Background: Converging evidence indicates prolactin (PRL) and diabetes play an important role in the pathophysiology of cognitive impairment. However, little is known about the mechanisms responsible for the effects of PRL and diabetes on cognitive impairment. Summary: We summarize and review the available literature and current knowledge of the association between PRL and diabetes on aspects of cognitive impairment. Key Messages: The phosphatidylinositol 3-kinase/protein kinase B pathway is central to the molecular mechanisms underlying how PRL and diabetes interact in cognitive impairment. Further work is needed to identify the interaction between PRL and diabetes, especially in the molecular aspects of cognitive impairment, which can suggest novel strategies for cognitive dysfunction treatment.

Converging evidence suggests that diabetes predisposes to cognitive impairment and results in dementia in both in vivo models and in humans with diabetes, including type 1 diabetes (T1D), type 2 diabetes mellitus (T2DM), and gestational diabetes [1‒3]. Unfortunately, diabetes and dementia are growing more prevalent around the world [4, 5]. Thus, there is an urgent need to gain knowledge of the pathophysiological disorder and to find out a promising molecule for treatment and pathways that could be enhanced therapy in the future.

Prolactin (PRL) is a polypeptide with numerous functions, including immune regulation, lactation, reproduction, metabolism, brain function, and behavior. PRL has the potential to protect against diabetes [6]. PRL has anti-inflammatory effects on the central nervous system (CNS). PRL may suppress tau phosphorylation by inactivating glycogen synthase kinase-3 (GSK3β) [7]. PRL also improves memory, cognition, and learning while reducing stress and anxiety. Several genes associated with PRL-induced microglial activation may be important for hippocampus neuroimmunomodulation or neuronal cell protection [7]. Although PRL involvement in the pathogenesis of diabetes and cognitive impairment has been recognized, the interaction of PRL and diabetes in cognitive impairment is rather unknown and remains to be elucidated.

In this review, we first describe the aspects of PRL in the contexts of different types of diabetes, including T1D, T2DM, gestational diabetes, and cognitive impairment. We further reviewed the association of PRL and diabetes, including pathways and mechanisms in cognitive impairment.

PRL has been related to glucose metabolism. At high levels, PRL inhibits lipogenesis, but at low physiological levels, it inhibits lipolysis due to a specific effect of PRL on adipocyte differentiation via activation of peroxisome proliferator-activated receptor-gamma [8]. In the middle-aged and elderly population, high circulating PRL levels are associated with a lower prevalence of diabetes and impaired glucose regulation [9]. However, hyperprolactinemia may lead to insulin resistance and impair islet cell function [10]. PRL hormone has also been implicated as a diabetogenic factor in the pathogenesis of T2DM [11]. Although the association between PRL levels and diabetes, especially T2DM, has been widely described, little is known about the relationship between PRL and other types of diabetes such as T1D, gestational diabetes, and diabetic angiopathy. Here, we describe the effects of PRL on T1D, T2DM, gestational diabetes, and diabetic angiopathy.

PRL and T1D

Autoimmune T1D is caused by T cells infiltrating self-antigens and B cells producing islet-specific autoantibodies, resulting in the destruction of pancreatic cells [12]. B lymphocytes produce cytokines that both drive T cell differentiation and regulate their excess in inflammation. B lymphocytes can also act as cellular adjuvants for the activation of CD4+ T cells [13]. Additionally, since the discovery of the Toll-like receptor family, innate immunity appears to have a significant role in increasing autoreactive T- and B-lymphocyte responses in causing T1D [14, 15].

