Top

09-09-2024 | Testosterone | Review

Testosterone levels and risk of newly diagnosed type 2 diabetes mellitus in adult men: systematic review and meta-analysis

Authors: Gustavo Adolfo Vásquez-Tirado, Juan Diego Guarniz-Salavarria, Claudia Vanessa Quispe-Castañeda, Jhuliana M. Contreras-Cabrera, María del Carmen Cuadra-Campos, Edinson Dante Meregildo-Rodriguez, Niler Manuel Segura-Plasencia, Yesenia Katherin Arbayza-Ávalos

Published in: Endocrine

Abstract

Introduction

Testosterone is a metabolically active hormone in males for metabolic homeostasis. Although the coexistence of low testosterone levels and type 2 diabetes mellitus (T2DM) have been associated, there are no reports that evaluate alterations in total testosterone (TT) levels and the risk of newly diagnosed T2DM. This review evaluates this question in adult men with high or low levels of total testosterone (TT), as well as the role played by other hormones such as free testosterone (FT), sex hormone binding globulin (SHBG), dihydrotestosterone (DHT), estrogens and testosterone bioavailable (bT).

Methods

We searched for studies published up to July 30, 2023, in five databases, following a PECO strategy. We found twenty-two studies for quantitative analysis and meta-analyzed the same quantity of studies.

Results

This first meta-analysis incorporates the assessment of the risk of low TT and T2DM in longitudinal studies. 43,038 adult men are included. Our meta-analysis shows that there is an association between low TT levels and the risk of newly diagnosed T2DM (OR 1.52; 95% CI 1.10–2.10; p < 0.05; I²: 79%). It is also evident that SHBG in low TT studies behaves as a risk factor for T2DM in the same way as FT, although without statistical significance. bT behaves as a protective factor. There is no association between estrogen, DHT and T2DM.

Conclusions

In adult men with low TT values, there is a greater risk of developing a newly diagnosed of T2DM. SHBG values in low TT patients also present a higher risk of T2DM as the same FT but without statistical significance. bT behaves as a protective factor We have not found an association between risk of T2DM and the levels of estrogen, DHT although there are very few studies that report these hormones.

Available only for authorised users

V. Tyagi, M. Scordo, R.S. Yoon, F.A. Liporace, L.W. Greene, Revisiting the role of testosterone: Are we missing something? Rev. Urol. 19, 16–24 (2017). https://doi.org/10.3909/riu0716CrossRefPubMedPubMedCentral

G. Navarro, C. Allard, W. Xu, F. Mauvais-Jarvis, The role of androgens in metabolism, obesity, and diabetes in males and females. Obesity 23, 713–9 (2015). https://doi.org/10.1002/oby.21033CrossRefPubMed

W. Xu, J. Morford, F. Mauvais-Jarvis, Emerging role of testosterone in pancreatic β cell function and insulin secretion. J. Endocrinol. 240, R97–105 (2019). https://doi.org/10.1530/JOE-18-0573CrossRef

W.T. Berg, M. Miner, Hypogonadism and metabolic syndrome: review and update. Curr. Opin. Endocrinol. Diab. Obes. 27, 404–10 (2020). https://doi.org/10.1097/MED.0000000000000582CrossRef

K. Kumari, R. Kumar, A. Memon et al. Treatment with testosterone therapy in type 2 diabetic hypogonadal adult males: A systematic review and meta-analysis. Clin. Pract. 13, 454–69 (2023). https://doi.org/10.3390/clinpract13020041CrossRefPubMedPubMedCentral

T.G. Travison, H.W. Vesper, E. Orwoll et al. Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the United States and Europe. J. Clin. Endocrinol. Metab. 102, 1161–73 (2017). https://doi.org/10.1210/jc.2016-2935CrossRefPubMedPubMedCentral

G.A. Kanakis, C.P. Tsametis, D.G. Goulis, Measuring testosterone in women and men. Maturitas 125, 41–4 (2019). https://doi.org/10.1016/j.maturitas.2019.04.203CrossRefPubMed

J.C.C. Kwong, Y. Krakowsky, E. Grober, Testosterone deficiency: A review and comparison of current guidelines. J. Sex. Med. 16, 812–20 (2019). https://doi.org/10.1016/j.jsxm.2019.03.262CrossRefPubMed

J.P. Mulhall, L.W. Trost, R.E. Brannigan et al. Evaluation and management of testosterone deficiency: AUA guideline. J. Urol. 200, 423–32 (2018). https://doi.org/10.1016/j.juro.2018.03.115CrossRefPubMed

10.

