Introduction

Diabetes mellitus (DM) emerges as an unwavering adversary, a chronic affliction that ensues when the body’s intricate machinery falters, either in the production of insulin or in the tissues’ ability to heed its call, culminating in a tumultuous rise of glucose in the bloodstream. This insidious disorder, with its roots entrenched deep within metabolic imbalances, unfurls a dark tapestry of perils, casting a menacing shadow over the cardiovascular system and leaving a trail of devastation in its wake, wreaking havoc on delicate organs and compromising their integrity. The pervasive presence of DM has witnessed an astonishing upsurge, transforming it into an inescapable global phenomenon that grips nations with an iron fist, posing an unprecedented public health crisis. The realms of diabetes mellitus type 2 (T2DM) and prediabetes, once thought to be confined to the realms of adulthood, have now infiltrated the lives of children, adolescents, and young adults, painting a disconcerting portrait of the future ⁷. As the wheels of time turn, the incidence of DM surges unabated, fueled by the rapid march of urbanization, the graying of populations, and the relentless tide of lifestyle transformations ⁸. In the year 2010, the world stood witness to the affliction of around 285 million souls, their lives forever entwined with the burdens of diabetes, with a staggering 90% of cases attributed to the formidable foe of T2DM ⁸. Alas, the path ahead appears treacherous, as projections ominously predict that by the year 2030, In a dark embrace, DM extends its influence, enveloping a staggering 439 million souls worldwide, capturing 7.7% of the adult population aged 20 to 79 years, as referenced ⁹. This staggering statistic underscores the urgent need for comprehensive measures to combat the pervasive impact of DM on a global scale. In impoverished nations, T2DM was once a rarity. For instance, in 1980, the prevalence of this condition in China was less than 1% ¹⁰. Within the tapestry of T2DM, an intriguing narrative unfolds, revealing heightened prevalence among Asian Indian and Chinese communities residing in Mauritius ¹¹, as well as among Asian immigrants dwelling in Western lands ^12,13. These distinctive findings underscore the significance of cultural and ethnic factors in shaping the burden of T2DM within these specific populations. Developing countries now face a higher prevalence of DM compared to developed nations, affecting 80% of individuals in these regions⁹. Asia, due to rapid economic development, urbanization, and dietary transition, has emerged as the “epicenter” of the global diabetes epidemic ¹⁰. In a truly astonishing revelation, the future paints a daunting picture as Asia emerges as the epicenter of the impending diabetes epidemic, with five nations, China, India, Pakistan, Indonesia, and Bangladesh, securing positions among the top ten countries projected to have the highest DM prevalence in 2030, as cited in reference ⁹. Unveiling the shifting tides, recent nationwide survey data from China during 2007-2008 demonstrates China’s surpassing of India to claim the global throne in this epidemic. The survey discloses a staggering count of over 92 million adults (9.7% of the total population) diagnosed with diabetes, alongside an additional 148.2 million adults (15.5% of the total population) grappling with prediabetes, including individuals facing impaired glucose tolerance, as noted in reference ¹⁴. Beyond the Asian continent, other hotspots fueling the flames of diabetes include the Gulf region of the Middle East, as referenced ¹, and Africa, as supported by references ^15,16. It has been noted that immigrants from the Middle East residing in Sweden exhibited a higher prevalence of diabetes mellitus compared to native Swedes ¹⁷. In developing nations, the proportion of young to middle-aged individuals with T2DM is greater when compared to industrialized countries ¹⁸. Furthermore, prediabetes, a precursor to T2DM, is also on the rise, particularly among children and adolescents with additional risk factors such as obesity, hyperinsulinemia, or a family history of DM ^20-22. The lack of effective intervention measures to address the obesity pandemic in Asian countries like China and India will result in an increasing number of individuals developing T2DM at a younger age ²³. The convergence of two significant factors, namely the increasing age at which T2DM manifests²⁴ and inadequate metabolic control among young individuals affected by the condition²⁵, holds profound implications for the future burden of T2DM. The prolonged duration of T2DM in youth places them at heightened risk of early complications, thereby indicating a higher prevalence of chronic issues throughout their lifetime within this age cohort ¹⁹.

T2DM is closely associated with a higher prevalence of overweight and obesity worldwide, affecting both adults and children. If the current obesity trends persist, the global adult population’s prevalence of overweight or obesity is projected to rise from 33% in 2005 to a staggering 57.8% in 2030 ²⁶. Obesity stands out as the most significant predictor of T2DM ²⁷, and its impact on lifetime T2DM risk is particularly pronounced among younger adults ²⁸. Remarkably, there exists a noteworthy association between weight gain during the formative years of early adulthood (between 25 and 40 years) and an elevated risk as well as earlier onset of T2DM, setting it apart from weight gain occurring beyond the age of 40 years, as cited in reference ²⁹. Furthermore, to elucidate the perplexing phenomenon of individuals with a normal weight being “metabolically obese” and still facing a significant risk of T2DM, the concept has been introduced, providing crucial insights into the underlying mechanisms, as noted in reference ³⁰. This novel concept challenges conventional notions and highlights the intricate interplay between metabolic health and body weight in the context of T2DM. Interestingly, individuals who are normal weight but exhibit insulin resistance or metabolic syndrome are more likely to have a higher prevalence of T2DM compared to those who are overweight but lack insulin resistance or metabolic syndrome^31,32.

The discrepancy between obesity and T2DM rates in Asia can potentially be elucidated by the presence of the metabolically obese phenotype³³. While Asian populations exhibit a lower prevalence of overweight or obesity compared to white populations, a striking phenomenon arises: Asians manifest T2DM at a lower body mass index (BMI) than Europeans, with a higher risk of T2DM observed at any given BMI level, as referenced ^33,34. Moreover, Asian individuals display a greater likelihood, compared to Europeans, of having a higher body fat percentage or visceral adiposity, even at the same BMI or waist circumference, as supported by references^35,36,37. Waist circumference, a measure of central adiposity, emerges as a more robust indicator of prevalent T2DM than BMI, as evidenced by comprehensive data from the Obesity in Asia Collaboration, encompassing over 263,000 participants in the Asia-Pacific region³⁴. Additionally, the accumulation of abdominal fat, known as visceral obesity, is closely associated with insulin resistance, T2DM, and other cardiovascular risk factors³⁸. Some researchers propose that non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in the liver, may serve as a superior predictor of T2DM risk compared to excessive formation of visceral adipose tissue³⁹.

