Diabetes, Protein Misfolding, and Heat Stress: Molecular Insights and Translational Perspectives

Abstract

Diabetes mellitus (DM), particularly type 1 (T1D) and type 2 (T2D), is a growing global health burden with complex pathophysiology extending beyond glucose dysregulation. Both forms of diabetes involve cellular stress, chronic inflammation, and β-cell dysfunction. Heat shock proteins (HSPs), key mediators of protein homeostasis and immune modulation, are emerging as critical players in the progression and complications of diabetes. In T1D, HSPs act at the crossroads of β-cell stress and autoimmunity, while in T2D, their dysregulation contributes to insulin resistance and mitochondrial dysfunction. Misfolded proteins, particularly amylin aggregates, further drive β-cell apoptosis in T2D and may influence immune activation in T1D. Hyperthermia (HT) and passive heat therapy (hT) activate protective stress responses through HSP induction, mimicking some benefits of exercise and improving glycemic control, insulin sensitivity, and vascular health. Preclinical and early clinical studies suggest that thermal interventions could complement standard care, especially in patients unable to engage in regular physical activity. This review consolidates current evidence on the roles of HSPs, amylin misfolding, and hT in the pathogenesis of diabetes, with a particular emphasis on vascular and thrombotic complications and their therapeutic implications. Targeting these converging molecular pathways may offer new avenues for preserving β-cell function, mitigating metabolic complications, and enhancing diabetes management.

Keywords

cardiovascular disease - heat shock proteins - heat therapy - hyperthermia - mitochondrial dysfunction - diabetes mellitus - endothelial progenitor cells - thrombosis - amylin

Introduction

Diabetes mellitus (DM) remains one of the most significant cardiovascular diseases and chronic metabolic disorders worldwide, with escalating prevalence due to global lifestyle shifts. Diabetes[1] [2] represents a harmful systemic environment that disrupts the processes of revascularization and tissue repair following ischemia[3] [4] but is also a significant risk factor in the progression of aortic valve stenosis and calcification.[5] Metabolic disorders and chronic hyperglycemia impair endothelial cells and increase the accumulation of advanced glycation end products (AGEs), which accelerate calcification.[5] [6] [7] [8] Since diabetic patients experience strong vascular disorders and faster disease progression and poorer outcomes after valve replacement, understanding diabetes and vascular or valvular disease interplay may lead to targeted therapeutic strategies.[5] Among its most common types, type 1 diabetes (T1D) is primarily characterized by autoimmune destruction of pancreatic β-cells, resulting in absolute insulin deficiency, whereas type 2 diabetes (T2D) involves insulin resistance and relative insulin deficiency. Beyond these canonical definitions, emerging research highlights complex molecular and cellular mechanisms that underlie disease onset and progression in both T1D and T2D.[9] [10]

Recent findings suggest that heat shock proteins (HSPs) play a pivotal role in the development of β-cell impairment, insulin resistance, and a range of diabetes-related complications, including both microvascular and macrovascular dysfunctions.[11] [12] In particular, HSP70 exerts protective effects on cells by mitigating oxidative stress, dampening inflammatory responses, preventing programmed cell death, and facilitating the repair and proper folding of damaged proteins.[13] In recent years, a compelling body of evidence has focused on the role of misfolded proteins, specifically islet amyloid polypeptide (IAPP, also known as amylin),[14] [15] and the protective function of HSPs as crucial modulators in diabetes.[16] [17] Additionally, novel interventions such as hyperthermia (HT) and heat therapy (hT) have been explored as potential therapeutic strategies.[18] [19] In particular, passive hT, such as sauna bathing and hot water immersion, has been traditionally used in various cultures and is known to improve cardiovascular health and glucose metabolism in non-diabetic individuals.[20] [21] Emerging evidence suggests that hT might activate similar metabolic and anti-inflammatory pathways as exercise, potentially enhancing insulin sensitivity and supporting glycemic control in patients with T2D.[22] The convergence of these pathways offers a complex and nuanced perspective on diabetes that goes beyond the traditional focus on glucose metabolism, incorporating immunological aspects, protein homeostasis mechanisms, and cellular stress responses.

This article aims to synthesize and critically examine the roles of misfolded proteins and HSPs in both T1D and T2D, with a particular focus on their contribution to vascular and thrombotic complications. Furthermore, it evaluates the potential of HT and hT as emerging interventions, drawing on recent findings from both preclinical and clinical studies.

Methods

This narrative review was developed through a structured literature search of peer-reviewed studies published between January 2000 and June 2025. We searched PubMed, Web of Science, and Scopus using combinations of keywords including “heat shock proteins,” “HSP,” “hyperthermia,” “heat therapy,” “diabetes,” “insulin resistance,” “vascular complications,” and “amylin.” Only articles in English and involving either human or animal models were included. Clinical trials, mechanistic studies, systematic reviews, and meta-analyses were prioritized. The reference list was managed using EndNote to ensure consistency and eliminate duplication.

Heat Shock Proteins and Type 1 Diabetes

HSPs, highly conserved molecular chaperones, play a fundamental role in maintaining cellular homeostasis, particularly under stress conditions. In the context of T1D, HSPs are increasingly recognized as major pathophysiology factors, pivotal immunological modulators acting at the interface of β-cell stress, autoimmunity, and inflammation[17] ([Table 1]). The central role of HSPs in both cellular protection and immune recognition makes them key contributors to the pathogenesis and progression of T1D.

Table 1 Differential roles of heat shock proteins in type 1 and type 2 diabetes pathogenesis

HSPs involvement in T1D		References
HSP27	In individuals recently diagnosed with fulminant or acute-onset T1D, presence of autoantibodies targeting HSP10 has been observed.	[52] [134] [162]
DNAJ family/HSP40	Patients exhibited increased urinary levels of HSP40 when normalized to creatinine concentration.	[163]
HSP60	In NOD mice, HSP60 was detected on the surface of pancreatic β-cells prior to the onset of islet inflammation. This endogenous protein may serve as an autoantigen recognized by β-cells in the early stages of immune activation.	[24] [164] [165]
HSP70	Impaired ability to upregulate HSP70 under stress conditions contributed to increase inflammatory environment targeting pancreatic β-cells. Moreover, elevated levels of IgA antibodies directed against HSP70 indicated a specific humoral autoimmune response. Finally, HSP70 was found to associate with a key antigenic region of proinsulin, enhancing its uptake and presentation by antigen-presenting cells. Under inflammatory stress, GRP78 translocates to the surface of human β-cells via the secretory pathway—mediated by DNAJC3—where it acts as a signaling receptor that triggers proapoptotic pathways, forming a self-destructive loop distinct from its antiapoptotic role in cancer, and highlighting its potential as a therapeutic target in type 1 diabetes.	[40] [45] [166] [167] [168]
HSP90	Increased IgG1 and IgG3 autoantibodies targeting HSP90. Increased HSP90 concentrations are observed in young individuals exhibiting β-cell autoimmunity; however, these levels do not reliably differentiate between those who will or will not develop type 1 diabetes—whether in youth or adults.	[47] [169]
HSPs involvement in T2D		References
HSP27	Suppressing the phosphorylation of IKK-β inducing insulin signaling, while also protecting β-cells from apoptosis by attenuating NF-κB activation and reducing caspase-3 enzymatic activity.	[170] [171]
DNAJ family/HSP40	β-cell integrity is maintained in part by limiting eIF2α phosphorylation, which reduces endoplasmic reticulum (ER) stress and prevents translational overload. Loss of DNAJB3 function has been linked to heightened β-cell vulnerability due to the mitochondrial activation of proapoptotic Bcl-2 family members. Within the ER, DNAJB9 (also known as Erdj4) supports insulin responsiveness by restraining IRE1 signaling and lowering SREBP1c expression. In the mitochondrial context, DNAJC15 contributes to insulin resistance by suppressing complex I activity in the electron transport chain and impeding supercomplex assembly. Meanwhile, in the nuclear compartment, DNAJC27 influences metabolic regulation by promoting inflammatory signaling cascades, thereby disrupting insulin signaling dynamics.	[172]
HSP60	HSP60 contributes to β-cell preservation by counteracting hypertrophic effects induced by advanced glycation end products (AGEs) and also prevents insulin resistance and β-cell dysfunction by reducing oxidative stress. HSP60 also decreases proinflammatory cytokine production allowing modulation of mitochondrial double-stranded RNA release. Under normoglycemic conditions, cellular survival is maintained through direct interaction of specific proteins with Bax, preventing its mitochondrial translocation and the initiation of apoptosis. However, during hyperglycemia, excessive O-GlcNAcylation of HSP60 disrupts this interaction, facilitating Bax-mediated apoptosis in β-cells. Extracellular HSP60 contributes to the development of insulin resistance by engaging TLR4 within adipose and skeletal muscle tissues.	[26] [173] [174]
HSP70	The HSP70 family plays diverse roles in metabolic regulation and cell survival. iHSP72, located in the cytosol and nucleus, reduces inflammation and insulin resistance by blocking JNK/IKK signaling and protects β-cells from apoptosis by interfering with apoptotic proteins and ER stress pathways. Its extracellular form, eHSP72, promotes inflammation and β-cell dysfunction through TLR1/2 activation. GRP75 (mitochondrial) influences insulin sensitivity by altering mitochondrial complexes but can trigger β-cell death when overexpressed. GRP78, in the ER, impairs insulin signaling via SKIP interaction yet supports β-cell survival by managing amyloid stress. GRP170 enhances insulin signaling in liver and muscle cells.	[57]
HSP90	HSP90α may enhance insulin signaling by modulating nitric oxide levels, while HSP90β reduces glucose utilization by stabilizing PDK4 expression. Moreover, Hsp90α as a glucose-regulated surface protein that, through interaction with annexin II, may contribute to diabetes-related vascular complications by promoting plasmin activity and potential clotting abnormalities.	[73] [74] [75]

Abbreviations: HSP, heat shock protein; iHSP, intracellular heat shock protein; NOD, non-obese diabetic; TLR, Toll-like receptor; T1D, type 1 diabetes; T2D, type 2 diabetes.

This table summarizes key findings on the involvement of various HSP families in the pathophysiology of T1D and T2D. It highlights their roles in autoimmunity, insulin signaling, β-cell survival, and stress response mechanisms.