PRL receptors (PRLRs) are found in a variety of immune cells (e.g., monocytes, macrophages, microglia, neutrophils, natural killer cells, and lymphocytes), and thus, PRL has the ability to mediate effects in all of them [16]. PRL also increases T-cell activation through a variety of mechanisms. First, PRL can activate and phosphorylate cluster of differentiation (CD) 3, second messenger kinase Fyn, and zeta chain of T-cell receptor-associated protein kinase 70 [17‒19]. Second, PRL can stimulate CD25, which is known to play an important role in controlling the expansion and proliferation of T-cell subsets [20]. Third, PRL can activate CD69, which is essential for the prolonged proliferation and stimulation of T-cells [20, 21]. Fourth, in antigen-presenting cells, PRL can increase the expression of CD40, CD80, and CD86 co-stimulatory molecules [22]. Fifth, PRL stimulates the production of cytokines that increase T-cell response, such as IL-1, IL-12, IL-16, and interferon-gamma [22, 23]. Sixth, PRL can regulate dopamine agonist sensitivity in the immune system [22]. On the other hand, PRL increases the expression of the T-box transcription factor TBX21 (T-bet) via JAK2/STAT5 in T cells [24]. Low concentrations of PRL (10–30 ng/mL) may stimulate the JAK2/STAT5-mediated signaling pathway in CD4+ T cells, whereas high concentrations of PRL (100 ng/mL) may stimulate the SOCS1 and 3 signaling pathways, resulting in T-bet suppression [24, 25].

PRL, as an immunomodulator, may play a role in the onset and progression of autoimmune disorders such as T1D [26]. PRL promotes insulin secretion and islet cell proliferation. In vitro studies found that pancreatic islets in PRLR-deficient mice are smaller, denser, and have less β-cell mass compared with wild-type littermates as early as 3 weeks of life and throughout maturity [27]. PRL also stimulates PI3-kinase/MAPK in the pancreatic islets of pregnant rats [28]. Other in vivo studies discovered that PRL increased a Th2 response, possibly reflecting PRLs role in protecting mice from developing repeated low-dose streptozotocin diabetes [29, 30]. In a study of 42 women, PRL levels had negative effects on the daily insulin dose, fasting glycemia, and HbA1c levels [31]. Table 1 describes the association between PRL and T1D in human and animal studies.

Table 1.

Association between PRL and T1D

 Association between PRL and T1D
 Association between PRL and T1D

PRL and T2DM

Although numerous epidemiological studies have established the role of PRL among individuals with T2DM, the association between PRL and T2DM is still debated. A lot of evidence show that subjects with prolactinomas are more likely to develop T2DM [49, 50]. A retrospective study of 174 T2DM patients observed that macroprolactinemia prevalence in T2DM patients is higher than in nondiabetic patients. T2DM patients with macroprolactinemia had higher HbA1c levels than T2DM patients without macroprolactinemia [51]. It is possible to explain that reduced adiponectin expression in adipose tissue is one mechanism underlying dysregulation of glucose homeostasis in the context of hyperprolactinemia, which leads to decreased fatty-acid oxidation in muscle and decreased fatty-acid uptake by hepatocytes, both of which negatively affect insulin sensitivity [52‒55]. There is evidence that treatment with dopaminergic agonists for hyperprolactinemia can improve metabolic homeostasis and decrease the risk of T2DM [55, 56]. However, another study found that the correlation between prolactinemia and glycemia, insulinemia, and lipacidemia was low in 98 T2DM patients, implying that hyperprolactinemia does not play an important role as an extra diabetogenic factor in T2DM patients [57].

PRL has been shown to protect beta cells at physiological levels [58‒60]. When diabetic rats are given low doses of PRL, their beta-cell activity and insulin sensitivity increase [61]. Beta-cell survival in culture is improved by recombinant PRL because apoptosis is reduced [59]. By stimulating glucokinase, PRL also increases insulin gene transcription and decreases the setpoint for glucose-induced insulin secretion [60]. A recent systematic review and meta-analysis also showed the positive effects of PRL levels within the normal range on the prevalence of developing T2DM but not the incidence of T2DM [6]. However, a cohort study of 3,232 T2DM patients observed that a 5-mg/dL increase in the PRL level was linked to a higher risk of developing T2DM in males (OR 1.70, 95% CI 1.04–2.78) [62]. Other evidence indicates an increased PRL serum level in T2DM patients is associated with diabetic complications, insulin resistance, and metabolic syndrome (which is a risk factor for T2DM) [62‒64]. Table 2 describes the association between PRL and T2DM in human and animal studies.