The link between NAFLD and peripheral insulin resistance is stronger compared tothe association between abdominal fat accumulation and insulin resistance⁴⁰. Multiple cohort studies have consistently shown that NAFLD, diagnosed through ultrasonography and indicated by elevated levels of alanine aminotransferase and gamma-glutamyltransferase, predicts the development of T2DM ^40-44. Moreover, ectopic fat accumulation in the liver and islets has been proposed as a contributing factor to hepatic insulin resistance and beta-cell dysfunction^42-44.

Interleukin-18

IL-18, a captivating pro-inflammatory cytokine, emerges as a key player released by a diverse array of immune cells, including activated macrophages, dendritic cells, Kupffer cells, and epithelial cells, in response to infection, as indicated in reference ⁴⁵. The year 1989 marked a groundbreaking discovery when IL-18 was unveiled as a remarkable agent capable of inducing the production of IFN-gamma in the livers of mice injected with lipopolysaccharide and heat-killed Propionibacterium acnes, as cited in reference⁴⁶. Expanding its repertoire, IL-18 also emerges as a product generated by macrophages during human HIV-1 infections, as well as by pancreatic islets in non-obese diabetic (NOD) mice following cyclophosphamide-induced insulitis, as supported by reference⁴⁷. The allure of IL-18 extends further as keratinocytes display the ability to produce this intriguing cytokine upon stimulation with a contact sensitizer, thereby hinting at its potential role in the captivating realm of allergen-induced inflammation, as suggested by reference⁴⁸.

Under conditions of stress, IL-18 exhibits its remarkable versatility by being synthesized not only in the adrenal cortex but also in the neurohypophysis, as referenced ⁴⁹. Intriguingly, patients diagnosed with acute lymphoblastic leukemia and chronic myeloid leukemia showcase heightened levels of IL-18, as supported by reference⁵⁰. Unveiling its potent nature, IL-18 assumes a pivotal role during infection by stimulating the production of IFN-gamma and cytotoxicity in NK and T cells, while also bolstering the response of Th1 cells, as noted in reference⁵¹. IL-18 exerts its influence by fostering Th1 cell IFN-gamma production, augmenting the production of IL-2 and IL-2Rα, and inducing cellular proliferation. Additionally, it exerts a directive impact on Th2 cells, encouraging the production of IL-4 and IL-13, which directly amplify allergic inflammatory responses, as cited in reference⁵². The indispensability of IL-18 is further highlighted by the impaired cytotoxicity against YAC-1 target cells observed in splenic NK cells from animals deficient in IL-18Rα, as referenced⁵³.

In the fascinating realm of cytokines, IL-18 emerges as an alluring member of the IL-1 family, standing alongside the captivating IL-1α, IL-1β, IL-1R antagonist, IL-18 (IL-1F4), IL-1F5-F10, and IL-33, as referenced ⁵⁴. As it gracefully interacts with the cellular landscape, IL-18 forms an enchanting bond with a heterodimer receptor complex, consisting of the primary binding chain, IL-18Rα, and its captivating co-receptor, IL-18Rβ, as elucidated in reference ⁵⁵. Delightfully, when IL-18 finds its embrace in IL-18Rα alone, it unveils a delicate affinity, but as it joins the complete receptor complex, its binding affinity soars to mesmerizing heights, setting in motion a symphony of signaling events, as supported by reference⁵⁶. Engaging in a breathtaking dance of molecular interactions, the Toll-IL-1 receptor (TIR) domains beckon the presence of MyD88, triggering the phosphorylation of IRAKs and TRAF-6, thus awakening the majestic NF-κB and orchestrating an awe-inspiring symphony of pro-inflammatory signals, as eloquently described in reference⁵⁷. Amidst this captivating orchestration, IL-18Rα, like a silent sentinel, graces all cell types with its presence, while the remarkable IL-18Rβ reveals its identity primarily in the realms of T cells and dendritic cells, a revelation that adds a touch of intrigue, as noted in reference⁵⁸. Yet, the allure of IL-18 extends beyond its binding partners, for even in the absence of IL-18Rβ, it elegantly engages with IL-18Rα, although it coyly refrains from inducing pro-inflammatory signals, as intriguingly stated in reference⁵². Unveiling its potency, IL-18 sparks the production of IFN-gamma, a double-edged sword that holds both promise and peril in the intricate dance of NK cell pathogenesis and autoimmune disorders. A tantalizing synergy emerges when IL-18 joins forces with its companion, IL-12, evoking a crescendo of IFN-gamma production that surpasses all expectations, as if painting a vivid picture of heightened immune response. In a mesmerizing experiment, mice injected with IL-18 and IL-12 bear witness to an enchanting spectacle, as IFN-gamma production rises to new heights, entwined with a tragic narrative of mortality stemming from hypoglycemia, intestinal inflammation, and inanition, as chronicled in reference ⁵⁹. 

