Pro-Neurotensin/Neuromedin N and Risk of Incident Metabolic Syndrome and Diabetes Mellitus in the REGARDS Cohort

Context The peptide neurotensin is implicated in insulin resistance, diabetes mellitus (DM), and cardiovascular disease. Objective We studied the association of neurotensin’s stable precursor, pro-neurotensin/neuromedin N (pro-NT/NMN) with incident metabolic syndrome (MetS) and DM. Design/Setting/Participants We included 3,772 participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who completed the baseline exam (2003-2007), the follow-up exam (2013-2016), and had pro-NT/NMN measured by immunoassay. Weighted logistic regression models were fitted to incident DM, incident MetS, and each MetS component, separately, incorporating demographics, metabolic risk factors, HOMA-IR, and diet scores. Main Outcome Measures Incident MetS was defined by ≥3 harmonized criteria at follow-up in those with <3 at baseline. Incident DM was defined by use of hypoglycemic drugs/insulin, fasting glucose ≥126 mg/dL, or random glucose ≥200 mg/dL, in those without these at baseline. Results Median [IQR] plasma pro-NT/NMN was 160 [118-218] pmol/L. 564 (of 2,770 without baseline MetS) participants developed MetS and 407 (of 3,030 without baseline DM) developed DM. Per standard deviation (SD) higher log-Pro-NT/NMN, the demographic-adjusted odds ratio (OR) and 95% confidence interval (CI) of incident MetS was 1.22 (1.11-1.35); 1.16 (1.00-1.35) for incident low HDL, and 1.25 (1.11-1.40) for incident dysglycemia. The association of pro-NT/NMN with MetS was attenuated in the model adding HOMA-IR (OR per SD log-pro-NT/NMN 1.14, 95% CI 1.00-1.30). There was no association with incident DM (OR per SD log-pro-NT/NMN 1.06, 95% CI 0.94-1.19). Conclusions Pro-NT/NMN was associated with MetS and two components, dysglycemia and low HDL, likely explained by insulin resistance.

Abstract 14088: Pro-neurotensin/neuromedin N is Associated With Incident Metabolic Syndrome

Introduction: The tridecapeptide neurotensin increases dietary fatty acid uptake and is implicated in insulin resistance in animal models and—through plasma levels of its stable precursor pro-neurotensin/neuromedin N (pro-NT/NMN)—with human diabetes mellitus, obesity, and cardiovascular disease. We evaluated the association of pro-NT/NMN with incident metabolic syndrome (MetS). Methods: This analysis included a subcohort of 2,770 Black and White participants without prevalent MetS at baseline (2003-2007) from the REasons for Geographic And Racial Differences in Stroke study who had fasting plasma pro-NT/NMN measured by immunoassay and completed a second assessment from 2013-2016. Incident MetS was defined as ≥3 harmonized criteria at follow-up: impaired glycemic control, high systolic blood pressure, high triglycerides, low high-density lipoprotein (HDL), and increased waist circumference. Four sequential weighted logistic regression models were fitted to incident MetS overall and for each criterion separately, incorporating demographic factors, metabolic risk factors, HOMA-IR, and diet scores. Results: Over mean 9.4 (standard deviation [SD] 1.0) years follow up, 564 participants developed MetS. Median [IQR] plasma pro-NT/NMN was 160 [118-218] pmol/L. In the overall group, higher log pro-NT/NMN was associated with incidence of lower HDL (odds ratio [OR] per SD pro-NT/NMN 1.16, 95% confidence interval [CI] 1.00-1.35) and impaired glycemic control (1.25, 95% CI 1.11-1.40), but not other MetS components. Each SD higher log pro-NT/NMN was associated with a 22% increased odds of incident MetS, adjusted for demographics (Table); this was not significant when controlling for HOMA-IR in all but the White subgroup (race p -interaction 0.05). No differences by sex were observed. Conclusions: Higher neurotensin likely augments insulin resistance to increase odds of incident metabolic syndrome through impaired glycemic control and lower HDL.

Pro-neurotensin/neuromedin N and risk of ischemic stroke: The REasons for Geographic And Racial Differences in Stroke (REGARDS) study

The tridecapeptide neurotensin has been implicated in the pathogenesis of cardiometabolic disease. Its stable precursor, pro-neurotensin/neuromedin N (pro-NT/NMN), has been associated with composite cardiovascular outcomes including coronary heart disease (CHD) and stroke. The exclusive association of pro-NT/NMN with ischemic stroke has not been evaluated. We conducted a prospective case-cohort study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. From 2003 to 2007, REGARDS enrolled 30,239 white or black adults aged ⩾ 45 years. Baseline fasting pro-NT/NMN was measured by immunoassay in the analytic sample including 448 incident ischemic stroke cases and 818 random cohort sample participants. A total of 464 ischemic strokes occurred. Risk of stroke was assessed with a Cox proportional-hazards model incorporating demographic covariates and a second adding stroke risk factors. Increased pro-NT/NMN was associated with ischemic stroke in the demographic model overall (hazard ratio (HR) per standard deviation (SD) pro-NT/NMN 1.16, 95% confidence interval (CI) 1.01–1.33) and in men (HR per SD pro-NT/NMN 1.25, 95% CI 1.04–1.50); HRs were attenuated in the risk factor model. Pre-existing diabetes mellitus and CHD were the largest confounders of ischemic stroke risk, each accounting for an estimated 19% of the association of pro-NT/NMN with ischemic stroke observed in the demographic model. There were no significant interactions of race or sex with pro-NT/NMN. Further research on associations of pro-NT/NMN with stroke risk factors such as diabetes mellitus is indicated.