HSP60, one of the most studied chaperones, has been linked to the initiation and propagation of islet autoimmunity. HSP60 has been identified as a β-cell autoantigen in non-obese diabetic (NOD) mice and in humans with T1D.[23] [24] It localizes predominantly in the mitochondria but also translocates to other cellular compartments during stress, which may render it immunogenic.[25] [26] Furthermore, altered expression or posttranslational modifications of HSP60 can lead to the presentation of novel epitopes, triggering autoreactive T-cell responses.[27] [28] Studies have demonstrated that in individuals with T1D, there is an increased presence of autoantibodies and autoreactive T cells specific for HSP60 and its derived peptides.[29] [30] Notably, the peptide p277 from HSP60 has been shown to shift immune responses from a Th1 to a Th2 phenotype, thereby modulating autoimmune responses in NOD mice and human clinical trials.[31] [32] This immune deviation is consistent with observations that T1D patients exhibit altered cytokine responses to HSP60.[29] [33] Recent meta-analyses have indicated that despite initial promise, certain clinical trials were withdrawn, and antigen-specific immunotherapies have failed to demonstrate efficacy in halting the advancement of autoimmune diabetes in individuals with a new diagnosis.[34]

The major histocompatibility complex (MHC) region encodes several HSPs, which are co-located with classical immune genes.[35] Polymorphisms in MHC-linked HSP genes have been associated with susceptibility to T1D.[36] These proteins, when aberrantly expressed or secreted during β-cell stress, may serve as danger-associated molecular patterns (DAMPs), further stimulating the innate immune system.[37]

HSP70, another critical player, is upregulated in pancreatic islets in response to cytokines and oxidative stress.[38] Its intracellular role involves protecting β-cells from nitric oxide and free radical-mediated damage.[39] Paradoxically, extracellular HSP70 can be immunostimulatory, activating dendritic cells and inducing proinflammatory cytokine release.[40] Elevated HSP70 levels have been documented in the serum and urine of T1D patients, and these increases correlate with disease activity and complications.[41] Exosomal pathways serve as conduits for HSP secretion. Studies indicate that β-cells under inflammatory stress release exosomes containing HSPs along with autoantigens such as glutamic acid decarboxylase 65-kDa isoform (GAD65) and proinsulin, potentially priming autoreactive lymphocytes.[42] This process may facilitate antigen cross-presentation and perpetuate autoimmunity. Additionally, HSP90, often secreted under similar conditions, has emerged as a marker of β-cell stress and may enhance antigen presentation by stabilizing peptide–MHC complexes.[43] Endoplasmic reticulum (ER) stress is a critical component of β-cell dysfunction in T1D, and HSPs are integral to managing this stress. Glucose-regulated protein 78/binding immunoglobulin protein (GRP78 (BiP)), a key ER chaperone, is translocated to the plasma membrane under cytokine stress, triggering apoptotic signaling in β-cells.[44] From a systems perspective, T1D may reflect a failure of immunological tolerance due to chronic inflammation and insufficient stress adaptation. HSPs act not only as molecular buffers but also as signaling molecules in immune networks. Their extracellular release—whether passive via necrosis or active via vesicle export—functions as an alarm system to alert immune cells to danger.[37] This dual role—protective within the cell and immunogenic outside—places HSPs at a unique crossroads of self-recognition and immune activation. Antibodies to HSPs, particularly HSP60 and HSP70, have been detected in various autoimmune and metabolic contexts. Elevated IgA responses to HSP70 correlate with vascular complications in diabetes, while anti-HSP60 titers are predictive of atherosclerotic risk.[45] [46] In T1D, these antibodies may represent not only diagnostic biomarkers but also reflect ongoing tissue injury and stress.[47] Moreover, the broader stress response system, including HSPs, interfaces with metabolic regulators and redox signaling. HSPs modulate antioxidant responses, and their upregulation is protective in models of oxidative β-cell injury.[39] Their dysfunction may thus compromise β-cell survival under immune assault. Emerging research supports the concept that enhancing HSP expression or function may bolster cellular resistance and immune tolerance, offering novel avenues for preserving β-cell mass in at-risk individuals.

Finally, T1D continues to rise globally and remains a serious condition despite advances in treatment.[1] [48] HSPs are implicated in disease onset, acting both as immune triggers and modulators. They can provoke autoimmune T-cell responses but also promote regulatory mechanisms that suppress inflammation. This duality makes HSPs promising candidates for combination therapies aimed at preserving β-cell function. Additionally, their early expression patterns suggest they may serve as useful biomarkers for disease prediction and prevention.

Heat Shock Proteins and Type 2 Diabetes

T2D is a complex metabolic disorder defined by insulin resistance, impaired insulin signaling, chronic inflammation, and β-cell dysfunction.[49] Central to the progression of this disease is the imbalance between cellular stress and the body's protective mechanisms ([Table 1]). Among these protective responses, HSPs serve as molecular chaperones that ensure protein stability and folding, and are crucial for maintaining cellular homeostasis under stress conditions.[16] In the context of T2D, their role is increasingly recognized as pivotal, not only in protein maintenance but also in modulating inflammatory pathways that influence insulin sensitivity. HSPs, particularly HSP60, HSP70, HSP72, and HSP90, are produced in response to various stressors, including hyperglycemia, oxidative stress, and inflammation, and participate in the pathophysiology of T2D and also its vascular complications.[50] [51] [52] [53] They are involved in critical processes, such as refolding misfolded proteins, preventing protein aggregation, and guiding proteins toward degradation pathways when irreparable damage occurs. Under normal circumstances, these functions maintain cellular integrity and protect against apoptosis. However, in the chronically inflamed and metabolically overloaded environment characteristic of T2D, the function of HSPs becomes altered, contributing to disease progression.[16] [54] One of the central stress responses activated during metabolic overload is the unfolded protein response, triggered by the accumulation of misfolded proteins in the ER. HSPs are key mediators of the unfolded protein response and help restore ER function. Yet, persistent ER stress can overwhelm this adaptive mechanism, resulting in the activation of inflammatory signaling cascades, such as the NF-κB pathway, which elevates levels of proinflammatory cytokines like IL-1β, TNF-α, and IL-6.[55] [56] [57] These cytokines further exacerbate insulin resistance by interfering with insulin receptor signaling. Extracellular HSPs also act as immune modulators. When secreted or released from damaged cells, HSPs such as HSP60 and HSP70 can function as DAMPs, activating pattern recognition receptors, such as Toll-like receptors (TLRs). For instance, HSP60 has been shown to engage TLR2 and TLR4, stimulating immune cells to release inflammatory cytokines, thereby contributing to the systemic inflammation observed in T2D patients.[58] [59] Similarly, extracellular HSP70 can activate antigen-presenting cells, enhancing the inflammatory response, despite having cytoprotective functions when retained intracellularly.[60] [61] In adipose tissue, a central organ in metabolic regulation, HSPs appear to mediate the inflammatory state associated with obesity-induced insulin resistance. Studies have revealed that intracellular levels of HSP70 are reduced in adipose tissue of obese and diabetic individuals, coinciding with elevated cytokine expression and macrophage infiltration.[62] [63] Moreover, Chung et al demonstrated that individuals with obesity and insulin resistance exhibit reduced levels of HSP72 in skeletal muscle.[64] This decrease in HSP70 is significant because the inducible form, HSP72, has been shown to inhibit stress kinases like JNK, which are known to impair insulin signaling through the serine phosphorylation of insulin receptor substrate-1 (IRS-1).[64] Conversely, overexpression of HSP72 in skeletal muscle improves insulin sensitivity and glucose uptake, highlighting its potential as a protective factor in metabolic tissues.[65] The use of pharmacological inducers of HSP expression further underscores their importance in T2D pathogenesis and therapy. BGP-15, a hydroxylamine derivative, has demonstrated the capacity to elevate HSP70 levels in various tissues.[66] [67] [68] Indeed, BGP-15 enhances insulin sensitivity in various insulin-resistant animal models and in human clinical trials. Its effect is comparable to rosiglitazone, highlighting its therapeutic potential for T2D.[69] [70] [71] Finally, HSP90α may enhance insulin signaling by modulating nitric oxide levels, while HSP90β reduces glucose utilization by stabilizing pyruvate dehydrogenase kinase 4 (PDK4) expression.[72] Hsp90α, as a glucose-regulated surface protein, through interaction with annexin II, may contribute to diabetes-related vascular complications by promoting plasmin activity and potential clotting abnormalities.[73] [74]

Mitochondrial function is another key area where HSPs exert influence. HSP60 and HSP10 are mitochondrial chaperonins that protect against oxidative stress and help maintain mitochondrial integrity. Their reduced expression in insulin-resistant states correlates with decreased oxidative phosphorylation capacity, especially in skeletal muscle and liver tissues, which are central to systemic glucose homeostasis.[75] HSPs are also implicated in immune system interactions beyond their role in innate signaling. Chronic inflammation, a hallmark of T2D, is perpetuated by the recruitment and activation of immune cells in metabolic tissues. HSPs contribute to the polarization and activation of these immune cells, directly influencing cytokine production. For example, HSP70 can act on monocytes and dendritic cells to promote a proinflammatory phenotype, reinforcing the vicious cycle between metabolic dysfunction and immune activation.[61] Importantly, lifestyle interventions such as physical exercise are potent inducers of HSP expression. Endurance and resistance training have both been shown to increase HSP72 levels in skeletal muscle, correlating with reductions in inflammatory markers and improvements in insulin sensitivity.[53] [62] [76] In individuals with T2D, the heat shock response is often blunted, and restoring this through regular exercise yields metabolic improvements. Similarly, dietary antioxidants like curcumin, resveratrol, and α-lipoic acid have been shown to induce HSPs and possess anti-inflammatory effects, offering another avenue for non-pharmacological intervention.[77] [78] Given their multifaceted roles in metabolic regulation, inflammation, and immune signaling, HSPs are being explored as both biomarkers and therapeutic targets in T2D. Circulating levels of HSP60 and HSP70 have been proposed as indicators of disease activity, although interpretation remains complex due to the dual nature of HSPs depending on their intracellular versus extracellular localization.[59] [75] [77] [79] [80] Other HSPs have also been shown to be regulated in diabetes, such as HSP47.[81] HSP47 has been previously identified as a stress-inducible collagen-binding chaperone,[12] and recent evidence suggests it plays a critical role in the retinal complications of diabetes.[81] In retinal Müller cells, high glucose induces HSP47 expression, which enhances its interaction with inositol-requiring enzyme 1 alpha (IRE1α), activating the IRE1α/spliced X-box binding protein 1 (XBP1-s)/hypoxia-inducible factor 1 alpha (HIF-1α) signaling pathway. Silencing HSP47 disrupts this pathway, reducing cytokine expression, suggesting a key role for HSP47 in diabetic retinal inflammation.[81] Moreover, in diabetic nephropathy (DN), HSP47 has emerged as a key player due to its role in promoting collagen synthesis, a major contributor to renal fibrosis and loss of function. HSP47 is overexpressed in human and experimental DN, particularly in mesangial cells, podocytes, and tubular epithelial cells, and co-localizes with increased type III and IV collagen.[52] [82] Its induction is linked to TGF-β1 signaling and AGE accumulation.[52] While inhibition of HSP47 has shown promise in reducing fibrosis in experimental kidney disease models,[83] [84] concerns remain due to impaired autophagy in DN, where HSP47 deletion may lead to procollagen accumulation and cell death.[85] Additionally, reduced HSP47 expression has been observed in diabetic wounds, suggesting that therapies targeting HSP47 could impair wound healing.[86] [87]

Finally, HSPs are deeply embedded in the molecular landscape of T2D ([Fig. 1]). Their ability to modulate protein homeostasis, cellular stress responses, and immune activation places them at the intersection of inflammation and insulin resistance. Modifying the heat shock response through pharmacological agents, exercise, or dietary compounds presents a viable approach to improving metabolic health. Further research into tissue-specific HSPs regulation and delivery methods may unlock new pathways for managing and potentially preventing T2D.

Fig. 1 Conceptual model illustrating the pathological cascade linking type 2 diabetes and progressive organ damage. In type 2 diabetes, chronic metabolic stress triggers mitochondrial impairment, which leads to increased reactive oxygen species (ROS) production and cellular damage. This contributes to β-cell dysfunction and/or systemic inflammation create a self-reinforcing cycle of dysfunction that accelerates complications such as nephropathy. Heat therapy or hyperthermia may interrupt this pathological sequence by upregulating heat shock proteins (HSPs). Created with BioRender.com and licensed for journal publication. Created in BioRender. Smadja, D. (2025) https://BioRender.com/39b4n3w.

