| Summary: | 博士 === 國立臺灣大學 === 臨床醫學研究所 === 103 === Background
The relationship between testosterone deficiency and type 2 diabetes mellitus has been well established in men. The connection is frequently observed in various clinical scenarios, such as late-onset hypogonadism and prostate cancer patients receiving androgen deprivation therapy. Both conditions have a significant negative impact on men’s health: they both cause lower urinary tract symptoms and erectile dysfunction; moreover, both of them are proved as an independent risk factor for cardiovascular disease and mortality. Nevertheless, the underlying mechanism of their coexistence remains not fully understood. Current evidence supports that testosterone deficiency can be either a cause or a consequence of insulin resistance. Besides, some other factors, such as obesity or sex hormone binding globulin, can also play a role within this relationship.
Previous related clinical studies were mainly based on subjects with overt type 2 diabetes, most of whom were receiving anti-diabetes treatment. Prediabetes is a state of increased serum glucose concentration, while it does not reach the criteria of overt diabetes mellitus. In many studies, it has been considered as a risk factor for cardiovascular disease and nephropathy. It raised the question of whether it is also associated testosterone deficiency. The purpose of defining the serum testosterone concentration of prediabetic subjects includes: 1) to clarify the role of testosterone deficiency in the development of type 2 diabetes; 2) to identify the potential subjects for testosterone replacement therapy.
On the other hand, it has been less addressed whether the treatment of type 2 diabetes can reverse the condition of testosterone deficiency. And the epidemiologic characteristics of untreated, newly-diagnosed type 2 diabetic men has been rarely addressed. To investigate the serum testosterone concentration of the untreated, newly-diagnosed type 2 diabetic men may help to further clarify whether testosterone deficiency is a cause or a consequence of insulin resistance.
Lastly, the optimal animal model for the study of the relationship between testosterone deficiency and glucose intolerance has not yet been established. While rats or mice are most widely used animal model in every field of medical research, previous studies evaluating the metabolic characteristics of rats or mice of testosterone deficiency were conflicting. We therefore aimed to evaluate the suitability of castrated male rats as an animal model for the related studies regarding testosterone deficiency, glucose intolerance, and metabolic syndrome.
Method
Clinical Studies: The prevalence and risk factors of testosterone deficiency in men at different stages of type 2 diabetes
This is a cross-sectional study. We obtained the data from the database of Health Management Center, National Taiwan University Hospital. In 2009, a total of 1,306 men receiving sex hormone measurement as part of their medical examination constituted the study subjects of the current study. The study protocol was approved by the institutional review board (IRB) of National Taiwan University Hospital (201207058RIC). All participants completed a self-administered questionnaire to collect their basic demographic data and medical histories. All subjects were then interviewed by an internal medicine physician, and a detailed physical examination was performed. Two blood samples were collected from each subject: the first sample was collected after an overnight fast between 8 am and 10 am, and was used to measure fasting blood glucose, sex hormones, and other biochemical data; the second blood sample was collected two hours after a standard lunch and was used to measure the postprandial glucose. Total testosterone and SHBG were measured by chemiluminescent microparticle immunoassay. Free testosterone was calculated by the formula proposed by Vermeulen. Low total testosterone was defined by total testosterone <300 ng/dL [16-18], and low free testosterone was defined by free testosterone <6 ng/dL. Prediabetes was diagnosed if any of the following criteria was met: 1) fasting glucose 100-125 mg/dL (IFG), 2) two-hour postprandial glucose 140-199 mg/dL (IPG), or 3) HbA1c 5.7%-6.4%. Diabetes was diagnosed if the patient had a prior history of diabetes or if the glycemic variables reached the criteria of diabetes: fasting glucose ≥126 mg/dL, two-hour postprandial glucose ≥200 mg/dL, or HbA1c ≥6.5%. Continuous data are presented as the mean ± standard deviation (SD), and categorical data are presented as count and percentage (%).Logistic regression was performed to obtain the odds ratios for TD in men with prediabetes and diabetes compared with those with normoglycemia. Five statistical models were used for multivariate analyses: Model 1, adjusted for age; Model 2, adjusted for age and body mass index (BMI); Model 3, adjusted for age and waist circumference; Model 4, adjusted for age and the number of MetS components; Model 5, adjusted for age and MetS. Multiple linear regression was performed to assess the association between total and free testosterone and prediabetes or diabetes.
