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Potential Role of CREM in Diabetes‐Associated Testicular Dysfunction:

Current Evidence and Future Perspectives

Article in Reproductive Medicine and Biology · June 2025

DOI: 10.1002/rmb2.12661

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Reproductive Medicine and Biology

REVIEW OPEN ACCESS

Potential Role of CREM in Diabetes-­Associated Testicular

Dysfunction: Current Evidence and Future Perspectives
Olabimpe Caroline Badejogbin1 | Oyedayo Phillips Akano1 | Oluwafisayo Elizabeth Boluwatife Julius1 |
Mary Olaoluwa Agunloye2 | Makinde Vincent Olubiyi3 | Ojichukwuka Ebere Chijioke-Agu4 | Matthew Agene Obekpa5 |
Adesina Paul Arikawe6 | Kehinde Samuel Olaniyi7

1Department of Physiology, College of Basic Medical Sciences, Babcock University, Ilishan-­Remo, Ogun State, Nigeria | 2 Department of

Physiology, Kampala International University, Western Campus, Ishaka, Uganda | 3Department of Medical Physiology, University of Rwanda,
Huye, Rwanda | 4Department of Physiology, Alex-­Ekwueme Federal University, Abakaliki, Ebonyi State, Nigeria | 5Department of Physiology,
University of Ilorin, Ilorin, Kwara State, Nigeria | 6Department of Physiology, College of Medicine, University of Lagos State, Idi-­A raba, Lagos State,
Nigeria | 7Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-­Ekiti, Ekiti State, Nigeria

Correspondence: Mary Olaoluwa Agunloye (agunloyeolaiya@[Link])

Received: 16 March 2025 | Revised: 30 April 2025 | Accepted: 21 May 2025

Funding: The authors received no specific funding for this work.

Keywords: CREM | male infertility | reproduction | spermatogenesis | testiculopathy | type 2 diabetes mellitus

ABSTRACT
Background: Type 2 diabetes mellitus (T2D) is a growing metabolic disorder affecting all age groups and is linked to testiculopa-
thy, a key contributor to male infertility. Testiculopathy disrupts spermatogenesis and the sperm microenvironment, with the cyclic
adenosine monophosphate (cAMP) response element modulator (CREM) playing a pivotal role in testicular function. Understanding
the interplay between T2D and CREM dysregulation is essential for developing targeted therapies for diabetic testicular dysfunction.
Methods: A systematic review of PubMed, Web of Science, Scopus, and Google Scholar was conducted to identify peer-­reviewed
studies, both preclinical and clinical, that explored CREM's role in diabetes-­induced testicular dysfunction. Extracted data fo-
cused on CREM expression, oxidative stress, apoptosis, and spermatogenic impairment in diabetic models.
Main Findings: Research from studies on diabetic patients and animal models highlights the detrimental effects of diabetes on
the reproductive system, including hypothalamic–pituitary–testicular (HPT) axis dysregulation. CREM regulates spermatogenic
gene expression, influenced by luteinizing hormone (LH), follicle-­stimulating hormone (FSH), and cAMP signaling.
Conclusion: CREM has a therapeutic role in maintaining testicular function, and its disruption may contribute to testiculopathy
in T2D, highlighting its potential therapeutic target for preserving male fertility in diabetic patients. Further research is needed
to explore its molecular mechanisms and therapeutic implications.

1   |   Introduction with over 462 million individuals diagnosed worldwide [1].

The increasing incidence of T2D among children and ado-
Type 2 diabetes mellitus (T2D) is a prevalent metabolic dis- lescents is alarming, primarily driven by lifestyle changes,
order affecting approximately 6.28% of the global population, obesity, high consumption of processed foods, and chronic

Abbreviations: AGE, advanced glycation end-­product; cAMP, cyclic adenosine monophosphate; CREM, cAMP response element modulator; DAPL1, death-­
associated protein-­like 1; DNA, deoxyribonucleic acid; FSH, follicle-­stimulating hormone; GnRH, gonadotropin-­releasing hormone; HDAC, histone deacetylase; HPT,
hypothalamic–pituitary–testicular; LH, luteinizing hormone; miR-­375, microRNA-­375; PDE inhibitors, phosphodiesterase inhibitors; PKC, protein kinase C; RA,
retinoic acid; ROS, reactive oxygen species; T2D, type 2 diabetes; TP1, transition protein 1.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2025 The Author(s). Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.

