successfully overcome, aptamers may transition from sophisticated binders to clinically applicable metabolic tools.

Background: Fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonists have emerged as an effective strategy for treatment intensification in type 2 diabetes mellitus (T2DM). However, long-term real-world data on their metabolic, β-cell, and renal effects remain limited. This study aimed to evaluate the 12-month real-world outcomes of insulin glargine/lixisenatide (iGlarLixi) therapy. Methods: This retrospective observational study included 78 patients with T2DM who were initiated on iGlarLixi and followed for 12 months. Clinical and laboratory parameters were assessed at baseline, 3 months, and 12 months. Changes in anthropometric, glycemic, biochemical, and renal parameters were analyzed. Early (3-month) changes were evaluated as predictors of long-term outcomes using correlation and receiver operating characteristic (ROC) analyses. Results: Median HbA1c decreased from 9.0% to 8.2% at 12 months (p = 0.015), with clinically meaningful improvement (≥1% reduction) observed in 21 (26.9%) patients. Body weight decreased significantly from 93.0 kg to 89.5 kg (p &lt; 0.001). C-peptide levels increased from 2.46 to 3.00 ng/mL (p = 0.016). Median albumin-to-creatinine ratio (ACR) showed statistically significant paired changes; however, group-level median values remained similar over time. A reduction in albuminuria was observed in 34 (54.8%) of patients with available paired data. Exploratory ROC analyses suggested that early changes in body weight (AUC: 0.82), HbA1c (AUC: 0.74), and C-peptide (AUC: 0.76) may be associated with long-term outcomes. A combined model incorporating early weight and C-peptide changes showed improved exploratory predictive performance (AUC: 0.88). Conclusions: In a real-world setting, iGlarLixi therapy was associated with significant improvements in glycemic control and body weight, along with increased C-peptide levels that may reflect improved endogenous insulin secretion. While group-level renal changes were modest, individual-level improvements in albuminuria were observed in a substantial proportion of patients. Early treatment responses may serve as practical predictors of long-term outcomes, supporting a personalized approach to diabetes management. These findings should be interpreted in the context of concomitant therapies and comorbidities that may have influenced metabolic and renal outcomes in routine clinical practice.

Type B insulin resistance syndrome (TBIRS) is an extremely rare autoimmune disorder characterized by severe insulin resistance and/or hypoglycemia caused by autoantibodies against the insulin receptor (IRAb). We report the case of a 52-year-old woman who presented with weight loss and severe hyperglycemia resistant to high-dose insulin therapy. Markedly elevated IRAb levels confirmed the diagnosis of TBIRS. Glucocorticoid-based immunosuppressive therapy with cyclosporine rapidly improved glycemic control, and clinical remission was achieved approximately 40 days after treatment initiation. Intermittently scanned continuous glucose monitoring enabled the visualization of the transition from extreme insulin resistance to near-normoglycemia and helped avoid severe hypoglycemia during the patient's antibody decline period.

How distinct hormones sculpt a common receptor: ligand-specific conformational pathways of the insulin receptor.

Glucose and paracrine regulation of α-cells, particularly with respect to sex differences, is still poorly understood. Here, we imaged islets from GluCre:GCaMP6f mice in pancreatic slices, additionally loaded with a red Ca²⁺ indicator, to precisely interrogate Ca²⁺ dynamics in α-cells and the adjacent β- and δ-cells. During a glucose ramp (1.8-10.8 mM), α-cell Ca²⁺ oscillations were heterogeneous, antiphasic to β-cells, and inversely correlated with δ-cells. Selective inhibition of insulin receptor (InsR) and somatostatin receptor subtypes-2 and 3 (SSTR2/3) shifted the majority of α-cells to hyperactivity, delayed the decline of α-cell activity and onset of β-cell Ca²⁺ oscillations during the ramp. While female α-cells exhibited greater sensitivity to SSTR2/3 inhibition, male α-cells were more responsive to InsR blockade. Under complete SSTR2/3 and InsR antagonism, α-cells exhibited elevated Ca²⁺ oscillations but remained glucose-dependent. We conclude that intra-islet coordination fine-tunes α-cell glucose responses, with sex-specific paracrine signaling potentially shaping glucagon profiles in metabolic disease.

Diabetes mellitus (DM) and hypercortisolemia are closely associated endocrine disorders that significantly affect glucose metabolism; however, their direct organ-specific interactions remain incompletely understood. This study aimed to comparatively evaluate the effects of experimental DM on the adrenal gland and glucocorticoid-induced hypercortisolemia on the pancreas. Thirty male Wistar albino rats were allocated into three groups: control, DM (streptozotocin, 20 mg/kg), and hypercortisolemia (prednisolone, 10 mg/kg/day) for 30 days. Postprandial glucose levels were measured. Pancreatic and adrenal tissues were examined using histopathological and immunohistochemical methods to assess insulin, glucagon, and insulin receptor expression. Both experimental conditions were associated with histopathological alterations in endocrine tissues. The DM group exhibited degenerative changes in pancreatic islets, while the hypercortisolemia group showed structural alterations in both pancreatic islets and adrenal cortex. Immunohistochemical analysis revealed reduced insulin and insulin receptor expression in both groups. Postprandial glucose levels were significantly elevated (p<0.001), including in the hypercortisolemia group, supporting the hyperglycemic effect of glucocorticoid exposure. These findings suggest that both DM and glucocorticoid excess are associated with structural and functional alterations in endocrine tissues. These findings suggest that both DM and glucocorticoid excess are associated with parallel structural and functional alterations in endocrine tissues, rather than indicating a direct bidirectional interaction. Further molecular studies are required to clarify the underlying mechanisms and causal relationships. These findings highlight that each condition induces structural alterations in the reciprocal endocrine organ, suggesting cross-organ vulnerability under metabolic stress.