Amylin and Type 1 and Type 2 Diabetes

A 37-residue peptide known as IAPP, also referred to as amylin, is released alongside insulin from the β-cells of the pancreas.[14] Under physiological conditions, amylin plays a crucial role in glycemic control by slowing gastric emptying, suppressing glucagon secretion, and promoting satiety.[14] Amylin is not a chaperone however, in pathological conditions (such as T2D), amylin forms toxic amyloid aggregates that are involved in the degeneration of pancreatic β-cells and mitochondrial dysfunction ([Fig. 2]). In humans, amylin interacts with at least three distinct receptor complexes—AMY1, AMY2, and AMY3—each formed by the association of the calcitonin receptor with a specific receptor activity-modifying protein (RAMP). Under physiological conditions, amylin exists in a soluble, monomeric state. However, under certain conditions, individual amylin molecules may misfold, adopting conformations rich in β-sheet structures. These misfolded monomers tend to cluster, forming small oligomeric assemblies. As aggregation progresses, these oligomers can develop into protofibrillar intermediates—elongated and structurally unstable forms—that ultimately mature into stable amyloid fibrils.

Fig. 2 Toxic amylin oligomer accumulation drives pancreatic β-cell and mitochondrial dysfunction. Elevated levels of oligomeric human islet amyloid polypeptide (IAPP) contribute to pancreatic β-cell stress by disrupting mitochondrial function, impairing membrane integrity, promoting oxidative stress, and ultimately leading to β-cell dysfunction and apoptosis. This mechanism is a key contributor to β-cell failure in type 2 diabetes. Created with BioRender.com and licensed for journal publication. Created in BioRender. Smadja, D. (2025) https://BioRender.com/jz3cfy7. ROS, reactive oxygen species.

In T2D, one of the hallmark pathological features is the misfolding and aggregation of amylin into amyloid fibrils, leading to plaque formation within the islets. These amyloid deposits disrupt islet structure, interfere with intercellular signaling, and cause direct cytotoxic effects on pancreatic β-cells. When pancreatic β-cells overproduce amylin, the accumulation can result in β-cell toxicity and destruction.[88] Insulin resistance, a hallmark of T2D, leads to chronic hyperglycemia and hyperinsulinemia.[89] This condition negatively impacts amyloid processing in the brain and in the pancreas while also stimulating mitochondrial oxidative stress. Though co-released with insulin, circulating amylin levels represent just 1% to 2% of insulin concentrations and increase in response to elevated glucose.[90] [91] Amylin is primarily degraded by insulin-degrading enzyme and neprilysin, both zinc-dependent proteases that also play a role in amyloid-β clearance, helping mitigate potential cytotoxic effects.[92] [93] [94] Aggregation of amylin in pancreatic islets is strongly associated with β-cell apoptosis and disease progression in T2D.[95] Paradoxically, in models of chemically induced diabetes, amylin administration improved β-cell viability by enhancing microvascular flow and modulating membrane polarization.[96]

Beyond their direct cytotoxic effects on pancreatic β-cells, mounting evidence indicates that mitochondria are a principal target of amylin oligomers.[97] [98] [99] The functional integrity of these organelles is crucial for maintaining cellular energy homeostasis, redox balance, and survival. Indeed, amylin oligomers localize to mitochondria and induce membrane permeabilization, triggering the activation of apoptotic pathways.[100] Subsequent studies have confirmed that exposure to oligomeric amylin leads to the collapse of mitochondrial membrane potential and a marked increase in reactive oxygen species, indicative of oxidative stress.[100] [101] These mechanisms collectively contribute to β-cell apoptosis and insulin deficiency. Importantly, the consequences of mitochondrial dysfunction extend beyond pancreatic islets. In the diabetic kidney, sustained mitochondrial impairment exacerbates tissue hypoxia, thereby amplifying oxidative damage and accelerating the progression of DN.[101] Thus, mitochondrial health represents a central axis linking β-cell failure, systemic metabolic stress, and end-organ complications in type 2 diabetes mellitus (T2DM).

Interestingly, while amyloid deposits are rare in T1D, there is evidence suggesting that misfolded amylin may contribute to β-cell stress and potentially to neoantigen formation.[102] [103] Inflammatory environments prevalent in T1D can exacerbate amylin misfolding, potentially accelerating β-cell dysfunction. Additionally, the functional role of amylin deficiency in T1D remains an area of active research. Loss of amylin due to β-cell destruction can exacerbate glycemic variability and postprandial hyperglycemia. The introduction of pramlintide, a synthetic amylin analog, has demonstrated clinical benefits in improving postprandial glucose control and reducing insulin requirements, suggesting a potential therapeutic avenue.[14] The dual nature of amylin—as both a regulator of glucose metabolism and a source of toxic aggregates—reflects the fine balance required in its expression and processing. Future therapies may focus on modulating amylin levels to preserve its physiological functions while preventing pathological aggregation.

A case–control study examining plasma amylin levels found that concentrations were lower than insulin in healthy individuals, increased with obesity, were nearly absent from T1D, and showed variable trends in T2D—suggesting that amylin may participate in glucose homeostasis alongside insulin.[104]

Heat, Hyperthermia, and Diabetes Treatment

Initial clinical trials in T2D suggest that hT may offer metabolic benefits, particularly in improving glycemic control. In T2D, hT interventions have consistently shown improvements in insulin sensitivity and glucose tolerance. Sebők et al conducted a systematic review and meta-analysis that consolidated evidence from human and animal studies, highlighting slight yet consistent improvements in glycemic control with hT.[22] The analysis included five studies comprising diverse thermal interventions, such as hot water immersion and sauna therapy. Overall, passive heating was associated with modest improvements in fasting plasma glucose and glycated hemoglobin (HbA1c) levels, though the changes did not always reach statistical significance. The weighted mean difference for HbA1c was −0.55%, suggesting a clinically meaningful, albeit small, benefit. While the effect size is limited, it parallels benefits seen with some lifestyle interventions and warrants further exploration. The benefits are thought to arise from improved endothelial function, enhanced insulin receptor signaling, and reductions in chronic low-grade inflammation. Notably, the systemic nature of hT allows for concurrent targeting of multiple tissues, including skeletal muscle, adipose tissue, and the liver, which are central to glucose homeostasis. While these findings are promising, translation to clinical practice requires careful consideration of safety, optimal thermal dosing, and individual patient characteristics. Future studies should aim to define standardized protocols and evaluate long-term outcomes in diverse diabetic populations. Future randomized controlled trials with standardized protocols, larger cohorts, and extended follow-up are essential to confirm these preliminary findings. Nevertheless, hT represents a novel, non-pharmacological intervention with the potential to complement existing lifestyle and pharmacologic treatments for T2D.

To better understand these clinical observations and guide future therapeutic applications, it is essential to explore the underlying mechanisms through which hT exerts its metabolic benefits—particularly those related to the heat shock response and HSP-mediated cellular adaptations demonstrated in both preclinical and emerging human studies. Recent scientific advances increasingly highlight hT as a promising alternative or complementary strategy to traditional physical exercise for improving metabolic health, particularly in individuals with T2D. Indeed, thermal exposure—such as through sauna use or immersion in hot water—represents a classic method for triggering the heat shock response (HSR) and stimulating the expression of HSPs.[105] This novel approach is especially relevant given the growing prevalence of sedentary lifestyles and the rising incidence of obesity and T2DM worldwide. While regular exercise remains a cornerstone intervention for improving insulin sensitivity and enhancing mitochondrial function, many patients encounter barriers to physical activity due to aging, chronic pain, musculoskeletal limitations, neurological impairments, or cognitive decline.[106] In this context, hT—including modalities such as sauna bathing, hot water immersion (e.g., hot tubs), and heated wraps—emerges as a feasible and practical option to stimulate similar physiological benefits.

There are several preclinical proofs of the beneficial effects of HT or hT on diabetes. In aged rodent models, applying HT twice weekly for 30 minutes over an 8-week period led to a marked upregulation of HSP70 expression in muscle tissue—doubling within 24 hours after a single session and tripling by the study's conclusion. The intervention also yielded metabolic benefits, including reduced HbA1c, enhanced insulin receptor signaling, and lower fasting insulin levels.[107] Similar outcomes were reported in low-density lipoprotein (LDL) receptor-deficient mice on a high-fat diet, where 8 weeks of weekly heat exposure elevated HSP72, HSP73, and HSP27 in endothelial cells of the aorta. This molecular response was accompanied by reductions in total cholesterol, triglycerides, LDL cholesterol (LDL-C), fasting glucose, insulin resistance, and oxidative stress, along with increased high-density lipoprotein (HDL) cholesterol.[108] In another rodent study, diabetic rats induced via streptozotocin and subjected to hot water immersion (42°C, 30 minutes, five times a week for 3 weeks) showed higher circulating HSP60 levels.[109]

Despite these promising findings in animal models, human research on HT's capacity to modulate both intracellular and extracellular HSPs expression remains limited. One study involving 14 lean and overweight individuals undergoing 60 minutes of passive heat exposure at 40°C reported elevated serum levels of HSP70 and IL-6 immediately following intervention. These increases coincided with higher energy expenditure and reduced postprandial glucose peaks.[110] However, the effects of HT on intracellular HSP (iHSP) expression in humans are less consistent. Some research has demonstrated iHSP72 upregulation in peripheral blood mononuclear cells (PBMCs) after 8 weeks of 60-minute hot water immersion at 40.5°C,[111] [112] and increased iHSP72 in skeletal muscle following 6 days of 2-hour localized heating via pulsed wave diathermy.[113] Conversely, another study with overweight male participants found that while 2 weeks of brief hot water immersion (39°C for 10 minutes) reduced fasting glucose, it did not significantly alter iHSP levels in monocytes.[114]

Heat exposure has been shown to activate molecular pathways that promote metabolic health, particularly through the induction of HSPs. The historical foundation for using heat as a therapeutic intervention in diabetes can be traced back to the work of Hooper, published in the New England Journal of Medicine,[115] who first reported that hot-tub therapy could lower HbA1c levels and improve overall glycemic control in patients with T2DM.[115] Building on this pioneering observation, Chung et al demonstrated that individuals with obesity and insulin resistance exhibit reduced levels of HSP72 in skeletal muscle.[64] Their study revealed that hT increases HSP72 expression, and when overexpressed in animal models, it protects against insulin resistance induced by high-fat diets.[64] Further supporting these findings, Gupte and colleagues conducted studies in rodents fed a high-fat diet and found that hT significantly improved glucose tolerance, enhanced skeletal muscle insulin sensitivity, and robustly induced the heat shock response.[116] Pallubinsky et al extended this evidence to humans by demonstrating that 10 days of passive heat exposure in overweight individuals led to improvements in glucose metabolism and increased fat oxidation, even in the absence of measurable changes in iHSP72 levels.[117] Such improvements may be partially mediated by the ability of hT to modulate insulin action through HSP regulation, suppress chronic low-grade inflammation, and enhance mitochondrial bioenergetics.[57] Interestingly, the effects of heat exposure differ depending on the duration and frequency of application. Acute heat exposure may transiently impair mitochondrial function due to increased mitochondrial fission; however, repeated treatments—applied daily or several times per week—promote mitochondrial remodeling, increase phosphorylation efficiency, and enhance overall respiratory capacity.[118] These adaptations are crucial because mitochondrial dysfunction is a key feature of metabolic diseases and contributes to insulin resistance and impaired glucose utilization. Furthermore, Laukkanen and Kunutsor provided a detailed analysis of heat therapy protocols, particularly focusing on Finnish sauna bathing and hot water immersion.[20] Their comprehensive review emphasized the broad spectrum of health benefits associated with regular passive hT, including improvements in cardiovascular health, enhanced endothelial function, and reduced systemic inflammation.[20] This evidence suggests that incorporating hT into lifestyle interventions may offer a viable and effective strategy for extending health span and managing chronic metabolic diseases.

