10.4081/btvb.2023.77
Type 2 diabetes is a key player in atherothrombosis. Inflammation participates in metabolic homeostasis interacting with adipose tissue-specific macrophages. Platelets appear as addresses and players carrying and transducing metabolic derangement into vascular injury. AGE-RAGE pathway is recognized as the driver of metabolic memory. Human platelets have insulin receptors that participate in the regulation of platelet function and platelets are potential sites of insulin resistance. The present mini-review addresses key pathophysiological aspects including i) the role of inflammation in the pathogenesis of diabetes; ii) platelets as inflammatory cells; iii) the involvement on inflammation in the interindividual variability in aspirin response. Taken together, these aspects may contribute to expand knowledge about the link between the extent of inflammation, platelet activation and turnover, and interindividual variability in the development of atherothrombosis and its prevention, in a view of precision medicine.
application/pdf
2785-5309
77
2
en
Rossella Liani
https://creativecommons.org/licenses/by-nc/4.0
Bleeding, Thrombosis and Vascular Biology
cytokines
Inflammation, platelets and diabetes
Text.Serial.Journal
https://www.btvb.org/btvb
2
Mini-reviews
2023-06-12
2023-04-17
2023-04-30
2023-06-12
Bleed Thromb Vascul Biol
Rossella Liani
2023/06/12
10.4081/btvb.2023.77
Department of Medicine and Aging, Center for Advanced Studies and Technology, University of Chieti
2785-5309
2
cytokines
en
Santilli F, Paloscia L, Liani R, et al. Circulating myeloid-related protein-8/14 is related to thromboxane-dependent platelet activation in patients with acute coronary syndrome, with and without ongoing low-dose aspirin treatment. J Am Heart Assoc 2014;3:e000903 .
Inflammation, platelets and diabetes
https://www.btvb.org/btvb/article/download/77/71
2
                                                                                                                        MINI-REVIEW

Inflammation, platelets and diabetes
Francesca Santilli, Paola Simeone, Rossella Liani

Department of Medicine and Aging, Center for Advanced Studies and Technology, University of Chieti, Italy



ABSTRACT
     Type 2 diabetes is a key player in atherothrombosis. Inflammation participates in metabolic homeostasis interacting with adipose tissue-
specific macrophages. Platelets appear as addresses and players carrying and transducing metabolic derangement into vascular injury. AGE-
RAGE pathway is recognized as the driver of metabolic memory. Human platelets have insulin receptors that participate in the regulation of
platelet function and platelets are potential sites of insulin resistance. The present mini-review addresses key pathophysiological aspects in-
cluding i) the role of inflammation in the pathogenesis of diabetes; ii) platelets as inflammatory cells; iii) the involvement on inflammation
in the interindividual variability in aspirin response. Taken together, these aspects may contribute to expand knowledge about the link between
the extent of inflammation, platelet activation and turnover, and interindividual variability in the development of atherothrombosis and its
prevention, in a view of precision medicine.




                                                                                                ly
                                                                                        on
  Correspondence: Francesca Santilli, Center for Advanced Studies            Inflammation in the pathogenesis of diabetes
  and Technology (CAST), “G. d’Annunzio” University, Luigi Po-
                                                                             and its complications



                                                                                  e
  lacchi, 66013 Chieti, Italy.
  Tel: +39.0871.541322 - Fax: +39.0871.541261.
  E-mail: francesca.santilli@unich.it

  Citation: Santilli F, Simeone P, Liani R. Inflammation, platelets
                                                                            us    Type 2 diabetes (T2DM) accounts for nearly 90% of the ap-
                                                                             proximately 537 million cases of diabetes worldwide.1 Observa-
                                                                             tional studies provided the first evidence for the possible
  and diabetes. Bleeding, Thrombosis, and Vascular Biology
                                                                            al
                                                                             association between inflammation and diabetes.1
  2023;2:77.
                                                                                  The hypothesis that inflammation plays a causal and poten-
                                                         ci

  Key words: type 2 diabetes, inflammation, platelet activation, car-        tially primordial role in the development and natural history of
  diovascular diseases, cytokines.                                           diabetes has been raised for many years.1 Several organs have
                                                       er


                                                                             been reported to participate in the metabolic homeostasis and in-
  Contributions: the authors contributed equally.                            flammatory state in T2DM, including the pancreas, adipose tissue,
                                                      m




                                                                             liver, gut, skeletal muscle.1
  Conflict of interest: the authors declare no potential conflict of in-
                                                                                  Inflammation can drive the development of diabetes through
                                          om




  terest.
                                                                             interacting with adipose tissue-specific macrophages, leading to
  Funding: none.                                                             an imbalance in adipokine production, ectopic fat deposition, and
                                                                             insulin resistance.1
                                    -c




