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Diabetes Care 29:1120-1122, 2006
DOI: 10.2337/dc06-0197
© 2006 by the American Diabetes Association
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Pathophysiology/Complications
Brief Report

Contrasting Testosterone Concentrations in Type 1 and Type 2 Diabetes

Rashmi Tomar, MD, Sandeep Dhindsa, MD, Ajay Chaudhuri, MD, Priya Mohanty, MD, Rajesh Garg, MD and Paresh Dandona, MD, PHD

From the Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Buffalo, New York; and Kaleida Health, Buffalo, New York

Address correspondence and reprint requests to Paresh Dandona, MD, PhD, Diabetes-Endocrinology Center of WNY, 3 Gates Circle, Buffalo, NY 14209. E-mail: pdandona{at}kaleidahealth.org

Abbreviations: bioI, bioavailable testosterone • LH, leutinizing hormone • FSH, follicle-stimulating hormone • FT, free testosteron • SHBG, sex hormone–binding globulin • TT, total testosterone


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
We have recently reported (1) that male patients with type 2 diabetes have frequent hypogonadotrophic hypogonadism. We have now asked whether a similar defect may be observed in type 1 diabetic males to determine whether diabetes per se is the cause of hypogonadotrophic hypogonadism.


   RESEARCH DESIGN AND METHODS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
Fifty patients with type 1 diabetes (age range 23–58 years) and 50 age-matched patients with type 2 diabetes (age range 28–51 years) were included in the study. Patients with known history of hypogonadism, panhypopituitarism, or chronic debilitating disease such as renal failure, cirrhosis, or HIV infection were excluded from the study. Fasting blood samples were obtained from the patients, and total testosterone (TT), free testosterone (FT), sex hormone–binding globulin (SHBG), leutinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured as previously described (1). FT and bioavailable testosterone (bioT) were calculated from SHBG and TT as previously described (1). Hypogonadism was defined as low FT or low calculated FT (2). Mann-Whitney rank-sum test or Student’s t test for unpaired data, {chi}2 test, and Spearman’s test were used as appropriate (Sigmastat software).


   RESULTS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
The mean TT, FT, calculated FT, and bioT concentrations in type 1 diabetic patients were in the middle of the normal range (Table 1). No patient had subnormal TT concentrations; three patients had supranormal TT, while two patients had subnormal FT and bioT concentrations.


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  		Table 1— Demographic and biochemical indices in type 1 and type 2 diabetic patients and type 2 diabetic patients with hypogonadotrophic hypogonadism

 
The mean TT concentration in patients with type 2 diabetes was significantly lower than that in type 1 diabetic subjects (Table 1). The prevalence of low TT concentrations was 24 of 50 (48%), while that of low measured and/or calculated FT was 13 of 50 (26%). LH and FSH concentrations in 12 of 13 hypogonadal patients were in the normal range, and were thus inappropriately low. One patient had elevated LH and FSH concentrations and thus had primary hypogonadism. The mean prolactin concentration was lower in type 2 than in type 1 diabetic subjects.

The mean SHBG concentration in type 1 diabetic subjects was at the upper end of the reference range. The level of SHBG was higher than normal in 16 patients. The mean SHBG in type 2 diabetic subjects was significantly lower than that in type 1 diabetic subjects (Table 1).

In type 1 diabetic subjects, plasma TT concentrations were negatively related to BMI (r = –0.52, P < 0.001), as were FT (r = –0.36, P < 0.05), calculated FT (r = –0.36, P < 0.05), and bioT (r = –0.36, P < 0.05). In type 2 diabetic subjects, BMI was also negatively related to FT (r = –0.55, P < 0.01), calculated FT (r = –0.42, P < 0.05), bioT (r = –0.45, P = 0.01), and TT (r = –0.382, P < 0.01) (Fig. 1). BMI was also inversely related to SHBG (r = –0.34, P < 0.05). Plasma FSH concentrations were positively related to age (r = 0.39, P = 0.01) and to LH concentrations (r = 0.38, P = 0.01). In type 2 diabetic subjects, FSH was positively related to age (r = 0.504, P < 0.01) and LH (r = 0.454, P < 0.01). The total insulin dose and insulin dose per kilogram was significantly related to SHBG (r = –0.53, P < 0.001). In a multiple linear regression model, only total daily insulin dose, and not BMI, was a significant predictor (P = 0.04) of SHBG concentration. HbA1c (A1C) did not relate to any of the parameters in the study either in type 1 or type 2 diabetes.


Figure 1
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  		Figure 1— Correlation of calculated free testosterone (nmol/l) with BMI (kg/m2) in type 1 ({circ}; r = –0.36, P < 0.05) and type 2 (•; r = –0.42, P < 0.05) diabetic subjects.

