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Cited by 598Thyroid Disorders and TreatmentsDiabetes Management and ResearchDiabetes, Cardiovascular Risks, and Lipoproteins

Thyroid dysfunction and diabetes mellitus: two closely associated disorders

Open access
Biondi, Bernadette, Kahaly, George J, Robertson, R Paul·2019·Endocrine Reviews
DOI 10.1210/er.2018-00163PMC PMC6507635
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Abstract

Thyroid dysfunction and diabetes mellitus are closely linked. Several studies have documented the increased prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. This review critically discusses the different underlying mechanisms linking type 1 and 2 diabetes and thyroid dysfunction to demonstrate that the association of these two common disorders is unlikely a simple coincidence. We assess the current state of knowledge on the central and peripheral control of thyroid hormone on food intake and glucose and lipid metabolism in target tissues (such as liver, white and brown adipose tissue, pancreatic β cells, and skeletal muscle) to explain the mechanism linking overt and subclinical hypothyroidism to type 2 diabetes and metabolic syndrome. We also elucidate the common susceptibility genes and the pathogenetic mechanisms contributing to the autoimmune mechanism involved in the onset of type 1 diabetes mellitus and autoimmune thyroid disorders. An untreated thyroid dysfunction can impair the metabolic control of diabetic patients, and this association can have important repercussions on the outcome of both of these disorders. Therefore, we offer recommendations for the diagnosis, management, and screening of thyroid disorders in patients with diabetes mellitus, including the treatment of diabetic patients planning a pregnancy. We also discuss the major causes of failure to achieve an optimal management of thyroid dysfunction in diabetic patients and provide recommendations for assessing and treating these disorders during therapy with antidiabetic drugs. An algorithm for a correct approach of these disorders when linked is also provided.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that thyroid dysfunction (TD) and diabetes mellitus (DM) are closely associated through shared autoimmunity, thyroid hormone effects on glucose/lipid metabolism, and drug interactions. It summarizes prevalence, mechanisms, prognosis, and management/screening recommendations, emphasizing that untreated TD can impair metabolic control in patients with diabetes.

Key findings

  • Autoimmune thyroid disease occurs in 17% to 30% of adults with type 1 diabetes (T1D), and autoimmune hypothyroidism is present in 25% of children with T1D.
  • TD is more common in type 2 diabetes (T2D) than in the general population; hypothyroidism prevalence in T2D ranges from 6% to 20%, and a meta-analysis found a 1.93-fold higher pooled prevalence of subclinical hypothyroidism in T2D versus healthy controls (95% CI, 1.66 to 2.24).
  • Subclinical hypothyroidism in T2D was associated with increased risks of diabetic nephropathy (OR 1.74; 95% CI, 1.34 to 2.28), diabetic retinopathy (OR 1.42; 95% CI, 1.21 to 1.67), peripheral arterial disease (OR 1.85; 95% CI, 1.35 to 2.54), and diabetic peripheral neuropathy (OR 1.87; 95% CI, 1.06 to 3.28), but not coronary heart disease.
  • Hyperthyroidism is found in 4.4% of adults with T2D, and subclinical hyperthyroidism in ~2% to 4%; preexisting DM is exacerbated by hyperthyroidism, and insulin treatment should be adjusted after TD occurs. Metformin lowers TSH in overt and subclinical hypothyroidism but not in euthyroid patients, with a TSH cut-off of 2.5 to 3 mU/L predicting the effect.

Methods

  • Narrative review based on personal files, MEDLINE articles, meta-analyses, references of relevant articles and textbooks published from 1977 to 2018, and recent international guidelines.
  • Search terms included thyroxine, triiodothyronine, hypothyroidism, hyperthyroidism, subclinical thyroid disease, type 1 and type 2 diabetes mellitus, insulin resistance, metabolic syndrome, gestational diabetes, prevalence, incidence, deiodinases, glucose metabolism, lipid metabolism, adipose tissue, appetite regulation, skeletal muscle, screening, morbidity, and mortality.
  • The authors performed a critical assessment of the literature, agreed on inclusion/exclusion criteria, preferred high-quality papers, meta-analyses, randomized controlled and longitudinal trials, and discussed limitations in study design or execution when identified.

