INTRODUCTION Insulin resistance is the cornerstone of type 2 diabetes (T2D), a global epidemic driven largely by obesity. Traditionally, research has focused on the effects of insulin in metabolic target tissues, such as skeletal muscle, adipose tissue, and the liver, where impaired signaling leads to dysregulated glucose homeostasis. However, the journey of insulin to these tissues relies on vascular delivery, a process modulated by endothelial cells (ECs) lining blood vessels. Endothelial insulin signaling promotes vasodilation through nitric oxide (NO) production and facilitates transendothelial insulin transport, both of which are critical for systemic insulin action. Disruptions in these vascular mechanisms have long been suspected to contribute to insulin resistance, but the underlying molecular pathways remained elusive until recently. In a groundbreaking study published in Science, Cho et al. unveil a novel mechanism whereby adrenomedullin (ADM), a peptide hormone elevated in obesity, induces endothelial insulin resistance.1 Through a combination of in vitro experiments in human ECs and in vivo studies in obese mouse models, the authors demonstrate that ADM activates the Gαs-protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CALCRL), leading to protein kinase A (PKA)-dependent activation of protein tyrosine phosphatase 1B (PTP1B). This culminates in dephosphorylation of the insulin receptor (IR), blunting downstream signaling, including endothelial NO synthase (eNOS) activation, and tissue perfusion. Critically, genetic or pharmacological blockade of this pathway ameliorates insulin resistance in obese mice, highlighting endothelial ADM signaling as a therapeutic target for obesity-associated T2D. This commentary explores the implications of these findings, emphasizing their novelty, methodological rigor, and potential to reshape our understanding of insulin resistance. UNRAVELING THE MECHANISM: FROM GαS SIGNALING TO PROTEIN TYROSINE PHOSPHATASE 1B ACTIVATION This study begins with an intriguing observation in human umbilical vein ECs (HUVECs): Knockdown of Gαs (encoded by GNAS) enhances insulin-induced phosphorylation of eNOS and Protein Kinase B (AKT), as well as NO production. This suggests that basal Gαs activity tonically suppresses endothelial insulin signaling. Screening of Gαs-coupled GPCRs expressed in HUVECs identified CALCRL, the endothelial receptor for ADM, functioning in complex with receptor activity–modifying protein 2 (RAMP2), as the principal upstream regulator of this pathway. ADM, secreted abundantly by ECs and adipocytes, inhibits IR autophosphorylation at tyrosine residues 1162/1163, reducing downstream phosphoinositide 3-kinase (PI3K) and AKT activation. This effect is PKA dependent, as it is reversed by the PKA inhibitor PKI. A pivotal discovery is that PTP1B mediates the inhibitory effects of ADM. PTP1B, a nonreceptor protein-tyrosine phosphatase primarily localized to the endoplasmic reticulum (ER), acts as a key negative regulator in the insulin signaling pathway. In general, PTP1B dephosphorylates the IR and IR substrates (IRS), attenuating downstream pathways, including PI3K-AKT and eNOS activation, which affect glucose uptake, vasodilation, and tissue perfusion. Mice with PTP1B knockout exhibit enhanced insulin sensitivity, reduced blood glucose levels, and resistance to obesity, confirming its role as a negative regulator.2 PTP1B activity is modulated by posttranslational modifications, including oxidation (induced by reactive oxygen species, ROS), phosphorylation (at Ser/Thr sites), and proteolytic cleavage. For instance, ER stress or ROS can oxidize the catalytic cysteine (Cys215) of PTP1B, temporarily inhibiting its activity and enhancing insulin signaling; however, chronic stress leads to PTP1B overexpression, exacerbating resistance.3 In addition, PTP1B regulates leptin signaling by dephosphorylating JAK2, thereby inhibiting appetite control and promoting obesity.4 In ECs, Cho et al. reveal a specific ADM-PKA-PTP1B axis underlying obesity-induced insulin resistance.1 ECs serve as the gateway for insulin to reach metabolic tissues, where insulin