Given that a substantial proportion of individuals with T2D or obesity are unable to perform regular physical activity due to physical limitations, acute injuries, or severe fatigue, hT stands out as an accessible and low-risk intervention. It offers a unique combination of metabolic, cardiovascular, and potentially cognitive benefits without the musculoskeletal strain or safety risks sometimes associated with exercise interventions.[106] As the global burden of metabolic diseases continues to grow, integrating heat-based modalities into clinical practice may provide an essential adjunct to traditional therapeutic strategies, ultimately improving patient outcomes and quality of life.

HT, or therapeutic heating, has emerged as an innovative strategy for modulating metabolic and inflammatory pathways involved in diabetes pathophysiology.[57] It has garnered special attention for individuals with T2DM who often face limitations to regular exercise due to obesity, musculoskeletal disorders, frailty, or other comorbidities.[20] Preclinical studies have provided strong support for the metabolic advantages of HT. For example, Kokura et al investigated the effects of whole-body hyperthermia (WBH) in obese diabetic mice and demonstrated significant reductions in fasting blood glucose levels after repeated sessions.[119] Additionally, WBH-treated mice showed improved insulin sensitivity, as indicated by enhanced glucose and insulin tolerance test results.[119] At the molecular level, skeletal muscle from these mice exhibited increased expression of glucose transporter type 4 (GLUT4), reflecting enhanced glucose uptake capacity in peripheral tissues.[119] Moreover, HT has been suggested to mimic several physiological effects typically induced by exercise, such as increased peripheral blood (PB) flow, enhanced mitochondrial efficiency, and upregulation of glucose transport mechanisms.[117] Exercise is widely known to improve insulin sensitivity through mechanisms independent of weight loss, and HT might provide a comparable metabolic stimulus, making it an attractive alternative or adjunct for patients unable to engage in sufficient physical activity.[106] Beyond metabolic regulation, HT has shown potent anti-inflammatory and antioxidative effects in preclinical models of diabetes. Chronic low-grade inflammation and elevated oxidative stress are major contributors to insulin resistance, endothelial dysfunction, and the progression of diabetic complications, including nephropathy and retinopathy.[120] Notably, WBH has been shown to reduce systemic inflammatory markers and oxidative damage, while also decreasing urinary albumin excretion in diabetic mice, indicating potential renoprotective effects.[119] [121] Furthermore, HT may positively influence lipid metabolism, modulate adipokine profiles, and increase energy expenditure, all of which can support long-term metabolic health.[21] Repeated heat exposure is also thought to promote mitochondrial remodeling and improve mitochondrial respiratory efficiency, crucial adaptations for maintaining cellular energy balance and metabolic flexibility.[118] Overall, these findings suggest that HT could serve as a valuable adjunctive therapy for diabetes management by leveraging endogenous protective mechanisms to improve glucose control, reduce inflammation, and potentially slow the progression of diabetes-related complications.[57] [64] [117] While promising, more clinical studies in humans are essential to validate these effects, define optimal treatment protocols, and ensure safety and feasibility for widespread use.[122] Beyond its effects on metabolic parameters, HT has shown immunomodulatory properties relevant to both T1D and T2D. In the context of T1D, fever-range WBH has demonstrated preventive effects in NOD mice. Capitano's team reported that weekly WBH sessions prevented the onset of T1D in NOD mice by enhancing natural killer (NK) cell activity and reducing pancreatic islet infiltration by autoreactive lymphocytes.[123] [124]

Literature supports the idea that fever-range HT recalibrates hypothalamic set points, modulates sympathetic output, and reduces chronic hypercortisolemia,[125] [126] thus improving insulin sensitivity and decreasing β-cell strain. Thermal activation of hypothalamic nuclei also normalizes hepatic gluconeogenesis and enhances β-cell responsiveness via vagal efferents, providing a neuroendocrine mechanism for improved fasting glycemia and postprandial insulin dynamics. The recalibration of central thermoregulatory and neuroimmune circuits links thermal therapy with pancreatic and hepatic outcomes,[127] [128] reinforcing a brain-centered approach to diabetes treatment, especially within the whole-body hyperthermia–brain-targeted therapy (WBH-BTT) framework.[129] [130] Beyond autonomic control, thermal stimulation of hypothalamic and limbic networks may engage the neuroimmune interface, transiently activating microglial and astroglial HSP responses that propagate anti-inflammatory signaling to peripheral organs. At the cellular level, HT induces HSP70/72, which helps preserve mitochondrial integrity by preventing permeability transition, enhancing oxidative phosphorylation, and limiting reactive oxygen species (ROS) generation in β-cells and kidneys. Repeated HSP70/72 induction may also confer a “proteostasis memory,” reinforcing chaperone networks and epigenetically stabilizing metabolic genes; such adaptive imprinting likely underlies sustained benefits seen with recurrent hyperthermic exposure in animals and humans. Parallel findings from exercise physiology and thermal conditioning studies suggest that recurrent subthreshold heat stress induces cross-tolerance, enhancing resilience against metabolic and oxidative insults. These actions may interrupt hyperglycemia-related organelle stress, slowing the development of nephropathy and neuropathy.[131] [132] Concomitantly, HT appears to normalize adipokine profiles—lowering leptin and resistin while restoring adiponectin secretion—which complements HSP-mediated improvements in insulin signaling and mitochondrial efficiency. In the vasculature, thermal preconditioning upregulates endothelial HSPs, boosts endothelial nitric oxide synthase (eNOS) coupling, and stabilizes nitric oxide (NO) bioavailability—key factors in preventing microvascular damage like retinal capillary dropout or renal ischemia.[133] [134] Furthermore, in T1D models, HT promotes immune tolerance by suppressing autoreactive T-cell infiltration in islets and enhancing NK cell activity and regulatory T-cell function, potentially reshaping the immune landscape to preserve β-cell function.[135] [136] In terms of dose–response, literature on therapeutic thermal hormesis indicates that controlled exposure (∼39.5–41.5°C) for approximately 60 minutes can robustly activate HSP responses, akin to exercise-induced stress resilience.[137] [138] Future studies should correlate thermal dose with mechanistic and clinical readouts—circulating/exosomal HSP70, IL-6/C-reactive protein (CRP), endothelial function (flow-mediated dilation [FMD]), and continuous glucose monitoring (CGM) metrics (time-in-range, glycemic variability) to anchor outcomes to the proposed pathways. Finally, thermal preconditioning upregulates endothelial HSPs, enhances eNOS coupling, and stabilizes NO bioavailability—countering microvascular rarefaction.[139] [140] Chronic HT could theoretically improve perfusion in the retina, kidneys, and peripheral nerves, altering the trajectory of complication development in this patient population.[141] [142] Taken together, coordinated neuroendocrine, mitochondrial, vascular, and immune adaptations converge to restore metabolic flexibility and slow progression of diabetic complications. Looking ahead, integrating standardized WBH protocols with real-time thermal monitoring could make HT safer for patients with autonomic neuropathy or heart failure, enhancing scalability and reproducibility across clinics. By simultaneously targeting neuroendocrine regulation, mitochondrial stability, vascular homeostasis, and immune tolerance, HT represents a unified systems-medicine strategy capable of addressing both metabolic dysfunction and its downstream complications ([Fig. 3]).

Fig. 3 Mechanisms of heat therapy-induced glycemic control via heat shock protein (HSP) pathways. This diagram illustrates the proposed pathways through which heat therapy (HT) induces HSP expression, leading to improved glycemic control and prevention of complications. HSP induction influences four major physiological systems: (1) The neuroendocrine axis, by recalibrating HPA set points and improving insulin sensitivity; (2) mitochondrial protection, through preserved oxidative phosphorylation and reduced reactive oxygen species (ROS); (3) vascular remodeling, enhancing endothelial function and microvascular repair; and (4) immune modulation, via reduced autoreactive infiltration and balanced NK/Treg activity. Created with BioRender.com and licensed for journal publication. Created in BioRender. Smadja, D. (2025) https://BioRender.com/7rhsuf6. NK, natural killer.

Vascular and Thrombotic Complications of Diabetes: Endothelial Stress and Repair Imbalance

DM markedly increases the risk of both microvascular (retinopathy, nephropathy) and macrovascular (myocardial infarction [MI], stroke) complications, primarily through chronic injury to the vascular endothelium. This endothelial dysfunction results from a dual imbalance: An overactivation of cellular stress pathways, particularly via HSPs, and a loss of vascular repair capacity, potentially due to the depletion of endothelial progenitor cells (EPCs).[143] [144] In patients with T2D and lower limb ischemia, Rabczynski et al found that anti-HSP60/65 antibodies were elevated and significantly correlated with von Willebrand factor (vWF), a marker of endothelial damage, indicating a potential autoimmune mechanism contributing to endothelial dysfunction in diabetic macroangiopathy.[145] Although the antibody levels were not significantly higher than in controls, their association with vWF suggests that immune responses against HSPs may exacerbate vascular injury in diabetes through chronic inflammatory and prothrombotic pathways.