ABSTRACTDiabetes is a global health concern, with type 2 diabetes mellitus (T2DM) being the most common form. T2DM is characterized by insulin resistance and impaired glucose uptake in skeletal muscle. Spexin shows hypoglycaemic effects, but its mechanism of action, especially in skeletal muscles, remains elusive. This study aims to investigate the effects of spexin on key genes associated with the insulin‐dependent pathway in C2C12 cells. The differentiation of C2C12 myoblasts to C2C12 myotubes was confirmed using the fusion index and gene expression of myogenic factor 5 (Myf5), myosin heavy chain (MyHC), and myogenic regulatory factor 4 (MRF4) analysis. Cytotoxicity of spexin at varying concentrations (100 nM, 200 nM, 400 nM, 800 nM, and 1000 nM) was assessed via MTS assay. Insulin resistance–like conditions were induced in C2C12 myotubes using a high‐glucose medium and characterized at the mRNA level by quantitative reverse transcription PCR (RT‐qPCR) of peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α), glucose transporter 4 (GLUT4), and hexokinase II (HKII) genes. Fusion index analysis evaluated high‐glucose effects on myogenesis. RT‐qPCR examined spexin's effects on insulin receptor substrate 1 (IRS‐1), phosphatidylinositol 3‐kinase (PI3K), and GLUT4 expression over different time points. Spexin concentrations at 1000 nM were not cytotoxic. High‐glucose incubation did not affect myogenesis yet was associated with downregulation of PGC‐1α and GLUT4 genes, consistent with a transcriptional profile typically observed in insulin‐resistant states. Spexin‐treated C2C12 cells statistically significantly downregulated the expression of IRS‐1 after 2 h of incubation. The effects of spexin on IRS‐1, PI3K, and GLUT4 gene expression were comparable to metformin‐treated in insulin resistance C2C12 myotubes.

MYCN drives pediatric glioma transformation from neural progenitors and creates distinct therapeutic vulnerabilities.

Insulin receptor-2 regulates 20-hydroxyecdysone synthesis and ecdysis in the German cockroach.

Insulin, an important regulator of peripheral blood glucose levels, can also act in the brain to influence energy metabolism. Insulin receptors are expressed in the dorsomedial hypothalamus (DMH), but nothing is known about the effects of insulin on synaptic function in this region. To determine the effect of insulin on glutamate transmission in the DMH, we used whole-cell patch clamp electrophysiology to examine glutamatergic currents in DMH neurons of young male and female Sprague-Dawley rats. Insulin decreased evoked glutamate current amplitude in both sexes and variance analysis suggested this was due to a postsynaptic change in quantal size. Blocking insulin receptors failed to remove the effect of insulin in both sexes, and further experiments revealed that both insulin receptors (IRs) and insulin-like growth factor-1 receptors (IGF-1Rs), and mechanistic target of rapamycin (mTOR), were necessary to completely block the effects of insulin. Tonic insulin significantly decreased glutamate transmission in the DMH through an IR and mTOR-mediated pathway. Overall, our data suggest that insulin acts through IRs and IGF-1Rs to alter synaptic transmission in the DMH and tonic insulin controls the activity of DMH neurons. This research contributes to our understanding of how insulin acts in the hypothalamus to alter synaptic function, with potential implications for diabetes and obesity research.

Microvascular dysfunction and neurovascular signalling impairment in diabetic silent myocardial ischemia.

