Understanding the Link Between Prediabetes, Insulin Resistance, and Thyroid Function

In the realm of metabolic health, prediabetes and insulin resistance (IR) have emerged as critical precursors to more serious conditions like diabetes. Prediabetes, characterized by elevated plasma glucose levels that aren’t high enough for a diabetes diagnosis, often coexists with insulin resistance. This condition poses significant challenges to individuals’ overall health, particularly affecting thyroid function, size, and nodules.¹Yasar HY, Ertuğrul O, Ertuğrul B, Ertuğrul D, Sahin M. Insulin resistance in nodular thyroid disease. Endocr Res. 2011;36(4):167-74.^,2ALYOUSIF, H., AHMED, M., KHAIR, A., ALHARBI, F., HASSAN, S., ELBADWI, N., MUSA, I.. The Prevalence and Associated Predictors for Diabetes Mellitus in Adult Patients With Thyroid Nodules. Journal of Clinical Medicine Research, North America, 15, mar. 2023.^,3Yasar HY, Ertuğrul O, Ertuğrul B, Ertuğrul D, Sahin M. Insulin resistance in nodular thyroid disease. Endocr Res. 2011;36(4):167-74.^,4Tang Y, Yan T, Wang G, Chen Y, Zhu Y, Jiang Z, Yang M, Li C, Li Z, Yu P, Wang S, Zhu N, Ren Q, Ni C. Correlation between Insulin Resistance and Thyroid Nodule in Type 2 Diabetes Mellitus. Int J Endocrinol. 2017;2017:1617458.^,5Demiral Sezer, S., Erdoğan Yücel, E. Does insulin resistance trigger thyroid nodule?. Intern Emerg Med 16, 2105–2108 (2021).^,6Yevgeniya S Kushchayeva, Sergiy V Kushchayev, Megan Startzell, Elaine Cochran, Sungyoung Auh, Yuhai Dai, Marissa Lightbourne, Monica Skarulis, Rebecca J Brown, Thyroid Abnormalities in Patients With Extreme Insulin Resistance Syndromes, The Journal of Clinical Endocrinology & Metabolism, Volume 104, Issue 6, June 2019, Pages 2216–2228^,7Kun Wang, Yu Yang, Yang Wu, Jie Chen, Danyu Zhang, Xiaodong Mao, Xinping Wu, Xianqin Long, Chao Liu, The Association Between Insulin Resistance and Vascularization of Thyroid Nodules, The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 1, 1 January 2015, Pages 184–192,^,

The Relationship Between Prediabetes and Insulin Resistance

Prediabetes, a state where blood sugar levels are higher than normal but not yet at diabetic levels, is closely intertwined with insulin resistance. In essence, insulin resistance occurs when cells fail to respond effectively to insulin, leading to elevated blood sugar levels. Individuals with prediabetes may experience fluctuations in blood sugar, even presenting with low or normal levels at times, especially when challenged by fasting or dietary changes.

Hypothyroidism, Metabolic Syndrome, and Insulin Resistance

The medical community recognizes the association between hypothyroidism, metabolic syndrome (MetS), and insulin resistance, although they always treat them as separate entities. However, research suggests a significant interplay among these conditions. Insulin Resistance, characterized by all the symptoms of an underactive thyroid gland, can exacerbate Hypothyroidism, contributing to metabolic dysfunction.

Impact on Thyroid Antibodies and Autoimmunity

Insulin resistance not only affects glucose metabolism but also triggers immune responses, leading to the production of thyroid antibodies. This phenomenon is particularly evident in individuals with euthyroidism, where insulin resistance can precipitate the development of Hashimoto’s thyroiditis. Elevated levels of thyroid autoantibodies often correlate with high fasting blood glucose levels, insulin levels, and markers of insulin resistance.⁸Jain, Amit & Dholariya, Sagar & Masroor, Mirza & Lali, P & Chandra, Lal & Dhanwal, Dinesh. (2020). Association of Anti-TPO Antibodies with Insulin Resistance in Patients of Hypothyroidism with Metabolic Syndrome: A Cross-sectional Study. JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH. 14. 10.7860/JCDR/2020/45695.14123.^,9Krishnamurthy H, Siriwardhane T, Krishna K, et al. Insulin resistance in thyroid disorders: association between anti-TPO and HOMA-IR. medRxiv; 2023.^,10Mazaheri T, Sharifi F, Kamali K. Insulin resistance in hypothyroid patients under Levothyroxine therapy: a comparison between those with and without thyroid autoimmunity. J Diabetes Metab Disord. 2014 Oct 30;13(1):103.^,