Among HSPs, HSP47 plays a central role in promoting thrombosis and fibrosis.[12] It facilitates platelet–collagen binding and stabilizes thrombus formation, and is overexpressed in diabetic conditions. Its inhibition has been shown to reduce thrombus size and platelet aggregation without affecting thrombin signaling.[146] Beyond its thrombotic role, HSP47 is also a key mediator of endothelial-to-mesenchymal transition in cardiac endothelial cells under stressors such as aging, obesity, and pressure overload. This transition is driven by TGF-β and oxidative stress and results in endothelial senescence and dysfunction—processes reversed by exercise, which downregulates HSP47 and restores vascular homeostasis.[147] Complementing this, Khalil et al demonstrated that HSP47 plays a critical role in cardiac fibrosis.[148] Using cell-specific gene deletion models, they showed that only deletion of HSP47 in myofibroblasts—not in cardiomyocytes or endothelial cells—was effective in blocking collagen deposition, reducing cardiac hypertrophy, and limiting fibrosis after injury. Endothelial-specific deletion of HSP47 mildly reduced collagen type I but did not alter overall fibrosis, indicating that endothelial cells contribute minimally to fibrotic remodeling in the heart. In parallel, other HSPs contribute to endothelial pathology in diabetes. HSP60, elevated in diabetic states, activates TLRs and NF-κB, driving chronic vascular inflammation. While improved glycemic control reduces systemic IL-6 levels, anti-HSP60 antibodies often remain elevated, suggesting persistent immune-mediated endothelial activation.[149] These stress-mediated pathways are not limited to large vessels. In the retina, HSP27 and HSP70 help counter oxidative stress, while in the kidney, HSP dysregulation is linked to podocyte–endothelial cross-talk and progression of DN.[52] Moreover, hyperglycemia-induced O-GlcNAcylation of key signaling proteins, such as Akt and eNOS, further impairs endothelial responses and reduces HSP72, a cytoprotective chaperone. These effects have been shown to be reversible with renin–angiotensin–aldosterone system (RAAS) inhibition, which may exert part of its renoprotective action through modulation of O-linked β-N-acetylglucosamine [a post-translational protein modification] (O-GlcNAc) signaling.[150] In the retina, HSP47 also plays a critical inflammatory role. Under high-glucose conditions, it activates the IRE1α/XBP1s/HIF-1α ER stress pathway in Müller glial cells, promoting production of VEGF, PDGF-B, and inducible nitric oxide synthase (iNOS). Silencing HSP47 blunts this inflammatory cascade, revealing its potential as a cross-organ mediator of vascular inflammation and fibrosis.[81] While HSPs amplify stress and senescence in diabetic vasculature, the loss of EPCs undermines the system's capacity for repair. EPCs, especially CD34⁺ subsets, are critical for vascular regeneration.[144] [151] Diabetes reduces their number and function, with lower circulating levels predicting progression of renal disease and albuminuria.[152] Importantly, EPC-based therapies are emerging as a potential intervention to restore vascular health in diabetes,[153] [154] [155] in particular, because of their anti-inflammatory properties.[156] [157] In preclinical models of DN and cardiomyopathy, EPC transplantation enhances microvascular density, reduces fibrosis, and improves both cardiac and renal function. These reparative effects are mediated via both direct incorporation and paracrine signaling, including the release of protective exosomes enriched in HSP20, p-Akt, superoxide dismutase 1 (SOD1), and survivin.[158] [159] Further complicating vascular pathology in diabetes, bone turnover markers like osteocalcin, procollagen type I N-terminal propeptide (PINP) and C-terminal telopeptide of type I collagen (CTX) are independently associated with intracranial and extracranial artery stenosis. These markers, tightly connected to HSP-regulated stress responses, correlate with HbA1c and LDL-C levels and may serve as biomarkers for vascular calcification and instability.[160] Salybekov et al provide pivotal insights into how DM disrupts immune and vascular repair responses following MI, through a detailed murine model of T2D.[161] Their study identifies profound dysfunction in the cardio–spleno–bone marrow axis, leading to both impaired immune cell mobilization and EPC activity. Despite normal immune cell production in bone marrow, diabetic mice exhibited reduced PB levels of CD45⁺ leukocytes, neutrophils, and macrophages, particularly during the acute phase (days 1–3 post-MI), indicating ineffective mobilization. Notably, neutrophil polarization shifted from proinflammatory (N1) to anti-inflammatory (N2) types in the spleen, while macrophage recruitment, especially of the reparative M2 subset, was delayed and diminished in diabetic hearts. In the adaptive immune compartment, CD8⁺ cytotoxic T cells predominated in diabetic hearts across all time points, contrasting with CD4⁺ helper T-cell dominance in controls, a pattern that may exacerbate inflammation and cardiac injury. B-cell infiltration and PB levels were also significantly suppressed in diabetic mice during early MI stages, suggesting impaired humoral immune involvement. Crucially, EPC-colony-forming capacity was markedly reduced in diabetic animals across the bone marrow, spleen, and PB compartments. The shift toward primitive EPC colonies over definitive, mature ones suggests a differentiation block under diabetic stress, with implications for compromised neovascularization and repair. These findings align with earlier clinical observations of reduced EPC mobilization in diabetic MI patients and underscore the synergistic impact of immune dysregulation and vascular repair failure in diabetic ischemic injury. This study complements the broader understanding that hyperglycemia-induced stress, immune imbalance, and EPC dysfunction form a “double-hit” mechanism that drives diabetic vascular complications, including endothelial senescence, thrombosis, and fibrotic remodeling across organ systems.[161]

In summary, diabetic vasculopathy stems from a converging imbalance between heightened endothelial stress—driven by the overexpression of HSPs—and a diminished capacity for vascular repair due to EPC depletion. This dysregulation promotes endothelial senescence, thrombosis, chronic inflammation, and fibrotic remodeling across key organs such as the retina, heart, and kidneys. Addressing this pathological interplay, through modulation of HSP-mediated stress responses or restoration of EPC function, offers a promising avenue for the prevention or attenuation of vascular complications in diabetes.

Conclusion and Future Perspectives

All in all, the interplay of misfolded proteins, amylin aggregation, ER stress, and inflammatory pathways underscores the complexity of diabetes beyond simple glucose dysregulation. Despite growing interest in thermal interventions, several limitations must be acknowledged. Human data remain limited and heterogeneous, with substantial variation in heat exposure duration, intensity, modality (e.g., sauna, hot water immersion, WBH), and outcome measures. Few studies use standardized temperature protocols or track long-term glycemic outcomes. Additionally, individual responses may be influenced by comorbidities, age, and fitness level. These gaps highlight the need for rigorous, multicenter, randomized controlled trials to clarify optimal dosing and clinical applications. Misfolded proteins and HSPs in general contribute significantly to β-cell dysfunction and death in both T1D and T2D, offering potential targets for therapeutic intervention. Amylin's dual roles—essential for glycemic regulation yet pathogenic when aggregated—highlight the need for nuanced approaches that preserve physiological functions while preventing toxic misfolding. The protective roles of HSPs, particularly HSP70, further emphasize the importance of cellular stress responses in diabetes pathophysiology. Strategies to enhance HSP expression may offer cytoprotective benefits, modulate immune responses, and improve insulin sensitivity. Emerging evidence supports the beneficial effects of HT and hT in both preclinical and clinical settings. These interventions harness endogenous stress response pathways to improve glucose metabolism, enhance insulin sensitivity, and modulate immune function. However, translation to clinical practice requires rigorous validation, careful patient selection, and standardized thermal protocols. The integration of HT-based therapies with conventional treatments and lifestyle modifications represents a promising frontier in diabetes management. Moving forward, research should focus on elucidating the precise molecular mechanisms underlying thermal interventions, optimizing dosing regimens, and evaluating long-term outcomes. In conclusion, the convergence of protein misfolding, amylin biology, HSP function, and HT interventions provides a rich landscape for innovative diabetes therapies. By addressing the disease at multiple molecular and cellular levels, these approaches hold the potential to transform diabetes care and improve patient outcomes.

Conflict of Interest

All data discussed are from peer-reviewed sources. M.M.A. is the founder of BTT Medical Institute and applies hyperthermia in clinical practice. To minimize bias, he did not participate in data extraction or interpretation of quantitative outcomes. All findings presented are based on published, peer-reviewed literature, and no unpublished proprietary data were included.

Contributors' Statement

M.M.A.: Conceptualization, writing–review and editing. V.H.S.: Conceptualization, writing–review and editing. D.M.S.: Conceptualization, writing–original draft, writing–review and editing.