 

   CONCLUSIONS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
Our data show that in contrast to type 2 diabetes with frequent occurrence of hypogonadotrophic hypogonadism, type 1 diabetes is associated with normal TT concentrations and with consistently high normal or elevated SHBG concentrations. FT, LH, and FSH concentrations also tended to be normal. SHBG tended to be elevated in contrast to the relatively suppressed levels observed in type 2 diabetes.

This pattern of testosterone is therefore different from that in age-matched type 2 diabetic subjects. The prevalence of low TT (48%) and FT (26%) concentrations in type 2 diabetes in this study was associated with inappropriately low LH and FSH concentrations. The prevalence of low TT and FT was 0 and 6%, respectively, in type 1 diabetic patients. Thus, hypogonadotrophic hypogonadism in type 2 diabetes is specific to that condition and is not the effect of diabetes and hyperglycemia per se.

The significance of lower prolactin concentrations in type 2 diabetes than those in type 1 diabetes is not clear but may point to an additional defect in the hypothalamico-hypophyseal axis, possibly at the dopaminergic level. Obesity is known to be associated with diminished prolactin secretion following pharmacological stimuli (3,4). The clinical or pathophysiological significance of this observation is not clear at this time.

It has been suggested that the lack of insulin in type 1 diabetes may contribute to the increase in SHBG concentrations and that treatment with insulin may lower it (5,6). The mean insulin dose per kilogram of body weight has been shown previously to be inversely related to SHBG concentrations in type 1 diabetic patients (7), consistent with our current observations. The degree of hyperglycemia and A1C were not related to the increase in SHBG in type 1 diabetic subjects.

Our data also show for the first time that calculated FT and bioT levels relate negatively to BMI in type 1 diabetic patients (Fig. 1), as previously shown in type 2 and type 1 diabetic patients. A study in TT and calculated FT concentrations on obese type 1 diabetic patients clearly needs to be carried out, especially in view of the increasing rates of obesity and the metabolic syndrome in general and in type 1 diabetic subjects in particular (8). Recent data from an epidemiological study (9) demonstrate that low concentrations of testosterone associated with high concentrations of cortisol (as seen in obesity) predict cardiovascular morbidity and mortality.

In conclusion, type 1 diabetes is associated with increased SHBG; normal TT, LH, and FSH concentrations; and normal FT and calculated FT concentrations in >90% of patients. In contrast, type 2 diabetic patients have frequent hypogonadotrophic hypogonadism and low SHBG concentrations. A higher BMI has a significant effect on calculated FT and FT in both patients with type 1 as well as in those with type 2 diabetes. This suggests that at higher levels of BMI, even type 1 diabetic subjects, may develop hypogonadism.


   Acknowledgments
 
Dr. Paresh Dandona is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK069805-02).


   Footnotes
 
A.C. has received honoraria/consulting fees from Aventis and Eli Lilly.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication January 25, 2005. Accepted for publication February 15, 2006.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

  1. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P: Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab89 :5462 –5468,2004[Abstract/Free Full Text]
  2. Vermeulen A, Kaufman JM: Diagnosis of hypogonadism in the aging male. Aging Male5 :170 –176,2002[Medline]
  3. Kopelman PG, White N, Pilkington TR, Jeffcoate SL: Impaired hypothalamic control of prolactin secretion in massive obesity. Lancet1 :747 –750,1979[Medline]
  4. Kopelman PG: Physiopathology of prolactin secretion in obesity. Int J Obes Relat Metab Disord24(Suppl. 2) :S104 –S108,2000
  5. Plymate SR, Matej LA, Jones RE, Friedl KE: Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab67 :460 –464,1988[Abstract]
  6. Pasquali R, Casimirri F, De Iasio R, Mesini P, Boschi S, Chierici R, Flamia R, Biscotestosteronei M, Vicennati V: Insulin regulates testosterone and sex hormone-binding globulin concentrations in adult normal weight and obese men. J Clin Endocrinol Metab80 :654 –658,1995[Abstract]
  7. Yki-Jarvinen H, Makimatestosteroneila S, Utriainen T, Rutanen EM: Portal insulin concentrations rather than insulin sensitivity regulate serum sex hormone-binding globulin and insulin-like growth factor binding protein 1 in vivo. J Clin Endocrinol Metab80 :3227 –3232,1995[Abstract]
  8. Thorn LM, Forsblom C, Fagerudd J, Thomas MC, Petestosteroneersson-Fernholm K, Saraheimo M, Waden J, Ronnback M, Rosengard-Barlund M, Bjorkesten CG, Taskinen MR, Groop PH: Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and glycemic control (the FinnDiane study). Diabetes Care28 :2019 –2024,2005[Abstract/Free Full Text]
  9. Smith GD, Ben-Shlomo Y, Beswick A, Yarnell J, Lightman S, Elwood P: Cortisol, testosterone, and coronary heart disease: prospective evidence from the Caerphilly study. Circulation112 :332 –340,2005[Abstract/Free Full Text]

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