Limitations

  • The paper states that limitations in study design or execution were discussed when identified, but it is a narrative review without new primary data and relies heavily on observational studies, meta-analyses, and guideline documents.
  • The authors note insufficient evidence to determine specific screening tests, exact screening intervals, and cost-benefit for TD screening in T2D; they also note no prospective randomized controlled trial evaluating whether treating subclinical hyperthyroidism improves adverse outcomes.
  • The text reports heterogeneity among included studies in meta-analyses of subclinical hypothyroidism and metabolic syndrome, conflicting results from Danish register-based studies on TD and diabetes incidence, and inconsistent findings on the D2 Thr92Ala polymorphism and insulin resistance/T2D.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/er.2018-00163

Cites

410 of 410 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 4 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    Asymptomatic thyroid dysfunction is common among T2D patients.

    “Asymptomatic TD is frequently observed in patients with T2D.”
    Quote in the paperSubstantial claim
  • Findingnone given

    Diagnosing TD in T2D patients is difficult because certain oral diabetes drugs can interfere with serum TSH assessment.

    “The diagnosis of TD in patients with T2D is difficult because some oral antidiabetic drugs can interfere with the evaluation of serum TSH levels.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Both hyperthyroidism and hypothyroidism can impair metabolic control in patients with diabetes.

    “Both hyperthyroidism and hypothyroidism can impair the metabolic control in patients with diabetes.”
    Quote in the paperNot a substantial claim
  • Premisereasoning

    Thyroid dysfunction and diabetes mellitus are closely associated.

    “Thyroid dysfunction and diabetes mellitus are closely linked.”
    • Also stated in: § Abstract · plain
      “DM and thyroid disease are two closely associated disorders.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    The association between thyroid dysfunction and diabetes mellitus is unlikely to be a simple coincidence.

    “to demonstrate that the association of these two common disorders is unlikely a simple coincidence.”
    Quote in the paperSubstantial claim
  • May combine two claims. 46
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Interpretationnone given

    Untreated thyroid dysfunction can impair metabolic control in diabetic patients and affect the outcome of both disorders.

    “An untreated thyroid dysfunction can impair the metabolic control of diabetic patients, and this association can have important repercussions on the outcome of both of these disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The prevalence of thyroid disorders is increased in patients with diabetes mellitus and vice versa.

    “Several studies have documented the increased prevalence of thyroid disorders in patients with diabetes mellitus and vice versa.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    UCP1 expression is required for brown adipose tissue thermogenesis and is synergistically regulated by noradrenaline and T3.

    “The expression of UCP is required for BAT thermogenesis, and UCP is synergistically regulated by both noradreanaline and T ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    High circulating insulin may induce increased thyroid proliferation, larger thyroid volume, and nodule formation.

    “Regarding the effects of insulin on the thyroid gland, high circulating levels of insulin may induce increased thyroid proliferation with the development of larger thyroid volume and the formation of nodules.This goitrogenic action of insulin may explain why the thyroid gland was considered another victim of the insulin resistance syndrome ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both autoimmune thyroid disease and female sex are risk factors for progression of thyroid dysfunction among patients with diabetes.

    “Both AITD and female sex are risk factors for progression of TD among patients with diabetes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Weight excess was reported in 54% of patients with overt hypothyroidism, reflecting body fat accumulation from decreased resting energy expenditure and increased body water from reduced free water excretion.

    “Regarding hypothyroidism, weight excess was reported in % patients with overt hypothyroidism, reflecting both the accumulation of body fat, due to decreased resting energy expenditure, and the increased water content of the body, consequent to a reduced capacity of excreting free water ().”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The similar effects of leptin and insulin on food intake may be mediated by a common IRS/phosphatidylinositol-3-OH kinase pathway in the hypothalamus.