Basic Studies: Evaluating castrated male rats as an animal model of glucose intolerance
Male Sprague-Dawley rats (10-12 weeks) were randomly divided into five groups (n=6-8 in each): sham-operated, castrated, and castrated with low- (intramuscular injection of testosterone propionate 0.5 mg/kg/week), intermediate- (2 mg/kg/week), and high-dose (8 mg/kg/week) of testosterone replacement. Each animal received intraperitoneal glucose tolerance test (IPGTT) twice on week 8 and 16 respectively; the area under the curve (AUC) of glucose concentrations were calculated to represent the glucose tolerance. Fasting and glucose-induced insulin concentrations were measured at 0 and 15 minutes during IPGTT respectively. After the rats were euthanized on week 16, visceral fat and pancreas were prepared for morphologic measurements.
Results
Clinical Studies: The prevalence and risk factors of testosterone deficiency in men at different stages of type 2 diabetes
Normoglycemia, prediabetes, and diabetes were diagnosed in 577 (44.2%), 543 (41.6%), and 186 (14.2%) men, respectively. Prediabetes was associated with an increased risk of subnormal total testosterone compared to normoglycemic individuals (age-adjusted OR=1.87; 95%CI=1.38-2.54). The risk remained significant in all multivariate analyses. After adjusting for MetS, the OR in prediabetic men equals that of diabetic patients (1.49 versus 1.50). IFG, IPG, and HbA1c 5.7%-6.4% were all associated with an increased risk of testosterone deficiency, with different levels of significance in multivariate analyses. However, neither prediabetes nor diabetes was associated with subnormal free testosterone in multivariate analyses. Men with previously known T2DM were older and had higher diastolic pressure and greater fasting glucose. There was no significant difference in total (358.0 [155.0] ng/dL vs 363.0 [154.0] ng/dL, P=0.68) and free (7.2 [2.5] ng/dL vs 7.4[2.4] ng/dL, P=0.84) testosterone and SHBG (27.3 [22.3] nmol/L vs 28.7 [14.9] nmol/L, P=0.46). The prevalence of low total and free testosterone were 28.4% and 21.0% in men with newly diagnosed T2DM, and were 26.7% and 19.0% in those with previously known T2DM. In men with previously known T2DM, better glycemic control (HbA1c<7%) was associated with a higher level of total testosterone and a lower risk of low total testosterone. Men with newly diagnosed and previously known T2DM shared similar risk factors of low total testosterone, including high HbA1c (≥7%), low SHBG (<20 nmol/L), obesity, hyperuricemia, hypertriglycemia, and metabolic syndrome. Elevated prostate-specific antigen (PSA) was a protective factor of low total testosterone. However, none of these factors was associated with low free testosterone.
Basic Studies: Evaluating castrated male rats as an animal model of glucose intolerance
Castration decreased the body weight and the adipocyte size, which were restored by testosterone replacement. Compared to controls, the castrated rats had a significantly greater AUC glucose and lower fasting and glucose-induced insulin concentrations on week 16. Testosterone replacement generally restored the insulin secretion and glucose tolerance in a dose-dependent fashion. The pancreatic islet morphology and the β-cell mass were not significantly different among groups.
Conclusion
Men with prediabetes are at an increased risk of subnormal total testosterone. The risk is reduced, but remains significant after adjustment for BMI, waist circumference, the number of MetS components, or MetS. After adjustment for MetS, the risk for TD in men with prediabetes is almost equal to that of men with diabetes. The substantially increased risk suggests that testosterone should be measured routinely in men with prediabetes. The prevalence and the risk factors of testosterone deficiency are similar between the newly diagnosed and previously known type 2 diabetic men. In men with previously known T2DM, the HbA1c is inversely associated with the serum testosterone. Men with newly diagnosed and previously known T2DM have common risk factors for low total testosterone, including high HbA1c, low SHBG, obesity, hyperuricemia, hypertriglycemia, and metabolic syndrome. Elevated PSA is associated with a lower risk of testosterone deficiency in type 2 diabetic men.
Castration-induced androgen deficiency in male rats reduces body weight and impairs glucose tolerance in part by attenuating fasting and glucose-induced insulin secretion. This is in contrast to the effect of androgen deficiency in humans, which frequently leads to obesity and impaired glucose tolerance through decreased insulin sensitivity. The interspecies difference should be carefully considered whenever male rats are applied in the research associated with the interaction between testosterone and metabolism.
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