Table 2.

Association between PRL and type 2 diabetes

 Association between PRL and type 2 diabetes
 Association between PRL and type 2 diabetes

PRL and Gestational Diabetes

PRL is essential for the maintenance of the corpora lutea during pregnancy and the synthesis of milk during lactation [95]. PRL levels were found to be higher than physiological levels during pregnancy or lactation, which is metabolically beneficial. In fact, this change is seen as part of a homeostatic response to the particular metabolic demands of the mother and child, rather than as a diabetogenic factor [6].

A cohort study followed up 367 women in the late-2nd/early-3rd trimester, suggesting that women with decreased PRL levels during pregnancy have a high risk of developing postpartum prediabetes or diabetes [96]. In vivo studies also showed that PRL signaling plays an important role in beta-cell proliferation during pregnancy and protection against gestational diabetes in PRLR knockout mice [97, 98]. Conversely, a cohort study reported that gestational diabetes risk was significantly and positively linked with PRL levels at weeks 10–14, implying that higher PRL levels in early pregnancy may play a role in the pathophysiology of gestational diabetes [99]. The association between PRL and gestational diabetes is still under debate (Table 3). Further work is needed to further clarify the mechanisms in which PRL is involved in the pathophysiology of gestational diabetes.

Table 3.

Association between PRL, gestational diabetes, and diabetic angiopathy

 Association between PRL, gestational diabetes, and diabetic angiopathy
 Association between PRL, gestational diabetes, and diabetic angiopathy

PRL and Diabetic Angiopathy

In diabetics, angiopathy can take the form of microangiopathy, macroangiopathy, or both. Retinopathy and nephropathy are microangiopathic consequences of diabetes that are two major types of diabetic microangiopathy that have been linked to cognitive impairments in diabetic patients.

There is a report of DM patients with impaired renal function showing high urine PRL levels compared to healthy controls. In that study, it was proposed that urine PRL excretion in proteinuria may contribute to renal impairment-induced PRL dysregulation [106]. Similarly, serum PRL and macroprolactin were elevated in 234 T2DM patients with different nephropathy stages, especially in patients with moderate to severe renal failure [105].

Regarding the association of PRL with diabetic retinopathy, PRL showed that it protected against diabetic retinopathy [109]. Because PRL is pro-angiogenic and acquires antiangiogenic properties after undergoing proteolytic cleavage to vasoinhibins, a PRL fragment is capable of preventing vasopermeability, vasodilation, and angiogenesis [111].

Factors Affecting PRL in Diabetes

As discussed above, the role of PRL in diabetes is becoming more widely acknowledged. However, there are several factors that can influence the excretion of PRL in diabetes.

Serum levels of several pituitary hormones (including PRL) were found to be affected by metformin. Previous research indicated that diabetic medication, primarily metformin, reduced PRL serum levels in T2DM patients by reducing insulin resistance [67]. Metformin medication may have some effects on hyperprolactinemic patients who are also on dopamine agonist therapy and have glucose metabolism disturbances [66]. In a study of 34 elderly women with subclinical hypothyroidism, 16 of whom were given antipsychotic medications. These women were also treated with metformin because they had T2DM (2.55–3 g daily). Serum PRL levels and HOMA1-IR were higher in antipsychotic-treated than in antipsychotic-naive women. Metformin only decreased serum PRL levels in antipsychotic-treated women, implying that the effect of metformin on serum PRL levels was stronger in antipsychotic-treated women than in antipsychotic-naive women [112]. In a study of 7 diabetics and 7 normal men treated with sodium valproate (400 mg), a drug capable of increasing cerebral GABA concentrations, a significant decrease in serum PRL levels from 30 to 120 min was found after administration in both groups [84]. Several studies have highlighted the role of RPL in diabetic retinopathy, mediated by different molecules or drugs such as sulpiride and levosulpiride. Its relationship to diabetic retinopathy is described in Table 3.