    “It is interesting that this IRS/ phosphatidylinositol--OH kinase pathway is also activated by leptin, and therefore the similar effects of leptin and insulin on food intake may be mediated via this common pathway in the hypothalamus ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Central infusion of BDNF reduces food intake and induces weight loss in rats.

    “The central infusion of BDNF reduces food intake and induces weight loss in rats ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Overt hypothyroidism is associated with hyperlipidemia, and subclinical hypothyroidism has been related to plasma lipid alterations, although results are conflicting.

    “Overt hypothyroidism is associated with hyperlipidemia, and even SHypo has been related to alterations in plasma lipids, although with conflicting results ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Type 1 diabetes is closely associated with autoimmune-induced thyroid dysfunction because both conditions share the same pathophysiological mechanism.

    “This disorder is closely associated with autoimmune-induced TD in clinical practice because these endocrine diseases are linked by the same pathophysiological mechanism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The correlation between TSH and BMI could be mediated by leptin because serum leptin and TSH are positively correlated in obese individuals, and TSH can stimulate leptin secretion by human adipose tissue via TSH receptors on adipocytes.

    “The correlation between TSH and BMI could be mediated by leptin produced by adipose tissue because a positive correlation has been identified between serum leptin and serum TSH levels in individuals who are obese.TSH in turn can stimulate leptin secretion by human adipose tissue via TSH receptors that are expressed on adipocytes (, , ).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both subclinical and overt hypothyroidism are frequently associated with weight gain, decreased thermogenesis, and decreased metabolic rate.

    “Both subclinical and overt hypothyroidism are frequently associated with weight gain, decreased thermogenesis, and metabolic rate (, ).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Central T3 activates mTOR signaling and is associated with increased AgRP and NPY expression and decreased POMC expression in the hypothalamic arcuate nucleus.

    “In fact, T can directly cross the blood-brain barrier, and the central administration of T activates the mTOR signaling pathway and is associated with increased expression of AgRP and NPY, as well as decreased POMC expression in hypothalamic ARC (, ).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TH has insulin-antagonistic effects in the liver and synergistic effects with insulin in peripheral tissues.

    “TH has insulin-antagonistic effects in the liver, whereas it acts synergically with insulin in the peripheral tissues.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [130] Brent, 2012, Mechanisms of thyroid hormone action, J Clin Invest source

      Not checked in the free run.

    • cites [134] Potenza, 2009, Excess thyroid hormone and carbohydrate metabolism, Endocr Pract source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Isolated hyperthyrotropinemia is frequently observed in obese patients and is spontaneously reversible by weight loss without specific treatment.

    “Isolated hyperthyrotropinemia is frequently observed in patients who are obese.It is a condition spontaneously reversible by losing weight without the necessity of specific treatment; in fact, it is usually associated with FT levels that are at the upper limit of the normal range ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    An increase in total cholesterol and its subfractions is common in hypothyroidism, and a direct relationship between serum TSH and total cholesterol has been described.

    “An increase of total cholesterol and its subfractions is a common finding in hypothyroidism, and a direct relationship between serum TSH and total cholesterol levels has been described ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Thyroid hormone exerts profound effects on the regulation of glucose homeostasis and lipid metabolism.

    “TH exerts profound effects on the regulation of glucose homeostasis and lipid metabolism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TSH injected centrally into rats reduces food intake and may be involved in seasonal changes in food intake and body weight.

    “TSH has also been shown to reduce food intake when injected centrally into rats and could be involved with the seasonal alterations in food intake and body weight that occur in some species (, ).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Insulin administered intracerebroventricularly reduces food intake and body weight, and its anorectic effect involves insulin receptors on arcuate neurons.

    “Insulin has anorectic effects in the central nervous system and its ICV administration reduces food intake and body weight () (Fig. ).Its anorectic effect involves insulin receptors on ARC neurons ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Mitochondrial dysfunction may be a common mechanism linking diabetes mellitus and thyroid dysfunction that can be aggravated by statins.

