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Thyroid hormone and pancreas development: diabetes culprit or innocent bystander?

2017; Wiley; Volume: 595; Issue: 11 Linguagem: Inglês

10.1113/jp274090

1469-7793

Kent L. Thornburg, Natasha N. Chattergoon,

Pancreatic function and diabetes

There is, perhaps, no parallel in history where massive numbers of people have rapidly become ill without an infectious agent as perpetrator. But in the past 30 years the increase in diabetes mellitus has reached epidemic proportions. In the USA, the prevalence of diabetes has increased some 10 times since the early ’60 s (CDC, 2016). This fact and the parallel global trend has scientists scrambling for explanations. However, too few people are asking the question: why are human beings now so vulnerable for acquiring the disease? Fortunately, this question is being considered not only by a few evolutionary biologists, but also by medical scientists who study the origins of chronic disease that begin in the womb. Over the past 25 years, scientists have uncovered powerful new links between environmental conditions that modify developmental patterns and elevate risks for chronic disease in later life (Gluckman et al. 2008). The biological process that links early life stressors and later disease is often called ‘developmental programming’. Scientists at Cambridge University have been leaders in unravelling the development of endocrine systems during ovine fetal development over several decades (Fowden & Comline, 1984; Fowden & Forhead, 2004). They have previously shown that the surge in active thyroid hormone (3,3,5, triodo-l-thyronine, T3) in the near-term sheep fetus is driven by the preceding late gestational cortisol surge which increases the expression of the deiodinases that converts thyroxine (T4) to T3 (Forhead et al. 2006). Beyond that foundational discovery, the Cambridge team, with colleagues from afar, now contribute a new and exciting report showing that thyroid hormones powerfully influence the development of the pancreas (Harris et al. 2017). Pancreatic beta cells secrete insulin and therefore regulate plasma glucose concentrations for life. The experimental data presented in this paper, beautifully demonstrate that when the concentrations of fetal thyroid hormones are decreased by thyroidectomy, proliferation of pancreatic beta cells increases, as does total beta cell mass, but not alpha cell mass. In the study, hypothyroidism led to enhanced fetal beta cell growth and increased plasma insulin and leptin concentrations. In contrast, thyroid hormone inhibited fetal beta cell proliferation in culture. The take-home message is that thyroid hormones condition the milieu in which pancreatic beta cells grow and thrive at the stage of development when they are establishing their functional capacity. We should not be surprised by the finding that thyroid hormones are important in development. Thyroid hormones are powerful developmental hormones in lower vertebrates and the primary drivers of metamorphosis in amphibians (Brown & Cai, 2007). Furthermore, there are additional examples of thyroid hormone driving development, as in determining cardiomyocyte endowment in the ovine fetal heart (Chattergoon et al. 2007). The endowment of cardiomyocytes in the myocardium at birth influences the lifelong durability of the myocardium and thus its later risk for heart disease. Elevated levels of T3 powerfully suppress cardiomyocyte proliferation and lead to early cell maturation. Thus, elevated T3 concentrations in the fetus are a major determinant of cardiomyocyte endowment thereafter. It appears that the same is true for the beta cell endowment in the endocrine pancreas. The pancreas study raises an important question: in what way might gestational thyroid hormone production be related to pancreatic function and the recent epidemic of diabetes mellitus? While it is not yet known to what degree maternal hypo- and hyper-thyroidism affect beta cell growth and maturation in human fetuses, one group found that small-for-gestation-age babies have elevated levels of T3 (Radetti et al. 2004) and animal studies find low levels of insulin-like growth factor-1. We can now speculate that the beta cell mass in such babies is under-endowed at birth. Thus, it is possible, perhaps even likely, that abnormalities in thyroid hormone production by mother and fetus are culprits in programming the pancreas. Out-of-normal-range thyroid hormone levels could result in an elevated risk for acquiring diabetes and heart disease later in life. The findings of this manuscript emphasize that appropriate thyroid hormone concentrations in the fetus are required for normal development of the pancreas as has been shown for the heart. This requirement may apply to other fetal organs as well. The authors have no conflicts of interest to declare.