Decoding the Genomics of Abdominal Aortic Aneurysm.

A key aspect of genomic medicine is to make individualized clinical decisions from personal genomes. We developed a machine-learning framework to integrate personal genomes and electronic health record (EHR) data and used this framework to study abdominal aortic aneurysm (AAA), a prevalent irreversible cardiovascular disease with unclear etiology. Performing whole-genome sequencing on AAA patients and controls, we demonstrated its predictive precision solely from personal genomes. By modeling personal genomes with EHRs, this framework quantitatively assessed the effectiveness of adjusting personal lifestyles given personal genome baselines, demonstrating its utility as a personal health management tool. We showed that this new framework agnostically identified genetic components involved in AAA, which were subsequently validated in human aortic tissues and in murine models. Our study presents a new framework for disease genome analysis, which can be used for both health management and understanding the biological architecture of complex diseases. VIDEO ABSTRACT.

Randomized Trial of Patient Outreach Approaches to De-implement Outdated Colonoscopy Surveillance Intervals.

BACKGROUND AND AIMS: Guidelines now recommend patients with low-risk adenomas receive colonoscopy surveillance in 7-10 years and those with the previously recommended 5-year interval be re-evaluated. We tested 3 outreach approaches for transitioning patients to the 10-year interval recommendation. METHODS: This was a 3-arm pragmatic randomized trial comparing telephone, secure messaging, and mailed letter outreach. The setting was Kaiser Permanente Northern California, a large integrated healthcare system. Participants were patients 54-70 years of age with 1-2 small (<10 mm) tubular adenomas at baseline colonoscopy, due for 5-year surveillance in 2022, without high-risk conditions, and with access to all 3 outreach modalities. Patients were randomly assigned to the outreach arm (telephone [n = 200], secure message [n = 203], and mailed letter [n = 201]) stratified by age, sex, and race/ethnicity. Outreach in each arm was performed by trained medical assistants (unblinded) communicating in English with 1 reminder attempt at 2-4 weeks. Participants could change their assigned interval to 10 years or continue their planned 5-year interval. RESULTS: Sixty-day response rates were higher for telephone (64.5%) and secure messaging outreach (51.7%) vs mailed letter (31.3%). Also, more patients adopted the 10-year surveillance interval in the telephone (37.0%) and secure messaging arms (32.0%) compared with mailed letter (18.9%) and rate differences were significant for telephone (18.1%; 97.5% confidence interval: 8.3%-27.9%) and secure message outreach (13.1%; 97.5% confidence interval: 3.5%-22.7%) vs mailed letter outreach. CONCLUSIONS: Telephone and secure messaging were more effective than mailed letter outreach for de-implementing outdated colonoscopy surveillance recommendations among individuals with a history of low-risk adenomas in an integrated healthcare setting. (ClinicalTrials.gov, Number: NCT05389397).

A recombinant herpes virus expressing influenza hemagglutinin confers protection and induces antibody-dependent cellular cytotoxicity.

Despite widespread yearly vaccination, influenza leads to significant morbidity and mortality across the globe. To make a more broadly protective influenza vaccine, it may be necessary to elicit antibodies that can activate effector functions in immune cells, such as antibody-dependent cellular cytotoxicity (ADCC). There is growing evidence supporting the necessity for ADCC in protection against influenza and herpes simplex virus (HSV), among other infectious diseases. An HSV-2 strain lacking the essential glycoprotein D (gD), was used to create ΔgD-2, which is a highly protective vaccine against lethal HSV-1 and HSV-2 infection in mice. It also elicits high levels of IgG2c antibodies that bind FcγRIV, a receptor that activates ADCC. To make an ADCC-eliciting influenza vaccine, we cloned the hemagglutinin (HA) gene from an H1N1 influenza A strain into the ΔgD-2 HSV vector. Vaccination with ΔgD-2::HAPR8 was protective against homologous influenza challenge and elicited an antibody response against HA that inhibits hemagglutination (HAI+), is predominantly IgG2c, strongly activates FcγRIV, and protects against influenza challenge following passive immunization of naïve mice. Prior exposure of mice to HSV-1, HSV-2, or a replication-defective HSV-2 vaccine (dl5-29) does not reduce protection against influenza by ΔgD-2::HAPR8 This vaccine also continues to elicit protection against both HSV-1 and HSV-2, including high levels of IgG2c antibodies against HSV-2. Mice lacking the interferon-α/ß receptor and mice lacking the interferon-γ receptor were also protected against influenza challenge by ΔgD-2::HAPR8 Our results suggest that ΔgD-2 can be used as a vaccine vector against other pathogens, while also eliciting protective anti-HSV immunity.