• References

• 1 de Ferranti SD, de Boer IH, Fonseca V. et al. Type 1 diabetes mellitus and cardiovascular disease: A Scientific Statement from the American Heart Association and American Diabetes Association. Circulation 2014; 130 (13) 1110-1130
• 2 Fox CS, Golden SH, Anderson C. et al; American Heart Association Diabetes Committee of the Council on Lifestyle and Cardiometabolic Health, Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Surgery and Anesthesia, Council on Quality of Care and Outcomes Research, and the American Diabetes Association. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: A Scientific Statement from the American Heart Association and the American Diabetes Association. Circulation 2015; 132 (08) 691-718
• 3 Silvestre J-S, Smadja DM, Lévy BI. Postischemic revascularization: From cellular and molecular mechanisms to clinical applications. Physiol Rev 2013; 93 (04) 1743-1802
• 4 Li Q, Qian Z, Huang Y. et al. Mechanisms of endothelial senescence and vascular aging. Biogerontology 2025; 26 (04) 128
• 5 Liu F, Cai H. Diabetes and calcific aortic valve disease: Implications of glucose-lowering medication as potential therapy. Front Pharmacol 2025; 16: 1583267 . Accessed July 26, 2025 at: https://www.frontiersin.org/articles/10.3389/fphar.2025.1583267/full
• 6 Rosa M, Paris C, Sottejeau Y. et al. Leptin induces osteoblast differentiation of human valvular interstitial cells via the Akt and ERK pathways. Acta Diabetol 2017; 54 (06) 551-560
• 7 Rosa M, Dupont A, Smadja DM. et al. Aortic valve calcification is induced by the loss of ALDH1A1 and can be prevented by agonists of retinoic acid receptor alpha: Preclinical evidence for drug repositioning. Circulation 2025; 151 (18) 1329-1341
• 8 Blandinières A, Rossi E, Gendron N. et al. Unveiling the angiogenic potential and functional decline of valve interstitial cells during calcific aortic valve stenosis progression. J Cell Mol Med 2025; 29 (07) e70511
• 9 Ortega HI, Udler MS, Gloyn AL. et al. Diabetes mellitus polygenic risk scores: Heterogeneity and clinical translation. Nat Rev Endocrinol 2025; 21: 530-545 . Accessed July 14, 2025 at: https://www.nature.com/articles/s41574-025-01132-w
• 10 Chen D, Sindone A, Huang MLH. et al. Clinical management of diabetic cardiomyopathy with insights into pathophysiology and diagnosis. J Mol Cell Cardiol 2025; 206: 55-69 . Accessed January 23, 2026 at: https://www.sciencedirect.com/science/article/pii/S0022282825001117
• 11 de Oliveira AA, Mendoza VO, Rastogi S, Nunes KP. New insights into the role and therapeutic potential of HSP70 in diabetes. Pharmacol Res 2022; 178: 106173
• 12 Smadja DM, Chocron AF, Abreu MM. HSP47 at the crossroads of thrombosis and collagen dynamics: Unlocking therapeutic horizons and debates. TH Open 2025; 9: a25994925
• 13 Bielecka-Dabrowa A, Barylski M, Mikhailidis DP, Rysz J, Banach M. HSP 70 and atherosclerosis–protector or activator?. Expert Opin Ther Targets 2009; 13 (03) 307-317
• 14 Walker CS, Aitken JF, Vazhoor Amarsingh G. et al. Amylin: Emergent therapeutic opportunities in overweight, obesity and diabetes mellitus. Nat Rev Endocrinol 2025; 21: 482-494 . Accessed July 14, 2025 at: https://www.nature.com/articles/s41574-025-01125-9
• 15 Li G, Zhang D. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus. Open Med (Wars) 2025; 20 (01) 20241124
• 16 Esmaeilzadeh A, Mohammadi V, Elahi R, Rezakhani N. The role of heat shock proteins (HSPs) in type 2 diabetes mellitus pathophysiology. J Diabetes Complications 2023; 37 (11) 108564
• 17 Moin ASM, Nandakumar M, Diane A, Dehbi M, Butler AE. The role of heat shock proteins in type 1 diabetes. Front Immunol 2021; 11: 612584
• 18 Abreu MM, Chocron AF, Smadja DM. From cold to hot: Mechanisms of hyperthermia in modulating tumor immunology for enhanced immunotherapy. Front Immunol 2025; 16: 1487296
• 19 Smadja DM, Abreu MM. Hyperthermia and targeting heat shock proteins: Innovative approaches for neurodegenerative disorders and long COVID. Front Neurosci 2025; 19: 1475376
• 20 Laukkanen JA, Kunutsor SK. The multifaceted benefits of passive heat therapies for extending the healthspan: A comprehensive review with a focus on Finnish sauna. Temperature 2024; 11 (01) 27-51
• 21 Laukkanen JA, Laukkanen T, Kunutsor SK. Cardiovascular and other health benefits of sauna bathing: A review of the evidence. Mayo Clin Proc 2018; 93 (08) 1111-1121
• 22 Sebők J, Édel Z, Váncsa S. et al. Heat therapy shows benefit in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Int J Hyperthermia 2021; 38 (01) 1650-1659
• 23 Birk OS, Elias D, Weiss AS. et al. NOD mouse diabetes: The ubiquitous mouse hsp60 is a beta-cell target antigen of autoimmune T cells. J Autoimmun 1996; 9 (02) 159-166
• 24 Brudzynski K, Martinez V, Gupta RS. Secretory granule autoantigen in insulin-dependent diabetes mellitus is related to 62.  kDa heat-shock protein (hsp60). J Autoimmun 1992; 5 (04) 453-463
• 25 Quintana FJ, Cohen IR. The HSP60 immune system network. Trends Immunol 2011; 32 (02) 89-95
• 26 Juwono J, Martinus RD. Does Hsp60 provide a link between mitochondrial stress and inflammation in diabetes mellitus?. J Diabetes Res 2016; 2016: 8017571
• 27 Horváth L, Cervenak L, Oroszlán M. et al. Antibodies against different epitopes of heat-shock protein 60 in children with type 1 diabetes mellitus. Immunol Lett 2002; 80 (03) 155-162
• 28 Vives-Pi M, Somoza N, Vargas F. et al. Expression of glutamic acid decarboxylase (GAD) in the alpha, beta and delta cells of normal and diabetic pancreas: Implications for the pathogenesis of type I diabetes. Clin Exp Immunol 1993; 92 (03) 391-396
• 29 Abulafia-Lapid R, Elias D, Raz I, Keren-Zur Y, Atlan H, Cohen IR. T cell proliferative responses of type 1 diabetes patients and healthy individuals to human hsp60 and its peptides. J Autoimmun 1999; 12 (02) 121-129
• 30 Verrijn Stuart AA, de Jager W, Klein MR. et al. Recognition of heat shock protein 60 epitopes in children with type 1 diabetes. Diabetes Metab Res Rev 2012; 28 (06) 527-534
• 31 Elias D, Meilin A, Ablamunits V. et al. Hsp60 peptide therapy of NOD mouse diabetes induces a Th2 cytokine burst and downregulates autoimmunity to various beta-cell antigens. Diabetes 1997; 46 (05) 758-764
• 32 Schloot NC, Meierhoff G, Lengyel C. et al. Effect of heat shock protein peptide DiaPep277 on beta-cell function in paediatric and adult patients with recent-onset diabetes mellitus type 1: Two prospective, randomized, double-blind phase II trials. Diabetes Metab Res Rev 2007; 23 (04) 276-285
• 33 Raz I, Eldor R, Naparstek Y. Immune modulation for prevention of type 1 diabetes mellitus. Trends Biotechnol 2005; 23 (03) 128-134
• 34 Rizava C, Bekiari E, Liakos A. et al. Antigen-based immunotherapies do not prevent progression of recent-onset autoimmune diabetes: A systematic review and meta-analysis. Endocrine 2016; 54 (03) 620-633
• 35 Gaskins HR, Prochazka M, Nadeau JH, Henson VW, Leiter EH. Localization of a mouse heat shock Hsp70 gene within the H-2 complex. Immunogenetics 1990; 32 (04) 286-289
• 36 Brorsson C, Hansen NT, Lage K, Bergholdt R, Brunak S, Pociot F. Diabetes Genetics Consortium. Identification of T1D susceptibility genes within the MHC region by combining protein interaction networks and SNP genotyping data. Diabetes Obes Metab 2009; 11 Suppl 1 (Suppl. 01) 60-66
• 37 De Maio A. Extracellular heat shock proteins, cellular export vesicles, and the Stress Observation System: A form of communication during injury, infection, and cell damage. It is never known how far a controversial finding will go! Dedicated to Ferruccio Ritossa. Cell Stress Chaperones 2011; 16 (03) 235-249
• 38 Bellmann K, Wenz A, Radons J, Burkart V, Kleemann R, Kolb H. Heat shock induces resistance in rat pancreatic islet cells against nitric oxide, oxygen radicals and streptozotocin toxicity in vitro. J Clin Invest 1995; 95 (06) 2840-2845
• 39 Burkart V, Liu H, Bellmann K. et al. Natural resistance of human beta cells toward nitric oxide is mediated by heat shock protein 70. J Biol Chem 2000; 275 (26) 19521-19528
• 40 Fong JJ, Sreedhara K, Deng L. et al. Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 and Siglec-14. EMBO J 2015; 34 (22) 2775-2788
• 41 El-Horany HE-S, Abd-Ellatif RN, Watany M, Hafez YM, Okda HI. NLRP3 expression and urinary HSP72 in relation to biomarkers of inflammation and oxidative stress in diabetic nephropathy patients. IUBMB Life 2017; 69 (08) 623-630
• 42 Cianciaruso C, Phelps EA, Pasquier M. et al. Primary human and rat β-cells release the intracellular autoantigens GAD65, IA-2, and proinsulin in exosomes together with cytokine-induced enhancers of immunity. Diabetes 2017; 66 (02) 460-473
• 43 Watkins RA, Evans-Molina C, Terrell JK. et al. Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes. Transl Res 2016; 168: 96-106.e1
• 44 Vig S, Buitinga M, Rondas D. et al. Cytokine-induced translocation of GRP78 to the plasma membrane triggers a pro-apoptotic feedback loop in pancreatic beta cells. Cell Death Dis 2019; 10: 309 . Springer Science and Business Media LLC. Accessed July 24, 2025 at: https://www.nature.com/articles/s41419-019-1518-0
• 45 Figueredo A, Ibarra JL, Rodriguez A. et al. Increased serum levels of IgA antibodies to hsp70 protein in patients with diabetes mellitus: Their relationship with vascular complications. Clin Immunol Immunopathol 1996; 79 (03) 252-255
• 46 Bason C, Corrocher R, Lunardi C. et al. Interaction of antibodies against cytomegalovirus with heat-shock protein 60 in pathogenesis of atherosclerosis. Lancet 2003; 362 (9400): 1971-1977
• 47 Qin H-Y, Mahon JL, Atkinson MA, Chaturvedi P, Lee-Chan E, Singh B. Type 1 diabetes alters anti-hsp90 autoantibody isotype. J Autoimmun 2003; 20 (03) 237-245
• 48 Rawshani A, Sattar N, Franzén S. et al. Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: A nationwide, register-based cohort study. Lancet 2018; 392 (10146): 477-486
• 49 Wang L, Li L, Liu J. et al. Associated factors and principal pathophysiological mechanisms of type 2 diabetes mellitus. Front Endocrinol 2025; 16: 1499565 . Accessed July 24, 2025 at: https://www.frontiersin.org/articles/10.3389/fendo.2025.1499565/full
• 50 Krause M, Heck TG, Bittencourt A. et al. The chaperone balance hypothesis: The importance of the extracellular to intracellular HSP70 ratio to inflammation-driven type 2 diabetes, the effect of exercise, and the implications for clinical management. Klink M, ed. Mediators Inflamm 2015; 2015: 249205 . Wiley. Accessed July 24, 2025 at: https://onlinelibrary.wiley.com/doi/10.1155/2015/249205
• 51 Archer AE, Von Schulze AT, Geiger PC. Exercise, heat shock proteins and insulin resistance. Philos Trans R Soc Lond B Biol Sci 2018; 373 (1738): 20160529
• 52 Bellini S, Barutta F, Mastrocola R, Imperatore L, Bruno G, Gruden G. Heat shock proteins in vascular diabetic complications: Review and future perspective. Int J Mol Sci 2017; 18 (12) 2709
• 53 Rowles JE, Keane KN, Gomes Heck T, Cruzat V, Verdile G, Newsholme P. Are heat shock proteins an important link between type 2 diabetes and Alzheimer disease?. Int J Mol Sci 2020; 21 (21) 8204
• 54 Halban PA, Polonsky KS, Bowden DW. et al. β-cell failure in type 2 diabetes: Postulated mechanisms and prospects for prevention and treatment. J Clin Endocrinol Metab 2014; 99 (06) 1983-1992
• 55 Dokladny K, Myers OB, Moseley PL. Heat shock response and autophagy. –cooperation and control. Autophagy 2015; 11 (02) 200-213