There is evidence that hormonal changes can affect PRL levels in diabetes. An in vivo investigation of streptozotocin-induced diabetes (100 mg/kg) in rats revealed that testosterone has a function in regulating PRL and PRLR levels in diabetes [113]. A group of 13 juvenile-onset T1D in the middle to late stages of puberty (stages 3–4) was recruited to examine PRL response to TRH. In terms of maximum value and maximum increment above baseline value, the PRL response to TRH was slightly but significantly supranormal under similar conditions of metabolic control [114]. Anovulation in diabetic patients is caused by hypothalamic and/or pituitary abnormalities. Diabetic women with secondary amenorrhea showed lower serum PRL levels than nondiabetic women with amenorrhea and normal controls [83].

Possible Mechanisms between PRL and Diabetes

The exact mechanisms of PRL and diabetes are still unclear. In reality, the effect of PRL on glucose metabolism and insulin resistance is dependent on the levels of PRL in circulation [9]. By increasing hepatic insulin sensitivity and beta-cell mass, physiologically elevated PRL levels can promote normal adaptive increases in glucose-stimulated insulin production [27, 115]. Physiologically elevated PRL concentrations also have an indirect effect by enhancing hypothalamic dopamine production, which helps to maintain energy and glucose balance [90, 116]. A previous study showed that increased PRL concentrations in T2DM may represent a compensatory mechanism against hyperglycemia because PRL plays a critical role in the increase of pancreatic-cell activity to overcome insulin resistance [117]. Several possible mechanisms can explain the association between PRL and diabetes, such as (1) PRL can stimulate expression of Pparg and Xbp1s, ADIPOQ, and glucose transporter 4 in visceral adipose tissue and increased circulating adiponectin levels, which can promote healthy adipose tissue function and systemic insulin sensitivity [75]; (2) the activation of protein kinase and phosphatidylinositol-3 kinase by PRL can modulate insulin sensitivity and islet density [118]; (3) PRL acts as an adipokine in downregulating fatty-acid synthase and lipoprotein lipase and regulating the bioactivities of leptin, interleukin-6, and adiponectin, which play an important role in the pathology of diabetes [54, 119]; (4) PRL, as an immunomodulator, may play an important role in the onset and development of T1D [26].

PRL is a multifunctional pleiotropic hormone in the brain. In lactating rats and PRL-treated ovariectomized animals, for example, PRL can protect the hippocampus from excitotoxicity [120, 121]. PRL expression is regulated by the pituitary transcriptional factor-1, which is of critical importance to the production of PRL in the pituitary gland. Furthermore, the PRL regulatory element-binding protein (Preb), which binds to and activates the PRL promoter in GH3 rat pituitary cells, is one of the key transcription factors controlling PRL. Our recent review literature and meta-analysis indicate that serum PRL levels in patients with Alzheimer’s disease vary depending on the different conditions (e.g., stage of disease and treatment) [7, 122].

There is mounting evidence that PRL is believed to be a potential molecule for the treatment of cognitive impairment [7]. First, PRL can enhance memory, cognition, and learning abilities in vivo by several mechanisms because PRL regulates Drd2 gene expression [123, 124]. Second, several genes related to PRL-induced microglial activation such as Tac1, Adora2a, Drd2, Egr2, Car3, Hif3a, Sema3A, Notch, Ttr, Chat, Penk, and Penk may play essential roles in hippocampus neuroimmunomodulation or neuronal-cell protection [7, 124]. Third, PRL can stimulate AKT (ak strain transforming/protein kinase B), resulting in GSK3 inactivation and tau phosphorylation inhibition in the female brain [125]. Fourth, neuroinflammation plays an important role in the pathogenesis of cognitive impairment [126]. In the CNS, PRL mediates both pro- and anti-inflammatory properties [7, 25]. As mentioned above, high concentrations of PRL may activate the signaling pathway via SOCS1 and 3, suppressing T-bet activation [24]. PRL signaling via STAT3 promotes anti-inflammatory effects and IL-10 production in macrophages, suggesting that PRL signaling via STAT3 has antiapoptotic and proliferative properties [25, 127]. Taken together, PRL could potentially modulate neuro-inflammation to either prevent or delay the progression of cognitive impairment [7].