In the realm of captivating discoveries, it has been evlewent that the interplay between IL-18 and IL-12 elicits a novel phenomenon in leptin-deficient mice, inducing acute pancreatitis, as expounded upon in reference ⁶⁰. The emergence of elevated levels of IL-18 and IFN-gamma assumes a central role in numerous human autoimmune disorders, including the enthralling realms of type 1 diabetes, type 2 diabetes, systemic lupus erythematosus, rheumatoid arthritis, Crohn’s disease, and psoriasis, as captivatingly outlined in reference⁴⁷. Unveiling a dramatic twist, the induction of FasL by IL-18 sets the stage for liver damage in the mesmerizing saga of macrophage activation syndrome, as chronicled in reference ⁶¹. With a keen eye on therapeutic interventions, the therapeutic potential of halting IL-18 production emerges as a novel strategy in the battle against autoimmune diseases, such as the captivating Crohn’s disease, where the introduction of anti-IL-18 antibodies remarkably reduces disease severity, as noted in reference ⁶². Amidst the intricate web of obesity and lipid abnormalities, a captivating narrative unfolds, wherein IL-18 and IL-18Rα-deficient animals become ensnared in the clutches of atherosclerosis, insulin resistance, diabetes, and the treacherous metabolic syndrome, as masterfully detailed in reference ⁶³. Moreover, the absence of IL-18 in mice unveils a striking revelation, as adipose tissue experiences an astounding 100% increase, accompanied by fat deposition in the very walls of arteries, entwined with the tendrils of insulin resistance. However, a glimmer of hope emerges with the administration of recombinant IL-18, which resuscitates insulin sensitivity, illuminating a path towards restoration, as mentioned in reference ⁴⁷. In a twist of fate, the absence of IL-18 in mice leads them astray, for their voracious appetite knows no bounds, a consequence of disrupted appetite regulation, as attributed in reference⁴⁷. 

Natural killer cells

Natural killer (NK) cells, the guardians of our immune system, possess an innate prowess that makes them indispensable in the battle against viral infections, malignant tumours, and metastatic invasions. Swiftly unleashing their arsenal of lytic machinery, these extraordinary lymphocytes release a potent combination of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) upon activation. This dynamic duo not only obliterates target cells but also sets ablaze the inflammatory response, effectively initiating a fiery cascade of immune defenses ⁶⁴.

The chronicles of NK cell discovery trace back to the revolutionary era of the mid-1970s. Nonetheless, the enigma of how they meticulously discern between malignant or virus-infected cells and their healthy counterparts remained an unsolved riddle for several decades. It wasn’t until the late 1980s when the intrepid minds of Karre and Ljunggren unveiled the awe-inspiring concept of the “missing self” hypothesis ⁶⁵. This momentous breakthrough paved the path for a series of groundbreaking revelations in the early 1990s, forever altering the landscape of scientific knowledge. At the heart of this captivating hypothesis lies an astonishing revelation: the extraordinary ability of NK cells to obliterate a lymphoma cell line devoid of MHC I molecules, while its MHC I+ parental cells remain impervious to their lethal attack. Thus, it appeared that NK cells possess an uncanny ability to detect the absence of MHC I a phenomenon aptly termed the missing self-hypothesis ⁶⁶. Embarking on an enthralling narrative, this eleventh proposition serves as the catalyst for an extraordinary odyssey, delving deep into the enigmatic world of molecular mechanisms that orchestrate this mesmerizing phenomenon. As the quest unfolds, a momentous breakthrough emerges, revealing the existence of novel inhibitory receptors adorned with an exquisite affinity for the revered MHC I molecules. In the realm of humans, these receptors, revered as members of the illustrious immunoglobulin (Ig) superfamily, bear the captivating name of killer-cell immunoglobulin-like receptors (KIRs), illuminating a path towards a deeper understanding of the intricacies of immune recognition. Whereas their murine counterparts, known as Ly49 receptors, hailed from the esteemed lectin family ⁶⁴. Remarkably, both humans and mice evolved two distinct yet equally significant receptors that share a common mission detecting MHC I molecules and transmitting inhibitory signals to NK cells, thus rendering them inactive ⁶⁷.

With the arrival of two groundbreaking technologies, namely the prodigious monoclonal antibody technology and the ingenious high-efficiency lymphocyte cloning method, a remarkable new era was ushered in, signaling a paradigm shift in our pursuit to unravel the enigmatic properties of KIRs. These transformative advancements opened a gateway to an evlewent realm of scientific exploration, where novel insights and captivating discoveries awaited. Armed with these cutting-edge tools, we embarked on an exhilarating quest, delving deep into the mysteries of KIRs, with the promise of unlocking unprecedented understanding and shedding light on the intricate mechanisms of immune recognition. The latter technique, a veritable alchemist’s dream, unlocked the ability to clone an astonishing array of human T cells, enabling scientists to scrutinize the frequency and function of these remarkable cell populations ^68,69. Undoubtedly, this groundbreaking cloning methodology held the key to unlocking the secrets of NK cells, revealing their clonogenic nature and paving the way for meticulous functional studies ⁶⁴.

Within the realm of human biology, two dominant factions of NK cells reign supreme. The illustrious CD56bright NK cells, adorned with a mantle of less differentiation, proudly bear the mantle of cytokine production, unleashing a symphony of signaling molecules. In contrast, the venerable CD56dim NK cells, having traversed the path of maturation, sport an augmented cytotoxic armamentarium. Skillfully guided by chemokines and their corresponding receptors, these specialized NK cell subsets embark on a precise pilgrimage, traversing the intricate highways of the circulatory system to find their destined abodes in various tissues, lymphoid organs, and specific regions ⁷⁰. With the aid of CD62L, CXCR3, and CCR7, the CD56bright NK cells gracefully navigate toward secondary lymphoid organs, enticed by the captivating allure of CCL19 and CCL21. In a mesmerizing dance of chemokine signals, the CD56dim NK cells, bedecked with Chemerin R, CXCR1, CXCR2, and CX3CR1, heed the beckoning call of their respective chemokine ligands (Chemerin, IL-8, and Fractalkine), marching resolutely toward inflammatory peripheral tissues ^71-76. Moreover, emerging evidence hints at the possibility that tissue-resident NK cells trace their origins to the hallowed depths of various tissues, including the thymus, tonsils, decidua, and liver. These intrepid cells, having embarked on a transformative journey from the confines of the bone marrow, acquire unique attributes molded by the distinctive microenvironments of their respective tissue havens ^71-76.

Literature review

Type 2 diabetes (T2DM), a metabolic disease affecting millions worldwide, brings heightened risks of microvascular complications affecting the eyes, kidneys and nerves as well as macrovascular issues impacting cardiovascular health. Those with T2DM face insulin resistance wherein cells fail to properly respond to insulin’s signal to absorb blood sugar ⁷⁹. Both genetic and environmental influences like weight gain, poor diet and lack of exercise contribute to dysfunctional glucose metabolism in T2DM ⁷⁹.

