While the term ‘diabetes’ is defined as an individual’s inability to regulate blood glucose concentrations with resultant chronic hyperglycemia, traditionally two major clinically distinct subtypes have been characterized. Type 1 diabetes (T1D) results from the complete autoimmune mediated destruction of the insulin producing beta (β) cells within the pancreatic islets (1). In contrast, type 2 diabetes (T2D) arises because the β-cell population cannot satisfy insulin demand and/or peripheral tissues are resistant to the actions of insulin (2). Although T1D and T2D have been clinically classified as separate disease entities with distinct pathogeneses, there is now increasing evidence that they share disease sequalae. Loss of β-cell function and mass is the common underlying mechanism driving the progression of both conditions, and β-cell death/dysfunction is caused by pro-inflammatory responses largely initiated and perpetuated by macrophages (3).

The incidence of T1D and T2D have been exponentially increasing in recent decades, with the global prevalence predicted to reach almost 600 million cases by 2035 (4). Such rapid increases in disease prevalence cannot be attributable to genetic modifications, and instead suggest the removal of a protective environmental factor or introduction of a predisposing agent (5, 6). Initially, epidemiological studies established a robust inverse relationship between the incidence of multiple autoimmune/inflammatory diseases, and the prevalence of endemic helminth infections (7). Subsequently, compelling results from several human and animal studies have corroborated a protective effect of helminthic infection (or their excretory/secretory [ES] molecules) against the development of both TID and T2D (8). It has been broadly proposed that this positive impact on disease outcome is mediated by the potent ability of helminths to regulate pro-inflammatory host immune responses.

Interestingly, macrophages have been identified as the key players in both the modulation of host responses during helminth infections (9), and the initiation and perpetuation of pro-inflammatory responses during diabetes development. Over the years, the central role of macrophages in β-cell differentiation and homeostasis has been well demonstrated (10). However, more recently macrophages have emerged as central players in the initiation of autoimmune insulitis (immune cell infiltration of the islets) in T1D, and as the dominant immune cell population causing intra-islet inflammation in T2D (11, 12). Macrophages are highly dynamic and adopt distinct phenotypes and functions in response to cues received from adjacent cells and the surrounding microenvironment (13, 14). Further, macrophages are among the first immune cells to traffic to the islets during the development of T1D and T2D (11, 12). Thus, it is not surprising that macrophages can, and do, communicate intimately with β-cells, and vice versa. This intercell crosstalk determines if the islet micro-environment becomes pro- or anti-inflammatory, thereby promoting or mitigating the development of diabetes, respectively (15, 16).

This review discusses the evidence suggesting that modulation of the host immune responses by helminths alters the interplay between macrophages and β-cells to prevent β-cell dysfunction and death, and therefore prevent the development of both T1D and T2D. Helminth infection has also been shown to alter host metabolism (17), suggesting an additional effect on cells with endocrine function, such as β-cells. Therefore, this review also explores the biological changes mediated by helminths, and their ES products, to determine if they may directly alter the communication between β-cells and macrophages, to enhance β-cell survival and function, thereby preventing the development of T1D and T2D.

In T1D, β-cells are lost due to a sustained process of autoimmune destruction driven by pro-inflammatory immune cells. This destructive process progresses over several years such that at diagnosis approximately only 10-20% of β-cell mass remains (1). Within the autoimmune islet environment, dying β-cells are phagocytosed by antigen presenting cells (macrophages and dendritic cells), and autoantigens are processed and presented to autoreactive Th1 and Th17 CD4⁺ cells. Subsequently, autoreactive cytotoxic CD8⁺ T cells undergo activation and clonal expansion, and traffic to the pancreas where they infiltrate the islets and destroy β-cells (18, 19). During insulitis, infiltrating immune cells, such as macrophages and T cells, secrete pro-inflammatory cytokines (notably IL-1β, TNF, and IFNγ), which further promotes β-cell apoptosis (20, 21) ( Figure 1 ). These pro-inflammatory macrophages are pivotal to T1D development as their deletion attenuates disease development (22).

