Circulating Prolactin and Risk of Type 2 Diabetes

A Prospective Study

TiangeWang; Yu Xu; Min Xu; Guang Ning; Jieli Lu; Meng Dai; Baihui Xu; Jichao Sun; Wanwan Sun; Shenghan Lai; Yufang Bi; Weiqing Wang*


Am J Epidemiol. 2016;184(4):295-301. 

In This Article


In the present study, a high circulating prolactin level was significantly associated with a lower incidence of type 2 diabetes in postmenopausal women, but not in middle-aged and elderly men. To the best of our knowledge, this is the first study to investigate the association between circulating prolactin and incident diabetes in a prospective study.

During pregnancy, prolactin levels together with prolactin receptors elevate in parallel with the increased β-cell mass and glucose-stimulated insulin secretion to upregulate islet cell function and maintain a normal glucose homeostasis.[9–11] During the nonpregnant period, prolactin regulates whole-body insulin sensitivity and glucose metabolism by expanding β-cell mass,[12] improving hepatic insulin sensitivity,[13] and modulating immune function[5,7,14] and has an indirect action by increasing hypothalamic dopamine synthesis to improve energy and glucose homeostasis.[15,16] In addition, prolactin acts as an adipokine in down-regulating lipoprotein lipase and fatty acid synthase,[17,18] as well as regulating the bioactivities of adiponectin, interleukin-6, and possibly leptin.[19,20] Collectively, experimental studies raise the prospect that prolactin has an important role in the manifestation of glucose and energy homeostasis.[21] It is noteworthy that physiologically high circulating prolactin and pathological hyperprolactinemia have different effects on glucose metabolism. Physiologically elevated prolactin could protect against the impairment of glucose homeostasis through the mechanisms that were mentioned above, whereas excessively high levels of prolactin exacerbate insulin resistance and impair insulin-secretory capacity in not only diabetic mice[12] but also patients with hyperprolactinemia caused by prolactinoma.[22] Pituitary prolactinoma often accompanied by hyperglycemia, obesity and insulin resistance, and a dopamine-2 agonist, such as bromocriptine, can be used to reverse these symptoms.[15,22]

Our previous cross-sectional analysis found that individuals with higher prolactin levels had a significantly lower prevalence of type 2 diabetes in both men and women.[8] However, in the present study, physiologically higher levels of prolactin were prospectively associated with a lower risk of incident type 2 diabetes in women but not in men. After further adjustment for hormone use and parity status, the association between prolactin and incident type 2 diabetes remained significant in women, suggesting that the association may not be confounded by hormone use and parity. Although the exact underlying mechanisms are not clear, several potential reasons may explain this apparent discrepancy between men and women. As an estrogen-responsive pituitary hormone, prolactin was expressed at higher levels in females than males.[23,24] Although serum prolactin levels in women decrease steadily with age, especially with a significant decline after the menopause,[23] prolactin levels were still higher in postmenopausal women than in men in the present study (9.87 (SD, 4.17) ng/mL vs. 8.95 (SD, 3.21) ng/mL) (P < 0.0001). Another possible explanation may be the more pronounced activity of prolactin in females than in males, especially in aspects of energy regulation, immune response, and food intake,[25,26] which play important roles in glucose and insulin regulation. Moreover, females were more likely to be affected to a greater extent by the variations of prolactin or its receptor levels. For instance, females experienced a more progressive reduction in abdominal fat mass and plasma leptin concentrations in the absence of prolactin receptors than males did.[27] Thus, it is possible that the long-term effect of circulating prolactin on glucose metabolism may be more significant in women than that in men.

In addition to pregnancy, several environmental factors, such as physical activity, sleep, and stress, could affect the concentration of circulating prolactin.[1] Our data also suggested potential correlations of prolactin with smoking and low density lipoprotein cholesterol in men, which was in line with the previous findings that circulating prolactin was inversely associated with smoking and low density lipoprotein cholesterol.[28,29] However, the underlying mechanisms were unclear and validations are warranted.

Several limitations must be considered. First, the present study included a relatively small number of participants, and the follow-up duration was not long, which could potentially result in a lack of statistical power to detect associations. Second, considering the variation of prolactin secretion in different stages of the menstrual cycle, we preformed the current study only in postmenopausal women. Further study in premenopausal women is needed. Third, potential unmeasured confounders (such as physical activity, sleep, and stress) for this association may exist.

In conclusion, our findings lend support to the postulation that the variation of serum prolactin levels associated with incident type 2 diabetes outside pregnancy suggests that prolactin may be a mediator in the pathogenesis of type 2 diabetes. Potential sex-specific mechanisms and associations between circulating prolactin levels and incident diabetes in humans need to be elucidated in future studies.