Metabolic changes in type 2 diabetes are reflected in peripheral blood cells, revealing aberrant cytotoxicity, a viral signature, and hypoxia inducible factor activity.

BACKGROUND: Metabolic syndrome (MetS) is characterized by central obesity, insulin resistance, dysglycemia, and a pro-atherogenic plasma lipid profile. MetS creates a high risk for development of type 2 diabetes (T2DM) and cardiovascular disease (CVD), presumably by altering inflammatory responses. Presently, it is unknown how the chronic metabolic disturbances in acute hyperglycemia, MetS and T2DM affect the immune activity of peripheral blood cells. METHODS: We performed genome-wide expression analysis of peripheral blood cells obtained from patients with T2DM (n = 6) and age-, sex- , BMI- and blood pressure-matched obese individuals with MetS (n = 4) and lean healthy normoglycemic controls (n = 3), both under fasting conditions and after controlled induction of acute hyperglycemia during a 70 min hyperglycemic clamp. Differential gene expression during fasting conditions was confirmed by real-time PCR, for which we included additional age-, sex-, BMI-, and blood pressure-matched obese individuals with (n = 4) or without (n = 4) MetS. RESULTS: Pathway and Gene ontology analysis applied to baseline expression profiles of peripheral blood cells from MetS and T2DM patients revealed metabolic changes, highly similar to a reoviral infection gene signature in T2DM patients. Transcription factor binding site analysis indicated that increased HIF-1α activity, a transcription factor induced by either hypoxia or oxidative stress, is responsible for this aberrant metabolic profile in peripheral blood cells from T2DM patients. Acute hyperglycemia in healthy controls resulted in reduced expression of cytotoxicity-related genes, representing NK- and CD8(+) cells. In obese controls, MetS and especially T2DM patients, baseline expression of genes involved in cytotoxicity was already low, compared to healthy controls and did not further decrease upon acute hyperglycemia. CONCLUSIONS: The reduced activity of cytotoxic genes in T2DM is explained by chronic hyperglycemia, but its acute effects are restricted to healthy controls. Genome expression of circulating leukocytes from T2DM patients differs from MetS individuals by a specific reovirus signature. Our data thus suggest a role for suppressed anti-viral capacity in the etiology of diabetes.

The effects of the aromatase inhibitor anastrozole on bone metabolism and cardiovascular risk indices in ovariectomized, androgen-treated female-to-male transsexuals.

OBJECTIVE: Cases of men with estrogen resistance and aromatase deficiency have highlighted the effects of estrogens on bone metabolism, the cardiovascular system and biochemical variables of the metabolic syndrome. In eugonadal men, administration of an aromatase inhibitor induces a substantial elevation of LH and testosterone due to the decreased negative-feedback signal of estrogen and may thwart the interpretation of results. As there is no gonad for LH to act on, no increase of serum testosterone concentration will be seen in female-to-male transssexuals. The aim of this study was to investigate the effects of estrogen deprivation on bone metabolism and vascular parameters without the interference of counter-regulatory effects as seen in eugonadal men. DESIGN: Thirty ovariectomized female-to-male transsexuals participated in this double-blind, randomized trial. During 3 months, subjects received the aromatase inhibitor anastrozole 1 mg/day (n = 16) or a placebo (n = 14) in addition to parenteral testosterone esters (Sustanon 250 every 2 weeks). RESULTS: Serum 17beta-estradiol (E(2)) concentration fell significantly from 134.0 +/- 78.8 to 77.7 +/- 130.6 pmol/l compared with placebo (P < 0.01). LH and FSH levels rose without the rise of testosterone levels observed in eugonadal men. Within the placebo group, E(2) remained at baseline levels. Of the endpoint variables measured (bone metabolism and vascular parameters) no significant changes were observed compared with placebo, or within the anastrozole-treated group. CONCLUSIONS: These results may indicate that the negative effects of estrogen deprivation in men only become manifest when the concentration falls below the levels induced by our intervention with anastrozole (77 pmol/l). This assumption is supported by the observation in the anastrozole group that, although effects of the reduction of serum E(2) on vascular parameters could not be demonstrated in subjects as a group, there was a correlation between individual serum E(2) and several vascular parameters.

Transsexuals and competitive sports.