C.A. Salter, J.P. Mulhall, Guideline of guidelines: testosterone therapy for testosterone deficiency. BJU Int. 124, 722–9 (2019). https://doi.org/10.1111/bju.14899CrossRefPubMed

11.

J. Anaissie, K.J. DeLay, W. Wang, G. Hatzichristodoulou, W.J. Hellstrom, Testosterone deficiency in adults and corresponding treatment patterns across the globe. Transl. Androl. Urol. 6, 183–91 (2017). https://doi.org/10.21037/tau.2016.11.16CrossRefPubMedPubMedCentral

12.

P. Gyawali, S.A. Martin, L.K. Heilbronn et al. The role of sex hormone-binding globulin (SHBG), testosterone, and other sex steroids, on the development of type 2 diabetes in a cohort of community-dwelling middle-aged to elderly men. Acta Diabetologica 55, 861–72 (2018). https://doi.org/10.1007/s00592-018-1163-6CrossRefPubMed

13.

M.S. Ccorahua-Ríos, N. Atamari-Anahui, I. Miranda-Abarca, A.B. Campero-Espinoza, E.A. Rondón-Abuhadba, C.J. Pereira-Victorio, Type 2 diabetes mellitus prevalence between 2005 and 2018 in population under 30 using data from the Ministry of Health of Peru. Medwave 19, e7723 (2019). https://doi.org/10.5867/medwave.2019.10.7723CrossRefPubMed

14.

American Diabetes Association Professional Practice Committee. 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes—2024. Diab. Care 47, S20–S42 (2024). https://doi.org/10.2337/dc24-S002.CrossRef

15.

M.W. O’Reilly, M. Glisic, B. Kumarendran et al. Serum testosterone, sex hormone-binding globulin and sex-specific risk of incident type 2 diabetes in a retrospective primary care cohort. Clin. Endocrinol. 90, 145–54 (2019). https://doi.org/10.1111/cen.13862CrossRef

16.

G. Corona, M. Monami, G. Rastrelli et al. Type 2 diabetes mellitus and testosterone: a meta-analysis study. Int. J. Androl. 34, 528–40 (2011). https://doi.org/10.1111/j.1365-2605.2010.01117.xCrossRefPubMed

17.

J. Zhang, X. Li, Z. Cai, H. Li, B. Yang, Association between testosterone with type 2 diabetes in adult males, a meta-analysis and trial sequential analysis. Aging Male 23, 607–18 (2020). https://doi.org/10.1080/13685538.2018.1557139CrossRefPubMed

18.

Q.M. Yao, B. Wang, X.F. An, J.A. Zhang, L. Ding, Testosterone level and risk of type 2 diabetes in men: a systematic review and meta-analysis. Endocr. Connect. 7, 220–31 (2018). https://doi.org/10.1530/EC-17-0253CrossRefPubMed

19.

Cochrane Handbook for Systematic Reviews of Interventions. Accessed December 27, 2023. https://training.cochrane.org/handbook/archive/v6.3

20.

D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6, e1000097 (2009). https://doi.org/10.1371/journal.pmed.1000097CrossRefPubMedPubMedCentral

21.

B.J. Shea, B.C. Reeves, G. Wells et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 358, j4008 (2017). https://doi.org/10.1136/bmj.j4008CrossRefPubMedPubMedCentral

22.

M. Karakas, S. Schäfer, S. Appelbaum et al. Testosterone levels and type 2 diabetes—no correlation with age, differential predictive value in men and women. Biomolecules 8, 76 (2018). https://doi.org/10.3390/biom8030076CrossRefPubMedPubMedCentral

23.

S.A. Holmboe, T.K. Jensen, A. Linneberg et al. Low testosterone: A risk marker rather than a risk factor for type 2 diabetes. J. Clin. Endocrinol. Metab. 101, 3180–90 (2016). https://doi.org/10.1210/jc.2016-1778CrossRefPubMed

24.

M. Harrer, P. Cuijpers, T.A. Furukawa, D.D. Ebert. Welcome! | Doing Meta-Analysis in R. Accessed March 26, 2024. https://bookdown.org/MathiasHarrer/Doing_Meta_Analysis_in_R/

25.

