The largest investigation of testosterone treatment ever undertaken has shown that, over and above the effect of a lifestyle program, treatment with testosterone prevents or reverses newly diagnosed type 2 diabetes in men.
The study, known as T4DM (Testosterone for the prevention of Diabetes Mellitus), was led by the University of Adelaide and involved six specialist centers across Australia.
T4DM was a two-year randomized, double-blind, placebo-controlled clinical trial. The results are published online today in The Lancet Diabetes & Endocrinology.
The T4DM study included more than 1000 men aged between 50 and 74 years old who were overweight or obese. All men were enrolled in the WW (formerly known as Weight Watchers) lifestyle program.
They could attend groups, use the website, the app, or any combination of those. Half of the men were injected with long-acting testosterone every three months and the other half were injected with placebo.
After two years of treatment, 87 out of 413 (21%) men in the placebo group had type 2 diabetes (based on an oral glucose tolerance test) compared with 55 out of 443 (12%) men in the testosterone group.
Men in both groups lost weight (on average 3 to 4kg) and glucose tolerance normalized in 43% and 52% of men in the placebo and testosterone groups, respectively.
Other findings at two years in men treated with testosterone compared to placebo:
- A lower fasting blood sugar
- A greater decrease in body fat
- An increase in skeletal muscle mass and hand grip strength
- Improvements in sexual function
- There were no differences in wellbeing or quality of life.
The most common adverse effect occurring in 22% of men treated with testosterone was an increase in the concentration of red cells in the blood, which could potentially lead to “sludgy” blood.
Lead researcher Professor Gary Wittert, director of the Freemason’s Center for Male Health and Wellbeing, University of Adelaide, said: “The results of the study show that, on top of modest weight loss achieved with healthy eating and increased activity, testosterone has some added benefit to prevent or reverse newly diagnosed type 2 diabetes.
“However, the results do not necessarily mean that a script for testosterone should be written. We know that men at risk of type 2 diabetes are usually overweight and either have, or are at risk of, other chronic disorders that have not been detected or adequately managed. Not infrequently these men are also drinking too much alcohol and have sleep or mood disorders. Weight loss achieved through healthy lifestyle behaviors remains the benchmark.”
More research is needed to determine whether the beneficial effects of testosterone persist beyond two years, whether longer term treatment is safe and whether other forms of testosterone have similar benefits or risks.
“Writing a prescription might be quick and easy but it does not replace the need for undertaking a comprehensive assessment and providing holistic management towards improving men’s health,” Professor Wittert said.
Professor Bu Yeap from the University of Western Australia’s Medical School, and president of the Endocrine Society of Australia, who was an investigator on the study, said: “This is a landmark study which will prompt renewed interest in preventing diabetes in at-risk men.”
Reduced testosterone concentrations are commonly encountered in men with type 2 diabetes mellitus (T2DM). Dhindsa et al. 1 first described the syndrome of hypogonadotropic hypogonadism (HH) in men with T2DM.
This syndrome occurs in approximately one‐third of patients with diabetes and is associated with obesity, but not with severity or duration of diabetes, or age. 2 Obesity, without diabetes, was associated with HH in approximately 25% of patients. 3 Patients with HH also exhibited an inflammatory state, beyond that experienced by eugonadal patients with T2DM and had significantly greater insulin resistance than eugonadal patients with T2DM. 4 , 5
Testosterone therapy (TTh) reduced insulin resistance in such patients, according to homeostatic model assessment of insulin resistance (HOMA‐IR). 6 , 7 Men with T2DM and hypogonadism have more fat mass and a 36% lower glucose infusion rate during hyperinsulinaemic‐euglycaemic clamps than eugonadal men, as well as reduced insulin signalling at the cellular level in adipose tissue. 5 , 8 , 9 , 10 , 11
Testosterone deficiency (TD), also termed “hypogonadism”, contributes to reduced glucose disposal, increased insulin resistance and onset of T2DM. 12 , 13 , 14 Androgen deprivation therapy for prostate cancer is associated with significantly increased risk of incident diabetes. 15 , 16 TTh in men with TD and T2DM increases insulin sensitivity and induces greater expression of insulin receptor‐β, insulin receptor substrate‐1, AKT‐2 and GLUT‐4 in adipose tissue, thus providing a mechanistic explanation for the increased insulin sensitivity. 5 , 17 We have previously shown that long‐term TTh halted the progression of prediabetes to overt diabetes. 13
The primary objectives of this registry study were, firstly, to examine the effect of TTh on the course of glucose intolerance, with glycated haemoglobin (HbA1c) and insulin secretion as target variables, and, secondly, to assess the impact of TTh on weight control and major cardiovascular risk factors (lipids, blood pressure, inflammation).
