CME INDIA Presentation by Prof (Dr.) Prabhat Agrawal, Department of Medicine, S. N. Medical College, Agra.
Based on a presentation at APICON 2023, Ahmedabad.
Why this association matters?
- The estimates in 2021 showed that approx. 89 million adults had diabetes in India, which is expected to rise to over 134 million by 2045.
- It has been estimated that about 42 million people in India suffer from thyroid disorders.
- A 3.5-fold increased risk of autoimmune thyroiditis was noticed in GADA positive patients.
- Thyroid disorders seem to be the most frequent autoimmune disorders seen in type 1 diabetes mellitus patients.
Clinical aspects of diabetes and thyroid disease coexistence
- Hyperthyroidism has shown to promote hyperglycemia.
- Due to hyperthyroidism, the half-life of insulin is reduced. This could most likely be secondary to an increased rate of degradation and an increased release of biologically inactive insulin precursors.
- Untreated hyperthyroidism was associated with a reduced C-peptide to proinsulin ratio and thus an underlying defect in proinsulin processing ensues.
- There is also an increase in glucose gut absorption in presence of excess thyroid hormones.
- Thyroid hormones increase the plasma membrane concentrations of GLUT2 in liver cells(hepatocytes), which is the main glucose transporter in the liver.
- This increase in GLUT2 contributes to an increased hepatic glucose output.
- Increased lipolysis in hyperthyroidism causes an increase in Free Fatty Acids (FFA) that serve as a substrate for hepatic gluconeogenesis.
- There is increased catecholamine stimulated lipolysis in presence of excess thyroid hormones which further adds to a rise in circulating FFAs.
Facts worth knowing
- Diabetic patients with hyperthyroidism experience worsening of their glycemic control and excessive thyroid hormones as seen in thyrotoxicosis has been associated with precipitation of diabetic ketoacidosis in patients of diabetes.
- Hepatic glucose production is reduced in hypothyroidism, which accounts for a decrease in insulin requirement in diabetic patients with hypothyroidism.
- Recurrent episodes of hypoglycemia are the presenting signs for the development of hypothyroidism in patients with type 1 diabetes.
- Treatment with thyroid hormones reduces the fluctuations in blood glucose levels.
- Both clinical and subclinical hypothyroidisms have been recognized as insulin resistant states.
- Studies have shown that this may be due to impaired insulin stimulated glucose utilization in peripheral tissues.
- It is seen that patients of DM have an increased tendency to develop diabetic nephropathy and retinopathy in the setting of Thyroid disorders.
- This makes it prudent to consider evaluating thyroid hormone status in patients with prolonged diabetes.
- The association between Autoimmune Thyroid disorders (AITD) and T1DM has been recognized as a variant of Autoimmune Polyendocrine Syndrome (APS) referred to as APS3 variant.
Currently, at least four shared genes have been identified
- These confer a risk of developing both AITD and T1DM.
- These are:
- HLA
- CTLA-4
- PTPN22 [24, 25]
- FOXP3 genes
- In diabetics, the nocturnal TSH peak is blunted or abolished.
- The effect of TRH on TSH secretion is also impaired.
- There is a “low T3 state” in patients with uncontrolled diabetes. This could be explained by an impairment in peripheral conversion of T4 to T3 due to raised blood sugar levels and it usually normalizes with glycemic control
- A higher incidence of dysthyroid optic neuropathy is observed in diabetics with Graves ophthalmopathy compared to nondiabetics.
- A 1.38- fold-increased risk for thyroid cancer in women with pre-existing diabetes has been noted and a 20% increase in thyroid cancer in DM patients.
Take into consideration which can impact your treatment plans. It would call for dose adjustments or even changes in the initial treatment plan.
The effects of a few known OHAs on Thyroid Functions
- It is known to reduce TSH levels in a patient with regular use and thus is being explored as a potential Agent for simultaneous treatment of T2DM and Hypothyroidism.
- A few studies suggest that it reduces the risk of thyroid cancer. It has a role in people with nodular thyroid enlargement as it reduces both the overall size of the gland and the nodule size.
Sulfonylureas
- It has been shown to Increase the risk of thyroid neoplasms, hypothyroidism, and goitre.
- Thus, it should be used carefully in patients of T2DM with thyroid dysfunction.
Thiazolidinediones
- Using Thiazolidinediones has been associated with inhibition of the activity of thyroid hormone receptors, an Increase in TSH and IGF-1, a decrease in Free T4 levels, and an aggravation of thyroid-associated orbitopathy.
Effects of Thyroid drugs on glycemic control
Methimazole
- It has been associated with the development of insulin autoimmune syndrome and may cause hypoglycemia in patients with diabetes.
Carbimazole
- Insulin autoimmune syndrome has been reported in some studies with the use of carbimazole.
Levothyroxine
- Helps in Reducing fasting and postprandial glucose. An overall reduction in HbA1C levels is also noted with Levothyroxine use.
Clinical guidelines for screening thyroid status in diabetics.
- There is no general consensus on the annual screening of T2DM patients for Thyroid status, but it goes without a doubt that patients with diabetes are at increased risk for thyroid disorders.