D.P. McKenzie, C. Thomas. Relative risks and odds ratios: Simple rules on when and how to use them. Eur J Clin Invest. Published online April 20, 2020:e13249. https://doi.org/10.1111/eci.13249

26.

G.A. Wells, B. Shea, D. O’Connell et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Published online December 2021. https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

27.

L. Lin, H. Chu, Quantifying publication bias in meta-analysis. Biometrics 74, 785–94 (2018). https://doi.org/10.1111/biom.12817CrossRefPubMed

28.

T.D. Stanley, H. Doucouliagos, J.P.A. Ioannidis, E.C. Carter, Detecting publication selection bias through excess statistical significance. Res Synth. Methods 12, 776–95 (2021). https://doi.org/10.1002/jrsm.1512CrossRefPubMed

29.

N. Meader, K. King, A. Llewellyn et al. A checklist designed to aid consistency and reproducibility of GRADE assessments: development and pilot validation. Syst. Rev. 3, 82 (2014). https://doi.org/10.1186/2046-4053-3-82CrossRefPubMedPubMedCentral

30.

A. Granholm, W. Alhazzani, M.H. Møller, Use of the GRADE approach in systematic reviews and guidelines. Br. J. Anaesth. 123, 554–9 (2019). https://doi.org/10.1016/j.bja.2019.08.015CrossRefPubMed

31.

S.M. Haffner, J. Shaten, M.P. Stem, G.D. Smith, L. Kuller, Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulin-dependent diabetes mellitus in men. Am. J. Epidemiol. 143, 889–97 (1996). https://doi.org/10.1093/oxfordjournals.aje.a008832CrossRefPubMed

32.

R.K. Stellato, H.A. Feldman, O. Hamdy, E.S. Horton, J.B. McKinlay, Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diab. Care 23, 490–4 (2000). https://doi.org/10.2337/diacare.23.4.490CrossRef

33.

J.Y. Oh, E. Barrett-Connor, N.M. Wedick, D.L. Wingard, Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diab. Care 25, 55–60 (2002). https://doi.org/10.2337/diacare.25.1.55CrossRef

34.

K.M. Lakshman, S. Bhasin, A.B. Araujo, Sex hormone-binding globulin as an independent predictor of incident type 2 diabetes mellitus in men. J. Gerontol. Ser. A: Biol. Sci. Med. Sci. 65A, 503–9 (2010). https://doi.org/10.1093/gerona/glq002CrossRef

35.

G.K. Jasuja, T.G. Travison, M. Davda et al. Circulating estrone levels are associated prospectively with diabetes risk in men of the framingham heart study. Diab. Care 36, 2591–6 (2013). https://doi.org/10.2337/dc12-2477CrossRef

36.

K.E. Joyce, M.L. Biggs, L. Djoussé et al. Testosterone, dihydrotestosterone, sex hormone binding globulin and incident diabetes among older men: the cardiovascular health study. J. Clin. Endocrinol. Metab. 102, jc.2016-2623 (2016). https://doi.org/10.1210/jc.2016-2623CrossRef

37.

J. Hu, A. Zhang, S. Yang et al. Combined effects of sex hormone-binding globulin and sex hormones on risk of incident type 2 diabetes. J. Diab. 8, 508–15 (2016). https://doi.org/10.1111/1753-0407.12322CrossRef

38.

X. Liu, J. Jiang, X. Liu et al. Association of serum testosterone with different classes of glucose metabolism and the mediation effect of obesity: The Henan Rural Cohort Study. Diab./Metab. Res. Rev. 35, e3133 (2019). https://doi.org/10.1002/dmrr.3133CrossRef

39.

N. Li, C. Huang, B. Lan et al. Association of gonadal hormones and sex hormone binding globulin with risk of diabetes: A cohort study in middle‐aged and elderly Chinese males. Int. J. Clin. Pract. 75, e14008 (2021). https://doi.org/10.1111/ijcp.14008CrossRefPubMed

40.

L. Wang, X. Liu, D. Wei et al. The mediation role of SOCS3 methylation in the effect of serum testosterone on type 2 diabetes. J. Diab. 13, 701–12 (2021). https://doi.org/10.1111/1753-0407.13167CrossRef

41.

D.E. Laaksonen, L. Niskanen, K. Punnonen et al. Testosterone and sex hormone–binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diab. Care 27, 1036–41 (2004). https://doi.org/10.2337/diacare.27.5.1036CrossRef

42.