Successful Design and Implementation of a POEM Program for Achalasia in an Integrated Healthcare System.

BACKGROUND: Per Oral Endoscopic Myotomy (POEM) is a minimally invasive treatment for achalasia with results comparable to laparoscopic Heller myotomy (LHM). Studies have described the development of proficiency for endoscopists learning to perform POEM, and societies have defined educational and technical objectives for advanced endoscopy fellows in training. However, there is limited guidance on the organizational strategy and educational plan necessary to develop an achalasia service with POEM expertise. AIMS: We aim to outline the steps for design and implementation of a successful POEM program. METHODS: We reported our experience developing a multi-disciplinary clinical program for POEM and the steps taken to achieve procedural proficiency. We also reported our technical success (successful tunneling into the gastric cardia and myotomy of LES muscle fibers) and clinical success (post-procedure Eckardt score ≤ 3) at 3-6 months and 12 months post-procedure. Adverse events were classified per the ASGE lexicon for endoscopic adverse events. RESULTS: After creating a multi-disciplinary clinical program for achalasia and completing procedural proficiency for POEM, our technical success rate was 100% and clinical success rate 90% for the first 41 patients. One adverse event (2.4%) occurred, moderate in severity per the American Society of Gastrointestinal Endoscopy (ASGE) lexicon for adverse endoscopic events. CONCLUSION: In this study, we outlined the steps involved to establish a POEM service in a large integrated healthcare system. Prior competency in interventional endoscopy, procedural training models, POEM observation and education, proctorship, and interdisciplinary patient care are recommended.

Chemerin regulates formation and function of brown adipose tissue: Ablation results in increased insulin resistance with high fat challenge and aging.

Apart from its role in inflammation and immunity, chemerin is also involved in white adipocyte biology. To study the role of chemerin in adipocyte metabolism, we examined the function of chemerin in brown adipose tissue. Brown and white adipocyte precursors were differentiated into adipocytes in the presence of Chemerin siRNA. Chemerin-deficient (Chem-/- ) mice were compared to wild-type mice when fed a high-fat diet. Chemerin is expressed during brown adipocyte differentiation and knock down of chemerin mRNA results in decreased brown adipocyte differentiation with reduced fatty acid uptake in brown adipocytes. Chem-/- mice are leaner than wild-type mice but gain more weight when challenged with high-fat diet feeding, resulting in a larger increase in fat deposition. Chem-/- mice develop insulin resistance when on a high-fat diet or due to age. Brown adipose depots in Chem-/- mice weigh more than in wild-type mice, but with decreased mitochondrial content and function. Compared to wild-type mice, male Chem-/- mice have decreased oxygen consumption, CO2 production, energy expenditure, and a lower respiratory exchange ratio. Additionally, body temperature of Chem-/- mice is lower than that of wild-type mice. These results revealed that chemerin is expressed during brown adipocyte differentiation and has a pivotal role in energy metabolism through brown adipose tissue thermogenesis.

Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence.

Worldwide control of the tuberculosis (TB) epidemic has not been achieved, and the latest statistics show that the TB problem might be more endemic than previously thought. Although drugs and a TB vaccine are available, TB eradication faces the challenges of increasing occurrences of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains. To forestall this trend, the development of drugs targeting novel pathways is actively pursued. Recently, enzymes of the electron transport chain (ETC) have been determined to be the targets of potent antimycobacterial drugs such as bedaquiline. We focused on the three NADH dehydrogenases (Ndh, NdhA, and Nuo) of the Mtb ETC with the purpose of defining their role and essentiality in Mtb Each NADH dehydrogenase was deleted in both virulent and BSL2-approved Mtb strains, from which the double knockouts ΔndhΔnuoAN and ΔndhAΔnuoAN were constructed. The ΔndhΔndhA double knockout could not be obtained, suggesting that at least one type II NADH dehydrogenase is required for Mtb growth. Δndh and ΔndhΔnuoAN showed growth defects in vitro and in vivo, susceptibility to oxidative stress, and redox alterations, while the phenotypes of ΔndhA, ΔnuoAN, and ΔndhAΔnuoAN were similar to the parental strain. Interestingly, although ΔnuoAN had no phenotype in vivo, ΔndhΔnuoAN was the most severely attenuated strain in mice, suggesting a key role for Nuo in vivo when Ndh is absent. We conclude that Ndh is the main NADH dehydrogenase of Mtb and that compounds that could target both Ndh and Nuo would be good candidates for TB drug development.