- Undiagnosed thyroid disorders can worsen glycemic control and increase the cardiovascular risk in these patients hence screening diabetics for thyroid disorders can only render more benefits than harms.
- Studies done in this regard recommend that all patients with diabetes should be screened for TSH and anti-TPO at baseline.
- In euthyroid T1DM, annual TSH screening is required. In euthyroid T2DM patients, an annual TSH test is only needed in those with TSH more than 2.0mU/L or detectable anti-TPO. In others, a TSH test is enough for every 3–5 year.
Recommendations for Thyroid Screening in diabetes patients
| Guidelines | Screening recommendations |
| 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum | In high-risk women, serum TSH to be tested at baseline; reflex anti-TPO if TSH is 2.5–10 mU/L |
| 2012 Clinical Practice Guidelines for Hypothyroidism in Adults: cosponsored by The American Association of Clinical Endocrinologists and The American Thyroid Association | Thyroid palpation and serum TSH measurement at baseline and at regular intervals in T1DM patients, especially if goitre or autoimmune disease present |
| 2006 UK Guidelines for the Use of Thyroid Function Tests by the British Thyroid Association and the Association of Clinical Biochemistry Guidelines | TFT at baseline and annually for T1DM. In T1DM, TSH, FT4, and anti-TPO measured preconception, at booking, and at 3 months postpartum. TFT at baseline for T2DM |
| Standards of Medical Care in Diabetes – 2017 by the American Diabetes Association | Thyroid palpation at presentation. At T1DM diagnosis, tests recommended for anti-TPO, anti-TG, and TSH. Frequent rechecking if symptoms suggest TD |
| Italian Association of Clinical Endocrinologists and Italian Association of Clinical Diabetologists Position Statement: Diabetes Mellitus and Thyroid Disorders: Recommendations for Clinical Practice | TFT at baseline and annually for T1DM patients TFT during DKA with careful evaluation Re-evaluation of newly detected hyperglycaemia in hyperthyroid subjects Serum TSH assay in case of repeated hypoglycaemia In diabetic patients with SCH, TSH check every 6 months |
Quick Take-Aways
- Newly diagnosed T1DM patients should be checked for TSH levels, Anti TTG and anti TPO antibodies for baseline levels.
- All diabetic patients should be checked for at least baseline TSH values.
- Uncontrolled sugar levels in diabetic patients (on adequate treatment) could be due to an underlying Thyroid disorder and hence such patients should be screened for Thyroid disorders.
- Patients of thyroid disorders should also be screened for their glycaemic control. Presence of Diabetes mellitus can worsen thyroid disorders.
- Modification of treatment plans in coexisting TD And DM can help achieve better treatment goals in such patients. Avoid using drugs that can worsen the progress of the other endocrinopathy.
CME INDIA Learning Points
- The association between thyroid dysfunction and diabetes mellitus is evident.
- Thyroid dysfunction chiefly comprises hypothyroidism and hyperthyroidism.
- The association points to the same organ but with vast difference in pathophysiology as well as clinical picture happens.
- Hypoadrenalism as well as hypopituitarism have strong linkage with hypothyroidism and consequently diabetes mellitus.
- New evidence has emerged about the intricate bond between subclinical hypothyroidism and diabetes mellitus which deceptively contribute to the major complications especially retinopathy and neuropathy.
- Cardiovascular events and micro- or macro-angiopathies are now said to be the counter reflection of resurgence of heavily disturbed lipid metabolism which is due to thyroid dyscrasias.
- Insulin resistance bears an indispensable role in connecting T2DM and thyroid dysfunction.
- It is important to diagnose thyroid dysfunction in T2DM patients.
References:
- Dr. P. Perros, R.J. McCrimmon, G. Shaw, B.M. Frier. Frequency of Thyroid Dysfunction in Diabetic Patients: Value of Annual Screening https://doi.org/10.1111/j.1464-5491.1995.tb00553.x
- Hage M, Zantout MS, Azar ST. Thyroid disorders and diabetes mellitus. J Thyroid Res. 2011;2011:439463. doi: 10.4061/2011/439463. Epub 2011 Jul 12. PMID: 21785689; PMCID: PMC3139205.
- Kalra S, Aggarwal S, Khandelwal D. Thyroid Dysfunction and Type 2 Diabetes Mellitus: Screening Strategies and Implications for Management. Diabetes Ther. 2019 Dec;10(6):2035-2044. doi: 10.1007/s13300-019-00700-4. Epub 2019 Oct 3. PMID: 31583645; PMCID: PMC6848627.
- Ogbonna Stanley U., Ezeani Ignatius U.Risk Factors of Thyroid Dysfunction in Patients With Type 2 Diabetes Mellitus .Frontiers in Endocrinology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/articles/10.3389/fendo.2019.00440
- Wang C. The Relationship between Type 2 Diabetes Mellitus and Related Thyroid Diseases. J Diabetes Res. 2013;2013:390534. doi: 10.1155/2013/390534. Epub 2013 Apr 4. PMID: 23671867; PMCID: PMC3647563.
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