As has been described, there is a strong association between dementia risk and diabetes, including T1D, T2DM, and gestational diabetes. The symptoms and prognosis of diabetes-related cognitive impairment differ depending on the type of diabetes and age onset [128]. Consequently, we will describe the risk factors as well as the mechanism by which different types of diabetes participate in the pathology of cognitive impairment.

T1D Mellitus and Cognitive Impairment

The effectiveness of the cognitive functions (e.g., cognitive flexibility, information processing speed, intelligence, visual perception, visual and constant attention, and psychomotor efficiency) was lower in T1D patients than in nondiabetic controls [129]. Diabetes duration and HbA1c levels affected the severity of cognitive deficits in T1D patients [129‒131]. A cohort study of 3,433 US adults aged ≥50 years with T1D observed a significant association between HbA1c concentration and dementia risk. More specifically, adults with a majority of HbA1c exposure of 8–9% had an increased risk of developing dementia, whereas adults with a majority of HbA1c exposure of 6–7.9% had reduced risk [130].

There are several factors, such as hyperglycemia, hypoglycemia, diabetic ketoacidosis, and angiopathy, which were considered as potential predictors of cognitive function in T1D patients. T1DM patients commonly experience hyperglycemia, hypoglycemia, or both. Unfortunately, both hyperglycemia and hypoglycemia were found to be associated with cognitive changes. In 117 T1D children aged 5–16 years, increased exposure to hyperglycemia can reduce verbal intelligence, but repeated hypoglycemia can diminish spatial intelligence and delayed recall. The effects of hypoglycemia and hyperglycemia on cognitive performance in T1D children are qualitatively distinct and are reliant in part on the exposure time during development, regardless of beginning age [132]. Another longitudinal study reported that hyperglycemia was related to decreased working memory, whereas hypoglycemia has been shown to have a negative impact on verbal ability, working memory, and nonverbal processing speed in 106 youth with T1D diagnosed 12 years previously [133]. Acute hyperglycemia (blood glucose levels ≥15 mmol/L) in both T1D and T2DM adults is characterized by poor performance on psychomotor activities, increased subtraction errors, and slow mental subtraction speed [134]. T1D patients who have recurrent server hypoglycemia, on the other hand, have poorer cognitive performance than those who have never had severe hypoglycemia [135, 136]. The cognitive abilities of young T1D patients aged 7–18 years with diabetic ketoacidosis are significantly lower than those of age-matched T1D patients without diabetic ketoacidosis [137, 138].

Microangiopathy (e.g., retinopathy and nephropathy) or macroangiopathy (e.g., myocardial infarction and stroke), or both, can occur in T1DM patients. In adults with T1DM, diabetic retinopathy is associated with a decline in intelligence, information processing, and attention/concentration abilities [139]. However, macrovascular complications, diabetes duration, proliferative retinopathy, and autonomic neuropathy can predict a decline in psychomotor speed in adult T1D patients [140].

T2DM and Cognitive Impairment

T2D has consistently been linked with a greater risk of dementia (e.g., vascular dementia, cognitive decline, mild cognitive impairment, and AD). In a recent systematic review, the authors concluded that there was conclusive evidence based on 144 prospective studies to support the association between T2DM and dementia [141]. The level of cognitive dysfunction in T2DM patients can be loosely classified into three stages: mild cognitive impairment, dementia, and diabetes-related cognitive impairment [142].