Reproductive Medicine and Biology, 2025; 24:e12661 1 of 13

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stress [2–4]. Characterized by chronic hyperglycemia, T2D diabetes-­induced testicular damage could provide novel insights
results from progressive β-­cell dysfunction, excessive insu- into its pathophysiology and therapeutic targets for male infer-
lin production, insulin resistance, and oxidative stress, ulti- tility associated with T2D.
mately impairing glucose regulation and insulin signaling.
Without effective management, hyperglycemia contributes to Therefore, this review explores CREM's role in testiculop-
widespread organ damage, leading to complications such as athy associated with T2D, focusing on its regulatory influ-
retinopathy, neuropathy, nephropathy, and notably, testicu- ence on gene expression and cellular function in the testes.
lopathy [5–9]. Additionally, it evaluates the potential therapeutic implica-
tions of targeting CREM to mitigate diabetes-­induced repro-
Testiculopathy, a significant yet often overlooked consequence ductive complications.
of T2D, is a major contributor to male infertility. It manifests
as spermatogenic abnormalities, reduced sperm function, and
impaired testicular microenvironment integrity [10]. Poor 2   |   Methods
sperm quality, a key factor in male infertility, is further in-
fluenced by obesity, smoking, alcohol consumption, and high A comprehensive literature search was conducted across
intake of sugary beverages [4, 11–13]. Over the past decades, PubMed, Web of Science, Scopus, and Google Scholar to identify
declining male fertility rates have raised global concerns, par- relevant studies on the potential role of CREM in diabetic testic-
ticularly as diabetes among adolescent males continues to rise ulopathy. The search focused on peer-­reviewed articles, experi-
[14–17]. Studies on diabetic patients and animal models re- mental studies, and literature published in English.
veal that T2D disrupts the hypothalamic–pituitary–testicular
(HPT) axis, leading to reduced testosterone production, tes- Studies were screened based on predefined eligibility criteria.
ticular dysfunction, and impaired spermatogenesis. This con- Inclusion criteria encompassed studies investigating CREM
tributes to erectile dysfunction, decreased libido, increased expression and function in diabetes-­related testicular dysfunc-
impotence, and infertility, all stemming from metabolic and tion, preclinical (animal models) and clinical studies assessing
endocrine disruptions within the HPT axis and testicular tis- CREM-­regulated pathways in male reproductive health, and re-
sue [18–20]. search discussing diabetes-­induced spermatogenic impairment,
oxidative stress, apoptosis, and endocrine disruption, provided
Diabetes-­induced hypogonadism further impairs testicular they were published in peer-­reviewed journals. Conversely, ex-
function by disrupting the pulsatile release of gonadotropin-­ clusion criteria involved studies not directly assessing CREM's
releasing hormone (GnRH) and suppressing luteinizing role in testicular dysfunction, non-­English articles, conference
hormone (LH), follicle-­stimulating hormone (FSH), and tes- abstracts without full-­text availability, and research focusing on
tosterone production [2]. The hypothalamic–pituitary-­gonadal female reproductive health or non-­diabetic conditions unrelated
(HPG) axis plays a central role in regulating spermatogene- to testicular function.
sis, which is initiated at puberty by gonadotropin release. LH
stimulates Leydig cells to produce testosterone, which binds Titles and abstracts of all identified articles were initially
to androgen receptors on Sertoli cells, Leydig cells, and per- screened, followed by a full-­ text review of eligible studies.
itubular myoid cells, triggering spermatogonia differentiation Relevant data were extracted using a structured approach, with
into mature sperm [21]. This process is highly dependent on a focus on CREM's involvement in spermatogenesis under dia-
testosterone and retinoic acid (RA), with germ cells synthesiz- betic conditions, diabetes-­induced oxidative stress and apoptosis
ing RA to regulate genes essential for meiosis, DNA condensa- in testicular cells, and potential molecular mechanisms linking
tion, and spermiogenesis. CREM dysfunction to male infertility. The methodology is sum-
marized as shown in Figure 1.
One of the key transcription factors governing spermatogene-
sis is the cyclic adenosine monophosphate (cAMP) Response
Element Modulator (CREM), encoded by the CREM gene, 3   |   Overview of HPT Axis and Its Dysfunction
which produces over 30 isoforms with diverse regulatory func-
tions [22]. CREM plays a crucial role in germ cell differentiation The testis is a dynamic endocrine organ, crucial for germ cell
by modifying gene expression and is highly expressed in cell nu- development, sperm differentiation, and testosterone synthe-
clei across various tissues. During puberty, gonadotropins stim- sis [24]. Proper testicular function depends on the HPT axis,
ulate the upregulation of CREMτ, an activator isoform, through which regulates steroidogenesis and spermatogenesis [21]. The
cAMP signaling pathways, facilitating spermatogenesis [23]. hypothalamus secretes GnRH that prompts the release of the
However, in diabetic conditions, CREM dysregulation may im- gonadotropins supporting intragonadal steroidogenesis and
pair testicular function, disrupting key transcriptional networks spermatogenesis, with feedback control on GnRH and gonad-
involved in sperm development. otropin levels [25, 26]. The hypothalamic neurons that secrete
GnRH, released into the hypophyseal portal system stimulat-
While testicular dysfunction is a well-­established complication ing LH and FSH secretion, are controlled via the hypothalamic
of T2D, the molecular mechanisms underlying diabetes-­induced network of kisspeptin/neurokinin B/dynorphin A (KNDy)
testiculopathy remain an area of active research. The CREM is neurons. FSH is important in Sertoli cell function and sper-
a pivotal transcription factor in spermatogenesis, yet its role matogenesis, while LH acts on the Leydig cells to produce tes-
in diabetic testicular dysfunction remains poorly character- tosterone from cholesterol. Testosterone, produced in the testes,
ized. Understanding how CREM dysregulation contributes to maintains a high local concentration for spermatogenesis and is

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FIGURE 1    |    Methodology flowchart.