In the present paper, we report the results of long‐term TTh (11 years) in men with hypogonadism and T2DM and compare the outcomes with data derived from a parallel group of patients who remained untreated (control) during the entire follow‐up period.
DISCUSSION
Our findings show that, in patients with TD and T2DM, TTh significantly reduced fasting blood glucose by more than 1.5 mmol/L, even after adjustments for baseline variables, including age, waist circumference, weight, systolic and diastolic blood pressure, total cholesterol and triglycerides. The reductions in blood glucose in response to TTh were sustained throughout the treatment period.
In contrast, no significant reductions in blood glucose were noted in the untreated patients. In fact, we observed an increase in blood glucose with extended follow‐up periods in the untreated patients. It is not clear if this rise in glucose implies worsening insulin resistance or insulin secretion.
We observed a significant reduction in HbA1c, exceeding 9 mmol/mol (3%), in patients with hypogonadism and T2DM treated with testosterone, even after adjustments for baseline variables. These reductions in HbA1c were sustained throughout the treatment period. In contrast, we observed an increase in HbA1c in the control group.
We also observed a steeper rise in HbA1c similar to that recorded with glucose after ~6 years of follow‐up, suggesting loss of β‐cell function and advanced pathophysiological state of diabetes over extended periods of time contributing to increased HbA1c as a marker of dysfunction of glucose metabolism. It is unclear why such a rise in glucose and HbA1c concentrations occurred during long‐term observation, but it could be related to a decline in β‐cell function or apoptosis.
There were profound changes in fasting insulin levels in patients with T2DM and TD who had never received exogenous insulin treatment but had undergone TTh. Remarkably, insulin concentration decreased gradually with TTh and was sustained throughout the treatment course, even after adjustments for baseline variables. In contrast, in the control group, we observed a progressive increase in insulin concentration over the entire duration of follow‐up.
There was a significant, progressive and sustained decrease in HOMA‐IR in patients treated with testosterone but an increase in the untreated group. These findings strongly suggest that TTh in patients with diabetes and hypogonadism improved blood glucose, HbA1c and insulin resistance. Such findings have important clinical implications in the management of men with T2DM and TD.
HOMA‐IR correlates significantly with clamp insulin resistance, not only before, but also after treatment in patients with T2DM. 20 Recently, the original HOMA‐IR equation has been superseded by a new computer model, HOMA2‐IR. 21 Although this computer model gives a value for insulin resistance, clinical judgement is required because of variables in glucose levels or assay methods. In our registry study, we analysed the data using both HOMA‐IR and HOMA2‐IR, with similar results.
We had calculated homeostatic model assessment of β‐cell function (HOMA‐β) and found that it decreased in the testosterone group, suggesting reduced β‐cell insulin secretion compared to the untreated control group. However, we believe that this is attributable in part to the improved glycaemia and increased insulin sensitivity in the testosterone group.
Because insulin secretion is largely reduced in the testosterone group as a result of profoundly increased insulin sensitivity, less insulin was needed. This is reflected in the steady decline in fasting insulin. Future studies should comprehensively evaluate β‐cell secretion with stimulatory tests to better define the effect of testosterone on β‐cell function.
The significant changes in fasting glucose, insulin and HbA1c reflect the importance of TTh in regulating hyperglycaemia and management of patients with hypogonadism and T2DM. The marked and significant changes from baseline in response to TTh in the various anthropometric, lipid profile and vascular variables (Table (Table2)2) reflect the potential reduction in the risk of cardiovascular disease in patients with T2DM, who are treated with TTh.