The ENPP1 (Ectonucleotide pyrophosphatase/phosphodiesterase 1) gene, encoding a protein that negatively modulates insulin receptor activation, remains relatively understudied in obesity genetics. K121Q (rs1044498; chr6:132,172,368: A > C) and other ENPP1 genetic variants (rs1799774; chr6:132,203,471: insT> delT and rs7754561; chr6:132,212,694: A > G), as well as the risk haplotype Q-delT-G have been investigated for their association with obesity risk mostly in populations from Central and Northern Europe, yielding controversial findings. Given the significance of reproducibility in genetic association studies and the scarcity of data from Southern Europe, we performed a case-control replication study to test the hypothesis that ENPP1 variants and haplotypes are associated with severe obesity in the underexplored and high-risk Greek population. A total of 979 Greek individuals (mean age: 47.6 ± 12.5years old), including 510 adults with severe obesity (BMI≥35Kg/m2) and 469 normal-weight (18.5 < BMI<25Kg/m2) controls, were studied. Three ENPP1 variants (rs1044498, rs1799774 and rs7754561) were genotyped using the TaqMan allelic discrimination assay. Logistic regression was applied to detect association of variants with obesity. Linkage disequilibrium among the three variants was assessed, and haplotype frequencies were compared between groups. The three variants did not exhibit any association with adult severe obesity. The three variants were in partial linkage disequilibrium (r2 ≤ 0.43). ENPP1 haplotype distribution differed significantly between normal-weight individuals and those with adult severe obesity (likelihood ratio x2 = 13.38, P = 0.020), with the Q-delT-G haplotype found to be present exclusively in individuals with adult severe obesity (frequency 3.3%) and to be associated with adult severe obesity (x2 = 5.66, P = 0.017; reference haplotype K-InsT-A, consisting of the three major alleles of the three variants). Our replication findings contribute novel evidence regarding the genetic architecture of adult severe obesity in a Southern-European population, however larger studies are necessary to validate these results.

Background and Aim: In vitro maturation (IVM) is an essential assisted reproductive technology that improves oocyte competence and supports the conservation and utilization of valuable livestock genetic resources. The Kacang goat is an indigenous Indonesian breed with important economic and genetic significance. Insulin-like growth factor 1 (IGF-1) has been reported to regulate oocyte maturation through multiple intracellular signaling pathways; however, its molecular effects on maturation-associated genes in Kacang goat oocytes remain poorly characterized. This study evaluated the influence of IGF-1 supplementation during IVM on the expression of Harvey rat sarcoma viral oncogene homolog (HRas), Cell division cycle 25 phosphatase (Cdc25), and insulin receptor substrate-2 (IRS-2), which are associated with meiotic progression and metabolic signaling. Materials and Methods: Cumulus–oocyte complexes were collected from Kacang goat ovaries and cultured under IVM conditions either without supplementation (control) or with 100 ng/mL IGF-1. Relative expression of HRas and Cdc25 was quantified using quantitative polymerase chain reaction, while IRS-2 protein expression was assessed by immunocytochemistry. Statistical comparisons between groups were performed using appropriate parametric or non-parametric tests, and correlations among molecular markers were evaluated using Spearman’s rank correlation analysis. Results: IGF-1 supplementation significantly increased the expression of both HRas and Cdc25 compared with the control group (p &lt; 0.05). The relative expression of HRas increased approximately 2.03-fold, whereas Cdc25 expression increased 1.62-fold following IGF-1 treatment. Immunocytochemical analysis demonstrated significantly greater IRS-2 protein expression in IGF-1-treated oocytes than in controls (p &lt; 0.05). Furthermore, strong positive correlations were observed among HRas, Cdc25, and IRS-2 expression levels, with the strongest association detected between HRas and Cdc25 (r = 0.85). These findings indicate coordinated activation of signaling pathways involved in meiotic regulation and cellular metabolism during oocyte maturation. Conclusion: Supplementation of IVM medium with 100 ng/mL IGF-1 enhanced the expression of HRas, Cdc25, and IRS-2 in Kacang goat oocytes, suggesting activation of molecular pathways associated with meiotic resumption and metabolic regulation. These findings provide mechanistic insights into IGF-1-mediated signaling during oocyte maturation and may help optimize IVM systems for indigenous goat breeds. Nevertheless, further studies evaluating nuclear maturation, fertilization, and embryo developmental competence are required to confirm the functional significance of these molecular responses. Keywords: insulin-like growth factor 1, IRS-2, signal transduction, sustainable livestock production, zero hunger.

Glycemic index (GI) and glycemic load (GL) are markers for postprandial glucose level. Since insulin, a hormone secreted to control hyperglycemia, is likely to promote the progression of tumor cells, the association between GI/GL and risk of colorectal cancer (CRC) has been researched for decades but still remains controversial. This study investigated the association between GI/GL and CRC risk, considering subtypes based on insulin receptor beta (IRβ) expression. In a large-scale, population-based prospective cohort study involving 18,537 Japanese participants, a total of 415 CRC cases were evaluated for IRβ expression using immunohistochemistry. GI and GL were calculated using a validated food frequency questionnaire. The Cox proportional hazards model was used to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) of the risk of CRC and its specific subtypes. Additionally, we conducted sensitivity analyses to confirm the robustness of the results. No significant associations were observed between dietary GI, GL and overall CRC risk. Further, no significant associations were detected in IRβ-stratified analyses. The heterogeneities in the associations by IRβ status were also not statistically significant. (GI: p for heterogeneity 0.83 for men and 0.96 for women; GL: p for heterogeneity 0.84 for men and 0.60 for women) Sensitivity analyses yielded robust results. This study did not observe a significant association between GI/GL and overall CRC or IRβ-defined subtypes. These results, particularly those from the assessment of IRβ status, do not support a possible association between GI/GL and CRC development.

Duration-dependent effects of sucrose intake on fear extinction via distinct mechanisms in the amygdala and hippocampus.