Exploring barriers medical residents and established physicians face counselling patients on physical activity by stage of the transtheoretical model.

Physical activity (PA) counselling by physicians increases patients' PA levels and improves health outcomes. Physician PA counselling remains low as a result of several barriers which may differ based on a patient's stage within the Transtheoretical Model (TTM) or by physician career status (i.e. between residents and established physicians). A convenience sample of physicians in Ontario (N = 38, n = 24 residents) completed a cross-sectional, online survey assessing perception of barriers to PA counselling based on hypothetical patients' TTM stage of change. Compared with other barriers, physicians agree less with feeling adequately reimbursed, having other professionals intervene, and having adequate resources for PA counselling. Based on responses to each barrier, physicians were more likely to counsel patients in the contemplation, preparation and action stages. Compared with established physicians, residents report less agreeance with being adequately reimbursed and having enough time for PA counselling, and greater agreeance with having other professionals intervene. This study communicates physicians' barriers when counselling patients at different stages of PA behaviour change and the influence of career status on barrier experience. Developing patient-stage- and career-stage-specific medical training, interventions and policy changes may enhance PA counselling among physicians, and ultimately patient PA behaviour and health outcomes.

Prochemerin cleavage by factor XIa links coagulation and inflammation.

Chemerin is a chemoattractant and adipokine that circulates in blood as inactive prochemerin (chem163S). Chem163S is activated by a series of C-terminal proteolytic cleavages resulting in diverse chemerin forms with different levels of activity. We screened a panel of proteases in the coagulation, fibrinolytic, and inflammatory cascades to identify those that process prochemerin in plasma. Factor XIa (FXIa) cleaved chem163S, generating a novel chemerin form, chem162R, as an intermediate product, and chem158K, as the final product. Processing at Arg162 was not required for cleavage at Lys158 or regulation of chemerin bioactivity. Contact phase activation of human platelet-poor plasma by kaolin led to cleavage of chem163S, which was undetectable in FXI-depleted plasma and markedly enhanced in platelet-rich plasma (PRP). Contact phase activation by polyphosphate in PRP resulted in 75% cleavage of chem163S. This cleavage was partially inhibited by hirudin, which blocks thrombin activation of FXI. After activation of plasma, levels of the most potent form of chemerin, chem157S, as well as inactive chem155A, increased. Plasma levels of chem163S in FXI-deficient patients were significantly higher compared with a matched control group (91 ± 10 ng/mL vs 58 ± 3 ng/mL, n = 8; P < .01) and inversely correlated with the plasma FXI levels. Thus FXIa, generated on contact phase activation, cleaves chem163S to generate chem158K, which can be further processed to the most active chemerin form, providing a molecular link between coagulation and inflammation.

Enhanced respiration prevents drug tolerance and drug resistance in Mycobacterium tuberculosis.

Persistence, manifested as drug tolerance, represents a significant obstacle to global tuberculosis control. The bactericidal drugs isoniazid and rifampicin kill greater than 99% of exponentially growing Mycobacterium tuberculosis (Mtb) cells, but the remaining cells are persisters, cells with decreased metabolic rate, refractory to killing by these drugs, and able to generate drug-resistant mutants. We discovered that the combination of cysteine or other small thiols with either isoniazid or rifampicin prevents the formation of drug-tolerant and drug-resistant cells in Mtb cultures. This effect was concentration- and time-dependent, relying on increased oxygen consumption that triggered enhanced production of reactive oxygen species. In infected murine macrophages, the addition of N-acetylcysteine to isoniazid treatment potentiated the killing of Mtb Furthermore, we demonstrate that the addition of small thiols to Mtb drug treatment shifted the menaquinol/menaquinone balance toward a reduced state that stimulates Mtb respiration and converts persister cells to metabolically active cells. This prevention of both persister cell formation and drug resistance leads ultimately to mycobacterial cell death. Strategies to enhance respiration and initiate oxidative damage should improve tuberculosis chemotherapies.

FMRI of spinal and supra-spinal correlates of temporal pain summation in fibromyalgia patients.