While the events initiating β-cell loss are different, T2D is also ultimately an inflammatory syndrome of the islets. Indeed, conditions of overnutrition trigger inflammation and insulin resistance, along with elevated levels of inflammatory factors, such as circulating glucose and free fatty acids (FFA) (23). This induces β-cell endoplasmic reticulum (ER) stress and β-cell secretion of pro-inflammatory cytokines/chemokines (such as IL-1β, TNF, and IFNγ) as well as islet amyloid polypeptide (IAPP). In turn, this pro-inflammatory milieu leads to the recruitment of macrophages to the islet, akin to insulitis development in T1D, in addition to the activation of islet resident macrophages. These macrophage populations exhibit a pro-inflammatory M1-like phenotype and release the same inflammatory cytokines/chemokines characteristic of T1D development (24, 25). This inflammatory sequalae is exacerbated by stressed and/or necrotic adipocytes, which similarly cause the recruitment of pro-inflammatory macrophages, and reductions in anti-inflammatory macrophage and regulatory T cell populations within the adipose tissue. This, in turn, triggers inflammation in organs targeted by insulin and initiates insulin resistance. To compensate for these adverse metabolic events, β-cells produce and secrete increased amounts of insulin, resulting in β-cell hyperplasia, stress, exhaustion, and ultimately death (26–28). Collectively, these processes lead to the perpetuation and maintenance of a pro-inflammatory environment within the islet, ultimately culminating in β-cell dysfunction, death and T2D (2) ( Figure 1 ).

The destructive consequences of insulitis on β-cells led to the long-held paradigm that β-cells were passive victims of the detrimental pro-inflammatory islet environments characteristic of T1D and T2D. However, this notion has been challenged by more recent evidence that β-cells are active participants in their own demise (1, 29).

The neonatal phase of pancreatic remodeling is characterized by waves of β-cell proliferation, apoptosis and neogenesis. While this is intended as a physiological phenomenon, the process can lead to the generation of β-cell autoantigens, and the stimulation of autoreactive T-cells, which play a major role in the β-cell destruction that leads to diabetes progression. However, the frequencies of these autoreactive T-cell populations in the peripheral blood of T1D patients is comparable to those observed in healthy individuals. This suggests that the activation of insulitis, which underpins the initiation and progression of diabetes, requires the immune tolerance to β-cell autoantigens to be broken (1, 30).

Analyses of human insulitis lesions have suggested that signals released from stressed β-cells precedes, and putatively initiates, the development of insulitis (31). This sequence of events is recapitulated in a humanized mouse model of diabetes, in which the presence of autoreactive T-cells alone was insufficient to induce disease, which was triggered only when β-cells were stressed by the addition of the diabetogenic agent, streptozotocin (STZ) (32). Furthermore, immunosuppressive therapies that solely target T-cells fail to provide long-term protection against T1D as they do not typically address the underlying loss of β-cell immune tolerance (33). Thus, it has now been proposed that activation of the cellular stress response in β-cells due to their metabolic activities promotes cell death pathways, and participates in the initiation and amplification of inflammation and the active destruction of β-cells in T1D (34). Likewise, β-cells undergo metabolic stress in T2D due to overnutrition and inflammation that causes β-cell compensatory insulin secretion, followed by exhaustion and ultimately death (2).

Beta cells rapidly respond to the minute-to-minute fluctuations in blood glucose levels by tightly regulating insulin secretion. Such high metabolic demand to produce and secrete insulin can render the β-cells susceptible to exceeding ER protein folding capacity, in turn leading to accumulation of misfolded proteins and ER stress (35). This can dysregulate several processes, such as inhibition of β-cell function, induction of apoptosis and activation of cytosolic post-translational modification (PTM) enzymes (36), which can generate a group of neoantigens called hybrid insulin peptides (HIPs) by covalently linking insulin peptides to β-cell granule peptides, such as insulin c-peptide and IAPP. These HIPs contribute to autoimmune responses and ultimately β-cell destruction, as they are recognized by autoreactive CD4⁺ T cells in both mouse models and human patients of T1D (37, 38). Beta cells from diabetic patients also express increased levels of MHC-I and MHC-II molecules (HLA-I and HLA-II, respectively, in humans), the latter being conventionally expressed only by antigen presenting cells. This enables β-cells to present peptides (notably autoantigens) to CD8⁺ and CD4⁺ T cells, respectively (39, 40). Moreover, immune cells have direct access to islets through the dense network of islet vasculature, which can be particularly detrimental in the presence of activated pro-inflammatory immune cells and cytokines that induce β-cell stress and apoptosis (34, 41).