M. Salminen, T. Vahlberg, I. Räihä, L. Niskanen, S.L. Kivelä, K. Irjala, Sex hormones and the risk of type 2 diabetes mellitus: A 9‐year follow up among elderly men in F inland. Geriatrics Gerontol. Int. 15, 559–64 (2015). https://doi.org/10.1111/ggi.12312CrossRef

43.

S.A. Holmboe, R. Jasuja, B. Lawney et al. Free testosterone and cardiometabolic parameters in men: comparison of algorithms. Endocr. Connect. 10, 220–9 (2021). https://doi.org/10.1530/EC-20-0552CrossRefPubMedPubMedCentral

44.

T. Vikan, H. Schirmer, I. Njølstad, J. Svartberg, Low testosterone and sex hormone-binding globulin levels and high estradiol levels are independent predictors of type 2 diabetes in men. Eur. J. Endocrinol. 162, 747–54 (2010). https://doi.org/10.1530/EJE-09-0943CrossRefPubMed

45.

F. Soriguer, E. Rubio‐Martín, D. Fernández et al. Testosterone, SHBG and risk of type 2 diabetes in the second evaluation of the Pizarra cohort study. Eur. J. Clin. Investig. 42, 79–85 (2012). https://doi.org/10.1111/j.1365-2362.2011.02559.xCrossRef

46.

S. Schipf, R. Haring, N. Friedrich et al. Low total testosterone is associated with increased risk of incident type 2 diabetes mellitus in men: results from the Study of Health in Pomerania (SHIP). Aging Male 14, 168–75 (2011). https://doi.org/10.3109/13685538.2010.524955CrossRefPubMed

47.

A. Goto, A. Morita, M. Goto et al. Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): a case control study. Cardiovascular Diabetol. 11, 130 (2012). https://doi.org/10.1186/1475-2840-11-130CrossRef

48.

S. Minooee, F. Ramezani Tehrani, M. Rahmati et al. The association between serum total testosterone and progression of hyperglycemia: a 15‐year prospective cohort study. Andrology 7, 148–55 (2019). https://doi.org/10.1111/andr.12568CrossRefPubMed

49.

M. Hyuk Park, S. Eon Kim, Y. Won, Relationship between testosterone deficiency and the cardiovascular risk factors, diabetes, and hypertension. J. Men.’s. Health 16, 97–106 (2020)

50.

G. Corona, V.A. Giagulli, E. Maseroli et al. Testosterone supplementation and body composition: results from a meta-analysis of observational studies. J. Endocrinol Investig. 39, 967–81 (2016). https://doi.org/10.1007/s40618-016-0480-2CrossRef

51.

J. Van Cauwenberghe, C. De Block, D. Vanderschueren, L. Antonio, Effects of treatment for diabetes mellitus on testosterone concentrations: A systematic review. Andrology 11, 225–33 (2023). https://doi.org/10.1111/andr.13318CrossRefPubMed

52.

M. Grossmann, R. Hoermann, G. Wittert, B.B. Yeap, Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Clin. Endocrinol. (Oxf). 83, 344–51 (2015). https://doi.org/10.1111/cen.12664CrossRefPubMed

53.

E.L. Ding, Y. Song, V.S. Malik, S. Liu, Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 295, 1288–99 (2006). https://doi.org/10.1001/jama.295.11.1288CrossRefPubMed

54.

A. Yassin, A. Haider, K.S. Haider et al. Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes: Eight-year data from a registry study. Diab. Care 42, 1104–11 (2019). https://doi.org/10.2337/dc18-2388CrossRef

55.

G. Wittert, K. Bracken, K.P. Robledo et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. Lancet Diab. Endocrinol. 9, 32–45 (2021). https://doi.org/10.1016/S2213-8587(20)30367-3CrossRef

56.

F. Huang, Is a previously or currently reduced testosterone level in male patients with type 2 diabetes mellitus a risk factor for the development of coronary artery disease? a systematic review and meta-analysis. Diab. Ther. 9, 1061–72 (2018). https://doi.org/10.1007/s13300-018-0415-3CrossRef

57.

J.S. Brand, M.M. Rovers, B.B. Yeap et al. Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: An individual participant data meta-analysis of observational studies. PLoS ONE 9, e100409 (2014). https://doi.org/10.1371/journal.pone.0100409CrossRefPubMedPubMedCentral

58.

