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Immune dysfunction in developmental programming of type 2 diabetes mellitus


Intrauterine growth restriction (IUGR) is a common complication of pregnancy and increases the risk of the offspring developing type 2 diabetes mellitus (T2DM) later in life. Alterations in the immune system are implicated in the pathogenesis of IUGR-induced T2DM. The development of the fetal immune system is a delicate balance as it must remain tolerant of maternal antigens whilst also preparing for the post-birth environment. In addition, the fetal immune system is susceptible to an altered intrauterine milieu caused by maternal and placental inflammatory mediators or secondary to nutrient and oxygen deprivation. Pancreatic-resident macrophages populate the pancreas during fetal development, and their phenotype is dynamic through the neonatal period. Furthermore, macrophages in the islets are instrumental in islet development as they influence β-cell proliferation and islet neogenesis. In addition, cytokines, derived from β-cells and macrophages, are important to islet homeostasis in the fetus and adult and, when perturbed, can cause islet dysfunction. Several activated immune pathways have been identified in the islets of people who experienced IUGR, with alternations in the levels of IL-1β and IL-4 as well as changes in TGFβ signalling. Leptin levels are also altered. Immunomodulation has shown therapeutic benefit in T2DM and might be particularly useful in IUGR-induced T2DM.

Key points

  • Fetal immune development is susceptible to an abnormal intrauterine milieu, and alterations have been implicated in the development of type 2 diabetes mellitus (T2DM) following intrauterine growth restriction (IUGR).

  • Pancreatic islet macrophages are instrumental in islet development and homeostasis in adults.

  • Levels of cytokines and immune mediators that are involved in T2DM pathogenesis are also elevated in offspring exposed to IUGR.

  • Leptin stimulates IL-1β production in islets, and levels of leptin are reduced in fetal islets and elevated in adult islets of offspring exposed to IUGR.

  • The results of limited reports evaluating the therapeutic effect of immunomodulation are promising for the treatment of IUGR-induced T2DM.

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Fig. 1: Fetal immune development.
Fig. 2: Pancreatic immune development.
Fig. 3: Macrophages influence islet development.
Fig. 4: Resident macrophages sense their micro and systemic environments.
Fig. 5: Pancreatic inflammation subsequent to IUGR.


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The authors acknowledge the support of the National Institutes of Health grant #DK114054 (R.A.S.) and ES01985 (T.N.G.).

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T.N.G. and R.A.S. researched data for the article, contributed to discussion of its content, wrote the article, and reviewed and edited the manuscript before submission.

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Correspondence to Rebecca A. Simmons.

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Small for gestational age

(SGA). Birth weight that is below the 10th percentile.

Uteroplacental insufficiency

A complication of pregnancy when the placenta is unable to deliver an adequate supply of nutrients and oxygen to the fetus.

Parabiosis studies

A laboratory technique to study physiology whereby two living organisms are joined together surgically to develop a single, shared physiological system.

Glucose disposal

Storage of glucose as glycogen in tissues.

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Golden, T.N., Simmons, R.A. Immune dysfunction in developmental programming of type 2 diabetes mellitus. Nat Rev Endocrinol 17, 235–245 (2021).

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