Fibromyalgia syndrome (FM) is a debilitating chronic pain condition, which afflicts primarily females. Although the etiology of this illness is not completely understood, FM pain is thought to rely on enhanced pain sensitivity maintained by central mechanisms. One of these mechanisms is central pain amplification, which is characterized by altered temporal summation of second pain (TSSP). Here we use a TSSP paradigm and functional MRI (fMRI) of the spinal cord, brainstem, and brain to noninvasively examine the central nervous system contributions to TSSP in FM patients and normal controls (NC). Functional MRI of pain-free female adults (N = 15) and FM patients (N = 14) was conducted while brief, repetitive heat pain stimuli (0.33 Hz) were applied to the thenar eminence of the hand (C6 dermatome). The stimulus intensity was adjusted to each participant's heat pain sensitivity to achieve moderate pain. Data were analyzed by means of a General Linear Model and region-of-interest analyses. All participants demonstrated significant pain summation in the TSSP condition. FM subjects, however, required significantly lower stimulus intensities than NC to achieve similar TSSP. fMRI analyses of perceptually equal TSSP identified similar brain activity in NC and FM subjects; however, multiple areas in the brainstem (rostral ventromedial medulla and periaqueductal grey region) and spinal cord (dorsal horn) exhibited greater activity in NC subjects. Finally, increased after-sensations and enhanced dorsal horn activity was demonstrated in FM patients. In conclusion, the spinal and brainstem BOLD responses to TSSP are different between NC and FM patients, which may indicate alterations to descending pain control mechanisms suggesting contributions of these mechanisms to central sensitization and pain of FM patients.

Targeting complement component 5a promotes vascular integrity and limits airway remodeling.

Increased microvascular dilatation and permeability is observed during allograft rejection. Because vascular integrity is an important indicator of transplant health, we have sought to limit injury to blood vessels by blocking complement activation. Although complement component 3 (C3) inhibition is known to be vasculoprotective in transplantation studies, we recently demonstrated the paradoxical finding that, early in rejection, C3(-/-) transplant recipients actually exhibit worse microvascular injury than controls. In the genetic absence of C3, thrombin-mediated complement component 5 (C5) convertase activity leads to the generation of C5a (anaphylatoxin), a promoter of vasodilatation and permeability. In the current study, we demonstrated that microvessel thrombin deposition is significantly increased in C3(-/-) recipients during acute rejection. Thrombin colocalization with microvessels is closely associated with remarkably elevated plasma levels of C5a, vasodilatation, and increased vascular permeability. Administration of NOX-D19, a specific C5a inhibitor, to C3(-/-) recipients of airway transplants significantly improved tissue oxygenation, limited microvascular leakiness, and prevented airway ischemia, even in the absence of conventional T-cell-directed immunosuppression. As C3 inhibitors enter the clinics, the simultaneous targeting of this thrombin-mediated complement activation pathway and/or C5a itself may confer significant clinical benefit.

Thrombin cleavage of osteopontin disrupts a pro-chemotactic sequence for dendritic cells, which is compensated by the release of its pro-chemotactic C-terminal fragment.

Thrombin cleavage alters the function of osteopontin (OPN) by exposing an integrin binding site and releasing a chemotactic C-terminal fragment. Here, we examined thrombin cleavage of OPN in the context of dendritic cell (DC) migration to define its functional domains. Full-length OPN (OPN-FL), thrombin-cleaved N-terminal fragment (OPN-R), thrombin- and carboxypeptidase B2-double-cleaved N-terminal fragment (OPN-L), and C-terminal fragment (OPN-CTF) did not have intrinsic chemotactic activity, but all potentiated CCL21-induced DC migration. OPN-FL possessed the highest potency, whereas OPNRAA-FL had substantially less activity, indicating the importance of RGD. We identified a conserved (168)RSKSKKFRR(176) sequence on OPN-FL that spans the thrombin cleavage site, and it demonstrated potent pro-chemotactic effects on CCL21-induced DC migration. OPN-FLR168A had reduced activity, and the double mutant OPNRAA-FLR168A had even lower activity, indicating that these functional domains accounted for most of the pro-chemotactic activity of OPN-FL. OPN-CTF also possessed substantial pro-chemotactic activity, which was fully expressed upon thrombin cleavage and its release from the intact protein, because OPN-CTF was substantially more active than OPNRAA-FLR168A containing the OPN-CTF sequence within the intact protein. OPN-R and OPN-L possessed similar potency, indicating that the newly exposed C-terminal SVVYGLR sequence in OPN-R was not involved in the pro-chemotactic effect. OPN-FL and OPN-CTF did not directly bind to the CD44 standard form or CD44v6. In conclusion, thrombin cleavage of OPN disrupts a pro-chemotactic sequence in intact OPN, and its loss of pro-chemotactic activity is compensated by the release of OPN-CTF, which assumes a new conformation and possesses substantial activity in enhancing chemokine-induced migration of DCs.