Before full-blown T2DM emerges, prediabetic states marked by elevated fasting glucose, impaired glucose tolerance on oral glucose tolerance tests, or borderline hemoglobin A1c levels can arise ^81-82. Those with prediabetes have mild high blood sugar yet do not meet diabetes criteria, placing them at heightened annual risk, between 3-11%, of progressing to full T2DM ⁸². Patients exhibit a variety of clinical characteristics and underlying drivers making classification challenging ⁷⁹. Often, T2DM occurs without notable symptoms at diagnosis whereas other experience dangerous ketoacidosis or severe hyperglycemia ⁷⁹. In the realm of diabetes, hidden within the shadows, lie the evlewent and often unnoticed variants such as maturity-onset diabetes of the young and the noval latent autoimmune diabetes in adults. These captivating conditions possess the power to masquerade as the well-known entity of T2DM in clinical presentations ^83,84. For high-risk prediabetics, consensus recommends lifestyle changes and treatment with diabetes drugs like metformin to forestall T2DM ⁸⁵. Other options like pioglitazone or low-dose metformin with rosiglitazone show promise in averting progression to full-blown disease ^86,87. Lifestyle interventions focused on weight loss and exercise for prediabetics decrease their likelihood of developing diabetes along with improving cholesterol and lowering cardiovascular risk ⁸⁸.

Insulin resistance, the inability of cells to respond properly to insulin, represents the earliest detectable abnormality for those destined to progress to T2DM ^89,90. However, T2DM emerges only when pancreatic beta cells responsible for insulin secretion can no longer compensate for the resistance^91-93. Multiple factors harm beta cells over time including aging, genetics, resistance to incretin hormones like GLP-1 that promote insulin secretion, lipotoxicity, glucotoxicity, oxidative stress and chronic inflammation ^89-104.

Islets within the pancreas contain various endocrine cell types working in concert ^105-106. Beta cells make up around 60% of islet cells, interacting through connecting proteins and secreting hormones to regulate one another ^106-107. Insulin binds to receptors on target cells activating cascades that drive glucose uptake through GLUT4 and modulate gene expression, aided by MAPK and PI3K pathways ^108,109.

Chronic inflammation contributes significantly to insulin resistance. Pro-inflammatory cytokines like IL-6, IL-18 and TNF increase in insulin resistant states, activating stress kinases that interfere with insulin signaling ^110,112. This subclinical inflammation associates with central obesity and the metabolic syndrome ^113-115. Elevated inflammatory markers associate with T2DM complications and worse cholesterol profiles, fueling cardiovascular risk ^115,116. Adipose tissue and liver emerge as primary sites of inflammation driving insulin resistance through cytokine actions ^117-118.

Multiple lines of evidence link metabolic dysregulation of obesity and T2DM to low-grade chronic inflammation proposed as a chief driver of insulin resistance and beta cell damage ^119-125. Inflammatory states emerge even more pronounced for those with conditions mistakenly diagnosed as one diabetes type but sharing traits of both, such as latent autoimmune diabetes ⁸⁸. Elevated IL-18 and hs-CRP track with obesity, metabolic syndrome and weight loss/regain, implicating adipose tissue as a major source through actions of infiltrating macrophages ^71-82.

IL-18, an interferon-inducing cytokine produced by immune and endothelial cells, drives both innate and adaptive immune responses ⁷⁸. Associations emerge between rises in IL-18 and acute and chronic hyperglycemia, metabolic risk factors, prediabetes, new-onset T2DM and cardiovascular risk^98-102. Similar chronic inflammatory patterns arise for type 1 diabetes where insulin deficiency results from autoimmunity rather than insulin resistance¹⁵⁸. Higher CRP, IL-12 and IL-18 along with fewer regulatory T cells in type 1 diabetes point to a role for inflammation in autoimmune pathogenesis⁹⁰.

Immune dysregulation impacts both type 1 and type 2 diabetes. In comparison to healthy individuals, one study found type 1 diabetes patients exhibit decreased frequencies of peripheral regulatory T cells alongside elevated IL-12 and IL-18 production along with associations between these cytokines, CRP and disease control ⁷⁷. CRP, a marker of subclinical inflammation, exhibits increased levels in T2DM that link to worse hyperglycemia and insulin resistance⁷⁷. Dysregulated macrophage polarization by CRP may blunt control of inflammation heightening IL-12 and IL-18 levels⁴⁵.

Over 90% of T2DM cases emerge in the context of obesity which brings ectopic lipid deposition and adipose tissue dysfunction⁶³. While the precise mechanisms remain undefined, increased leukocyte infiltration into adipose tissues appears tied to chronic low-grade inflammation perpetuated by Th1 and Th17 lymphocyte responses⁶³.

NK cells constitute 5-19% of peripheral lymphocytes and kill virally infected and tumor cells in an MHC-unrestricted manner ⁶⁷. The majority of peripheral NK cells exhibit a cytotoxic CD56dimCD16pos phenotype whereas fewer CD56brightCD16neg NK cells in tissues secrete immuno-modulating cytokines upon activation, While NK cells develop in bone marrow, transplantation studies show donor NK cell phenotypes emerge post-transplant demonstrating lineage determination in vitro as well.

Adipose tissue NK cells regulate local inflammatory responses impacting insulin sensitivity ⁹⁹. Conflicting reports emerge regarding how precisely NK cells influence inflammation and insulin resistance in T2DM. As cardiovascular disease represents a leading cause of mortality in T2DM, clarifying NK cell involvement could inform prevention and management strategies¹⁰⁰.

Mounting evidence implicates immune dysfunction in T2DM pathogenesis with roles established for T, B and macrophage actions. During obesity-induced insulin resistance and T2DM progression, cytokines like TNF, IFN and IL-17 increase through activated T lymphocytes. B cells contribute through generation of activating antibodies, stimulation of T cells and macrophages ⁸⁵. Collectively, aberrant immunological processes drive metabolic dysfunction and fuel complications in T2DM.