stimulates IR to activate eNOS, promoting NO-mediated vasodilation and insulin transport. In obesity, plasma ADM levels rise primarily from adipocytes, binding to endothelial CALCRL (with RAMP2) to activate Gαs, increasing cyclic adenosine monophosphate (cAMP) and stimulating PKA. PKA directly phosphorylates PTP1B at serine 205 (Ser205), located in the N-terminal S-loop (residues 201–209) at the catalytic domain. This phosphorylation enhances PTP1B phosphatase activity, overriding insulin-induced IR tyrosine phosphorylation and suppressing downstream AKT, PI3K, and eNOS activation. In vitro experiments confirm: ADM treatment of ECs increases PTP1B activity and weakens insulin signaling; PKA inhibitor PKI or PTP1B Ser205A mutant reverses this effect. Phosphoproteomics shows that Ser205 phosphorylation aligns with PTP1B activation kinetics, whereas Ser378 phosphorylation shows no correlation. In vivo, mice fed a high-fat diet (HFD) with endothelium-specific knockout of CALCRL or Gαs show improved insulin sensitivity, enhanced skeletal muscle perfusion, and increased eNOS phosphorylation. ADM infusion mimics obesity, inducing systemic resistance, but not in endothelial knockout models. Complement factor H (CFH), an ADM-binding protein, amplifies this axis and correlates with body mass index (BMI) in obese patients. This mechanism highlights that endothelial PTP1B not only affects metabolic tissues but also amplifies systemic resistance. S-loop phosphorylation influences the conformation of the WPD-loop (residues 177–188), thereby boosting catalytic efficiency. These in vitro findings extend to microvascular ECs from human adipose and skeletal muscle, where ADM also impairs insulin transcytosis, further limiting insulin delivery to target tissues. NOVELTY AND IMPLICATIONS FOR PHYSIOLOGY AND PATHOPHYSIOLOGY This work shifts the paradigm of insulin resistance from a purely metabolic disorder to one with a significant vascular component. While the prior study has shown that endothelial IR KO reduces systemic insulin sensitivity, the mechanisms underlying endothelial dysfunction in obesity remain unclear.5 Cho et al. identify ADM as a specific obesity-linked culprit, linking adipocyte-derived signals to endothelial impairment.1 This echoes emerging evidence that adipose-vascular crosstalk, via factors like ADM, exacerbates metabolic disease. Physiologically, the findings underscore the dual role of ADM: Protective in cardiovascular homeostasis (e.g., vasodilation) but detrimental in obesity, where it antagonizes insulin. The PKA-PTP1B axis serves as a molecular bridge between GPCR signaling and tyrosine kinase receptors, with broader implications for crosstalk in other systems. For instance, Ser205 phosphorylation may regulate PTP1B in non-ECs, influencing insulin signaling in muscle or the liver, where cAMP elevations (e.g., via glucagon) promote resistance. Pathophysiologically, the study explains why vascular insulin effects are blunted in patients with T2D, as noted in the human study.6 Elevated ADM and CFH in obese humans correlate with BMI, suggesting translational relevance. This could account for the “insulin delivery defect” in obesity, where reduced perfusion and transcytosis limit insulin access to tissues, perpetuating a vicious cycle. METHODOLOGICAL STRENGTHS AND LIMITATIONS The strength of this study lies in its multi-tiered approach: From unbiased GPCR screening and phosphoproteomics to conditional KOs and real-time perfusion imaging. Human data validate mouse findings and therapeutic interventions demonstrate feasibility by using antagonist treatment. Controls for off-target effects, such as normal-chow-fed KOs that show no phenotype, ensure specificity to obesity. Limitations include the focus on skeletal muscle and visceral white adipose tissue, with less emphasis on the liver. The study could not isolate the effects of transcytosis in vivo due to dominant perfusion changes, leaving room for future clarification. Human data are correlative; interventional studies by ADM blockade in T2D patients are needed. In addition, the effects of ADM on other GPCRs or tissues warrant exploration.Figure 