S. Chaudhary, M. Kaushik, V. Jaswal et al. Testosterone levels in men with type 2 diabetes mellitus. Int. J. Res. Med. Sci. 6, 2313–7 (2018). https://doi.org/10.18203/2320-6012.ijrms20182809CrossRef

59.

M. De Paoli, G.H. Werstuck, Role of estrogen in type 1 and type 2 diabetes mellitus: A review of clinical and preclinical data. Can. J. Diab. 44, 448–52 (2020). https://doi.org/10.1016/j.jcjd.2020.01.003CrossRef

60.

H. Usmani, R. Kant, Testosterone: An insight into its clinical and biochemical assessments. Indian J. Med. Biochem. 25, 24–30 (2021). https://doi.org/10.5005/jp-journals-10054-0173CrossRef

61.

M.M. Shores, M.L. Biggs, A.M. Arnold et al. Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the cardiovascular health study. J. Clin. Endocrinol. Metab. 99, 2061–8 (2014). https://doi.org/10.1210/jc.2013-3576CrossRefPubMedPubMedCentral

Title: Testosterone levels and risk of newly diagnosed type 2 diabetes mellitus in adult men: systematic review and meta-analysis
Authors: Gustavo Adolfo Vásquez-Tirado
Juan Diego Guarniz-Salavarria
Claudia Vanessa Quispe-Castañeda
Jhuliana M. Contreras-Cabrera
María del Carmen Cuadra-Campos
Edinson Dante Meregildo-Rodriguez
Niler Manuel Segura-Plasencia
Yesenia Katherin Arbayza-Ávalos
Publication date: 09-09-2024
Publisher: Springer US
Keywords: Testosterone
Type 2 Diabetes
Stanolone
Published in: Endocrine
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-024-04019-4

EASD 2024

‘Noninferior’ reduction of type 1 diabetes HbA1c by weekly insulin efsitora alfa

12-09-2024
Type 1 Diabetes
News

Weekly treatment with insulin efsitora is noninferior to daily insulin degludec for the reduction of HbA1c in adults with type 1 diabetes, show the findings of the QWINT-5 trial.

12-09-2024
Obesity
News

Tirzepatide significantly reduces UACR in individuals with obesity and type 2 diabetes

12-09-2024
Type 2 Diabetes
News

Liraglutide reduces BMI for young children with obesity

11-09-2024
Pediatric Obesity
News

» View more highlights on the EASD 2024 hub page

2024 ESC Congress

Noise pollution dangerous for heart health

02-09-2024
Myocardial Infarction
News

Two studies underscore the adverse impact of noise pollution on the risk for and prognosis after myocardial infarction.

Antihypertensives: more effective at morning or night?

02-09-2024
Hypertension
News

Low Lp(a) levels unlikely to increase the risk of diabetes

02-09-2024
Type 2 Diabetes
News

» View more highlights on the 2024 ESC Congress hub page

A quick guide to ECGs

Electrocardiography
Training Course

Improve your ECG interpretation skills with this comprehensive, rapid, interactive course. Expert advice provides detailed feedback as you work through 50 ECGs covering the most common cardiac presentations to ensure your practice stays up to date.

PD Dr. Carsten W. Israel

Developed by: Springer Medizin

Start the cases

At a glance: The STEP trials

Obesity
Clinical Trial Summary

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on modern management of frailty

Springer Medicine

Testosterone levels and risk of newly diagnosed type 2 diabetes mellitus in adult men: systematic review and meta-analysis

Abstract

Introduction

Methods

Results

Conclusions

EASD 2024

‘Noninferior’ reduction of type 1 diabetes HbA1c by weekly insulin efsitora alfa

Weight loss with new obesity drug amycretin

Tirzepatide significantly reduces UACR in individuals with obesity and type 2 diabetes

Liraglutide reduces BMI for young children with obesity

» View more highlights on the EASD 2024 hub page

2024 ESC Congress

Noise pollution dangerous for heart health

Post-TAVI follow up: deploying virtual assistants

Antihypertensives: more effective at morning or night?

Low Lp(a) levels unlikely to increase the risk of diabetes

» View more highlights on the 2024 ESC Congress hub page

A quick guide to ECGs

At a glance: The STEP trials

Keynote webinar | Spotlight on modern management of frailty

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

Please log in to get access to this content

EASD 2024

2024 ESC Congress