also secreted into the circulation, influencing distant androgen-­ sensitivity potentially, clinical trial outcomes have been incon-
sensitive tissues. Proper testosterone levels are crucial, and a sistent [21, 26]. Testicular failure is frequently identified during
feedback mechanism reduces LH and GnRH secretion when fertility evaluations. A thorough history and physical examina-
levels are sufficient. The testes produce over 95% of circulating tion, especially of the testes, are essential for diagnosing and
testosterone in post-­pubertal men. This testosterone equilibrates managing male infertility, as uncovering the underlying pathol-
between protein-­bound and free forms in the bloodstream, with ogy may reveal reversible factors for targeted treatment [12, 28].
the free form being biologically active. Testosterone undergoes
metabolism in peripheral tissues, influencing various physiolog-
ical functions [21, 26]. 4   |   Testiculopathy in Type 2 Diabetes Mellitus

Disruptions in the HPT axis can lead to testosterone deficiency, Diabetes mellitus can cause testiculopathy through pre-­
causing hypogonadism. Hypogonadism can be classified into testicular (hypogonadotropic hypogonadism), testicular, and
two types: primary and secondary. Primary hypogonadism, also post-­testicular mechanisms as shown in Figure 2. It can induce
known as hypergonadotropic hypogonadism, is relatively rare hypogonadism via central mechanisms, such as hyperleptin-
and occurs when the testes are underactive despite the normal emia or disrupted hypothalamic GnRH release in individuals
function of the hypothalamus and anterior pituitary. In contrast, with obesity, and through peripheral mechanisms, like Leydig
secondary hypogonadism, or hypogonadotropic hypogonadism, cell dysfunction. These disruptions result in reduced serum
is more prevalent and results from dysfunction within the hy- gonadotropin and testosterone levels. The HPG axis, essen-
pothalamic–pituitary axis. Both congenital and acquired condi- tial for puberty, steroidogenesis, and reproductive capacity, is
tions can interfere with the HPT axis at various levels, leading often disrupted in diabetes. Studies show that both type 1 di-
to male hypogonadism. The clinical manifestations of hypogo- abetes mellitus (T1DM) and T2D can lower FSH and LH pro-
nadism depend on the age of onset, the extent of androgen defi- duction, affecting spermatogenesis and reducing seminiferous
ciency, and the underlying cause of the condition [21, 27]. tubule diameter and sperm count. Impaired brain insulin sig-
naling pathway in diabetic conditions can diminish hormonal
Aging, obesity, and type 2 diabetes are key risk factors for hy- output necessary for Leydig cell function and spermatogenesis.
pogonadism. Diabetes can impair the HPT axis at multiple Treating diabetic rats with insulin has been shown to restore
levels, contributing to both primary (testicular) and second- normal sperm count, either by influencing the HPT axis or by
ary (hypogonadotropic) hypogonadism. Central dysfunctions, reducing oxidative stress in the testis, highlighting the interplay
such as impaired GnRH secretion, and peripheral factors, like between obesity, insulin resistance, and testosterone deficiency
Leydig cell failure, may coexist and lead to reduced testosterone in diabetes [30, 31]. Leptin, correlated with insulin levels, plays
levels. Epidemiological studies have established a connection a role in regulating reproductive function but is often decreased
between low testosterone levels and an elevated risk of diabe- in T1DM patients [29, 32].
tes and metabolic syndrome. Severe testosterone deficiency
can exacerbate insulin resistance, and while testosterone ther- Diabetes increases oxidative stress, leading to reactive oxy-
apy has been shown to reduce body fat and improve insulin gen species (ROS) production in seminal fluid, sperm DNA

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FIGURE 2    |    Testiculopathy in diabetes mellitus [2, 21, 29]. DM can potentially cause testiculopathy through pre-­testicular, testicular, and post-­
testicular mechanisms. (a) At the pre-­testicular level, DM may induce hypogonadism by disrupting the hypothalamic release of GnRH and altering
Leydig cell function, leading to decreased levels of serum gonadotropins and testosterone. (b) At the testicular level, DM is associated with increased
oxidative stress, which contributes to apoptosis and inflammation. This leads to elevated production of reactive oxygen species (ROS), increased
expression of pro-­apoptotic factors, decreased anti-­apoptotic factors, heightened pro-­inflammatory cytokines, and reduced anti-­inflammatory cy-
tokines. (c) At the post-­testicular level, complications like erectile dysfunction may arise due to DM, further impairing spermatogenesis, reducing
semen quality, and causing damage to testicular tissues.