The general picture that comes from the numerous studies on the risk factors for cognitive impairment in T2DM is that there are numerous factors at play, each with very minor impacts. First, converging evidence shows chronically elevated glucose levels or HbA1c levels are related to cognitive decrements and dementia risk [141, 143] and second, vascular risk factors. Although the data are inconsistent despite a large amount of research, micro- or macrovascular disease, in particular hypertension and dyslipidemia, may be linked to cognitive impairment in T2DM patients [144]. Third, other risk factors for cognitive dysfunction in T2DM patients were identified as depression, insulin resistance, advanced glycation end products (AGEs), impaired neurogenesis, blood-brain barrier dysfunction, oxidative stress, and inflammation [3, 144‒146].

Gestational Diabetes Mellitus and Cognitive Impairment

High blood pressure and preeclampsia are well-known risks of gestational diabetes mellitus (GDM), but less attention has been paid to its impact on cognitive function. A cross-sectional study of 44 GDM patients and 45 normal pregnant women aged above 30 years observed cognitive impairment in GDM patients [147]. In a case-control study of 12 GDM patients and 28 healthy pregnant controls who experienced an oral glucose tolerance test (75 g), the authors observed that the GDM group had a longer auditory response latency than the healthy control group (296 ± 82 ms vs. 206 ± 74 ms) after 60 min of testing, implying that the fetal neural activity of GDM mothers is slower than fetal healthy controls [148]. A systematic review and meta-analysis evaluated the cognitive performance of offspring from GDM mothers. Based on the 12 studies with 6,140 infants included, the authors found that offspring from GDM mothers had poorer scores for mental and psychomotor development, (a mean standardized difference for mental and psychomotor development were −0.41 and −0.31, respectively), compared to offspring from healthy pregnant women [149].

Not only the mother but also the offspring are affected by GDM in terms of cognitive function. However, the effect on the offspring has been researched more than that on the mothers. Despite the fact that the complex pathophysiology of maternal cognitive impairment is unknown, it shares certain characteristics with T2DM [1]. On the other hand, there is mounting evidence that GDM can cause maternal cognitive impairment through neuroinflammation, insulin resistance, hyperglycemia, and oxidative stress [150‒156].

Insulin regulates a variety of biological processes by binding to and activating the insulin receptor and two closely related tyrosine kinase receptors [157]. Insulin receptors and their common downstream pathways are widely dispersed throughout the brain, and these pathways serve as regulators of brain function, neurogenesis, metabolism, and whole-body energy balance [158]. Several parts of the brain, such as the hippocampus, hypothalamus, cerebellum, cerebral cortex, olfactory bulb, and amygdala, contain the highest levels of insulin receptors [159]. Thus, insulin is believed to have neurotrophic and neuroprotective effects on CNS neurons because it has positive impacts on cognitive processes and emotions (e.g., executive functioning, attention, learning, and memory) [160].

After insulin binds to the insulin receptor, the receptor autophosphorylates, and the activated insulin receptor phosphorylates insulin receptor substrate (IRS) proteins, triggering the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) cascade, a crucial downstream pathway [157]. It is worth noting that the PRLR-S or PRLR-L isoform can also stimulate the PI3K/AKT signaling pathway activation [161].

Converging data have shown the important role of the PI3K/AKT signaling pathway in neuroprotective mechanisms in the brain, especially in the hippocampus [162, 163]. For example, activation of the PI3K/AKT signaling pathway promotes neuronal survival by inhibiting cleavage of mitochondrial release of cytochrome c, Bcl-xL, ischemia-induced mitochondrial translocation of BAD, and caspase activation [164, 165]. AKT also inhibits GSK3β, which has been linked with the pathogenesis of various neurodegenerative diseases [166].