Non‐HDL cholesterol is calculated by subtracting HDL cholesterol from total cholesterol, and includes cholesterol in all atherogenic particles causing cardiovascular disease. Non‐HDL cholesterol is more strongly associated with reduced risk of atherosclerotic coronary heart disease than changes in LDL cholesterol. 22
Remnant cholesterol is calculated as total cholesterol minus HDL cholesterol minus LDL cholesterol, and has been shown to be a causal risk factor for low‐grade inflammation, cardiovascular disease and all‐cause mortality, even in patients with optimal LDL cholesterol levels. 23 , 24 The improvements in these emerging lipid‐related risk factors for cardiovascular disease, in addition to the improvements in the standard lipid panel, may have contributed largely to the observed reductions in major adverse cardiovascular events in the testosterone group.
Marked improvements in eGFR were observed in patients treated with testosterone but not in the control group. These changes reflect improvement in renal function and reduction in cardiovascular disease risk.
In addition, the changes in the AMS quality‐of‐life score and the IIEF‐EF score with TTh reflect improvement in overall and sexual quality of life.
In the present study, we did not observe any serious adverse effects of long‐term TTh. In fact there were fewer deaths (Figure (Figure4),4), myocardial infarctions and strokes as compared with the control group (Table S1). Our observations are consistent with other studies showing reduced mortality in men with hypogonadism and T2DM receiving TTh. 25 , 26
For many decades, initiating prostate cancer or activating occult prostate cancer has been a concern when treating older men with testosterone. In the present study, the incidence of prostate cancer was significantly lower in the testosterone group compared to the control group (Table S1). This is consistent with the most recent literature. 27 , 28
Several pathophysiological mechanisms may account for the link between TD and onset of T2DM or worsening its pathophysiology and the potential reversal of these pathophysiological pathways with TTh.
Among these postulated mechanisms, are: 1) the role of androgens in regulating expression, synthesis and translocation of glucose transporters, which play an important role in glucose utilization and disposal; 2) the role of androgens in regulating glucagon‐like peptide‐1 receptor (GLP‐1R), which modulates glucose metabolism; 3) the role of androgens in maintaining pancreatic β‐cell function; and 4) role of inflammation in mediating insulin resistance.
The translocation of the glucose transporter GLUT4 from an intracellular membrane compartment to the plasma membrane after insulin stimulation activates the phosphatidylinositol‐3 kinase (PI3K) and other protein kinases, such as serine/threonine kinase AKT and PKC‐f/k. 29 In 3T3‐L1 adipocytes, TTh increased GLUT4‐dependent glucose uptake through the LKB1/AMPK signalling pathway. 30
Thus, TD may contribute to reduced expression of glucose transporters and, in turn, impede glucose utilization and contribute to increased insulin secretion and insulin resistance. TTh may reverse this pathophysiological mechanism by facilitating the expression and translation of glucose transporters and their activities.
In patients with hypogonadism and T2DM, a significant increase in insulin resistance was associated with reduced expression of IRβ, IRS‐1, AKT kinase and GLUT‐4, and testosterone treatment led to the reversal of the extra insulin resistance and the restoration of the expression of IRβ, IRS‐1, AKT‐1 and GLUT4. 5
In addition, the expression of AMP kinase and phosphorylated AMP kinase was diminished in the adipose tissue and skeletal muscle of patients with TD and T2DM. Phosphorylated AMP kinase expression increased after TTh. 31 , 32 These observations are important since metformin and physical exercise also mediate the increase in glucose through AMP kinase and AKT kinase and GLUT4.
In addition, GLP‐1R is thought to be a key target for the pharmacological treatment of T2DM since it maintains glucose homeostasis and promotes β‐cell proliferation. GLP‐1R mRNA expression levels were positively correlated with testosterone concentrations. In vitro and in vivo studies demonstrated that expression and translation of GLP‐1R are under androgen regulation. 33
Thus, it is likely that in TD, the expression and activities of GLP‐1R are attenuated and this contributes to higher glucose levels and increased insulin resistance. TTh would contribute to activation of GLP‐1R gene expression and translation into proteins and promote glucose uptake and utilization, thus reducing insulin secretion and insulin resistance.
There is emerging evidence that androgens are critical for maintaining pancreatic β‐cell function. 11 , 34 Testosterone action via the androgen receptor in β‐cells enhances glucose‐stimulated insulin secretion by potentiating the insulinotropic action of glucagon‐like peptide‐1.
Androgen receptor‐deficient islets exhibit altered expression of genes involved in inflammation and insulin secretion, demonstrating the importance of androgen action in β‐cell health in men, with implications for T2DM development in men. 35 Interleukin (IL)‐1β is a proinflammatory cytokine which may impair β‐cell function in T2DM.