These β-cell characteristics make them vulnerable to destruction, and this is exacerbated in the pathogenic conditions of T1D and T2D, in which there are increased levels of pro-inflammatory cytokines, reactive oxygen species (ROS) and nitric oxide (NO), which are especially detrimental since β-cells have limited antioxidant defense capabilities (42, 43), and are highly sensitive to cytokine mediated damage. The central pro-inflammatory cytokines, IL-1β, TNF and IFNγ, have been shown to inhibit β-cell function and activate apoptotic pathways in β-cell lines, human islets, and rodent models (34, 44). In turn, this inflammatory milieu stimulates the β-cells themselves to secrete pro-inflammatory cytokines and chemokines, thereby actively contributing to their own destruction (45). Indeed, β-cells of diabetic animals and within the islets of T2D patients were observed to produce IL-1β (46). This is corroborated by in vitro studies, wherein cultured human islets exposed to high glucose were observed to secrete IL-1β, with production increasing due to autocrine feedback (47).

Furthermore, β-cells produce several chemokines: (i) C-C ligand 5 (CCL5), also named RANTES, (ii) C-X-C motif chemokine ligand 10 (CXCL10), also called IP-10, and (iii) C-C ligand 2 (CCL2), also termed monotype chemoattractant protein or MCP1 (34). CXCL10 and CCL5 are secreted by murine islets, β-cell lines, and cultured human islets after exposure to IL-1β, TNF, and IFNγ. Both chemokines attract activated immune cells to the islets (48, 49), and CXCL10 has been shown to exert direct toxicity on the β-cells (50). Similarly, CCL2 is produced by human and murine islets in response to IL-1β and can be induced in vivo by environmental triggers (such as viral infections), causing inflammation and macrophage recruitment (51–53).

Collectively, these β-cell vulnerabilities, along with the signals they release under conditions of stress within the islet microenvironment, can create a self-perpetuating cycle of β-cell destruction, which is exacerbated in conjunction with pro-inflammatory immune cells ( Figure 2 ).

Macrophages constitute a heterogeneous and dynamic immune cell population whose phenotype and function are highly dependent on the tissue microenvironment. Macrophages can derive from embryonic hematopoietic precursors and inhabit specific tissues, in which they actively participate in maintaining homeostasis under physiological conditions. Following pathogen infection, tissue damage, release of inflammatory mediators, or metabolic cues, circulating monocytes are recruited in different tissues where they differentiate into resident macrophages. Here, stimuli in the surrounding micro-environment induce macrophages to adopt pro-inflammatory or anti-inflammatory phenotypes and functions, thereby mediating inflammatory/autoimmune or homeostatic/reparative responses, respectively (22, 54).

Macrophages are among the first cells to traffic to the pancreas under both physiological and diabetogenic conditions. This is because macrophages play central roles during neonatal islet remodeling, which is characterized by waves of β-cell differentiation, proliferation, and apoptosis, due to their potent phagocytic abilities. After taking up residence in the islets, macrophages remain in intimate contact with the β-cells, where they act as exquisite sensors of the function and viability of β-cells (15). Through a two-way exchange of signals, such as cytokines and chemokines, hormones and growth factors, insulin-containing vesicles and exosomes, and metabolites, macrophages are highly responsive to β-cell activities, and the composition of their secretions is modulated accordingly to promote β-cell survival and metabolic activity (under physiological cues). On the other hand, macrophage/β-cell crosstalk can drive β-cell dysfunction and apoptosis when physiological equilibrium is disturbed by the inflammatory signals present during the development of T1D and T2D (16) ( Figure 3 ).

In the context of T1D, the populations of resident islet macrophages in both animal models and humans display an pro-inflammatory phenotype, characterized by the secretion of cytokines (such as IL-1β and TNF), upregulated expression of MHC-II and increased antigen presentation capacity, and decreased phagocytosis of apoptotic β-cells (55–57). Decreased uptake of dying β-cells by macrophages and/or increased rates of β-cell apoptosis leads to an accumulation of dying β-cells, and their progression to necrosis, during the intended physiological process of neonatal islet remodeling. Also, after the phagocytosis of apoptotic β-cells, macrophages secrete increased levels of pro-inflammatory IL-12 and decreased levels of IL-10, which contradicts the expected anti-inflammatory pro-resolving response (58–60). Aside from this cytokine profile, intra-islet macrophages secrete NO and chemokines, and express chemokine receptors (notably CCR5, CXCR3 and CCR8) which further recruits and activates other pro-inflammatory immune cells (61, 62). These phenomena modulate the crosstalk between β-cells and macrophages to trigger the initiation of disease.

