In a sample of community-dwelling older people of 64–93 years, we found a borderline significant association between T2DM and elevated plasma OXT levels which was further diminished after adjustment for concurrent risk factors. However, driven by a significant interaction between T2DM and anxiety on OXT levels, indicating a potential modifying role of anxiety on the T2DM-OXT link, we revealed a substantially 44% higher mean level of OXT in T2DM subjects with anxiety compared to their non-T2DM counterparts with anxiety. Notably, a significant association between T2DM and OXT levels in subjects without anxiety was not found. While increasing evidence points to positive effects of OXT in attenuating metabolic risks [2, 27] as well as its profound anxiolytic behavioral effect , our findings seem to be counterintuitive at first sight.
However, the findings of heightened levels of OXT in T2DM subjects with anxiety do not come unexpectedly: both the impact of OXT on fear and anxiety, and its role in the metabolic regulation has yielded contradictory findings. Concerning human social behavior, OXT is widely acknowledged as a candidate molecule to facilitate fear extinction and anxiolysis  and, thus, is emerging as a target for mood treatment approaches . However, opposing experimental data are available. Grillon et al. (2012) exposed healthy subjects to an electrical startle experiment and evidenced that OXT increased anxiety to unpredictable threat . Likewise, Eckstein et al. subjected 97 healthy male probands to a Pavlovian fear learning experiment and disclosed that OXT enhanced CNS responses to social stimuli during fear conditioning, provoking increased vigilance and heightened alertness to threat .
Peters et al. (2014) showed that chronic intra-cereberoventricular infusion of high doses of OXT in male mice induces an anxiogenic phenotype while a low dose of OXT prevents hyperanxiety . Thus, the specific nature, dosage, and timing of OXT are key aspects in orchestrating OXT responses and, instead of acting unidirectional, may result in both anxiolytic and anxiogenic behavioral effects . A low dose of OXT administration is likely to alleviate the effects of stress, while a chronic high dose of OXT may increase anxiety-like behavior . Furthermore, chronic administration of OXT increases adreno-corticotropic hormone (ACTH) and corticosterone levels, indicating a potentiating effect of OXT on the hypothalamic-pituitary-adrenal (HPA) axis stress reactivity [35, 36].
Of note, the positive association between T2DM and OXT levels in subjects with anxiety remained strong even after adjustment for potentially important influential lifestyle factors (e.g. physical activity, smoking and alcohol consumption). This suggests a robust association of anxiety in T2DM patients independent from unfavorable lifestyle habits and highlights chronic anxiety as a clinically relevant phenotype .
Comparable to its role in affect regulation, a functional dichotomy of OXT is also apparent in metabolic regulation: On the one hand, evidence indicated that high OXT levels were positively associated with T2DM and obesity [38, 12, 39, 14, 13], reflecting the role of OXT as a signal of energy availability . High OXT levels may appropriately signal the need to reduce caloric intake and increase energy expenditure . On the other hand, conflicting evidence comes from studies showing low endogenous OXT levels in people with obesity (Fu-Man et al., 2019; Maestrini et al., 2018) or T2DM (Eisenberg et al., 2018; Qian et al., 2014; Yuan et al., 2016). In the present investigation, we assert a weak association between high OXT levels and T2DM. Most studies showing low OXT levels in T2DM subjects were conducted in samples of newly diagnosed or uncontrolled T2DM patients. In the present study, the majority of T2DM subjects (77%, n = 133) were under ongoing treatment. In a sensitivity analysis that considered only T2DM participants under treatment, we found that the results of our analyses remained unaltered (data are not shown).
To date, there is no clear understanding of sexual dimorphism related to the OXT regulation. Although sexual dimorphism has been recognized in the OXT system , both genders seem to be involved in the OXT-regulated energy homeostasis [41, 42]. The present study adds to the conflicting evidence by showing that neither sex differences nor interaction of T2DM by sex influences OXT levels. Our data also demonstrate that endogenous plasma OXT levels were unaffected by increasing age, supporting a previous report that showed OXT response during the insulin tolerance test had similar patterns and magnitudes in all groups . However, it is also likely that the increase in OXT levels of older T2DM subjects could be a compensatory mechanism for the maintenance of metabolic homeostasis where age-related metabolic impairments may have already developed.
Study strengths and limitations
This present study was conducted in a large population-based sample of older subjects from the KORA-Age study. The random sampling of the study population, the low loss to follow-up rate, and the strict quality assessment ensured the quality of the data. The substantially larger sample size of this study compared to other relevant studies to date made it easier to draw firm conclusions based on analytical results. The study design involved extensive assessments of psychological tests and biomarkers, providing the possibility to consider potential modifying factors and to produce robust results adjusting for covariates. The current study contributes to the understanding of endogenous OXT-T2DM association in an older population.
Limitations exist in this study. First, due to its cross-sectional design, we could not infer causality on the anxiety driven association between increased OXT levels and T2DM, and the findings from our study may not be generalizable to other populations. Second, the OXT levels of participants were measured from a single blood sample which may not accurately represent the average metabolic status of an individual. However, in this epidemiologic setting, the quality of the data was ensured by highly standardized procedures and a very strict quality assessment. The non-extracted plasma OXT enzyme immunoassay method used in our study may yield levels of higher magnitude than traditional radioimmunoassays because the samples may contain interfering substances . Therefore, we acknowledge that OXT levels from immunoassays are measuring OXT immunoreactive products, not absolute values of OXT, preventing comparisons of absolute OXT levels between studies. However, the optimal method measuring endogenous OXT is still in active development, and “discrepancies between methods (i.e., extracted or unextracted) are not necessarily an indicator that some methods are valid whereas others are not” . Furthermore, previous reports have shown a robust correlation between extracted and unextracted serum oxytocin levels , as well as associations between non-extracted OXT levels with body dysmorphic disorder (BDD)  or relationship distress , providing evidence for biologic relevance in these sample preparations. Therefore, in the current study, we valued the non-extracted plasma OXT enzyme immunoassay for comparing relative levels of peripheral OXT in participants with T2DM without T2DM.