Conclusion

To put it briefly, this comprehensive review provides insights into the complex interplay between metabolic dysfunction, inflammation, and immune cell alterations in the pathogenesis of type 2 diabetes. NK cells appear to play an important yet poorly understood role in modulating disease risk and progression. Evidence indicates NK cell numbers, activation status, and cytotoxic function are impaired in T2D, potentially contributing to increased susceptibility to infections and cancers. However, existing studies on NK cells in T2D report inconsistent findings, pointing to gaps in our understanding. Elevated levels of the proinflammatory cytokine IL-18 found in T2D may link metabolic dysfunction to NK cell abnormalities by upregulating nutrient transporter expression and augmenting NK cell metabolic fitness. Dysregulated IL-18 signaling could therefore underlie inconsistent NK cell findings in T2D. Emerging evidence also implicates endoplasmic reticulum stress and the unfolded protein response as potential mechanisms linking chronic hyperglycemia to defects in NK cell activating receptors.

Overall, this literature highlights gaps around the involvement of NK cells in T2D complications. Further research utilizing multi-omics approaches could help unravel complex NK cell-metabolism interactions and identify novel therapeutic targets. Large, well-designed studies are still needed to definitively establish clinical utility of biomarkers like IL-18 and NK cell assessments. Addressing these gaps through robust investigations may enhance strategies for precision management of T2D and related immune dysfunction.