Men generally have an inherent performance advantage over women due to their average greater height and muscle mass and power, as the result of correspondingly different exposures to androgens. Therefore, it is considered fair that in sports men and women compete in separate categories. The question now emerging is whether reassigned transsexuals can compete in fairness with others of their new sex. The pertinent question is how far the previous effects of testosterone in male-to-female transsexuals (M-F) are reversible upon androgen deprivation so that M-F have no advantage over women, and, vice versa, what the effects are of androgen exposure in female-to-male transsexuals (F-M) on variables relevant to competition in sports. Before puberty, boys and girls do not differ in height, muscle and bone mass. Recent information shows convincingly that actual levels of circulating testosterone determine largely muscle mass and strength, though with considerable interindividual diversity. This study analyzed the effects of androgen deprivation in 19 M-F and of androgen administration to 17 F-M on muscle mass, hemoglobin (Hb) and insulin-like growth factor-1 (IGF-1). Before cross-sex hormone administration, there was a considerable overlap in muscle mass between M-F and F-M. In both M-F and F-M, height was a strong predictor of muscle mass. Androgen deprivation of M-F decreased muscle mass, increasing the overlap with untreated F-M, but mean muscle mass remained significantly higher in M-F than in F-M. Androgen administration to F-M increased muscle mass without inducing an advantage over nontreated M-F. The conclusion is that androgen deprivation in M-F increases the overlap in muscle mass with women but does not reverse it, statistically. The question of whether reassigned M-F can fairly compete with women depends on what degree of arbitrariness one wishes to accept, keeping in mind, for instance, that similar blood testosterone levels in men have profoundly different biologic effects on muscle properties, rendering competition in sports intrinsically a matter of how nature endows individuals for this competition.

Androgen replacement therapy: present and future.

The major goal of androgen substitution is to replace testosterone at levels as close to physiological levels as is possible. For some androgen-dependent functions testosterone is a pro-hormone, peripherally converted to 5alpha-dihydrotestosterone (DHT) and 17beta-estradiol (E2), of which the levels preferably should be within normal physiological ranges. Furthermore, androgens should have a good safety profile without adverse effects on the prostate, serum lipids, liver or respiratory function, and they must be convenient to use and patient-friendly, with a relative independence from medical services. Natural testosterone is viewed as the best androgen for substitution in hypogonadal men. The reason behind the selection is that testosterone can be converted to DHT and E2, thus developing the full spectrum of testosterone activities in long-term substitution. The mainstays of testosterone substitution are parenteral testosterone esters (testosterone enantate and testosterone cipionate) administered every 2-3 weeks. A major disadvantage is the strongly fluctuating levels of plasma testosterone, which are not in the physiological range at least 50% of the time. Also, the generated plasma E2 is usually supraphysiological. A major improvement is parenteral testosterone undecanoate producing normal plasma levels of testosterone for 12 weeks, with normal plasma levels of DHT and E2 also. Subcutaneous testosterone implants provide the patient, depending on the dose of implants, with normal plasma testosterone for 3-6 months. However, their use is not widespread. Oral testosterone undecanoate dissolved in castor oil bypasses the liver via its lymphatic absorption. At a dosage of 80 mg twice daily, plasma testosterone levels are largely in the normal range, but plasma DHT tends to be elevated. For two decades transdermal testosterone preparations have been available and have an attractive pharmacokinetic profile. Scrotal testosterone patches generate supraphysiological plasma DHT levels, which is not the case with the nonscrotal testosterone patches. Transdermal testosterone gel produces fewer skin irritations than the patches and offers greater flexibility in dosage. Oromucosal testosterone preparations have recently become available. Testosterone replacement is usually of long duration and so patient compliance is of utmost importance. Therefore, the patient must be involved in the selection of type of testosterone preparation. Administration of testosterone to young individuals has almost no adverse effects. With increasing age the risk of adverse effects on the prostate, the cardiovascular system and erythropoiesis increases. Consequently, short-acting testosterone preparations are better suited for aging androgen-deficient men.

Transdermal testosterone delivery: testosterone patch and gel.

Testosterone replacement treatment is usually life-long. Fortunately, testosterone administration is relatively safe and until the age of 50 years few side effects are noted with normal doses of testosterone. After the age of 50 years when prostate disease becomes more prevalent, shorter-acting testosterone preparations, allowing a fast reduction of circulating testosterone levels, may be an advantage. Testosterone has an impact on sexual and non-sexual behaviour and short-acting testosterone preparations may be better suited for the initiation of long-term administration allowing the monitoring of behavioural effects. Testosterone can be delivered to the circulation through the intact skin, both genital and non-genital. Transdermal administration delivers testosterone at a controlled rate into the systemic circulation, avoiding hepatic first pass and reproducing the diurnal rhythm of testosterone secretion and without the peak and trough levels observed with the use of the traditional long-acting testosterone injections. In conclusion, both the testosterone patch and testosterone gel are valuable contributions to androgen replacement treatment meeting the requirements specified for testosterone replacement treatment.