Neural correlates of temporal summation of second pain in the human brainstem and spinal cord.

Temporal summation of second pain (TSSP) occurs when painful stimuli are presented repetitively (≥ 0.33 Hz) and results from a C-fibre evoked enhancement (or "wind-up") of the dorsal horn neurons. Based on electrophysiological studies in intact animals, windup is considered a purely central phenomenon. With advancements in functional MRI (fMRI), we can now probe the central mechanisms of this pain response in humans. The aim of this study is to characterize the fMRI responses in the healthy human brainstem and spinal cord that correspond to TSSP. Functional MRI of healthy female adults (N = 15) was conducted while brief, repetitive heat pain stimuli were applied to the right thenar eminence (C6 dermatome), and TSSP (0.33 Hz) and control (0.17 Hz) heat pain paradigms were employed. The stimulus intensity was adjusted to each participant's heat pain sensitivity. Data were analyzed by means of a general linear model, and region-of-interest analyses. As predicted, participants demonstrated significant behavioural summation of pain in the TSSP condition. FMRI results identified enhanced activity in the spinal cord dorsal horn at C6 in response to the TSSP condition. Additionally, multiple areas of the brainstem (RVM and PAG) showed greater responses with the TSSP condition. These results suggest that, in humans, increased pain perception in the TSSP condition is reflected by greater responses in the dorsal horn and in regions known to play a role in the descending modulation of pain, which may modulate the spinal cord response.

Thrombin-cleaved fragments of osteopontin are overexpressed in malignant glial tumors and provide a molecular niche with survival advantage.

Osteopontin (OPN), which is highly expressed in malignant glioblastoma (GBM), possesses inflammatory activity modulated by proteolytic cleavage by thrombin and plasma carboxypeptidase B2 (CPB2) at a highly conserved cleavage site. Full-length OPN (OPN-FL) was elevated in cerebrospinal fluid (CSF) samples from all cancer patients compared with noncancer patients. However, thrombin-cleaved OPN (OPN-R) and thrombin/CPB2-double-cleaved OPN (OPN-L) levels were markedly increased in GBM and non-GBM gliomas compared with systemic cancer and noncancer patients. Cleaved OPN constituted ∼23 and ∼31% of the total OPN in the GBM and non-GBM CSF samples, respectively. OPN-R was also elevated in GBM tissues. Thrombin-antithrombin levels were highly correlated with cleaved OPN, but not OPN-FL, suggesting that the cleaved OPN fragments resulted from increased thrombin and CPB2 in this extracellular compartment. Levels of VEGF and CCL4 were increased in CSF of GBM and correlated with the levels of cleaved OPN. GBM cell lines were more adherent to OPN-R and OPN-L than OPN-FL. Adhesion to OPN altered gene expression, in particular genes involved with cellular processes, cell cycle regulation, death, and inflammation. OPN and its cleaved forms promoted motility of U-87 MG cells and conferred resistance to apoptosis. Although functional mutation of the RGD motif in OPN largely abolished these functions, OPN(RAA)-R regained significant cell binding and signaling function, suggesting that the SVVYGLR motif in OPN-R may substitute for the RGD motif if the latter becomes inaccessible. OPN cleavage contributes to GBM development by allowing more cells to bind in niches where they acquire anti-apoptotic properties.

A mutation in the Ebola virus envelope glycoprotein restricts viral entry in a host species- and cell-type-specific manner.