    “Mitochondrial dysfunction can represent the common mechanism related to both DM and TD that can be aggravated by statins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Thyroid hormones modulate cholesterol synthesis, mobilization, and breakdown; they increase cholesterol synthesis via HMG-CoA reductase and stimulate removal by enhancing hepatic LDL receptor expression.

    “THs modulate cholesterol synthesis, mobilization, and breakdown.In particular, they increase cholesterol synthesis via the rate-limiting enzyme -OHmethylglutaryl coenzyme A reductase and, in turn, stimulate its removal by enhancing the expression of low-density lipoprotein (LDL) receptors in the liver ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the HUNT Study of 30,656 euthyroid individuals, serum TSH within the euthyroid range was positively and significantly associated with total cholesterol, LDL-C, and triglycerides, and inversely associated with HDL-C.

    “In the HUNT Study, among , euthyroid individuals, serum TSH levels within the euthyroid range were positively and significantly associated with total cholesterol, LDL-C, and triglycerides, with an inverse relationship between serum TSH and HDL-C ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Metabolic syndrome independently raises the risk of cardiovascular disease and type 2 diabetes.

    “A prothrombotic state and a proinflammatory state are usually associated with MetS, which is as an independent risk factor for CVDs and TD (, ).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    T3 and noradrenaline separately double UCP1 expression, but combined they induce a 20-fold increase.

    “T and noradreanaline increase UCP expression by twofold separately.On the contrary, when both agents are combined they induce a -fold expression of UCP ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    T3-treated rats have lower plasma leptin, fourfold higher hypothalamic NPY mRNA, and about 80% lower hypothalamic POMC and CART mRNA than controls.

    “T-treated rats have significantly lower plasma leptin levels compared with control rats; hypothalamic expression of NPY mRNA is increased fourfold, and hypothalamic POMC and CART mRNA are reduced by ~%, compared with control rats.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Thyroid hormones affect food intake, resting energy expenditure, and thermogenesis, so metabolic alterations can develop in thyroid dysfunction.

    “TH affects food intake, resting energy expenditure, and thermogenesis, and consequently metabolic alterations can develop in patients with TD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hypothyroidism is a risk factor for incident chronic kidney disease, progression of chronic kidney disease, and higher death risk in kidney disease patients.

    “A growing body of evidence suggests that hypothyroidism is a risk factor for incident chronic kidney disease, progression of chronic kidney disease , and higher death risk in kidney disease patients (, ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The combination of high serum TSH and thyroid autoimmunity in early pregnancy was associated with a fourfold increased risk for gestational diabetes (RR 4.3; 95% CI 2.1-8.9) and a threefold increased risk for low birth weight neonates (RR 3.1; 95% CI 1.2-8.0) after adjustment for confounders.

    “Conversely, the combination of high serum TSH and thyroid autoimmunity in early pregnancy was associated with a fourfold increased risk for GMD (RR, .; % CI, . to .) and a threefold increased risk for low birth weight neonates (RR, .; % CI, . to .) after adjustment for several confounders ().”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Diabetes caused 1.5 million deaths in 2012, with excess relative mortality risk ranging from 1.15 to 3.15, mainly from cardiovascular causes.

    “DM caused . million deaths in , with an excess relative risk of mortality, ranging from . to ., mainly attributable to cardiovascular causes (-).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both metabolic syndrome and hypothyroidism are independent risk factors for cardiovascular disease.

    “Both MetS and hypothyroidism are independent risk factors for CVDs ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The authors of that meta-analysis concluded that subclinical hypothyroidism is prevalent in type 2 diabetes and may be responsible for greater risk of diabetic nephropathy, retinopathy, peripheral arterial disease, and peripheral neuropathy, but not coronary heart disease.