Thyroid Hormones and Glucose Metabolism

Thyroid hormones play a crucial role in regulating glucose metabolism, influencing insulin secretion and cellular glucose uptake. However, disturbances in metabolic function, such as insulin resistance, can further disrupt these processes, as a consequence of thyroid under-conversion and over-conversion dysfunction. High insulin levels can prevent the body from converting the inactive thyroid hormone (T4) to the active thyroid hormone (T3).¹¹Vyakaranam S, Vanaparthy S, Nori S, Palarapu S, Bhongir AV. Study of Insulin Resistance in Subclinical Hypothyroidism. Int J Health Sci Res. 2014 Sep;4(9):147-153.^,12Gierach M, Gierach J, Junik R. Insulin resistance and thyroid disorders. Endokrynol Pol. 2014;65(1):70-6. doi: 10.5603/EP.2014.0010. PMID: 24549605.^,13Stanická S, Vondra K, Pelikánová T, Vlcek P, Hill M, Zamrazil V. Insulin sensitivity and counter-regulatory hormones in hypothyroidism and during thyroid hormone replacement therapy. Clin Chem Lab Med. 2005;43(7):715-20.^,14Kazukauskiene N, Podlipskyte A, Varoneckas G, Mickuviene N. Insulin Resistance in Association with Thyroid Function, Psychoemotional State, and Cardiovascular Risk Factors. Int J Environ Res Public Health. 2021 Mar 25;18(7):3388.^,15Demetriou E, Fokou M, Frangos S, Papageorgis P, Economides PA, Economides A. Thyroid Nodules and Obesity. Life. 2023; 13(6):1292.^, Despite thyroid replacement therapy, insulin-mediated glucose uptake may remain impaired in individuals with insulin resistance.

The Role of Red Blood Cell Agglutination

Insulin resistance has been consistently associated with red blood cell (RBC) agglutination, where RBCs clump together, impeding oxygen delivery to tissues. This phenomenon exacerbates the metabolic dysfunction associated with insulin resistance, depriving cells of both glucose and oxygen, essential for cellular metabolism.¹⁶Ellisor SS, Toy PT, Reid ME, Avoy DR. Agglutination of red blood cells from patients with diabetes mellitus by a polyclonal human antibody specific for D-glucose. Vox Sang. 1990;58(3):215-8.^,17Ziegler O, Guerci B, Muller S, Candiloros H, Méjean L, Donner M, Stoltz JF, Drouin P. Increased erythrocyte aggregation in insulin-dependent diabetes mellitus and its relationship to plasma factors: a multivariate analysis. Metabolism. 1994 Sep;43(9):1182-6.^,18Fowler M. J. (2008). Microvascular and macrovascular complications of diabetes. Clin. Diabetes. 26, 77–82.^,19Ellinger VC, Carlini LT, Moreira RO, Meirelles RM. Relation between insulin resistance and hematological parameters in a Brazilian sample. Arq Bras Endocrinol Metabol. 2006 Feb;50(1):114-7.

Insulin Resistance and Thyroid Morphological Abnormalities

Recent research has unveiled a compelling link between insulin resistance and thyroid morphological abnormalities. Hyperinsulinemia, a hallmark of insulin resistance, has been associated with larger thyroid gland size and a higher prevalence of thyroid nodules and cancer. Conversely, treatment with metformin, a medication commonly used to manage insulin resistance, has shown promise in reducing thyroid volume and lowering the risk of thyroid nodules and cancer.

The Impact of Metformin on Thyroid Function

Metformin therapy not only improves insulin sensitivity but also exerts beneficial effects on thyroid function. Studies have reported a decrease in serum thyroid-stimulating hormone (TSH) levels in diabetic patients treated with metformin, potentially enhancing thyroid hormone activity. Interestingly, metformin use has also been linked to decreased TSH levels in hypothyroid patients, and reduction of thyroid nodules independent of thyroid autoimmunity and thyroxine treatment.²⁰Miao Sui, Yuan Yu, Huifeng Zhang, Hongjie Di, Chao Liu, Yaofu Fan. Efficacy of Metformin for Benign Thyroid Nodules in Subjects With Insulin Resistance: A Systematic Review and Meta-Analysis. Frontiers in endocrinology, August 2018^,21Sui M, Yu Y, Zhang H, Di H, Liu C, Fan Y. Efficacy of Metformin for Benign Thyroid Nodules in Subjects With Insulin Resistance: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). 2018 Aug 28;9:494.^,

Conclusion

The intricate relationship between prediabetes, insulin resistance, and thyroid function underscores the importance of comprehensive metabolic assessment and management. Recognizing the interconnected