  Acknowledgments: this manuscript is based on an invited presen-
                                                                                  Inflammation has been suggested to be a common driver of
  tation at the 9th Roberto Lorenzet Memorial “L’infiammazione
                           on




  base comune delle malattie cronico-degenerative”, held on January          both atherothrombosis and diabetes, in part through activation of
  13,2023 - Pozzilli (IS, Italy).                                            the NOD-like receptor protein 3 (NLRP3) inflammasome, and
                                                                             the production of interleukin (IL)-1β and IL-18, both potent proin-
                     N




  Ethical approval and consent to participate: not required.                 flammatory cytokines.1
                                                                                  T2DM, as a typical metabolic inflammatory disease, is under
  Availability of data and material: data and materials are available
  by the authors.                                                            the joint regulation of environmental factors and genetics, com-
                                                                             bining with a variety of epigenetic changes. The inflammation-
  Received: 29 March 2023.                                                   related epigenetics is one of the core pathomechanisms leading
  Accepted: 17 April 2023.                                                   to β-cell dysfunction and insulin resistance. Epigenetic modifica-
                                                                             tions of immune cells can indirectly regulate the inflammatory
  Publisher’s note: all claims expressed in this article are solely those
  of the authors and do not necessarily represent those of their affili-     state of the body and affect insulin resistance and insulin secretion
  ated organizations, or those of the publisher, the editors and the re-     dysfunction.1
  viewers. Any product that may be evaluated in this article or claim             A large body of evidence shows that high glucose-exposed
  that may be made by its manufacturer is not guaranteed or endorsed         cells or diabetic animals and patients continue to develop inflam-
  by the publisher.
                                                                             mation and vascular damage even after achieving glycemic con-
  ©
   Copyright: the Author(s), 2023                                            trol. The AGE-RAGE pathway (AGE, advanced glycation
  Licensee PAGEPress, Italy                                                  endproducts; RAGE, receptor for advanced glycation endprod-
  Bleeding, Thrombosis and Vascular Biology 2023; 2:77                       ucts) and its role as amplifier of local inflammation and oxidant
  doi:10.4081/btvb.2023.77                                                   stress through irreversible glycation of the various proteins and
                                                                             lipids, is recognized as the main driver of metabolic memory.2
  This work is licensed under a Creative Commons Attribution-
  NonCommercial 4.0 International License (CC BY-NC 4.0).                         The RAGE, a member of the immunoglobulin superfamily
                                                                             of transmembrane cell surface molecules, engages various ligands


                                              Bleeding, Thrombosis and Vascular Biology 2023; 2:77
22                                                               F. Santilli et al.




relevant to the pathogenesis of atherosclerosis and is highly over-           creatic islet produces LIGHT and its receptors. By immunofluo-
expressed at sites of vascular pathology.3 Blockade of AGE-                   rescence staining, LIGHT is shown to be co-localized in both
RAGE interaction can be achieved by truncated soluble forms of                alpha and beta cells. During high glucose exposure, LIGHT at-
the receptor, referred to as total soluble RAGE (sRAGE), includ-              tenuates insulin release due to LIGHT-induced apoptosis of pan-
ing both an endogenous splice variant of RAGE lacking the trans-              creatic islet cells, further contributing to hyperglycemia.11
membrane domain of the receptor (endogenous secretory receptor
or esRAGE).
     Our study showed for the first time that plasma sRAGE levels             Inflammation and interindividual variability
were lower in diabetic patients as compared to controls.3 Glycated
hemoglobin (HbA1c) and urinary 8-iso-Prostaglandin F2α (8-iso-
                                                                              in aspirin response
PGF2α), were correlated inversely with sRAGE, suggesting that                      Finally, platelets from patients with diabetes show increased
oxidative stress and up regulation of the ligand-RAGE axis are,               turnover, resulting in a higher number of reticulated platelets, and
at least in part, related to glycemic control.                                increased adhesion to endothelial cells.4 Increased platelet
                                                                              turnover contributes to the hyperreactive status of T2DM platelets.
                                                                              In normal conditions, approximately 10% to 15% of circulating
Platelets as inflammatory cells                                               platelets are replaced every day. Diabetic patients have a greater
                                                                              number of large and hypersensitive younger platelets and a more
     Platelet hyperactivity is typically observed in diabetes and




                                                                                                         ly
                                                                              abundant fraction of small, exhausted platelets compared to non-
plays a key role in thromboinflammation.4 Hyperglycemia was                   diabetics. Aspirin irreversibly acetylates and inactivates COX-1