fragmentation, and mitochondrial bioenergy alterations. pathway can reduce diabetic complications [40]. This thorough
Elevated ROS levels in diabetes can damage germ cell DNA, understanding of diabetes-­induced testiculopathy emphasizes
reduce sperm quality, and cause infertility [33]. The oxidative the complex interaction of hormonal, oxidative, inflammatory,
imbalance in the testicular tissue is a primary pathophysiolog- and metabolic factors contributing to male reproductive dys-
ical state, and apoptosis of germ cells is common. Increased function in diabetes.
apoptosis, driven by pro-­apoptotic factors like Bax and caspases,
leads to testicular dysfunction [34]. Inflammation, another dia- Most diabetic patients experience disruptions in reproductive
betic complication, can further damage testicular cells through functions, including compromised spermatogenesis, increased
hyperglycemia-­induced pro-­inflammatory factors like TNF-­α germ cell apoptosis, and reduced steroidogenesis, which con-
and iNOS, affecting sperm maturation and semen quality tribute to decreased libido, higher rates of impotence, and in-
[35, 36]. fertility [19]. These dysfunctions result from metabolic and
endocrine disturbances in the testes and alterations in the
Diabetes can cause sperm damage or impair seminal fluid re- HPT axis [41, 42]. The precise molecular and cellular mecha-
lease due to male accessory gland infection/inflammation nisms underlying diabetes-­related testicular abnormalities have
(MAGI) and erectile/ejaculatory dysfunction. Erectile dysfunc- not been fully clarified. Despite several proposed mechanisms
tion (ED) is prevalent among men with diabetes and is linked to through which T2D affects male reproductive function, effec-
factors like reduced nitric oxide synthesis, increased oxidative tive treatments to reverse T2D-­induced testicular damage are
stress, and vascular complications [37]. Ejaculation problems, still underexplored. Several studies have emphasized the role of
including premature, delayed, or retrograde ejaculation, are also the CREM gene in spermatogenesis and male fertility over the
common, often resulting from neuropathy [38, 39]. years [43, 44]. However, the specific influence of the CREM gene
in T2D-­ induced testicular dysfunction remains incompletely
Hyperglycemia in diabetes can damage organs through the understood.
polyol pathway, advanced glycation end-­product (AGE) forma-
tion, and protein kinase C (PKC) activation. These pathways
lead to oxidative stress and organ damage. AGE formation, 5   |   Understanding CREM: Role and Regulation in
linked to male infertility, is prevalent in diabetic conditions, Testicular Function
affecting testicular function and semen quality. The polyol
pathway, active in testicular cells, also influences its metab- The CREM is a transcription factor belonging to the basic
olism and sperm production. Blocking the diacylglycerol domain-­leucine zipper family. It functions by forming homo-­or

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heterodimers that bind to the cAMP response element (CRE), and translational mechanisms. Disruptions in its regulation
a palindromic DNA sequence located in the promoter regions are strongly associated with male infertility and testicular
of cAMP-­responsive genes [45]. CREM plays a critical role in dysfunction [59]. While its role in normal testicular function
spermatogenesis, serving as a key transcription factor in the tes- is well established, its regulation under diabetic conditions re-
tes. It exists in over 30 isoforms, many of which are highly ex- mains poorly understood. Given the metabolic and hormonal
pressed in testicular tissue and are essential for activating genes disturbances associated with diabetes, CREM expression and
involved in sperm development [23]. function may be significantly altered. However, direct evi-
dence linking CREM dysfunction to diabetic testiculopathy
CREM isoforms function as either activators or repressors, de- remains limited, underscoring the need for further investiga-
pending on the testicular microenvironment [46]. Repressive tion. The molecular and cellular mechanisms of CREM regu-
isoforms include CREMα, β, γ, CREM-­ S, and ICER, while lation in the testis under both normal and diabetic conditions
CREMτ1 and CREMτ2 act as activators crucial for spermatogen- are illustrated in Figure 3.
esis [47]. Notably, infertile men exhibit higher expression of re-
pressor isoforms, while activators are predominantly expressed
in fertile males [48]. Among these, CREMτ is the primary activa- 6   |   Mechanisms Linking CREM to Testiculopathy
tor isoform, highly expressed in post-­meiotic germ cells, where in Type 2 Diabetes Mellitus
it drives the transcription of spermatid-­specific genes [49]. In
contrast, CREMα, a repressor isoform, plays a regulatory role 6.1   |   CREM-­Mediated Effects on Oxidative Stress
during early spermatogenesis, ensuring proper timing and co- in the Testes
ordination of gene activation [46]. Disruptions in the balance of
these isoforms have been linked to male infertility and defective Enhanced CREM expression has been associated with the res-
sperm formation [50]. The significance of CREM in spermato- toration of testicular function, primarily through its role in re-
genesis is evident in animal models, where CREM deficiency ducing oxidative stress in testicular tissues. Increased levels of
leads to azoospermia, characterized by the complete absence of ROS, indicated by elevated malondialdehyde levels, have been
spermatozoa in the ejaculate [51]. shown to inhibit CREM expression [60]. Furthermore, upreg-
ulation of the CREM gene correlates with increased activity of
During puberty, the gonadotropin hormones FSH and LH regulate antioxidant enzymes such as glutathione peroxidase and super-
CREM expression by binding to receptors on Sertoli and Leydig oxide dismutase, contributing to the mitigation of testicular in-
cells, increasing cAMP levels and influencing gene expression. jury [46]. Additionally, antioxidant treatment has been shown
Specifically, FSH induces the expression of CREMτ, the activator to enhance CREM activity, leading to improved sperm quality,
isoform essential for germ cell differentiation into spermatozoa increased spermatogenesis, and preservation of testicular histo-­
[23, 52]. CREM recognizes and binds to CREs in gene promoter architecture [25].
regions, regulating the transcription of genes vital for spermato-
genesis. This process is further influenced by interactions with While oxidative stress is a major contributor to testicular dys-
coactivators such as CREB-­binding protein [25, 53]. function in diabetes, the specific role of CREM in mediating
or responding to oxidative damage remains unclear. Given its
The regulation of CREM occurs at multiple levels, including the critical function in activating genes essential for sperm develop-
transcriptional level, where FSH significantly regulates CREM ment, further investigation into CREM's response to oxidative
mRNA expression in Sertoli cells, though its exact mechanisms stress in diabetic testes could provide new insights into its role
remain unclear. Interestingly, some studies indicate that rats in male infertility.
lacking functional FSH receptors still exhibit normal CREM
expression and fertility, suggesting alternative regulatory path-
ways [25]. Additionally, proteins like death-­associated protein-­ 6.2   |   CREM in the Regulation of Testicular
like 1 (DAPL1) can reduce CREM transcript levels, indirectly Inflammation
affecting testosterone production [54].
Although the direct involvement of CREM in testicular inflamma-
At the post-­ transcriptional level, the splicing of CREM tion remains to be fully elucidated, emerging evidence highlights
mRNA is influenced by proteins such as DAZAP1 (Deleted in its potential indirect role through the modulation of cytokines and
Azoospermia-­ Associated Protein 1), which modulate isoform immune responses. Notably, studies have shown that CREM can
expression critical for spermatogenesis [55]. Additionally, at the bind to the promoter region of interleukin-­2 (IL-­2) in T cells, lead-
translational level, CREM activity is further regulated by post-­ ing to the transcriptional repression of this key cytokine, which
translational modifications like phosphorylation. Testis-­specific plays a crucial role in T cell proliferation and immune function [61].
kinases (TSSK4) phosphorylate CREM, enhancing its transcrip-
tional activity during the late stages of sperm development [56]. This regulatory mechanism implies that CREM may influence
Coactivators such as coactivator-­ associated arginine methyl- cytokine expression, thereby impacting inflammatory pro-
transferase 1 (CARM1) and sperm-­associated antigen 8 (SPAG8) cesses. According to Mali and Yadav, testicular inflammation
interact with CREM-­associated proteins, fine-­tuning gene ex- (orchitis) results from immune cell infiltration and the release
pression essential for spermatogenesis [57, 58]. of pro-­inflammatory cytokines within the testicular environ-
ment [62]. Given CREM's role in cytokine regulation, abnormal
In conclusion, CREM is a master regulator of spermatogen- expression or dysfunction could disrupt testicular immune ho-
esis, controlled through transcriptional, post-­t ranscriptional, meostasis. For instance, impaired CREM activity may lead to