    “Therefore, the authors concluded that SHypo is prevalent in patients with TD and may be responsible for a greater risk of diabetic complications such as DN, DR, PAD, and DPN, but not CHD ().”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Higher TSH levels were associated with higher triglycerides and lower HDL, and this relationship was stronger among overweight individuals (BMI >25 kg/m2).

    “Higher TSH levels were also associated with higher triglycerides and lower HDL; furthermore, this relationship was stronger among individuals who were overweight (BMI .kg/m  ) ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Current evidence is insufficient to determine which screening tests to use, how often to screen, and whether the benefits outweigh the costs for TD screening in patients with T2D.

    “There are insufficient data to assess the specific tests for screening (TSH alone, TSH and TPO, or TSH and FT4), the exact interval of periodic screening, and the cost-benefit ratio.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Severe maternal hypothyroidism is associated with increased risk of adverse pregnancy complications (fetal death, premature birth, low birth weight, pregnancy loss, gestational hypertension) and detrimental effects on fetal neurocognitive development, leading to lower IQ in offspring.

    “Severe maternal hypothyroidism is associated with an increased risk of adverse pregnancy complications (fetal death, premature birth, low birth weight, pregnancy loss, and gestational hypertension) as well as detrimental effects on fetal neurocognitive development, leading to a lower intelligence quotient in the offspring (-).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The prevalence of gestational diabetes mellitus in pregnant women ranges from 1.7% to 20%, varying by country, screening strategy, and diagnostic criteria.

    “The prevalence of GDM in pregnant women ranges from .% to %, with a wide difference according to country, screening strategy, and diagnostic criteria (, -).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Thyroid dysfunction was observed in 22.5% of women with type 1 diabetes in the first trimester and 18.4% in the third trimester; the prevalent form was subclinical or overt hypothyroidism.

    “TD was observed in .% of women with TD in the first trimester and .% in the third trimester; the prevalent form of TD was subclinical or overt hypothyroidism ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The incidence of thyroid dysfunction during pregnancy in women with type 1 diabetes is threefold higher than in the general population, particularly in the first trimester and first year postpartum.

    “The incidence of TD during pregnancy in women with TD is threefold higher than in the general population, particularly in the first trimester of pregnancy and in the first year postpartum ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Subclinical hypothyroidism was associated with albuminuria in patients with type 2 diabetes, and increased serum TSH was an independent risk factor for albuminuria.

    “SHypo was associated with albuminuria in patients with TD, and an increased serum TSH was an independent risk factor for the presence of albuminuria ().”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Individual participant data meta-analyses reported that subclinical hypothyroidism was associated with increased risk for coronary heart disease events and mortality and heart failure, especially in patients with serum TSH >10 mU/L.

    “Individual participant data meta-analyses reported that SHypo was associated with an increased risk for coronary heart disease (CHD) events and mortality () and heart failure (), especially in patients with serum TSH .mU/L.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The clinical presentation of postpartum thyroiditis can vary from hyperthyroidism to hypothyroidism or both and is associated with a significantly increased incidence of depression.

    “The clinical presentation can vary from hyperthyroidism to hypothyroidism or both and is associated with a significant increased incidence of depression ().”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A large meta-analysis reported that thyroid autoantibodies did not increase the risk of gestational diabetes in euthyroid pregnant women, and their positivity in the first trimester did not predict gestational diabetes risk.

    “A large meta-analysis reported that the presence of thyroid autoantibodies did not increase the risk of GDM in euthyroid pregnant women, and their positivity in the first trimester did not have a predictive value for the risk of GDM ().”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Patients with diabetes have increased risk of heart disease, stroke, heart failure, kidney disease, blindness, amputations, and neuropathy.

    “Patients with DM have an increased risk of heart disease, stroke, heart failure, kidney disease, blindness, amputations, and neuropathy (-).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The reviewed studies suggest that atherogenic dyslipidemia, insulin resistance, and hypertension can be linked with overt and subclinical hypothyroid states, and thyroid hormone deficiency is significantly associated with some components of metabolic syndrome.