Testosterone administration suppress IL‐1β in patients with TD. 5 T2DM is a pro‐inflammatory state and there is an increased synthesis and secretion of cytokines and mediators which interfere with insulin signal transduction while also being toxic to the β cell. Increased TNF‐α concentrations block insulin signalling at IRS‐1 level.
IL‐1β interferes with insulin signalling while also being toxic to the β‐cell. Both of these cytokines have been shown to be increased in people with diabetes and TD and they decrease after testosterone treatment. 5 Testosterone was also shown to protect against glucotoxicity‐induced β‐cell apoptosis by reducing the action of the angiotensin II receptor type 1(AGTR1) signalling pathway both in vitro and ex vivo. 36
One small observational pilot study has suggested a marked improvement in homeostatis model assessment‐2 of beta‐cell function (HOMA%B) as a result of TTh for a duration of up to 29 months. 37
Of note is the improvement in the eGFR and the marked improvements in lipid profiles and anthropometric variables, all contributing to improved overall health and reduced cardiovascular risk.
It is also noteworthy that inhibition of testosterone conversion to 5α‐DHT, one of the two metabolites of testosterone, contributes to the pathogenesis of non‐alcoholic fatty liver disease and increases susceptibility to glucose intolerance and hyperinsulinaemia. 38 , 39
This also promotes fat accumulation in liver with impairment of enzymes involved in fatty acid β‐oxidation and gluconeogenesis, with increased enzymatic activities involved in triglyceride esterification and cholesterol synthesis and excretion. 38 In the liver, 5α‐DHT reduces lipid accumulation and cholesterol synthesis via increasing expression of carnitine palmitotyltransferase1 and phosphorylation of 3‐hydroxy‐3‐methyl‐glutaryl‐CoA reductase. 40
In men, inhibition of 5α‐reductase resulted in hepatic insulin resistance, hepatic lipid accumulation, and decreased adipose lipid mobilization. 41 , 42 A recent study has demonstrated the close association between weight loss, hepatic lipoprotein export and remission of T2DM in humans, further supporting findings that successful weight management can result in remission of T2DM. 43 , 44 , 45 The present results showed profound and sustained weight loss with long‐term TTh in patients with TD and T2DM, consistent with previously published data from our registry study in patients with TD and with or without T2DM. 46
It is important to note that this registry study has some limitations. It was not a randomized clinical trial and therefore we would expect the testosterone‐treated group and the untreated group not to be balanced at baseline, for example, with regard to age, severity of disease, glycaemic variables, markers of inflammation, lipid profile and markers of insulin resistance.
However, for these reasons our data were adjusted for the differences between the two groups including age, waist circumference, weight, fasting glucose, systolic and diastolic blood pressure, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and AMS quality‐of‐life score.
Also, given that this study was carried over a median follow‐up of 8 to 10 years, a 2‐year difference in age over this period of time may have little or no effect. While patients in the testosterone group may have been seen by us slightly more often, there was very limited change in weight with respect to number of visits or motivations. 47 We should also note that treatment of diabetes was carried out by the patients’ diabetes physicians, which was not under our control.
Our findings show that long‐term TTh led to sustained remission of diabetes in one‐third of patients with T2DM and hypogonadism. Although studies on lifestyle interventions as well as bariatric surgery have shown that T2DM can go into remission, to our knowledge, this is the first study demonstrating that TTh achieves such a successful rate of diabetes remission.
The clinical significance of these results is further enhanced by the fact that one‐third of men with T2DM have hypogonadism. Hence, physicians encounter men with hypogonadism and diabetes very frequently. It is remarkable that, while T2DM leads to hypogonadism, treatment of hypogonadism results in remission of diabetes itself.
In the absence of randomized clinical trials, the data from this large, long‐term registry study are important since one‐third of all patients reversed their diabetes. Real‐world data such as these have unique significance and are important. The reversal of hyperglycaemia and diabetes after testosterone treatment has not previously been shown.
Randomized controlled trials are now needed to confirm these data. One such trial is currently being conducted and the results are expected to be published soon. 48
referene link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689919/
More information: Gary Wittert, 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. The Lancet Diabetes & Endocrinology 2020. doi.org/10.1016/S2213-8587(20)30367-3