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FIGURE 3    |    Molecular and cellular mechanism of CREM regulation in normal and diabetic testis. The cellular and molecular mechanisms regu-
lating CREM activity in the testis under normal and diabetic conditions. In the normal testis, CREM is activated through the cAMP/PKA signaling
pathway, promoting the transcription of genes essential for spermatogenesis. Under diabetic conditions, hyperglycemia, oxidative stress, and inflam-
mation disrupt this pathway, leading to reduced CREM activity, germ cell apoptosis, impaired spermatogenesis, and testicular dysfunction.

dysregulated cytokine production, potentially exacerbating tes- dysfunction [65]. Furthermore, CREM has been found to sup-
ticular inflammation. press pancreatic beta cell proliferation by inhibiting the action
of glucagon-­like peptide 1 (GLP-­1). GLP-­1 normally stimulates
beta cell proliferation and serves as a potential therapeutic target
6.3   |   Modulation of Hyperglycemia-­Associated for diabetes treatment. However, under physiological conditions,
Pathways by CREM and Interaction With Insulin beta cells maintain a homeostatic mechanism to prevent exces-
Signaling Pathways sive GLP-­ 1–induced proliferation and subsequent hyperinsu-
linemia. This regulation is achieved through negative feedback
Certain forms of CREM are expressed in pancreatic beta cells, mechanisms, including CREM activation [66].
where they play a crucial role in regulating insulin gene expres-
sion. As a member of the cAMP-­response element binding pro- Moreover, CREM is involved in inhibiting the cAMP/PKA/
tein (CREB) family of transcription factors, CREM is involved in CREB signaling pathway, which plays a key role in GLP-­1–medi-
beta cell function by enhancing glucose-­stimulated insulin secre- ated beta cell proliferation [67]. In another study, sildenafil was
tion. This effect is partly attributed to its role in increasing the ex- found to prevent or ameliorate diabetes-­related complications,
pression of insulin receptor substrate 2 (IRS2) in beta cells [63]. an effect linked to CREM inhibition. This finding further sup-
ports the role of CREM in the pathophysiology of hyperglyce-
Additionally, CREM regulates the expression of microRNA-­375 mia, a defining feature of diabetes mellitus [68].
(miR-­375), which is abundantly present in pancreatic islet cells.
Elevated miR-­375 levels have been associated with impaired beta
cell function. Interestingly, CREM has been shown to repress 6.4   |   CREM'S Influence on Reproductive
miR-­375 expression, while miR-­375, in turn, inhibits CREM ac- Hormones
tivity. This reciprocal regulation suggests that CREM plays a role
in stimulating insulin production and action [64]. The activity of CREM is closely associated with reproductive
hormones such as FSH and LH, which regulate testicular func-
In an experiment involving hyperglycemia induction in rats, tion and sperm production through cAMP signaling cascades.
inhibition of CREM expression was observed. This was linked FSH binds to Sertoli cell receptors in the seminiferous tubules,
to reduced insulin gene expression and diminished glucose-­ triggering a signaling cascade that increases intracellular cAMP
stimulated insulin secretion, which is an indication of beta cell levels [69]. This rise in cAMP activates protein kinase A (PKA),