In insulin resistance conditions, the insulin-signaling pathway is predominantly inactivated by serine phosphorylation of insulin receptor substance [167]. This process inhibits the PI3K/AKT signaling cascade, preventing glucose transporter 4 translocation, and lowering glucose absorption [168]. It is worth noting that GSK3 is also activated, resulting in tau hyperphosphorylation and amyloid-β (Aβ) overexpression [169]. On the other hand, mitochondrial dysfunction is also recognized in cases of insulin resistance, causing oxidative stress [152]. Hyperglycemia causes an increase in the expression of pro-inflammatory cytokines due to the overproduction of AGEs and activation of the TREM1/DAP12 pathway [170, 171]. Furthermore, free fatty acid causes pro-inflammatory cytokines by activating microglia via nuclear factor kappa β (NF-κB) signaling. Thus, NF-κβ was produced via binding of Aβ with receptors of AGEs, worsening the inflammatory situation [172]. Inactivation of the insulin-signaling pathway, oxidative stress, and inflammation was considered as the common mechanisms for diabetes-induced cognitive impairment. However, in hyperglycemia, AGEs are overproduced, resulting in a reduction in cerebral blood flow. Cerebral flow dysfunction can contribute to cognitive failure by disrupting the blood-brain barrier transport system, which carries important substances (e.g., choline) into the brain and clearing unwanted compounds (e.g., Aβ protein) [173].

In terms of the association of PRL with AKT signaling, PRL has a neuroprotective role in female rat neurodegeneration and inactivated GSK3 on Ser9 in W53 lymphoid cells, which was involved in PI3K/AKT/GSK3 pathway activation [125, 174]. Following AKT-mediated phosphorylation of IκB kinase, PRL induces NF-κB activation, leading to survival gene activation (e.g., Bcl-2) [175]. During neuroprotection, PRL induces NF-κB activation against oxidative stress by overexpression of p65 and excitotoxicity in the hippocampus [176]. Several studies have found that PRL-induced NF-κB activation is associated with an increase in protein content and activity of Cu2+/Zn2+/Mn2+-SOD enzymes [177, 178]. Furthermore, activation of the PI3K/AKT pathway has a role in the regulation of glutathione synthesis [179]. High levels of PRL, as previously mentioned, can suppress T-bet activation by the signaling pathway activation through SOCS1 and 3 [24]. PRL signaling via STAT3 has both antiapoptotic and proliferative features [25, 127]. Several genes related to microglial activation induced by PRL also play essential roles in hippocampus neuroimmunomodulation or neuronal-cell protection. Of note, PRL can improve memory, cognition, and learning ability by regulating Drd2 gene expression [2, 111].

We analyzed the TREM-1/DAP12 pathway and PRL, PRLR-S, PRLR-L, Preb, Pit-1, and pro-inflammatory cytokine mRNA levels in the hippocampus of diabetic mice and compared them to those measured in metformin-treated diabetes mice and controls [180]. We discovered that the TREM-1 pathway (TREM-1, DAP12, and casp1), pro-inflammatory cytokines (Cox2, IL-1, and iNOS), Pit-1, and PRL expression levels were significantly increased in the hippocampus of diabetic mice, whereas these pro-inflammatory cytokines, as well as PRLR-S, PRLR-L, and Preb expression levels, were significantly decreased in diabetes mice treated with metformin. Furthermore, the levels of p-Tau and GSK3β in the diabetic mice were significantly higher than those in the control mice and significantly lower than those in the diabetic mice treated with metformin.

Taken together, inflammation, oxidative stress, hyperglycemia, and insulin resistance are all factors that contribute to diabetes-induced cognitive impairment. PRL is neuroprotective, improves memory, cognition, and learning and has immunomodulatory and antioxidant properties. PRL can protect beta cells at physiological levels. Of note, PRL can improve glucose and HbA1C levels in diabetes patients. Although little is known about the relationship between PRL and diabetes in terms of cognitive dysfunction, the two share PI3K/AKT signaling pathways. However, it is critical to draw attention to it as a potential research topic for the future. To comprehend the interacting molecular actions of PRL and diabetes in both pathological and physiological settings, an understanding of interaction signaling pathway activation between PRL and diabetes is required. Figure 1 is a summary of the proposed mechanisms of cognitive impairment associated with diabetes and PRL.