                                                                                                 on
shown to prime thromboinflammatory responses by increasing                    in circulating platelets and has only a 20-minute half-life. There-
platelet activation/adhesion and by promoting the release of neu-             fore, there is the theoretical possibility that a single daily dose
trophil- and platelet-derived microparticles in human and murine              could not be sufficient to exert a full inhibitory effect on the new




                                                                                           e
samples.4                                                                     platelets generated and released by the bone marrow during the
     Platelets of individuals with diabetes, compared with those of
healthy controls, show dysregulation at both the receptor and the
intracellular signal transduction levels, leading to hyperreactive
                                                                                      us
                                                                              course of the 24 hours after aspirin intake.9,12
                                                                                   An imbalance between platelet production and clearance, with
                                                                              accelerated megakaryopoiesis/platelet production and reduced
                                                                            al
adhesion, activation, degranulation, and aggregation.4 Human                  clearance/prolonged survival, characterizes patients with poor as-
platelets have insulin receptors that participate in the regulation           pirin response, as reflected by the accelerated recovery of platelet
                                                             ci

of platelet functions;5 thus, platelets are potential sites of insulin        COX-1 activity, especially those with diabetes.9,12 This imbalance
resistance, which translates into an impairment in the physiolog-             translates into increased platelet count and enhanced TX-depen-
                                                           er


ical antiaggregating and vasodilating effects exerted by insulin,             dent platelet activation.
mediated by nitric oxide.5 Reduced insulin sensitivity also causes                 Specifically, by employing an integrated approach including
                                                          m




increased signaling of P2Y purinoceptor 12 (P2Y12 receptor), the              biochemistry, proteomics, flow cytometry, cell biology, and a
main platelet receptor for adenosine diphosphate.4 Platelet hyper-
                                                om




                                                                              mechanism-based endpoint to monitor aspirin pharmacodynam-
reactivity in patients with T2DM is also associated with increased            ics, we analyzed the platelet proteome, platelet turnover, as re-
platelet production of thromboxane.6                                          flected by thrombopoietin (TPO) and glycocalicin (GC)
     The observation that biochemical evidence of thromboxane
                                          -c




                                                                              circulating levels, galactose exposure and GPIbα ectodomain
(TX)-dependent platelet activation may be detectable as early as              shedding, megakaryocyte (Mk) cell maturation and proplatelet
                                  on




within one year since the diagnosis of T2DM,7 together with its               formation in patients at high cardiovascular risk with or without
correlation with glycemic control and reversal with its improve-              T2DM stratified according to the kinetics of COX-1 recovery. We
ment, point-out to hyperglycemia, both fasting and postprandial,              show that reduced platelet GPIbα shedding characterizes patients
                            N




as the main trigger for platelet activation,8 and suggests that TX            with accelerated COX-1 recovery and may contribute to higher
biosynthesis is an early event in the natural history of the disease.9        TPO production and higher rates of newly formed platelets, es-
     Along these lines, TXA2-dependent platelet activation was at             caping aspirin inhibition over 24 hours. The TPO/GC ratio, a rel-
least as high in patients with prediabetes (impaired glucose toler-           atively simple, mechanism-based biochemical tool, may identify
ance) as in patients with T2DM and further increased over time,               with significant diagnostic accuracy aspirin-poor responders due
especially in those who progressed to overt diabetes.10 This latter           to accelerated renewal of the drug target.13 Myeloid-related protein
observation raises the hypothesis of TX as a potential predictor              (MRP)-8/14 is expressed in granulocytes during inflammatory
of the occurrence of T2DM in preclinical states, and of a bidirec-            conditions and secreted in response to tissue damage along with
tional link between platelet activation and beta cell dysfunction             the release of pro-inflammatory cytokines together with leukocyte
with platelets also contributing to a local inflammatory milieu fos-          recruitment and activation.14
tering beta cell apoptosis.11                                                      Hyperglycemia triggers thrombopoiesis by activating liver in-
     LIGHT is a protein primarily expressed on T-cells and den-               flammation. Indeed, MRP-8/14 and esRAGE interactions trigger
dritic cells, but has also been found in platelets, monocytes and             IL-6- mediated TPO production by liver cells in conditions of low-
granulocytes, being involved in innate and adaptive immunity as               grade inflammation and hyperglycemia. In our study,13 plasma
well as in the pathogenesis of atherosclerosis and vascular inflam-           levels of MRP-8/14 were higher, while esRAGE had a trend for
mation; we have shown that platelets from T2DM patients spon-                 lower levels in third vs. first tertile in patients with T2DM. TPO
taneously release in the circulation higher levels of LIGHT than              was directly related to MRP-8/14 circulating levels and inversely
platelets from healthy controls. On inflammatory stimulation with             related to esRAGE levels.
a cytokine such as IL-1β, tumor necrosis factor, and IFN-γ, pan-                   Thus, liver inflammation drives accelerated thrombopoiesis