• 56 Kravats AN, Hoskins JR, Reidy M. et al. Functional and physical interaction between yeast Hsp90 and Hsp70. Proc Natl Acad Sci U S A 2018; 115: E2210-E2219 . Accessed July 24, 2025 at: https://pnas.org/doi/full/10.1073/pnas.1719969115
• 57 Henstridge DC, Whitham M, Febbraio MA. Chaperoning to the metabolic party: The emerging therapeutic role of heat-shock proteins in obesity and type 2 diabetes. Mol Metab 2014; 3 (08) 781-793
• 58 Brzozowska MM, Havula E, Allen RB, Cox MP. Genetics, adaptation to environmental changes and archaic admixture in the pathogenesis of diabetes mellitus in Indigenous Australians. Rev Endocr Metab Disord 2019; 20 (03) 321-332
• 59 Calderwood SK, Gong J, Murshid A. Extracellular HSPs: The complicated roles of extracellular HSPs in immunity. Front Immunol 2016; 7: 159 . Accessed January 23, 2026 at: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2016.00159
• 60 Muoio DM, Newgard CB. Mechanisms of disease: Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 2008; 9 (03) 193-205
• 61 Kaneto H, Katakami N, Matsuhisa M, Matsuoka TA. Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Mediators Inflamm 2010; 2010: 453892
• 62 Nowotny K, Jung T, Höhn A, Weber D, Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 2015; 5 (01) 194-222
• 63 Gonzalez LL, Garrie K, Turner MD. Type 2 diabetes - An autoinflammatory disease driven by metabolic stress. Biochim Biophys Acta Mol Basis Dis 2018; 1864 (11) 3805-3823
• 64 Chung J, Nguyen A-K, Henstridge DC. et al. HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci U S A 2008; 105 (05) 1739-1744
• 65 Clark A, Jones LC, de Koning E, Hansen BC, Matthews DR. Decreased insulin secretion in type 2 diabetes: A problem of cellular mass or function?. Diabetes 2001; 50 (Suppl. 01) S169-S171
• 66 Budzyński MA, Crul T, Himanen SV. et al. Chaperone co-inducer BGP-15 inhibits histone deacetylases and enhances the heat shock response through increased chromatin accessibility. Cell Stress Chaperones 2017; 22 (05) 717-728
• 67 Sapra G, Tham YK, Cemerlang N. et al. The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice. Nat Commun 2014; 5: 5705
• 68 Xing B, Wang L, Li Q. et al. Hsp70 plays an important role in high-fat diet induced gestational hyperglycemia in mice. J Physiol Biochem 2015; 71 (04) 649-658
• 69 Literáti-Nagy B, Tory K, Peitl B. et al. Improvement of insulin sensitivity by a novel drug candidate, BGP-15, in different animal studies. Metab Syndr Relat Disord 2014; 12 (02) 125-131
• 70 Literáti-Nagy B, Kulcsár E, Literáti-Nagy Z. et al. Improvement of insulin sensitivity by a novel drug, BGP-15, in insulin-resistant patients: A proof of concept randomized double-blind clinical trial. Horm Metab Res 2009; 41 (05) 374-380
• 71 Literáti-Nagy B, Péterfai E, Kulcsár E. et al. Beneficial effect of the insulin sensitizer (HSP inducer) BGP-15 on olanzapine-induced metabolic disorders. Brain Res Bull 2010; 83 (06) 340-344
• 72 Jing E, Sundararajan P, Majumdar ID. et al. Hsp90β knockdown in DIO mice reverses insulin resistance and improves glucose tolerance. Nutr Metab (Lond) 2018; 15: 11
• 73 Lei H, Venkatakrishnan A, Yu S, Kazlauskas A. Protein kinase A-dependent translocation of Hsp90 alpha impairs endothelial nitric-oxide synthase activity in high glucose and diabetes. J Biol Chem 2007; 282 (13) 9364-9371
• 74 Lei H, Romeo G, Kazlauskas A. Heat shock protein 90alpha-dependent translocation of annexin II to the surface of endothelial cells modulates plasmin activity in the diabetic rat aorta. Circ Res 2004; 94 (07) 902-909
• 75 Yuan J, Dunn P, Martinus RD. Detection of Hsp60 in saliva and serum from type 2 diabetic and non-diabetic control subjects. Cell Stress Chaperones 2011; 16 (06) 689-693
• 76 Fakhruddin S, Alanazi W, Jackson KE. Diabetes-induced reactive oxygen species: Mechanism of their generation and role in renal injury. J Diabetes Res 2017; 2017: 8379327
• 77 Mahmoud FF, Haines D, Dashti AA, El-Shazly S, Al-Najjar F. Correlation between heat shock proteins, adiponectin, and T lymphocyte cytokine expression in type 2 diabetics. Cell Stress Chaperones 2018; 23 (05) 955-965
• 78 Cherian PT, Al-Khairi I, Sriraman D. et al. Increased circulation and adipose tissue levels of DNAJC27/RBJ in obesity and type 2-diabetes. Front Endocrinol 2018; 9: 423 . Accessed July 24, 2025 at: https://www.frontiersin.org/article/10.3389/fendo.2018.00423/full
• 79 Nakhjavani M, Morteza A, Khajeali L. et al. Increased serum HSP70 levels are associated with the duration of diabetes. Cell Stress Chaperones 2010; 15 (06) 959-964
• 80 Atkin AS, Moin ASM, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE. Plasma heat shock protein response to euglycemia in type 2 diabetes. BMJ Open Diabetes Res Care 2021; 9 (01) e002057
• 81 Sun X, Chen C, Liu H, Tang S. High glucose induces HSP47 expression and promotes the secretion of inflammatory factors through the IRE1α/XBP1/HIF-1α pathway in retinal Müller cells. Exp Ther Med 2021; 22 (06) 1411
• 82 Razzaque MS, Nazneen A, Taguchi T. Immunolocalization of collagen and collagen-binding heat shock protein 47 in fibrotic lung diseases. Mod Pathol 1998; 11 (12) 1183-1188
• 83 Sunamoto M, Kuze K, Tsuji H. et al. Antisense oligonucleotides against collagen-binding stress protein HSP47 suppress collagen accumulation in experimental glomerulonephritis. Lab Invest 1998; 78 (08) 967-972
• 84 Xia Z, Abe K, Furusu A. et al. Suppression of renal tubulointerstitial fibrosis by small interfering RNA targeting heat shock protein 47. Am J Nephrol 2008; 28 (01) 34-46
• 85 Kawasaki K, Ushioda R, Ito S, Ikeda K, Masago Y, Nagata K. Deletion of the collagen-specific molecular chaperone Hsp47 causes endoplasmic reticulum stress-mediated apoptosis of hepatic stellate cells. J Biol Chem 2015; 290 (06) 3639-3646
• 86 Wang Z, Li L. The plasmid encoding HSP47 enhances collagen expression and promotes skin wound healing in an alloxan-induced diabetic model. Cell Biol Int 2009; 33 (07) 705-710
• 87 Singh K, Agrawal NK, Gupta SK, Mohan G, Chaturvedi S, Singh K. Decreased expression of heat shock proteins may lead to compromised wound healing in type 2 diabetes mellitus patients. J Diabetes Complications 2015; 29 (04) 578-588
• 88 Ahmad S, Ahmad MFA, Khan S. et al. Exploring aldose reductase inhibitors as promising therapeutic targets for diabetes-linked disabilities. Int J Biol Macromol 2024; 280 (Pt 2): 135761
• 89 Craft S, Claxton A, Baker LD. et al. Effects of regular and long-acting insulin on cognition and Alzheimer's disease biomarkers: A pilot clinical trial. De La Monte S, ed. J Alzheimers Dis 2017; 57: 1325-1334 . SAGE Publications.
• 90 Riahi Y, Wikstrom JD, Bachar-Wikstrom E. et al. Autophagy is a major regulator of beta cell insulin homeostasis. Diabetologia 2016; 59 (07) 1480-1491
• 91 Dubey R, Patil K, Dantu SC. et al. Azadirachtin inhibits amyloid formation, disaggregates pre-formed fibrils and protects pancreatic β-cells from human islet amyloid polypeptide/amylin-induced cytotoxicity. Biochem J 2019; 476 (05) 889-907
• 92 Leissring MA, González-Casimiro CM, Merino B, Suire CN, Perdomo G. Targeting insulin-degrading enzyme in insulin clearance. Int J Mol Sci 2021; 22 (05) 2235
• 93 Guillemain G, Lacapere J-J, Khemtemourian L. Targeting hIAPP fibrillation: A new paradigm to prevent β-cell death?. Biochim Biophys Acta Biomembr 2022; 1864 (10) 184002
• 94 AlAnazi FH, Al-Kuraishy HM, Al-Gareeb AI. et al. Effects of neprilysin and neprilysin inhibitors on glucose homeostasis: Controversial points and a promising arena. J Diabetes 2023; 15 (05) 397-408
• 95 Sevcuka A, White K, Terry C. Factors that contribute to hIAPP amyloidosis in type 2 diabetes mellitus. Life (Basel) 2022; 12 (04) 583
• 96 Alrouji M, Al-Kuraishy HM, Al-Gareeb AI. et al. The potential role of human islet amyloid polypeptide in type 2 diabetes mellitus and Alzheimer's diseases. Diabetol Metab Syndr 2023; 15: 101 . Springer Science and Business Media LLC. Accessed July 26, 2025 at: https://dmsjournal.biomedcentral.com/articles/10.1186/s13098-023-01082-1
• 97 Höppener JWM, Lips CJM. Role of islet amyloid in type 2 diabetes mellitus. Int J Biochem Cell Biol 2006; 38 (5-6): 726-736
• 98 Li X-L, Chen T, Wong Y-S. et al. Involvement of mitochondrial dysfunction in human islet amyloid polypeptide-induced apoptosis in INS-1E pancreatic beta cells: An effect attenuated by phycocyanin. Int J Biochem Cell Biol 2011; 43 (04) 525-534
• 99 Guan H, Chow KM, Song E, Verma N, Despa F, Hersh LB. The mitochondrial peptidase pitrilysin degrades islet amyloid polypeptide in beta-cells. PLoS ONE 2015; 10 (07) e0133263
• 100 Alanazi M, Al-Kuraishy HM, Albuhadily AK. et al. The protective effect of amylin in type 2 diabetes: Yes or no. Eur J Pharmacol 2025; 996: 177593
• 101 Verma N, Despa F. The association between renal accumulation of pancreatic amyloid-forming amylin and renal hypoxia. Front Endocrinol (Lausanne) 2023; 14: 1104662
• 102 Westermark P, Andersson A, Westermark GT. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev 2011; 91 (03) 795-826
• 103 Moya-Gudiño V, Altamirano-Bustamante NF, Revilla-Monsalve C, Altamirano-Bustamante MM. Decoding the contribution of IAPP amyloid aggregation to beta cell dysfunction: A systematic review and epistemic meta-analysis of type 1 diabetes. Int J Mol Sci 2025; 26 (02) 767
• 104 Herder C, Dalmas E, Böni-Schnetzler M, Donath MY. The IL-1 pathway in type 2 diabetes and cardiovascular complications. Trends Endocrinol Metab 2015; 26 (10) 551-563
• 105 Krause M, Ludwig MS, Heck TG, Takahashi HK. Heat shock proteins and heat therapy for type 2 diabetes: Pros and cons. Curr Opin Clin Nutr Metab Care 2015; 18 (04) 374-380 . Wolters Kluwer Health.
• 106 Blankenship AE, Kemna R, Kueck PJ. et al. Improving glycemic control via heat therapy in older adults at risk for Alzheimer's disease (FIGHT-AD): A pilot study. J Appl Physiol 2025; 138 (03) 720-730
• 107 Silverstein MG, Ordanes D, Wylie AT. et al. Inducing muscle heat shock protein 70 improves insulin sensitivity and muscular performance in aged mice. J Gerontol Ser A Sci Med Sci 2015; 70: 800-808 . Oxford University Press
• 108 Bruxel MA, Tavares AMV, Zavarize Neto LD. et al. Chronic whole-body heat treatment relieves atherosclerotic lesions, cardiovascular and metabolic abnormalities, and enhances survival time restoring the anti-inflammatory and anti-senescent heat shock response in mice. Biochimie 2019; 156: 33-46
• 109 Nonaka K, Une S, Komatsu M, Yamaji R, Akiyama J. Heat stress prevents the decrease in succinate dehydrogenase activity in the extensor digitorum longus of streptozotocin-induced diabetic rats. Physiol Res 2018; 67 (01) 117-126
• 110 Faulkner SH, Jackson S, Fatania G, Leicht CA. The effect of passive heating on heat shock protein 70 and interleukin-6: A possible treatment tool for metabolic diseases?. Temperature 2017; 4 (03) 292-304
• 111 Brunt VE, Wiedenfeld-Needham K, Comrada LN, Minson CT. Passive heat therapy protects against endothelial cell hypoxia-reoxygenation via effects of elevations in temperature and circulating factors. J Physiol 2018; 596 (20) 4831-4845
• 112 Coombs GB, Tremblay JC. Passive heat therapy for cerebral protection: New ideas of age-old concepts. J Physiol 2019; 597 (02) 371-372
• 113 Hafen PS, Preece CN, Sorensen JR, Hancock CR, Hyldahl RD. Repeated exposure to heat stress induces mitochondrial adaptation in human skeletal muscle. J Appl Physiol 2018; 125 (05) 1447-1455