Furthermore, monocyte-derived macrophages are among the first, and most abundant, immune cells to traffic into the islet in both murine models and human patients (11, 63), and it is hypothesized that this initial influx is induced by increased levels of CCL2. Indeed, CCL2 overexpression in murine β-cells promoted monocyte recruitment to islets, infiltration, and β-cell destruction (53). Moreover, macrophages express C-C chemokine receptor 2 (CCR2) to which CCL2 can bind, thereby inducing macrophage secretion of the pro-inflammatory mediators, IL-1β, TNF, IL-12, and CXCL10. These islet infiltrating macrophages are predominantly characterized as a pro-inflammatory phenotype and release potent inflammatory mediators (such as IL-1β and CCL2) that promote β-cell apoptosis (64). Simultaneously, signals from apoptotic β-cells (IL-1β, CCL5, CXCL10, CCL2) amplify/maintain this pro-inflammatory phenotype (65).

This inflammatory environment can be exacerbated by priming factors that mediate crosstalk between macrophages and β-cells. For instance, β-cells and islet resident macrophages express toll-like receptors (TLRs), which are activated by pathogen activated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) released due to viral infection and other tissue damaging agents. This stimulates the secretion of pro-inflammatory cytokines (such as IL-1β and TNF) that can reinforce and amplify a pro-inflammatory function/phenotype of islet resident macrophages and activate apoptotic pathways within β-cells (66). As aforementioned, stressed and/or apoptotic β-cells release pro-inflammatory signals, which are endocytosed by macrophages, thereby perpetuating the cycle of inflammation. Furthermore, insulin vesicles secreted by β-cells contain immunogenic peptides, which can also be taken up by resident M1-like macrophages for processing and presentation to autoreactive T cells. Aside from the uptake of secreted vesicles, intracellular cargo from apoptotic β-cells can be transferred to macrophages during phagocytosis (64). Additionally, under the pro-inflammatory conditions β-cells begin to express MHC-II, which enables them to present autoantigens (notably insulin neoantigens) to antigen presenting cells (40). Ultimately, the activities of β-cells and macrophages culminate in the activation and clonal expansion of autoreactive T cells, which drive the accelerated and irreversible loss of β-cell mass leading to T1D.

Similarly, under T2D conditions the crosstalk between macrophages and β-cells plays a major initiating role in establishing β-cell dysfunction, and a pro-inflammatory macrophage phenotype. In T2D, overnutrition and transient hyperglycemia induce β-cell hyperactivation and hyperplasia to satisfy the increased insulin demand (23). Aside from increased insulin secretory rates, β-cells undergo multiple functional changes induced by the nutrient rich environment and increased metabolic rates, including the production of pro-inflammatory mediators, such as NO and ROS (67). As islet macrophages constantly probe their microenvironment for signals, they sense these fluctuations in β-cell activity, via uptake of insulin-containing vesicles or through overactivation of their purinergic receptors by ATP. This can lead to desensitization and downregulation of homeostatic cues, as supported by reports of decreased purinergic receptor gene expression in T2D macrophages (68). Islet resident macrophages also contribute to islet vascular remodeling that supports compensatory hyperinsulinemia (69). While this may be advantageous in the early phases of compensatory prediabetes, this advantage is nullified by the chronic background of inflammation in which β-cell hyperactivation and dysfunction are amplified, ultimately driving β-cell exhaustion and loss.

Moreover, in T2D patients, β-cells secrete IAPP along with insulin (70). The former can aggregate to form plaques and fibrils, which skew islet macrophages to a pro-inflammatory phenotype and induce IL-1β secretion in circulating monocyte-derived macrophages to facilitate their recruitment into the islet (71). Additionally, this inflammatory dialogue is amplified by increased levels of FFAs (i.e. overnutrition) and pro-inflammatory cytokines (IL-1β, TNF, IL-6, and IL-8) (72, 73). Collectively, this environment induces β-cell dysfunction and eventual death (due to the actions of inflammatory mediators and metabolic exhaustion) (15). In addition, pro-inflammatory M1-like macrophages in T2D mice were found to secrete exosomes containing the microRNA, miR-212-5p, that can be taken up by β-cells, in turn inhibiting SIRT2-mediated Akt activation and subsequently impairment of glucose stimulated insulin secretion (74).