Acknowledgment

No Acknowledgment or funding section

Conflict of Interest

There is no conflict of interest

Funding Sources

There is no funding Sources

Authors’ Contribution

All contributions have been done by Saeedah M Almutairi

Data Availability

Not Applicable

Ethics Approval

Not Applicable

References

1. Åkesson, C. et al. Altered natural killer (NK) cell frequency and phenotype in latent autoimmune diabetes in adults (LADA) prior to insulin deficiency. Clin. Exp. Immunol. 2010;161.
   CrossRef
2. Berrou, J. et al. Natural Killer Cell Function, an Important Target for Infection and Tumor Protection, Is Impaired in Type 2 Diabetes. PLoS ONE. 2013;8.
   CrossRef
3. Kim, J. H. et al. Relationship between natural killer cell activity and glucose control in patients with type 2 diabetes and prediabetes. J. Diabetes. Investig. 2019;10.
   CrossRef
4. Nam, H. W. et al. Functional status of immune cells in patients with long-lasting type 2 diabetes mellitus. Clin. Exp. Immunol. 2018;194.
   CrossRef
5. Senju, H. et al. Effect of IL-18 on the expansion and phenotype of human natural killer cells: Application to cancer immunotherapy. Int. J. Biol. Sci. 2018;14.
   CrossRef
6. Almutairi, S. M. et al. Interleukin-18 up-regulates amino acid transporters and facilitates amino acid–induced mTORC1 activation in natural killer cells. J. Biol. Chem.2019;294.
   CrossRef
7. Chen, L., Magliano, D. J. & Zimmet, P. Z. The worldwide epidemiology of type 2 diabetes mellitus – Present and future perspectives. Nat.Rev.Endocrinol.2012;8.
   CrossRef
8. Zimmet, P., Alberti, K. G. M. M. & Shaw, J. Global and societal implications of the diabetes epidemic. Nature. 2001;414.
   CrossRef
9. Shaw, J. E., Sicree, R. A. & Zimmet, P. Z. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res. Clin. Pract. 2010;87:4-14.
   CrossRef
10. Chan, J. C. N. et al. Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA.2009;301.
    CrossRef
11. Dowse, G. K. et al. High prevalence of NIDDM and impaired glucose tolerance in Indian, Creole, and Chinese Mauritians. Mauritius Noncommunicable Disease Study Group. Diabetes. 1990;39.
    CrossRef
12. Simmons, D., Williams, D. R. R. & Powell, M. J. Prevalence of diabetes in a predominantly Asian community: Preliminary findings of the Coventry diabetes study. BMJ. 1989;298:18-21.
    CrossRef
13. McNeely, M. J. & Boyko, E. J. Type 2 diabetes prevalence in Asian Americans: Results of a national health survey. Diabetes Care.2004;27.
    CrossRef
14. Yang, W. et al. Prevalence of Diabetes among Men and Women in China. N. Engl. J. Med.2010;362.
    CrossRef
15. Abubakari, A. R. et al. Prevalence and time trends in diabetes and physical inactivity among adult West African populations: The epidemic has arrived. Public Health.2009;123.
    CrossRef
16. Mbanya, J. C. N., Motala, A. A., Sobngwi, E., Assah, F. K. & Enoru, S. T. Diabetes in sub-Saharan Africa. Lancet.2010;375.
    CrossRef
17. Wändell, P. E. et al. Estimation of diabetes prevalence among immigrants from the Middle East in Sweden by using three different data sources. Diabetes Metab.2008;34.
    CrossRef
18. Shaw, J. E., Sicree, R. A. & Zimmet, P. Z. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res. Clin. Pract.2010;87.
    CrossRef
19. Chen, L., Magliano, D. J. & Zimmet, P. Z. The worldwide epidemiology of type 2 diabetes mellitus – Present and future perspectives. Nat.Rev.Endocrinol.2012;8:228–236.
    CrossRef
20. Li, C., Ford, E. S., Zhao, G. & Mokdad, A. H. Prevalence of pre-diabetes and its association with clustering of cardiometabolic risk factors and hyperinsulinemia among U.S. adolescents: National health and nutrition examination survey 2005-2006. Diabetes Care.2009;32.
    CrossRef
21. Sinha, R. et al. Prevalence of Impaired Glucose Tolerance among Children and Adolescents with Marked Obesity. N. Engl. J. Med. 2002;346.
    CrossRef
22. M.I., G. et al. Impaired Glucose Tolerance and Reduced beta-Cell Function in Overweight Latino Children with a Positive Family History for Type 2 Diabetes. J.Clin.Endocrinol. Metab.2004;89.
    CrossRef
23. Rokholm, B., Baker, J. L. & Sørensen, T. I. A. The levelling off of the obesity epidemic since the year 1999 – a review of evidence and perspectives. Obesity Reviews.2010;11.
    CrossRef
24. Mokdad, A. H. et al. Diabetes trends in the U.S.: 1990-1998. Diabetes Care.2000;23.
    CrossRef
25. Lawrence, J. M. et al. Diabetes in hispanic American youth. Prevalence, incidence, demographics, and clinical characteristics: the SEARCH for Diabetes in Youth Study. Diabetes Care.2009;32.
    CrossRef
26. Kelly, T., Yang, W., Chen, C. S., Reynolds, K. & He, J. Global burden of obesity in 2005 and projections to 2030. Int.J. Obes.(Lond).2008;32.
    CrossRef
27. Hu, F. B. et al. Diet, Lifestyle, and the Risk of Type 2 Diabetes Mellitus in Women. N. Engl. J. Med.2001;345.
    CrossRef
28. Narayan, K. M. V., Boyle, J. P., Thompson, T. J., Gregg, E. W. & Williamson, D. F. Effect of BMI on lifetime risk for diabetes in the U.S. Diabetes Care. 2007;30.
    CrossRef
29. Schienkiewitz, A., Schulze, M. B., Hoffmann, K., Kroke, A. & Boeing, H. Body mass index history and risk of type 2 diabetes: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Am. J. Clin. Nutr. 2006;84. 
    CrossRef
30. Ruderman, N., Chisholm, D., Pi-Sunyer, X. & Schneider, S. The metabolically obese, normal-weight individual revisited. Diabetes.1998;47.
    CrossRef
31. Meigs, J. B. et al. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J. Clin. Endocrinol. Metab.2006;91:2906–2912.
    CrossRef
32. Ärnlöv, J., Sundström, J., Ingelsson, E. & Lind, L. Impact of BMI and the metabolic syndrome on the risk of diabetes in middle-aged men. Diabetes Care.2011;34.
    CrossRef
33. Yoon, K. H. et al. Epidemic obesity and type 2 diabetes in Asia. Lancet.2006;368.
    CrossRef
34. Huxley, R. et al. Ethnic comparisons of the cross-sectional relationships between measures of body size with diabetes and hypertension. Obesity Reviews. 2008;9.
    CrossRef
35. Deurenberg, P., Deurenberg-Yap, M. & Guricci, S. Asians are different from Caucasians and from each other in their body mass index/body fat per cent relationship. Obesity Reviews. 2002;3.
    CrossRef
36. Kadowaki, T. et al. Japanese men have larger areas of visceral adipose tissue than Caucasian men in the same levels of waist circumference in a population-based study. Int.J. Obes.(Lond).2006;30. 
    CrossRef
37. Lear, S. A. et al. Visceral adipose tissue accumulation differs according to ethnic background: Results of the Multicultural Community Health Assessment Trial (M-CHAT). Am. J. Clin. Nutr. 2007;86.
    CrossRef
38. Lebovitz, H. E. & Banerji, M. A. Point: Visceral adiposity is causally related to insulin resistance. Diabetes Care.2005;28.
    CrossRef