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which phosphorylates and regulates transcription factors such as 6.6   |   Impact of CREM Dysregulation on Testicular
CREM. Specifically, the activator isoform CREMτ plays a crucial Microenvironment and Fertility
role in germ cell development by regulating the expression of
genes like transition protein 1 (Tnp1), transition protein 2 (Tnp2), CREM plays a crucial role in regulating genes involved in sper-
and protamine 1 (Prm1), all essential for chromatin remodeling matogenesis. Studies have shown that during spermiogenesis,
during spermatogenesis [51]. Scobey et al. reported that FSH the differentiation of sperm cells depends on CREM expression
stimulation significantly increases CREMτ expression, enhanc- in spermatids. Consequently, the inhibition or absence of CREM
ing the transcription of genes vital for sperm development [70]. disrupts the structural modifications required for spermatogene-
This process is further influenced by Sertoli cell-­secreted factors, sis [77]. Research indicates that men affected by azoospermia ex-
which interact with germ cells to ensure proper spermatogenesis. hibit significant downregulation or a complete absence of CREM,
CREM deficiency or dysfunction has been linked to severe sper- which impairs spermatid maturation [78]. Additionally, CREM is
matogenic defects, ultimately leading to male infertility. essential for the replacement of histones with protamines in the
sperm nucleus, a process critical for spermatid elongation. This
LH primarily regulates testicular function by stimulating Leydig histone-­protamine exchange is mediated by Transition Protein
cells to produce testosterone, the key androgen responsible for 1 (TP1), and CREM has been shown to stimulate TP1 activity,
spermatogenesis and male secondary sexual characteristics [71]. thereby facilitating sperm maturation [79].
While LH does not directly affect CREM activity, testosterone
indirectly modulates it by altering the Sertoli cell environment.
Testosterone enhances Sertoli cell function, thereby influencing 6.7   |   Experimental Evidence and Clinical Studies
the transcriptional activity of CREM-­dependent genes involved in
spermatogenesis [72]. Studies suggest that disruptions in testoster- Type 2 diabetes–associated testiculopathy presents a complex
one levels, such as those observed in hypogonadism, can impair clinical challenge, requiring a deeper understanding of its mo-
CREM-­regulated gene expression, leading to defective sperm mat- lecular mechanisms for effective management and treatment.
uration [71]. Additionally, testosterone has been shown to regulate Among the various implicated genes, CREM emerges as a po-
the expression of coactivators that interact with CREM, further tential key regulator in this condition.
shaping the transcriptional landscape of spermatogenic cells [70].

6.7.1   |   Animal Models and Human Studies Assessing

6.5   |   Role of CREM in Spermatogenesis CREM Expression and Function in Spermatogenesis
Impairment and Sperm Cell Apoptosis and Diabetes

CREM plays a crucial role in spermatogenesis, particularly in Animal models are essential tools for understanding the complex
regulating the expression of post-­meiotic genes in male germ mechanisms underlying diabetic testiculopathy. Rodent models,
cells. A study by Blendy et al. revealed that impaired spermatid particularly mice and rats, have been widely used to investigate
differentiation in male mice lacking CREM proteins was associ- the role of CREM [80–83]. These models enable researchers to
ated with reduced expression of post-­meiotic genes in the testes experimentally induce diabetes and analyze its effects on CREM
[50]. Similarly, CREM deficiency in mutant mice led to germ cell expression levels [68, 84, 85]. Studies have provided compelling
apoptosis and disruption of early spermiogenesis, resulting in evidence linking CREM dysregulation to various pathological
the absence of late spermatids [46]. testicular changes, including impaired spermatogenesis, altered
steroidogenesis, and oxidative stress [51, 86, 87]. Additionally,
Further emphasizing the role of CREM, patients with Klinefelter these models have facilitated the evaluation of potential thera-
syndrome who often experience hypogonadism, low testoster- peutic interventions targeting CREM-­related pathways [66, 88].
one levels, and infertility have been found to exhibit low CREM While gene knockout and overexpression studies have clari-
expression [73]. Additionally, testicular tissue from animals fied CREM's role in spermatogenesis, its specific contribution
infected with Toxoplasma gondii showed slight methylation to diabetic testiculopathy remains poorly understood. Further
changes in specific CREM promoter regions, correlating with research is needed to determine how diabetes-­induced CREM
a decline in sperm count [74]. Another study demonstrated an dysregulation affects testicular function and male fertility.
inverse relationship between sperm quality and CREM meth-
ylation, with abnormal methylation patterns contributing to An increasing number of studies have explored CREM expression
reduced sperm count, motility, and morphology. Thus, CREM and function in spermatogenesis [43, 89, 90] as well as in diabetic
gene DNA methylation status may serve as a potential biomarker conditions [68, 85] Techniques such as immunohistochemistry,
for male infertility [75]. gene expression analysis, and functional assays have been em-
ployed to assess CREM activity and diabetes-­related alterations
Apoptosis plays a critical role in the disruption of spermatogene- in testicular tissues or peripheral blood samples. Findings sug-
sis, leading to altered sperm parameters. Inhibition of the CREB/ gest that abnormal CREM expression is associated with impaired
CREM signaling pathway resulting in CREM downregulation semen quality [91] hormonal imbalances [24] and histological
has been linked to sperm cell apoptosis. This is evidenced by in- abnormalities [92]
creased caspase-­3 expression due to Bax upregulation and Bcl-­2
downregulation. Additionally, elevated p53 activity, a key regula- Although research has examined the impact of diabetes on testic-
tor of testicular apoptosis, further supports this process, while its ular dysfunction and the role of CREM in normal and patholog-
inhibition favors the suppression of apoptotic factors [76]. ical testicular physiology, the specific involvement of the CREM