Importantly, islet macrophages do not exclusively display an M1-like phenotype, expressing both pro-inflammatory (CD68) and anti-inflammatory (CD163) markers (75). Furthermore, it has been observed that in animal models of T2D, islet macrophages undergo local expansion and specific transcriptional changes, with two distinct subsets identified: intra-islet (CD11c⁺) and peri-islet (CD11c^-) macrophages. The former was found to inhibit β-cell function putatively through increased uptake of β-cell secreted insulin vesicles in a cell-to-cell contact dependent manner. On the other hand, both macrophage populations promoted compensatory β-cell proliferation (76). It has also been reported that in response to increased β-cell death in induced murine models of diabetes (STZ alone or in combination with a high fat diet) and in a genetic mouse model of T2D, islet macrophages exhibited increased expression levels of insulin like growth factor 1 (IGF-1), concomitant with decreased expression of IL-6 and TNF, a profile that is associated with a reparative phenotype (77). This functional activity is supported by a multitude of studies demonstrating that anti-inflammatory M2-like macrophages are induced in various models of pancreatic injury and inflammation and operate to promote β-cell survival, proliferation, and maintenance of functional β-cell mass, through the release of protective factors, such as IGF-1, epidermal growth factor (EGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF), and Wnt3a (78).

Collectively, these observations demonstrate that macrophages exhibit distinct expression profiles and associated functional activities that are highly specialized in response to the islet microenvironment. As a result, the crosstalk between β-cells and macrophages plays a central role in both the maintenance of islet homeostasis and the initiation/perpetuation of inflammation. Accordingly, the macrophage / β-cell crosstalk can dictate autoimmunity and β-cell destruction, or conversely, immune tolerance and preservation of β-cell mass and function. Manipulating this metabolic conversation offers a unique and new strategy to directly affect β-cell survival and preservation of β-cell mass, and thus prevent the islet inflammatory events underpinning T1D and T2D.

The inverse correlation between the prevalence of infection with helminths and the incidence of immune-mediated metabolic disease has been explained by the ‘old friends hypothesis’. This proposes that the coexistence of helminths and their human hosts over millennia has enabled them to potently regulate the mammalian immune system and skew responses to be anti-inflammatory/tolerogenic/reparative (79–81). This phenomenon affords mutual benefit by promoting longevity and tissue integrity for helminth and host, respectively.

Consequently, the elimination of helminths from human populations, due to enhanced sanitation practices, has also removed their regulatory influence on host immune responses. The result of this is the aberrant activation of inflammatory pathways, thereby increasing the incidence of immune-mediated diseases, such as T1D and T2D. Given these observations, live helminth infection, or the administration of their ES products, are being actively investigated for therapeutic potential (82–84).

In recent years, it has become evident that infection with helminth parasites triggers a remodelling of the systemic metabolism of the host, which is demonstrated by altered production of pancreatic hormones, namely incretins and adipokines (128). Additionally, there is a shift in metabolic pathways in both infected tissue and in organs beyond the location of the parasite (17). The current theoretical framework suggests that this metabolic shift is required to direct the host immune status, and eventually impacts cells and organs that are not directly involved in the immune response (17, 129). This rewiring of the host’s metabolism commonly manifests as a significant increase in insulin sensitivity in non-diabetic helminth infected humans and mice (114, 117).

T1D and T2D are characterised by a progressive dysfunction and loss of the insulin-producing β-cells in the pancreatic islets leading to insulin deficiency. Despite this knowledge, none of the currently prescribed anti-diabetic agents effectively target the maintenance of functional β-cell mass. In T1D, the focus remains on blocking autoreactive immune cells and their mediators. However, diabetes reversal is not achieved, protection of residual β-cell mass is short-term, and global immune suppression is induced (146–148). Due to the scarcity of organ donors, significant β-cell loss during islet preparation, and allogenic and recurrent autoimmune reactions, which mediate β-cell death post-transplant, islet transplantation is not a realistic cure for T1D. In T2D, therapeutic options, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, incretin-based drugs, and GLP-1 analogues, target β-cell function, but not all patients are responsive and approximately 50% ultimately require daily insulin injections due to β-cell exhaustion and death (149). Clearly, alternate, more effective strategies, are urgently required. By regulating the activities of islet macrophages and β-cells (and other endocrine cells), helminth parasites shape their crosstalk ( Figure 4 ). This offers a unique opportunity to exploit helminths’ mechanisms for survival in their mammalian hosts to establish an environment that preserves β-cell mass and function and thus offers the potential as a cure for both T1D and T2D.

IC, BO’B and SD conceived and planned the review. IC conducted the literature search, designed and wrote the first draft of the manuscript. BO’B and SD contributed to the writing and editing of the final manuscript. All authors contributed to the article and approved the submitted version.