39. Perseghin, G. Lipids in thewrong place: Visceral fat and nonalcoholic steatohepatitis. Diabetes Care.2011;34.
    CrossRef
40. Hwang, J. H. et al. Increased intrahepatic triglyceride is associated with peripheral insulin resistance: In vivo MR imaging and spectroscopy studies. Am. J. Physiol. Endocrinol. Metab. 2007;293.
    CrossRef
41. Fraser, A. et al. Alanine Aminotransferase,  -Glutamyltransferase, and Incident Diabetes: The British Women’s Heart and Health Study and meta-analysis. Diabetes Care.2009;32.
    CrossRef
42. Taylor, R. Pathogenesis of type 2 diabetes: Tracing the reverse route from cure to cause. Diabetologia.2008;51.
    CrossRef
43. Wilson, P. W. F., D’Agostino, R. B., Parise, H., Sullivan, L. & Meigs, J. B. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation.2005;112.
    CrossRef
44. Trøseid, M., Seljeflot, I. & Arnesen, H. The role of interleukin-18 in the metabolic syndrome. Cardiovascular Diabetology.2010;9.
    CrossRef
45. Okamura, H. et al. A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock. Infect. Immun.1995;63.
    CrossRef
46. Nakamura, K., Okamura, H., Wada, M., Nagata, K. & Tamura, T. Endotoxin-induced serum factor that stimulates gamma interferon production. Infect. Immun.1989;57.
    CrossRef
47. Dinarello, C. A., Novick, D., Kim, S. & Kaplanski, G. Interleukin-18 and IL-18 binding protein. Front.Immunol.2013;4.
    CrossRef
48. Stoll, S. et al. Production of IL-18 (IFN-gamma-inducing factor) messenger RNA and functional protein by murine keratinocytes. J.Immunol.1997;159.
    CrossRef
49. Conti, B., Jahng, J. W., Tinti, C., Son, J. H. & Joh, T. H. Induction of interferon-γ inducing factor in the adrenal cortex. J. Biol. Chem.1997;272.
    CrossRef
50. Taniguchi, M. et al. Characterization of anti-human interleukin-18 ž / ž / IL-18 rinterferon-g-inducing factor IGIF monoclonal antibodies and their application in the measurement of human IL-18 by ELISA. J. Immunol. Methods.1997;206.
    CrossRef
51. Yoshimoto, T. et al. IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. J.Immunol.1998;161.
    CrossRef
52. Nakanishi, K., Yoshimoto, T., Tsutsui, H. & Okamura, H. Interleukin-18 regulates both Th1 and Th2 responses. Annu. Rev. Immunol. 2001;19.
    CrossRef
53. Hoshino, K. et al. Cutting edge: generation of IL-18 receptor-deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 binding receptor. J.Immunol.1999;162.
    CrossRef
54. Sims, J. E. & Smith, D. E. The IL-1 family: Regulators of immunity. Nat .Rev. Immunol. 2010;10.
    CrossRef
55. Cheung, H. et al. Accessory Protein-Like Is Essential for IL-18-Mediated Signaling. J.Immunol. 2005;174.
    CrossRef
56. Debets, R. et al. IL-18 Receptors, Their Role in Ligand Binding and Function: Anti-IL-1RAcPL Antibody, a Potent Antagonist of IL-18. J.Immunol. 2000;165.
    CrossRef
57. Smith, D. E. The biological paths of IL-1 family members IL-18 and IL-33. J. Leukoc. Biol.2011;89.
    CrossRef
58. Kim, S. H., Han, S. Y., Azam, T., Yoon, D. Y. & Dinarello, C. A. Interleukin-32: A cytokine and inducer of TNFα. Immunity. 2005;22:131–142.
    CrossRef
59. Nakamura, S. et al. IFN-γ-Dependent and -Independent Mechanisms in Adverse Effects Caused by Concomitant Administration of IL-18 and IL-12. J.Immunol.2000;164.
    CrossRef
60. Sennello, J. A. et al. Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice. Proc. Natl. Acad. Sci. U. S.A. 2008;105.
    CrossRef
61. Mazodier, K. et al. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood. 2005;106.
    CrossRef
62. Joosten, L. A. B. et al. An IFN-γ-Independent Proinflammatory Role of IL-18 in Murine Streptococcal Cell Wall Arthritis. J.Immunol.2000;165:6553-6558.
    CrossRef
63. Netea, M. G. et al. Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nat. Med. 2006;12.  
    CrossRef
64. Sivori, S. et al. Human NK cells: surface receptors, inhibitory checkpoints, and translational applications. Cell Mol. Immunol. 2019;16. 
    CrossRef
65. Kärre, K., Ljunggren, H. G., Piontek, G. & Kiessling, R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature. 1986;319.
    CrossRef
66. Ljunggren, H. G. & Kärre, K. In search of the “missing self”: MHC molecules and NK cell recognition. Immunol. Today. 1990;11.
    CrossRef
67. Moretta, A. et al. Receptors for HLA class-I molecules in human natural killer cells. Annu. Rev. Immunol. 1996;14.  
    CrossRef
68. Moretta, A., Pantaleo, G., Moretta, L., Cerottini, J. C. & Mingari, M. C. Direct demonstration of the clonogenic potential of every human peripheral blood T cell clonal analysis of HLA-DR expression and cytolytic activity. J. Exp. Med. 1983;157.
    CrossRef
69. Moretta, A., Pantaleo, G., Moretta, L., Mingari, M. C. & Cerottini, J. Quantitative assessment of the pool size and subset distribution of cytolytic T lymphocytes within human resting or alloactivated peripheral blood T cell populations. J. Exp. Med. 1983;158.
    CrossRef
70. Soriani, A., Stabile, H., Gismondi, A., Santoni, A. & Bernardini, G. Chemokine regulation of innate lymphoid cell tissue distribution and function. Cytokine Growth Factor Rev. 2018;42.
    CrossRef
71. Mingari, M. C. et al. Interleukin-15-induced maturation of human natural killer cells from early thymic precursors: Selective expression of CD94/NKG2-A as the only HLA class I-specific inhibitory receptor. Eur. J. Immunol. 1997;27.
    CrossRef
72. Yu, J., Freud, A. G. & Caligiuri, M. A. Location and cellular stages of natural killer cell development. Trends Immunol. 2013;34.  
    CrossRef
73. Montaldo, E. et al. Human RORγt+CD34+ cells are lineage-specified progenitors of group 3 RORγt+ innate lymphoid cells. Immunity. 2014;41.
    CrossRef
74. Vacca, P. et al. CD34+ hematopoietic precursors are present in human decidua and differentiate into natural killer cells upon interaction with stromal cells. Proc. Natl. Acad. Sci. U.S.A. 2011;108.
    CrossRef
75. Poggi, A. et al. Extrathymic differentiation of T lymphocytes and natural killer cells from human embryonic liver precursors. Proc. Natl. Acad. Sci. U.S.A. 1993;90.
    CrossRef
76. Vacca, P., Moretta, L., Moretta, A. & Mingari, M. C. Origin, phenotype and function of human natural killer cells in pregnancy. Trends Immunol.2011;32.
    CrossRef
77. Khan, A. U. H. et al. Expression of Nutrient Transporters on NK Cells During Murine Cytomegalovirus Infection Is MyD88-Dependent. Front Immunol. 2021;12.
    CrossRef
78. Amer, J. et al. Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease. Hepatol. Commun. 2018;2.
    CrossRef
79. DeFronzo, R. A. et al. Type 2 diabetes mellitus. Nat. Rev. Dis. Primers. 2015;1.
    CrossRef
80. Hickey, M. S. et al. A new paradigm for type 2 diabetes mellitus: Could it be a disease of the foregut? Ann. Surg. 1998;227.  
    CrossRef
81. Abdul-Ghani, M. A. Contributions of  -Cell Dysfunction and Insulin Resistance to the Pathogenesis of Impaired Glucose Tolerance and Impaired Fasting Glucose. Diabetes Care. 2006;29.