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in diabetic testiculopathy remains unexplored. This gap in knowl- 7.1   |   Therapeutic Potential of Targeting CREM
edge underscores the need for further investigation into CREM's and cAMP Pathways in Testicular Dysfunction
regulatory mechanisms in diabetes-­induced testicular dysfunction.
Given the critical role of CREM and cAMP signaling in sper-
matogenesis, targeting this pathway presents a promising ther-
7   |   Summary of Findings and Therapeutic apeutic strategy for testicular dysfunction as shown in Figure 4.
Implication of CREM in T2DM-­Associated One potential approach is FSH therapy, which stimulates cAMP
Testiculopathy production, thereby enhancing CREM activation and promoting
sperm cell development [93–95]. Studies have shown that FSH
Despite significant progress in understanding CREM's role in induces CREM gene expression in Sertoli cells, emphasizing
spermatogenesis, its involvement in diabetic testiculopathy its significance in spermatogenesis. Additionally, phosphodi-
remains unclear. While animal models have provided valu- esterase (PDE) inhibitors, which prevent cAMP breakdown,
able mechanistic insights in non-­ diabetic contexts, translat- could prolong CREM activity, potentially restoring impaired
ing these findings to clinical practice is still in its early stages. spermatogenesis in testicular disorders. Moderate doses of PDE
Longitudinal studies are needed to explore the temporal dynam- inhibitors have been reported to improve sperm motility and vi-
ics of CREM dysregulation in diabetes and its impact on disease ability, highlighting their therapeutic potential [96, 97].
progression. Additionally, further research should investigate
how key diabetic mechanisms hyperglycemia, oxidative stress, Recent research has also explored epigenetic modulators that in-
inflammation, apoptosis, and hormonal imbalances affect fluence DNA modifications affecting CREM expression. These
CREM expression and function in the testes. interventions hold promise for reversing diabetes-­ induced
CREM suppression, thereby restoring normal sperm production.
Exploring CREM as a potential therapeutic target could open new Furthermore, antioxidant-­based therapies may indirectly pre-
avenues for managing diabetes-­related male infertility. However, serve CREM function by reducing oxidative stress in testicular
the development of targeted therapies modulating CREM activity tissue. Notably, short-­chain fatty acids (SCFAs) like butyrate and
requires rigorous preclinical and clinical validation. Collaborative acetate, produced through gut microbial fermentation of dietary
efforts between researchers, clinicians, and pharmaceutical indus- fiber, have emerged as potential epigenetic modulators. Sodium
tries are crucial to bridging the gap between experimental research butyrate, an HDAC inhibitor, may regulate CREM expression,
and clinical applications, ultimately improving outcomes for dia- offering a novel approach to mitigating testicular dysfunction
betic patients with testicular dysfunction. [98–100].

FIGURE 4    |    Therapeutic intervention of CREM in maintaining testicular function. CREM viz. transcriptional factor in regulating spermatogen-
esis, influencing expression of anti-­apoptotic factors may be responsible for male reproductive health functionality. Dysregulation of CREM led to
testiculopathy, affecting the regulation of CREM in testiculopathy. Therapeutic approaches such as hormonal therapies, antioxidants, drugs target-
ing epigenetic modifications, gene therapy, and small molecule activators may enhance testicular function, improving male reproductive health.

8 of 13 Reproductive Medicine and Biology, 2025

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Since FSH therapy, PDE inhibitors, and epigenetic modulators Second, human data are lacking. Few studies have performed
have demonstrated beneficial effects in both diabetes and tes- quantitative CREM expression analysis in testicular tissues
ticular dysfunction, they could play a crucial role in mitigating from diabetic men, and direct clinical investigations linking
CREM dysregulation in diabetic-­induced testiculopathy. FSH CREM expression to testicular impairment in diabetes are nota-
therapy enhances cAMP signaling, which is often impaired in di- bly absent. As a result, the role of CREM in this context remains
abetes, while PDE inhibitors sustain cAMP activity, potentially largely hypothetical.
counteracting diabetes-­induced disruptions in CREM function.
Additionally, epigenetic modulators like sodium butyrate could Moreover, the isoform-­specific functions of CREM, as well as
reverse hyperglycemia-­induced CREM suppression, restoring their tissue-­specific expression patterns, remain underexplored,
normal spermatogenesis. Integrating these strategies may pro- especially under chronic metabolic conditions such as diabetes.
vide a targeted approach to mitigating diabetes-­related testicular This knowledge gap limits both translational relevance and the
dysfunction through CREM modulation as shown in Figure 5. development of targeted therapeutic strategies.