                                           Bleeding, Thrombosis and Vascular Biology 2023; 2:77
                                                   Inflammation, platelets and diabetes                                                 23



which shortens the duration of aspirin effect over 24-hours. We          6. Santilli F, Simeone P, Liani R. Davì G. Platelets and diabetes
unraveled a clinical and molecular signature, including younger             mellitus. Prostaglandins Other Lipid Mediat 2015:28-39.
age, NAFLD, visceral obesity and high TPO/GC, identifying with           7. Santilli F, Formoso G, Sbraccia P, et al. Postprandial hyper-
high accuracy aspirin-poor responders, amenable for a twice daily           glycemia is a determinant of platelet activation in early type
dosing aspirin regimen.13                                                   2 diabetes mellitus. J Thromb Haemost 2010;8:828-37.
                                                                         8. Santilli F, Davì G, Consoli A, et al. Thromboxane-dependent
                                                                            CD40 ligand release in type 2 diabetes mellitus. J Am Coll
Conclusions                                                                 Cardiol 2006;47:391-7.
    Inflammation at different sites fuels the development of dia-        9. Di Minno G, Silver MJ, Cerbone AM, Murphy S. Trial of re-
betes and its complications. Hyperglycemia triggers throm-                  peated low-dose aspirin in diabetic angiopathy. Blood
bopoiesis by activating liver inflammation, which is central for            1986:886-91.
platelet turnover. The extent of inflammation may drive the re-         10. Santilli F, Zaccardi F, Liani R, et al. In vivo thromboxane-de-
sponse to antiplatelet agents. Future studies should develop patho-         pendent platelet activation is persistently enhanced in subjects
physiology-based markers predicting the development of                      with impaired glucose tolerance. Diabetes Metab Res Rev
atherothrombosis and the response to antiplatelet therapies in pa-          2020;36:e3232.
tients with different stages of diabetes mellitus.
                                                                        11. Halvorsen B, Santilli F, Scholz H, et al. LIGHT/TNFSF14 is




                                                                                           ly
                                                                            increased in patients with type 2 diabetes mellitus and pro-
                                                                            motes islet cell dysfunction and endothelial cell inflammation
References




                                                                                   on
                                                                            in vitro. Diabetologia 2016;59:2134-44.
 1. Donath M, Shoelson S. Type 2 diabetes as an inflammatory            12. Rocca B, Santilli F, Pitocco D, et al. The recovery of platelet
    disease. Nat Rev Immunol 2011;11: 98-107                                cyclooxygenase activity explains interindividual variability




                                                                             e
 2. Jax TW. Metabolic memory: a vascular perspective. Cardio-               in responsiveness to low-dose aspirin in patients with and
    vasc Diabetol 2010;9:51.
 3. Devangelio E, Santilli F, Formoso G, et al. Soluble RAGE in
                                                                      us    without diabetes. J Thromb Haemost 2012;10:1220-30.
                                                                        13. Simeone P, Liani R, Tripaldi R, et al. Reduced platelet glyco-
    type 2 diabetes: association with oxidative stress. Free Radic
                                                                 al
                                                                            protein Ibα shedding accelerates thrombopoiesis and COX-1
    Biol Med 2007;43:511-8.
                                                                            recovery: implications for aspirin dosing regimen. Haemato-
 4. Patti G, Cavallari I, Andreotti F, et al. Prevention of
                                                   ci

                                                                            logica 2023;108:1141-57.
    atherothrombotic events in patients with diabetes mellitus:
                                                                        14. Santilli F, Paloscia L, Liani R, et al. Circulating myeloid-re-
                                                 er


    from antithrombotic therapies to new-generation glucose-low-
    ering drugs. Nat Rev Cardiol 2019;16:113-30.                            lated protein-8/14 is related to thromboxane-dependent
                                                m



 5. Trovati M, Anfossi G. Influence of insulin and of insulin re-           platelet activation in patients with acute coronary syndrome,
    sistance on platelet and vascular smooth muscle cell function.          with and without ongoing low-dose aspirin treatment. J Am
                                      om




    J Diabetes Complications 2002;16:35-40.                                 Heart Assoc 2014;3:e000903.
                                -c
                        on
                   N




                                         Bleeding, Thrombosis and Vascular Biology 2023; 2:77