• 114 Hoekstra SP, Bishop NC, Faulkner SH, Bailey SJ, Leicht CA. Acute and chronic effects of hot water immersion on inflammation and metabolism in sedentary, overweight adults. J Appl Physiol 2018; 125 (06) 2008-2018
• 115 Hooper PL. Hot-tub therapy for type 2 diabetes mellitus. N Engl J Med 1999; 341 (12) 924-925
• 116 Gupte AA, Bomhoff GL, Swerdlow RH, Geiger PC. Heat treatment improves glucose tolerance and prevents skeletal muscle insulin resistance in rats fed a high-fat diet. Diabetes 2009; 58 (03) 567-578
• 117 Pallubinsky H, Phielix E, Dautzenberg B. et al. Passive exposure to heat improves glucose metabolism in overweight humans. Acta Physiol (Oxf) 2020; 229 (04) e13488
• 118 Von Schulze AT, Deng F, Fuller KNZ. et al. Heat treatment improves hepatic mitochondrial respiratory efficiency via mitochondrial remodeling. Function (Oxf) 2021; 2 (02) zqab001
• 119 Kokura S, Adachi S, Manabe E. et al. Whole body hyperthermia improves obesity-induced insulin resistance in diabetic mice. Int J Hyperthermia 2007; 23 (03) 259-265
• 120 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444 (7121): 860-867
• 121 Oishi Y, Manabe I. Macrophages in inflammation, repair and regeneration. Int Immunol 2018; 30 (11) 511-528
• 122 Ely BR, Clayton ZS, McCurdy CE. et al. Heat therapy improves glucose tolerance and adipose tissue insulin signaling in polycystic ovary syndrome. Am J Physiol Endocrinol Metab 2019; 317 (01) E172-E182
• 123 Capitano ML, Nemeth MJ, Mace TA. et al. Elevating body temperature enhances hematopoiesis and neutrophil recovery after total body irradiation in an IL-1-, IL-17-, and G-CSF-dependent manner. Blood 2012; 120 (13) 2600-2609
• 124 Capitano ML, Ertel BR, Repasky EA, Ostberg JR. Winner of the 2007 Society for Thermal Medicine Young Investigator Award. Fever-range whole body hyperthermia prevents the onset of type 1 diabetes in non-obese diabetic mice. Int J Hyperthermia 2008; 24 (02) 141-149
• 125 Sirviö J, Jolkkonen J, Pitkänen A. Adenohypophyseal hormone levels during hyperthermia. Endocrinologie 1987; 25 (01) 21-23
• 126 Leppäluoto J, Huttunen P, Hirvonen J, Väänänen A, Tuominen M, Vuori J. Endocrine effects of repeated sauna bathing. Acta Physiol Scand 1986; 128 (03) 467-470
• 127 Shepard AM, Bharwani A, Durisko Z, Andrews PW. Reverse engineering the febrile system. Q Rev Biol 2016; 91 (04) 419-457
• 128 Song K, Wang H, Kamm GB. et al. The TRPM2 channel is a hypothalamic heat sensor that limits fever and can drive hypothermia. Science 2016; 353 (6306): 1393-1398
• 129 Smadja DM. Hyperthermia for targeting cancer and cancer stem cells: Insights from novel cellular and clinical approaches. Stem Cell Rev Rep 2024; 20 (06) 1532-1539
• 130 Abreu MM, Smith RL, Ruskin K. et al. Previously unseen brain-eyelid thermal tunnel reveals biological waveguide and transorbital thermophysical pathway to the brain. . Authorea; October 2020. Accessed January 23, 2026 at: https://www.authorea.com/users/364278/articles/485634-previously-unseen-brain-eyelid-thermal-tunnel-reveals-biological-waveguide-and-transorbital-thermophysical-pathway-to-the-brain?commit=0898be4891196fcea3a794524bfeda14f9de2c65
• 131 Delalat S, Sultana I, Osman H. et al. Dysregulated inflammation, oxidative stress, and protein quality control in diabetic HFpEF: Unraveling mechanisms and therapeutic targets. Cardiovasc Diabetol 2025; 24 (01) 211
• 132 Calabrese V, Mancuso C, Sapienza M. et al. Oxidative stress and cellular stress response in diabetic nephropathy. Cell Stress Chaperones 2007; 12 (04) 299-306
• 133 Lazaro I, Oguiza A, Recio C. et al. Targeting HSP90 ameliorates nephropathy and atherosclerosis through suppression of NF-κB and STAT signaling pathways in diabetic mice. Diabetes 2015; 64 (10) 3600-3613
• 134 Barutta F, Pinach S, Giunti S. et al. Heat shock protein expression in diabetic nephropathy. Am J Physiol Renal Physiol 2008; 295 (06) F1817-F1824
• 135 Capitano ML, Ertel BR, Repasky EA, Ostberg JR. Winner of the 2007 Society for Thermal Medicine Young Investigator Award. Fever-range whole body hyperthermia prevents the onset of type 1 diabetes in non-obese diabetic mice. Int J Hyperthermia 2008; 24 (02) 141-149
• 136 Roth J, Blatteis CM. Mechanisms of fever production and lysis: Lessons from experimental LPS fever. Compr Physiol 2014; 4 (04) 1563-1604
• 137 Maiese K. New insights for oxidative stress and diabetes mellitus. Oxid Med Cell Longev 2015; 2015: 875961
• 138 Hirsch GE, Heck TG. Inflammation, oxidative stress and altered heat shock response in type 2 diabetes: The basis for new pharmacological and non-pharmacological interventions. Arch Physiol Biochem 2022; 128 (02) 411-425
• 139 Lee J-F, Wang D, Hsu Y-H, Chen HI. Oxidative and nitrosative mediators in hepatic injury caused by whole body hyperthermia in rats. Chin J Physiol 2008; 51 (02) 85-93
• 140 Ilangovan G, Osinbowale S, Bratasz A. et al. Heat shock regulates the respiration of cardiac H9c2 cells through upregulation of nitric oxide synthase. Am J Physiol Cell Physiol 2004; 287 (05) C1472-C1481
• 141 Cotter MA, Cameron NE. Effect of the NAD(P)H oxidase inhibitor, apocynin, on peripheral nerve perfusion and function in diabetic rats. Life Sci 2003; 73 (14) 1813-1824
• 142 Anderson CP, Pekas EJ, Park S-Y. Microvascular dysfunction in peripheral artery disease: Is heat therapy a viable treatment?. Int J Environ Res Public Health 2021; 18 (05) 2384
• 143 Jia G, Bai H, Mather B, Hill MA, Jia G, Sowers JR. Diabetic vasculopathy: Molecular mechanisms and clinical insights. Int J Mol Sci 2024; 25 (02) 804
• 144 Salybekov AA, Kobayashi S, Asahara T. Characterization of endothelial progenitor cell: Past, present, and future. Int J Mol Sci 2022; 23 (14) 7697
• 145 Rabczynski M, Fiodorenko-Dumas Z, Adamiec R, Paprocka-Borowicz M, Dumas I. Role of anti-HSP 60/65 antibodies in atherogenesis in patients with type 2 diabetes and lower limb ischemia. J Physiol Pharmacol 2012; 63 (06) 691-696
• 146 Teodoru M, Stoia O-M, Vladoiu M-G, Tonch-Cerbu AK. The role of HSP47 in thrombotic disorders: Molecular mechanism and therapeutic potential. Curr Issues Mol Biol 2025; 47 (04) 283
• 147 Hemanthakumar KA, Fang S, Anisimov A, Mäyränpää MI, Mervaala E, Kivelä R. Cardiovascular disease risk factors induce mesenchymal features and senescence in mouse cardiac endothelial cells. eLife 2021; 10: e62678
• 148 Khalil H, Kanisicak O, Vagnozzi RJ. et al. Cell-specific ablation of Hsp47 defines the collagen-producing cells in the injured heart. JCI Insight 2019; 4 (15) e128722
• 149 Blasi C, Kim E, Knowlton AA. Improved metabolic control in diabetes, HSP60, and proinflammatory mediators. Autoimmune Dis 2012; 2012: 346501
• 150 Gellai R, Hodrea J, Lenart L. et al. Role of O-linked N-acetylglucosamine modification in diabetic nephropathy. Am J Physiol Renal Physiol 2016; 311 (06) F1172-F1181
• 151 Fadini GP, Ferraro F, Quaini F, Asahara T, Madeddu P. Concise review: diabetes, the bone marrow niche, and impaired vascular regeneration. Stem Cells Transl Med 2014; 3 (08) 949-957
• 152 Makino H, Okada S, Nagumo A. et al. Decreased circulating CD34+ cells are associated with progression of diabetic nephropathy. Diabet Med 2009; 26 (02) 171-173
• 153 Tanaka R, Masuda H, Fujimura S. et al. Quality-quantity control culture enhances vasculogenesis and wound healing efficacy of human diabetic peripheral blood CD34+ cells. Stem Cells Transl Med 2018; 7 (05) 428-438
• 154 Tanaka R, Ito-Hirano R, Fujimura S. et al. Ex vivo conditioning of peripheral blood mononuclear cells of diabetic patients promotes vasculogenic wound healing. Stem Cells Transl Med 2021; 10 (06) 895-909
• 155 Ohtake T, Itaba S, Salybekov AA. et al. Repetitive administration of cultured human CD34+ cells improve adenine-induced kidney injury in mice. World J Stem Cells 2023; 15 (04) 268-280
• 156 Hassanpour M, Salybekov AA, Kobayashi S, Asahara T. CD34 positive cells as endothelial progenitor cells in biology and medicine. Front Cell Dev Biol 2023; 11: 1128134
• 157 Hassanpour M, Salybkov AA, Kobayashi S, Asahara T. Anti-inflammatory Prowess of endothelial progenitor cells in the realm of biology and medicine. NPJ Regen Med 2024; 9 (01) 27
• 158 Raleigh MJ, Pasricha SV, Nauth A, Ward MR, Connelly KA. Endothelial progenitor cells for diabetic cardiac and kidney disease. Stem Cells Transl Med 2024; 13 (07) 625-636
• 159 Wang X, Gu H, Huang W. et al. Hsp20-mediated activation of exosome biogenesis in cardiomyocytes improves cardiac function and angiogenesis in diabetic mice. Diabetes 2016; 65 (10) 3111-3128
• 160 Si S-C, Yang W, Luo H-Y, Ma YX, Zhao H, Liu J. Association of bone turnover biomarkers with severe intracranial and extracranial artery stenosis in type 2 diabetes mellitus patients. World J Diabetes 2023; 14 (05) 594-605
• 161 Salybekov AA, Tashov K, Sheng Y. et al. Cardioimmunology in health and diseases: Impairment of the cardio-spleno-bone marrow axis following myocardial infarction in diabetes mellitus. Int J Mol Sci 2024; 25 (21) 11833
• 162 Gruden G, Bruno G, Chaturvedi N. et al; EURODIAB Prospective Complications Study Group. Serum heat shock protein 27 and diabetes complications in the EURODIAB prospective complications study: A novel circulating marker for diabetic neuropathy. Diabetes 2008; 57 (07) 1966-1970
• 163 Yilmaz A, Gedikbasi A, Yuruk Yildirim Z. et al. Higher urine heat shock protein 70/creatinine ratio in type 1 diabetes mellitus. Ren Fail 2016; 38 (03) 404-410
• 164 Brudzynski K. Insulitis-caused redistribution of heat-shock protein HSP60 inside beta-cells correlates with induction of HSP60 autoantibodies. Diabetes 1993; 42 (06) 908-913
• 165 Brudzynski K, Cunningham IA, Martinez V. A family of hsp60-related proteins in pancreatic beta cells of non-obese diabetic (NOD) mice. J Autoimmun 1995; 8 (06) 859-874
• 166 Burkart V, Germaschewski L, Schloot NC, Bellmann K, Kolb H. Deficient heat shock protein 70 response to stress in leukocytes at onset of type 1 diabetes. Biochem Biophys Res Commun 2008; 369 (02) 421-425
• 167 Basu S, Binder RJ, Ramalingam T, Srivastava PK. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 2001; 14 (03) 303-313
• 168 Vig S, Buitinga M, Rondas D. et al. Cytokine-induced translocation of GRP78 to the plasma membrane triggers a pro-apoptotic feedback loop in pancreatic beta cells. Cell Death Dis 2019; 10 (04) 309
• 169 Ocaña GJ, Sims EK, Watkins RA. et al. Analysis of serum Hsp90 as a potential biomarker of β cell autoimmunity in type 1 diabetes. PLoS ONE 2019; 14 (01) e0208456
• 170 Dai T, Patel-Chamberlin M, Natarajan R. et al. Heat shock protein 27 overexpression mitigates cytokine-induced islet apoptosis and streptozotocin-induced diabetes. Endocrinology 2009; 150 (07) 3031-3039
• 171 Dodd SL, Hain B, Senf SM, Judge AR. Hsp27 inhibits IKKbeta-induced NF-kappaB activity and skeletal muscle atrophy. FASEB J 2009; 23 (10) 3415-3423
• 172 Diane A, Abunada H, Khattab N, Moin ASM, Butler AE, Dehbi M. Role of the DNAJ/HSP40 family in the pathogenesis of insulin resistance and type 2 diabetes. Ageing Res Rev 2021; 67: 101313
• 173 Liyanagamage DSNK, Martinus RD. Role of mitochondrial stress protein HSP60 in diabetes-induced neuroinflammation. Mediators Inflamm 2020; 2020: 8073516
• 174 Zimbone S, Di Rosa MC, Chiechio S, Giuffrida ML. Exploring the role of Hsp60 in Alzheimer's disease and type 2 diabetes: Suggestion for common drug targeting. Int J Mol Sci 2023; 24 (15) 12456

Publication History

Received: 15 October 2025

Accepted: 15 January 2026

Article published online:
09 February 2026