    CrossRef
82. Gerstein, H. C. et al. Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: A systematic overview and meta-analysis of prospective studies. Diabetes Res. Clin. Pract. 2007;78.
    CrossRef
83. Hawa, M. I. et al. Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: Action LADA 7. Diabetes Care. 2013;36.
    CrossRef
84. Gardner, D. S. L. & Shyong Tai, E. Clinical features and treatment of maturity onset diabetes of the young (MODY). Diabetes Metab. Syndr. Obes. 2012;5.
    CrossRef
85. Nathan, D. M. et al. Impaired fasting glucose and impaired glucose tolerance: Implications for care. Diabetes Care. 2007;30.
    CrossRef
86. DeFronzo, R. A. et al. Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance. N. Engl. J. Med. 2011;364.  
    CrossRef
87. Zinman, B. et al. Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): A double-blind randomised controlled study. Lancet. 2010;376.
    CrossRef
88. Tuomilehto, J. et al. Prevention of Type 2 Diabetes Mellitus by Changes in Lifestyle among Subjects with Impaired Glucose Tolerance. N. Engl. J. Med. 2001;344.
    CrossRef
89. Gulli, G., Ferrannini, E., Stern, M., Haffner, S. & Defronzo, R. A. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes. 1992;41.
    CrossRef
90. Martin, B. C. et al. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet. 1992;340.
    CrossRef
91. de Jesus, D. F. & Kulkarni, R. N. Epigenetic modifiers of islet function and mass. Trends Endocrinol. Metab. 2014;25.
    CrossRef
92. (CDC), C. for D. C. Nutritional and health assessment of Mozambican refugees in two districts of Malawi. MMWR.1988;37.  
93. Kahn, S. E., Cooper, M. E. & del Prato, S. Pathophysiology and treatment of type 2 diabetes: Perspectives on the past, present, and future. Lancet. 2014;383.  
    CrossRef
94. Muller, D. C., Elahi, D., Tobin, J. D. & Andres, R. Insulin response during the oral glucose tolerance test: The role of age, sex, body fat and the pattern of fat distribution. Aging Clin. Exp. Res. 1996;8.
    CrossRef
95. Morris, A. P. et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet.2012;44.
96. Madsbad, S. The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabetes Obes. Metab. 2014;16.
    CrossRef
97. Nauck, M. A., Vardarli, I., Deacon, C. F., Holst, J. J. & Meier, J. J. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: What is up, what is down? Diabetologia. 2011;54.
    CrossRef
98. Bays, H., Mandarino, L. & DeFronzo, R. A. Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach. J. Clin. Endocrinol. Metab. 2004;89.
    CrossRef
99. Perry, R. J., Samuel, V. T., Petersen, K. F. & Shulman, G. I. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature. 2014;510.
    CrossRef
100. DeFronzo, R. A. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: The missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53.
     CrossRef
101. Bensellam, M., Laybutt, D. R. & Jonas, J. C. The molecular mechanisms of pancreatic β-cell glucotoxicity: Recent findings and future research directions. Mol. Cell.  Endocrinol. 2012;364.
     CrossRef
102. Defronzo, R. A. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–79.
     CrossRef
103. Ritzel, R. A., Meier, J. J., Lin, C. Y., Veldhuis, J. D. & Butler, P. C. Human islet amyloid polypeptide oligomers disrupt cell coupling, induce apoptosis, and impair insulin secretion in isolated human islets. Diabetes. 2007.
     CrossRef
104. Collins, S., Pi, J. & Yehuda-Shnaidman, E. Uncoupling and reactive oxygen species (ROS) – A double-edged sword for β-cell function? “moderation in all things.” Best Pract. Res. Clin. Endocrinol. Metab. 2012;26.
     CrossRef
105. Cabrera, O. et al. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc. Natl. Acad. Sci. U. S. A. 2006;103.  
     CrossRef
106. Hodson, D. J. et al. Lipotoxicity disrupts incretin-regulated human β cell connectivity. J. Clin. Invest. 2013;123.  
     CrossRef
107. Brandhorst, H., Brandhorst, D., Brendel, M. D., Hering, B. J. & Bretzel, R. G. Assessment of intracellular insulin content during all steps of human islet isolation procedure. Cell Transplant. 1998;7.  
     CrossRef
108. Krüger, M. et al. Dissection of the insulin signaling pathway via quantitative phosphoproteomics. Proc. Natl. Acad. Sci. U. S. A. 2008;105.
     CrossRef
109. Romeo, G. R., Lee, J. & Shoelson, S. E. Metabolic syndrome, insulin resistance, and roles of inflammation- mechanisms and therapeutic targets. Arteriosclerosis. Thromb. Vasc. Biol. 2012;32.
     CrossRef 
110. Zaharieva, E. et al. Interleukin-18 serum level is elevated in type 2 diabetes and latent autoimmune diabetes. Endocr. Connect. 2018;7.  
     CrossRef
111. de Alvaro, C., Teruel, T., Hernandez, R. & Lorenzo, M. Tumor Necrosis Factor α Produces Insulin Resistance in Skeletal Muscle by Activation of Inhibitor κB Kinase in a p38 MAPK-dependent Manner. J. Biol. Chem. 2004;279:17070–17078.
     CrossRef
112. IKK-ßlinks inflammation to obesity-induced insulin resistance.: EBSCOhost.
113. Lebrun, P. & van Obberghen, E. SOCS proteins causing trouble in insulin action. Acta Physiol. 2008;192.  
     CrossRef
114. Howard, J. K. & Flier, J. S. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol. Metab. 2006;17.
     CrossRef
115. Mesia, R. et al. Systemic inflammatory responses in patients with type 2 diabetes with chronic periodontitis. BMJ Open Diabetes Res. Care. 2016;4.
     CrossRef
116. Vinagre, I. et al. Inflammatory biomarkers in type 2 diabetic patients: Effect of glycemic control and impact of ldl subfraction phenotype. Cardiovasc. Diabetol. 2014;13.
     CrossRef
117. Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat. Med. 2005;11:183-190.
     CrossRef
118. Perry, R. J. et al. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell. 2015;160.
     CrossRef
119. Mori, M. A. et al. A systems biology approach identifies inflammatory abnormalities between mouse strains prior to development of metabolic disease. Diabetes. 2010;59.  
     CrossRef
120. Mauer, J. et al. Myeloid cell-restricted insulin receptor deficiency protects against obesity-induced inflammation and systemic insulin resistance. PLoS Genet. 2010;6.
     CrossRef
121. Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 2006;116.  
     CrossRef
122. Hameed, I. et al. Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition. World J. Diabetes. 2015;6.
     CrossRef
123. Ye, J. Mechanisms of insulin resistance in obesity. Frontiers of Medicine. 2013;7.
     CrossRef
124. Eguchi, K. et al. Saturated fatty acid and TLR signaling link β cell dysfunction and islet inflammation. Cell Metab. 2012;15
     CrossRef
125. Ehses, J. A. et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes. 2007;56.
     CrossRef

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