    “All of these studies suggest that atherogenic dyslipidemia, insulin resistance, and hypertension can be linked with overt and subclinical hypothyroid states, and consequently TH deficiency is significantly associated with some components of MetS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Poor metabolic control, which is more common when TD develops, can mask the clinical symptoms of TD.

    “clinical symptoms of TD may be masked by a poor metabolic control, which is more frequent when TD develops”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Euthyroid subjects with TSH in the upper normal range (2.5-4.5 mU/L) were more obese (BMI >30), had higher triglyceride levels, and had increased likelihood of metabolic syndrome.

    “Euthyroid subjects with TSH values in the upper normal range (. to . mU/L) were more obese (BMI .kg/m  ), had higher triglyceride levels, and had an increased likelihood of having MetS ().”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Subclinical hypothyroidism was associated with an odds ratio of 3.15 (95% CI 1.48-6.69) for development of diabetic nephropathy and was also responsible for increased risk of cardiovascular events mediated by diabetic nephropathy.

    “SHypo was associated with an OR of . (% CI, . to .) for the development of DN and was also responsible for an increased risk of cardiovascular events mediated by DN ().”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mild subclinical thyroid disease progresses slowly, at roughly 1% over five years, which suggests a need for long-term screening.

    “Mild subclinical thyroid disease can progress at a low rate, suggesting a long-term screening program.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Hollowell, 2002, Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III), J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [4] Cooper, 2012, Subclinical thyroid disease, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Unrecognized thyroid disorders can worsen metabolic control and increase cardiovascular risk in T2D patients.

    “Undetected thyroid disorders can compromise the metabolic control and amplify the risk of cardiovascular events.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Because of these uncertainties, specific recommendations from major endocrine and diabetes society guidelines cannot be adopted.

    “These uncertainties do not allow us to adopt specific recommendations from the guidelines published by the major endocrine and diabetes societies”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    TD screening might prevent the serious cardiovascular complications associated with T2D.

    “The screening of TD could prevent the high cardiovascular complications of T2D.”
    Quote in the paperSubstantial claim
50 of 50

  • The paper relies on this without support.

    Insulin resistance is the main clinical and pathogenic feature of metabolic syndrome.

    “Isulin resistance is the main clinical and pathogenic feature of this syndrome.”

  • The paper relies on this without support.

    Human brown adipose tissue is more important in neonates than in adults.

    “However, human BAT is considered more important in neonates than in the adults.”

  • The paper relies on this without support.

    The prevalence of hypothyroidism in women of reproductive age is 2% to 3%.

    “The prevalence of hypothyroidism in women during the reproductive age is % to %, and chronic autoimmune thyroiditis is the main cause of hypothyroidism during pregnancy.”

  • The paper relies on this without support.

    Postpartum thyroiditis is caused by destructive autoimmune thyroiditis in the postpartum period, mediated by a rebound of cellular and humoral immunity.

    “Postpartum thyroiditis (PPTD) is caused by a destructive autoimmune thyroiditis in the postpartum period, mediated by a rebound of both cellular and humoral immunity.”

  • The paper relies on this without support.

    The cost-benefit ratio is favorable for screening thyroid dysfunction in type 1 diabetes.

    “• The cost-benefit ratio is favorable for a screening of TD.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Excess T3 leads to considerable impairment of islet function.

    “Furthermore, excess T3 leads to considerable impairment of the islet function, while physiological T3 treatment promotes beta-cell proliferation (57, 62).”

    From The progression of secondary diabetes: A review of modeling studies (2022) · cites this paper as [57]

    The section on central and peripheral thyroid-hormone effects states that hyperthyroidism and high-fat feeding significantly impair islet function. The paper also says thyroid-hormone excess increases beta-cell apoptosis, but it does not clearly attribute the reported islet impairment to excess T3 alone; the claim omits the high-fat-feeding condition. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Changes in serum TSH are associated with the incidence of T2DM, but the connection is merely significant in hypothyroidism.