However, despite their therapeutic potential, challenges remain To address these gaps, future research should emphasize robust
in developing CREM-­ specific treatments without disrupting preclinical studies (in vitro and in vivo) to generate quantitative
other essential cellular processes. Further research is needed and mechanistic data. The development of diabetic models with
to refine these therapeutic strategies and assess their long-­term testis-­specific CREM manipulation could help define isoform and
safety and efficacy in restoring male fertility. tissue-­specific roles. Additionally, translational studies are needed
to establish causal links and validate findings in human popula-
tions. Integrating omics-­based approaches (transcriptomics, pro-
7.2   |   Future Perspectives teomics, metabolomics) may further uncover downstream targets
and regulatory networks of CREM in diabetic testes. Finally,
Although the emerging role of the CREM in spermatogenesis is investigating the therapeutic potential of modulating CREM
increasingly recognized, and its involvement in diabetes-­induced through gene therapy or small-­molecule regulators could open
testicular dysfunction appears promising, several critical lim- new avenues for preserving male fertility in diabetic individuals.
itations remain. First, current evidence lacks quantitative and
definitive data demonstrating testis-­specific CREM downregu-
lation in diabetic models. Direct assessments in diabetic animal 8   |   Conclusion
models are scarce, and rescue experiments showing that forced
CREM expression can reverse testicular damage are limited. T2D affects approximately 6.25% of the global population, im-
Similarly, studies employing testis-­specific CREM knockdown to pacting over 462 million people. It disrupts the HPG axis, leading
replicate diabetic testicular phenotypes are insufficient. to reduced testosterone synthesis and impaired spermatogenesis.

FIGURE 5    |    Potential mechanism of diabetic-­induced testiculopathy and CREM-­targeted therapies. Mechanisms of diabetic-­induced testiculop-
athy, the involvement of CREM in these pathways, and the three potential therapeutic interventions (FSH therapy, PDE inhibtitors, and epigenetic
modulation).

9 of 13
 14470578, 2025, 1, Downloaded from [Link] by Mary Agunloye - Readcube (Labtiva Inc.) , Wiley Online Library on [05/06/2025]. See the Terms and Conditions ([Link] on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
The HPG axis regulates spermatogenesis through the release of 8. T. Zhu, M. Li, M. Zhu, et al., “Epigallocatechin-­3 -­Gallate Alleviates
LH and FSH. The CREM is a key transcription factor in sper- Type 2 Diabetes Mellitus Via-­Cell Function Improvement and Insulin
matogenesis, with its upregulation closely linked to LH and FSH Resistance Reduction,” Iranian Journal of Basic Medical Sciences 25, no.
4 (2022): 483, [Link] JBMS.​2 022.​58591.​13016​.
signaling. Given CREM's role in modulating gene expression and
cellular processes in the testes, it presents a promising therapeu- 9. J. S. Bhatti, A. Sehrawat, J. Mishra, et al., “Oxidative Stress in the
tic target for addressing T2D-­associated testicular dysfunction. Pathophysiology of Type 2 Diabetes and Related Complications: Current
Therapeutics Strategies and Future Perspectives,” Free Radical Biology
& Medicine 184 (2022): 114–134, [Link] reer​adbio​
med.​2 022.​03.​019.
Acknowledgments 10. R. Huang, J. Chen, B. Guo, C. Jiang, and W. Sun, “Diabetes-­Induced
The authors have nothing to report. Male Infertility: Potential Mechanisms and Treatment Options,”
Molecular Medicine 30, no. 1 (2024): 11, [Link]
0-­​023-­​0 0771​-­​x.
Disclosure
11. O. C. Badejogbin, O. E. Chijioke-­A gu, M. V. Olubiyi, and M. O.
The authors have nothing to report. Agunloye, “Pathogenesis of Testicular Dysfunction in Diabetes:
Exploring the Mechanism and Therapeutic Interventions,” Journal of
Ethics Statement Assisted Reproduction and Genetics 42 (2024): 1–13, [Link]
1007/​s1081​5 -­​024-­​03314​-­​3.
The authors have nothing to report.
12. T. D. Gundersen, N. Jorgensen, A. M. Andersson, A. K. Bang, L.
Nordkap, and N. E. Skakkebaek, “Association Between Use of Marijuana
Conflicts of Interest and Male Reproductive Hormones and Semen Quality: A Study Among
The authors declare no conflicts of interest. 1,215 Healthy Young Men,” American Journal of Epidemiology 182
(2015): 473–481, [Link] wv135.

Data Availability Statement 13. R. Sharma, A. Harlev, A. Agarwal, and S. C. Esteves, “Cigarette
Smoking and Semen Quality: A New Meta-­A nalysis Examining the
Data sharing is not applicable to this article as no new data were created Effect of the 2010 World Health Organization Laboratory Methods for
or analyzed in this study. the Examination of Human Semen,” European Urology 70 (2016): 635–
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