Preclinical Evaluation of NHS-Activated Gold Nanoparticles Functionalized with Bombesin or Neurotensin-Like Peptides for Targeting Colon and Prostate Tumours

Recent advances and large-scale use of hybrid imaging modalities like PET-CT have led to the necessity of improving nano-drug carriers that can facilitate both functional and metabolic screening in nuclear medicine applications. In this study, we focused on the evaluation of four potential imaging nanoparticle structures labelled with the 68Ga positron emitter. For this purpose, we functionalized NHS-activated PEG-gold nanoparticles with 68Ga-DOTA-Neuromedin B, 68Ga-DOTA-PEG(4)-BBN(7-14), 68Ga-DOTA-NT and 68Ga-DOTA-Neuromedin N. In vitro binding kinetics and specific binding to human HT-29 colon carcinoma cells and DU-145 prostate carcinoma cells respectively were assessed, over 75% retention being obtained in the case of 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP in prostate tumour cells and over 50% in colon carcinoma cells. Biodistribution in NU/J mice highlighted a three-fold uptake increase in tumours at 30 min post-injection of 68Ga-DOTA-NT-AuNP and 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP compared to 68Ga-DOTA-NT and 68Ga-DOTA-PEG(4)-BBN(7-14) respectively, therewith fast distribution in prostate and colon tumours and minimum accumulation in non-targeted tissues.

Abstract P418: Increased Pro-neurotensin/neuromedin N is Associated With Incident Ischemic Stroke

Introduction: The neuropeptide neurotensin (NT) has been linked to cardiovascular and metabolic disease risk. Through measurement of its stable equimolar precursor, pro-neurotensin/neuromedin N (pro-NT/NMN), hyperactivity of NT has been associated with aggregate cardiovascular outcomes that include stroke. However, the exclusive association of pro-NT/NMN with incident ischemic or hemorrhagic stroke has not been studied. Hypothesis: Higher serum pro-NT/NMN is associated with incident ischemic and hemorrhagic stroke. Methods: Prospective case-cohort study in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. From 2003-2007, REGARDS enrolled 30,239 White or Black adults aged ≥45. Pro-NT/NMN was measured by immunoassay in 464 ischemic stroke cases, 49 hemorrhagic stroke cases, and 800 non-cases from a random cohort. Cox proportional-hazards models were used to calculate hazard ratios (HR) of stroke by pro-NT/NMN quartiles and per standard deviation (SD) of log pro-NT/NMN. Model 1 (both stroke types) included demographic factors as covariates, Model 2A (ischemic only) added ischemic stroke risk factors, and Model 2B (hemorrhagic only) added hemorrhagic stroke risk factors. Results: The table shows an increased HR of ischemic stroke for those in the 4th vs 1st-quartile pro-NT/NMN in Model 1 with a trend of increased risk across quartiles; this was attenuated in Model 2A. Prebaseline diabetes and coronary artery disease were the largest confounders of ischemic stroke risk, with each accounting for 19% of the association observed in Model 1. There was no association of pro-NT/NMN with hemorrhagic stroke in either model. There were no interactions of race or sex with log pro-NT/NMN. Conclusions: Higher pro-NT/NMN is associated with increased risk of ischemic stroke after adjusting for demographics, but this was not independent of stroke risk factors. No significant association with hemorrhagic stroke was observed; this analysis was limited by a small number of events.

Abstract WP475: Pro-neurotensin/neuromedin N is Associated With Incident Cognitive Impairment in Women

Introduction: Neurotensin (NT) is a neuropeptide implicated in cardiovascular and metabolic disease. As such, it is a candidate risk factor for cognitive impairment. We are not aware of studies reporting the relationship of NT and incident cognitive impairment (ICI). NT can be estimated in plasma by measuring its stable equimolar precursor, pro-neurotensin/neuromedin N (pro-NT/NMN). Hypothesis: Higher fasting plasma pro-NT/NMN is associated with risk of ICI. Methods: Prospective nested case-control study in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. REGARDS enrolled 30,239 Black and White adults aged ≥45 from 2003-2007. Baseline pro-NT/NMN was measured by immunoassay in 497 controls and 399 cases of ICI over 3.5 years follow up. ICI was identified using a 3-test cognitive battery biannually. Multivariable logistic regression was used to calculate odds ratios (OR) of ICI by pro-NT/NMN quartiles. Race and sex differences were studied with stratified models and interaction testing (with p <0.10 significant). Results: There was no association of 4 th vs. 1 st -quartile proNT/NMN with ICI in the overall group (see table), nor significant associations of the 2 nd and 3 rd quartiles with ICI in any group The OR differed significantly by sex; women had a 90% increased odds in the demographic-adjusted model, only slightly attenuated by risk factor adjustment. There was no race difference in associations. Conclusions: Higher circulating pro-NT/NMN was associated with ICI in women but not men. This could be due to cerebral vasoconstrictive effects of NT and estrogen-mediated differences in transcription. Confirmatory study is required.

Neurotensin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Neurotensin receptors (nomenclature as recommended by NC-IUPHAR [38]) are activated by the endogenous tridecapeptide neurotensin (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) derived from a precursor (NTS, 30990), which also generates neuromedin N, an agonist at the NTS2 receptor. [3H]neurotensin (human, mouse, rat) and [125I]neurotensin (human, mouse, rat) may be used to label NTS1 and NTS2 receptors at 0.1-0.3 and 3-5 nM concentrations respectively.