    “Changes in serum TSH are also associated with the incidence of T2DM, but the connection is merely significant in hypothyroidism (57).”

    From The progression of secondary diabetes: A review of modeling studies (2022) · cites this paper as [57]

    The Hypothyroidism and T2D section says prospective studies investigated whether changes in serum TSH or thyroid hormones were associated with diabetes risk. It does not establish that the association is significant only in hypothyroidism. The Underlying Mechanisms section also reports an increased diabetes risk in one study of people with hyperthyroidism, while noting conflicting results across studies; page numbers were not available in the indexed passages. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

  • Thyroid dysfunction and diabetes mellitus are closely linked, and the liver is the main organ of glucose metabolism in the human.

    “Thyroid dysfunction and diabetes mellitus are closely linked, and the liver is the main organ of glucose metabolism in the human (Biondi et al., 2019; Sridhar et al., 2014).”

    From Exposure to per- and polyfluoroalkyl substances in early pregnancy, risk of gestational diabetes mellitus, potential pathways, and influencing factors in pregnant women: A nested case-control study (2023) · cites this paper as Biondi et al., 2019

    The Abstract explicitly states that thyroid dysfunction and diabetes mellitus are closely linked. The section on hepatic glucose production describes the liver’s role in glucose regulation, but does not establish that it is the main organ of glucose metabolism in humans. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • T3 exerts profound effects on the proliferation of pancreatic islet cells and insulin secretion.

    “Moreover, T3 exerts profound effects on the proliferation of pancreatic islet cells and insulin secretion (57, 59).”

    From The progression of secondary diabetes: A review of modeling studies (2022) · cites this paper as [57]

  • Diabetes mellitus is strongly associated with thyroid dysfunction.

    “There are strong associations between diabetes mellitus and numerous concurrent health issues, such as osteoporosis, thyroid dysfunction, and abnormalities in iron metabolism (2–4).”

    From Biological variation in serum thyroid, iron metabolism, and plasma bone metabolism biomarkers in patients with type 2 diabetes mellitus (2025) · cites this paper as [2]

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Centers for Disease Control and Prevention, 2011, National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011
  2. 2003, 26, 1181
  3. 2000, J Gorgan Uni Med Sci, 2, 5
  4. Efe, 1999, Effects of second generation sulfonylureas on the thyroid, Turk J Endocrinol Metab., 4, 173

Cited by

Sorted by citations

Related

Authors
Biondi, B., Kahaly, G. J., & Robertson, R. P.
Affiliations
  • Federico II University Hospital (IT)
  • University Medical Center of the Johannes Gutenberg University Mainz (DE)
  • University of Washington (US)
Corresponding author
Biondi, Bernadette
ORCID
Venue
Endocrine Reviews
Publisher
The Endocrine Society
Published
2019-01-14
Volume
40
Issue
3
Pages
789-824
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
DOI
10.1210/er.2018-00163
PMC
PMC6507635
OpenAlex
W2909632761
Semantic Scholar
5611ced84cb98c912f119fd45af52bec095d4953
Cited by
598
References
410
Citations by year
2026: 81 · 2025: 105 · 2024: 120 · 2023: 107 · 2022: 98 · 2021: 50 · 2020: 28 · 2019: 9
FWCI
7.09
Type
journal article
Language
en
Open access
Locations
  • Endocrine Reviews (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (NIDDK RO-1 38325-35)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
thyroid dysfunction, diabetes mellitus, type 1 diabetes, type 2 diabetes, subclinical hypothyroidism, overt hypothyroidism, metabolic syndrome, thyroid hormone regulation, glucose metabolism, lipid metabolism, adipose tissue, pancreatic beta cells, skeletal muscle, autoimmune thyroid disease, susceptibility genes, antidiabetic drugs, treatment algorithm
MeSH terms
Animals, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Humans, Hypothyroidism, Thyroid Diseases

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

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