Fig. 1.

Summary of the proposed association between cognitive impairment, diabetes, and PRL. The pink “X” shows inhibition or negative regulation. Solid and dashed arrows indicate for regulating in diabetes and PRL models, respectively. The left side of the figure showed eight mechanisms of diabetes (including T1D, type 2 diabetes, and gestational diabetes) induced cognitive impairment, which are insulin resistance, mitochondrial dysfunction, activation of pro-inflammatory cytokines, inflammation, oxidative stress, overexpression of Aβ, vascular damage, and BBB permeabilization. The right side of the figure described six mechanisms by which PRL can protect cognitive impairment, which are anti-inflammation ability; inhibition of T-bet activation; inhibition of protein degradation; activation of genes related to PRL-induced microglia; enhancement of memory, behavior, and learning; and inhibition of apoptosis. BBB, blood-brain barrier; P, serine phosphorylation; IRS-1, insulin receptor substance; GLUT4, glucose transporter 4; FFA, free fatty acid; TNF-α, tumor necrosis factor α; IL-1β, interleukin 1β; IL-6, interleukin 6; FOXO, forkhead box O; NFTs, neurofibrillary tangles; PRLR-I, prolactin receptor intermediate; SOD, superoxide dismutase gene; Bax, B-cell lymphoma protein 2-associated X.

Fig. 1.

Summary of the proposed association between cognitive impairment, diabetes, and PRL. The pink “X” shows inhibition or negative regulation. Solid and dashed arrows indicate for regulating in diabetes and PRL models, respectively. The left side of the figure showed eight mechanisms of diabetes (including T1D, type 2 diabetes, and gestational diabetes) induced cognitive impairment, which are insulin resistance, mitochondrial dysfunction, activation of pro-inflammatory cytokines, inflammation, oxidative stress, overexpression of Aβ, vascular damage, and BBB permeabilization. The right side of the figure described six mechanisms by which PRL can protect cognitive impairment, which are anti-inflammation ability; inhibition of T-bet activation; inhibition of protein degradation; activation of genes related to PRL-induced microglia; enhancement of memory, behavior, and learning; and inhibition of apoptosis. BBB, blood-brain barrier; P, serine phosphorylation; IRS-1, insulin receptor substance; GLUT4, glucose transporter 4; FFA, free fatty acid; TNF-α, tumor necrosis factor α; IL-1β, interleukin 1β; IL-6, interleukin 6; FOXO, forkhead box O; NFTs, neurofibrillary tangles; PRLR-I, prolactin receptor intermediate; SOD, superoxide dismutase gene; Bax, B-cell lymphoma protein 2-associated X.

Close modal

Given the significant evidence for PRLs neuroprotective activities in the brain and the link between PRL and diabetes-induced cognitive impairment, the current review discussed how PRL and diabetes are linked to cognitive dysfunction. The PI3K/AKT pathway is now being studied, and it could be the most involved in the molecular mechanisms that explain how PRL and diabetes interact in cognitive impairment. Identifying whether the interaction of PRL and diabetes is specifically linked to the biological features of cognitive dysfunction, as well as determining whether the mechanisms linking diabetes and PRL to cognitive dysfunction can suggest novel strategies for cognitive dysfunction treatment, which have been difficult areas of research. However, these are potential study areas in the fields of diabetes, PRL, and dementia, which could assist in minimizing the incidence of cognitive decline and dementia in diabetic patients and the general public.

The authors have no conflict of interest to declare.

This work was supported by a research promotion program of SCNU.

H.D.N.: conceptualization, methodology, formal analysis, investigation, resources, data curation, writing – original draft, writing – review and editing, and visualization. M.S.K.: visualization, supervision, and project administration. H.Y.C.: visualization. B.P.Y.: visualization. H.O.: visualization. Ngoc Minh Hong Hoang: visualization. Won Hee Jo: visualization.

The data supporting this review were obtained from cited studies.

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