1: Schematic overview of adrenomedullin (ADM)-induced endothelial insulin resistance. ADM, elevated in obesity primarily from adipocytes and bound to complement factor H, activates the calcitonin receptor-like receptor on endothelial cells. This triggers Gαs-mediated activation of adenylyl cyclase, increasing cyclic adenosine monophosphate and stimulating protein kinase A (PKA). PKA phosphorylates protein-tyrosine phosphatase 1B at serine 205, enhancing its activity and leading to dephosphorylation of the insulin receptor at tyrosine residues 1162/1163. Consequently, insulin signaling is impaired, reducing endothelial NO synthase activation, NO production, vasodilation, tissue perfusion, and transendothelial insulin transport. This mechanism contributes to the development of systemic insulin resistance in obesity-associated type 2 diabetes. Blockade of ADM signaling via receptor antagonists or genetic knockout restores insulin sensitivity. Adapted from concepts in Cho et al. 1 ADM: Adrenomedullin, CFH: Complement factor H, CALCRL: Calcitonin receptor-like receptor, AC: Adenylyl cyclase, cAMP: Cyclic adenosine monophosphate, PKA: Protein kinase A, PTP1B: Protein-tyrosine phosphatase 1B, IR: Insulin receptor, eNOS: Endothelial nitric oxide synthase, NO: Nitric oxide, PI3K: Phosphoinositide 3-kinase, RAMP2: Receptor activity–modifying protein 2.FUTURE DIRECTIONS AND THERAPEUTIC POTENTIAL These findings open avenues for research: Does ADM contribute to insulin resistance in nonobese T2D subtypes? How do sex differences (e.g., in ADM levels) influence outcomes? Integrating single-cell RNA-seq could map heterogeneity in ADM signaling in the endothelium. Therapeutically, targeting the ADM-CALCRL-PTP1B axis holds promise. PTP1B inhibitors, such as trodusquemine, and antisense oligonucleotides have shown reductions in blood glucose and improved sensitivity in preclinical models. However, early clinical candidates, such as ertiprotafib and ISIS-113715, were discontinued due to challenges with efficacy and selectivity.7 Liver-specific PTP1B inhibition restores IRS1-mediated signaling even in IRS2 absence.8 For the ADM-PTP1B axis, ADM receptor antagonists like ADM (24–50) improve glucose tolerance in HFD mice. Recent advances include allosteric inhibitors; for instance, DPM-1003 in phase 1 for Rett syndrome with metabolic potential, PROTACs achieving nanomolar PTP1B degradation and sustained hypoglycemic effects in models, and peptide-based MD-18, which demonstrated safety, 2.7% placebo-adjusted weight loss over 28 days, improved insulin sensitivity, and cardiometabolic benefits (reduced low-density lipoprotein, waist circumference) in phase 1b trials (2025),9 with phase 2 planned for 2026. Future developments of selective inhibitors to avoid off-target effects or endothelium-specific variants will aid in the treatment of obesity-related diabetes.10 Given the beneficial effects of ADM on the cardiovascular system, endothelium-specific targeting may minimize side effects. In summary, Cho et al. illuminate a critical vascular mechanism in obesity-associated T2D, positioning ADM as a linchpin of endothelial insulin resistance. PTP1B emerges as a central hub in insulin resistance, with its PKA-dependent activation in endothelium revealing the new layers of vascular-metabolic interaction, paving the way for novel therapies.1 Author contribution statement Julia Chu-Ning Hsu, Chun-Sheng Chuang, and Ming-Wei Chen: Writing–original draft. Tzong-Shyuan Lee: Conceptualization, Writing–review and editing, and Supervision. This research was funded by grants from the National Science and Technology Council, Taiwan (111-2320-B-002-016-MY3, 112-2320-B-005-002, 113-2320-B-005-009, 114-2320-B-005-010, and 114-2320-B-002-047-MY3), the National Taiwan University Hospital Research Program (NTUH.113-UN0028), and the Collaborative Research Projects of the National Taiwan University College of Medicine, National Taiwan University Hospital, and Min-Sheng General Hospital (109F005-112-E, 109F-005-113-C, and 109F-005-114-C). Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
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