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References

• 1
  Yasar HY, Ertuğrul O, Ertuğrul B, Ertuğrul D, Sahin M. Insulin resistance in nodular thyroid disease. Endocr Res. 2011;36(4):167-74.
• 2
  ALYOUSIF, H., AHMED, M., KHAIR, A., ALHARBI, F., HASSAN, S., ELBADWI, N., MUSA, I.. The Prevalence and Associated Predictors for Diabetes Mellitus in Adult Patients With Thyroid Nodules. Journal of Clinical Medicine Research, North America, 15, mar. 2023.
• 3
  Yasar HY, Ertuğrul O, Ertuğrul B, Ertuğrul D, Sahin M. Insulin resistance in nodular thyroid disease. Endocr Res. 2011;36(4):167-74.
• 4
  Tang Y, Yan T, Wang G, Chen Y, Zhu Y, Jiang Z, Yang M, Li C, Li Z, Yu P, Wang S, Zhu N, Ren Q, Ni C. Correlation between Insulin Resistance and Thyroid Nodule in Type 2 Diabetes Mellitus. Int J Endocrinol. 2017;2017:1617458.
• 5
  Demiral Sezer, S., Erdoğan Yücel, E. Does insulin resistance trigger thyroid nodule?. Intern Emerg Med 16, 2105–2108 (2021).
• 6
  Yevgeniya S Kushchayeva, Sergiy V Kushchayev, Megan Startzell, Elaine Cochran, Sungyoung Auh, Yuhai Dai, Marissa Lightbourne, Monica Skarulis, Rebecca J Brown, Thyroid Abnormalities in Patients With Extreme Insulin Resistance Syndromes, The Journal of Clinical Endocrinology & Metabolism, Volume 104, Issue 6, June 2019, Pages 2216–2228
• 7
  Kun Wang, Yu Yang, Yang Wu, Jie Chen, Danyu Zhang, Xiaodong Mao, Xinping Wu, Xianqin Long, Chao Liu, The Association Between Insulin Resistance and Vascularization of Thyroid Nodules, The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 1, 1 January 2015, Pages 184–192,
• 8
  Jain, Amit & Dholariya, Sagar & Masroor, Mirza & Lali, P & Chandra, Lal & Dhanwal, Dinesh. (2020). Association of Anti-TPO Antibodies with Insulin Resistance in Patients of Hypothyroidism with Metabolic Syndrome: A Cross-sectional Study. JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH. 14. 10.7860/JCDR/2020/45695.14123.
• 9
  Krishnamurthy H, Siriwardhane T, Krishna K, et al. Insulin resistance in thyroid disorders: association between anti-TPO and HOMA-IR. medRxiv; 2023.
• 10
  Mazaheri T, Sharifi F, Kamali K. Insulin resistance in hypothyroid patients under Levothyroxine therapy: a comparison between those with and without thyroid autoimmunity. J Diabetes Metab Disord. 2014 Oct 30;13(1):103.
• 11
  Vyakaranam S, Vanaparthy S, Nori S, Palarapu S, Bhongir AV. Study of Insulin Resistance in Subclinical Hypothyroidism. Int J Health Sci Res. 2014 Sep;4(9):147-153.
• 12
  Gierach M, Gierach J, Junik R. Insulin resistance and thyroid disorders. Endokrynol Pol. 2014;65(1):70-6. doi: 10.5603/EP.2014.0010. PMID: 24549605.
• 13
  Stanická S, Vondra K, Pelikánová T, Vlcek P, Hill M, Zamrazil V. Insulin sensitivity and counter-regulatory hormones in hypothyroidism and during thyroid hormone replacement therapy. Clin Chem Lab Med. 2005;43(7):715-20.
• 14
  Kazukauskiene N, Podlipskyte A, Varoneckas G, Mickuviene N. Insulin Resistance in Association with Thyroid Function, Psychoemotional State, and Cardiovascular Risk Factors. Int J Environ Res Public Health. 2021 Mar 25;18(7):3388.
• 15
  Demetriou E, Fokou M, Frangos S, Papageorgis P, Economides PA, Economides A. Thyroid Nodules and Obesity. Life. 2023; 13(6):1292.
• 16
  Ellisor SS, Toy PT, Reid ME, Avoy DR. Agglutination of red blood cells from patients with diabetes mellitus by a polyclonal human antibody specific for D-glucose. Vox Sang. 1990;58(3):215-8.
• 17
  Ziegler O, Guerci B, Muller S, Candiloros H, Méjean L, Donner M, Stoltz JF, Drouin P. Increased erythrocyte aggregation in insulin-dependent diabetes mellitus and its relationship to plasma factors: a multivariate analysis. Metabolism. 1994 Sep;43(9):1182-6.
• 18
  Fowler M. J. (2008). Microvascular and macrovascular complications of diabetes. Clin. Diabetes. 26, 77–82.
• 19
  Ellinger VC, Carlini LT, Moreira RO, Meirelles RM. Relation between insulin resistance and hematological parameters in a Brazilian sample. Arq Bras Endocrinol Metabol. 2006 Feb;50(1):114-7.
• 20
  Miao Sui, Yuan Yu, Huifeng Zhang, Hongjie Di, Chao Liu, Yaofu Fan. Efficacy of Metformin for Benign Thyroid Nodules in Subjects With Insulin Resistance: A Systematic Review and Meta-Analysis. Frontiers in endocrinology, August 2018
• 21
  Sui M, Yu Y, Zhang H, Di H, Liu C, Fan Y. Efficacy of Metformin for Benign Thyroid Nodules in Subjects With Insulin Resistance: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). 2018 Aug 28;9:494.