Zaire Ebola virus (EBOV) is a zoonotic pathogen that causes severe hemorrhagic fever in humans. A single viral glycoprotein (GP) mediates viral attachment and entry. Here, virus-like particle (VLP)-based entry assays demonstrate that a GP mutant, GP-F88A, which is defective for entry into a variety of human cell types, including antigen-presenting cells (APCs), such as macrophages and dendritic cells, can mediate viral entry into mouse CD11b(+) APCs. Like that of wild-type GP (GP-wt), GP-F88A-mediated entry occurs via a macropinocytosis-related pathway and requires endosomal cysteine proteases and an intact fusion peptide. Several additional hydrophobic residues lie in close proximity to GP-F88, including L111, I113, L122, and F225. GP mutants in which these residues are mutated to alanine displayed preferential and often impaired entry into several cell types, although not in a species-specific manner. Niemann-Pick C1 (NPC1) protein is an essential filovirus receptor that binds directly to GP. Overexpression of NPC1 was recently demonstrated to rescue GP-F88A-mediated entry. A quantitative enzyme-linked immunosorbent assay (ELISA) demonstrated that while the F88A mutation impairs GP binding to human NPC1 by 10-fold, it has little impact on GP binding to mouse NPC1. Interestingly, not all mouse macrophage cell lines permit GP-F88A entry. The IC-21 cell line was permissive, whereas RAW 264.7 cells were not. Quantitative reverse transcription (RT)-PCR assays demonstrate higher NPC1 levels in GP-F88A permissive IC-21 cells and mouse peritoneal macrophages than in RAW 264.7 cells. Cumulatively, these studies suggest an important role for NPC1 in the differential entry of GP-F88A into mouse versus human APCs.

Open aortic valve replacement in a patient with Glanzmann's thrombasthenia: a multidisciplinary strategy to minimize perioperative bleeding.

BACKGROUND: Glanzmann thrombasthenia (GT) is an autosomal recessive disorder in which the platelet (PLT) glycoprotein IIb/IIIa complex is either deficient or dysfunctional. In its most severe form, GT may result in spontaneous bleeding, although most cases are first detected in the setting of an invasive procedure. CASE REPORT: A 59-year-old male with Type I GT and a history of transfusion reactions to PLT infusions developed severe aortic stenosis secondary to bicuspid valve disease. He successfully underwent open aortic valve replacement with cardiopulmonary bypass without perioperative bleeding complications. RESULTS: A multidisciplinary team (anesthesia, hematology, cardiac surgery, and transfusion medicine) was established to optimize perioperative hematologic management. Bleeding risk was assessed given the patient's prior history and a dosing timeline for administration of blood products and recombinant clotting factors was established. Successful management was achieved during the operation by prophylactic administration of HLA-matched PLTs and Factor VIIa. Prophylactic PLT administration was continued through the immediate postoperative period and no bleeding complications occurred. Thromboelastograms (TEGs) were used in conjunction with traditional hematologic laboratory analysis to optimize clinical management. CONCLUSION: Patients with GT requiring cardiac surgical procedures are at high risk for perioperative bleeding complications. This case report illustrates the importance of multidisciplinary planning, TEG analysis, and the judicious use of recombinant factors to minimize operative bleeding risk.

EUS-Guided Cholecystoduodenostomy for a Poor Surgical Candidate With Chronic Octreotide-Associated Gallstones From Metastatic Neuroendocrine Tumor.

Chronic octreotide use has been associated with gallstone formation. Historically, cholecystectomy has been the defining treatment for those who have gallstone-related disease. For those who are poor surgical candidates, percutaneous and endoscopic approaches have been used. We describe the endoscopic management of a 74-year-old man with significant gallstone burden and associated sequelae because of chronic octreotide for metastatic neuroendocrine tumor through endoscopic ultrasound-guided cholecystoduodenostomy with gallstone extraction using lumen-apposing metal stents.

Chemerin Levels in Individuals with Type 2 Diabetes and a Normal Weight versus Individuals with Type 2 Diabetes and Obesity: An Observational, Cross-Sectional Study.

Chemerin acts as both a chemotactic agent and an adipokine that undergoes proteolytic cleavage, converting inactive precursors into their active forms before being subsequently inactivated. Elevated chemerin levels are linked to obesity and type 2 diabetes mellitus (T2D). This study aimed to elucidate the effects of T2D and obesity on chemerin levels by comparing plasma samples from individuals with a normal weight and T2D (BMI < 25; NWD group n = 22) with those from individuals who are overweight or obese and have T2D (BMI ≥ 25; OWD group n = 39). The total chemerin levels were similar in the NWD and OWD groups, suggesting that T2D may equalize the chemerin levels irrespective of obesity status. The cleavage of chemerin has been previously linked to myocardial infarction and stroke in NWD, with potential implications for inflammation and mortality. OWD plasma exhibited lower levels of cleaved chemerin than the NWD group, suggesting less inflammation in the OWD group. Here, we showed that the interaction between obesity and T2D leads to an equalization in the total chemerin levels. The cleaved chemerin levels and the associated inflammatory state, however, differ significantly, underscoring the complex relationship between chemerin, T2D, and obesity.