Sandeep Dhindsa, M.D. - Interview

Description

Type 2 diabetes and low testosterone are associated with each other. I became aware of this association during my fellowship days. At that time we were not aware that low testosterone is a very common problem in obesity and type 2 diabetes.

However erectile dysfunction was common, and investigation of erectile dysfunction often led to a diagnosis of hypogonadism as well, and that's when we started wondering if low testosterone is just associated with the metabolic syndrome itself. So we looked at around 100 men with type 2 diagnosis who came to our clinic in Buffalo, New York, where I was training under Dr. Dandona, and we found that a third of them had low free testosterone concentration, and that was a surprise to us. We did not know that there was this very common condition sitting in front of our eyes and that we had no clue about this. So as we then investigated this further and further, it turned out that those with low free testosterone did not have elevated LH and FSH concentration, and that made us start looking into their pituitaries by MRIs, wondering if we are missing out on a whole lot of large adenomas that we had not suspected, and all the MRIs came out to be normal. So it was not an anatomical defect as such, it’s more of a physiological defect. As to whether the problem lies in pituitary or hypothalamus or superior to that, we don't know that. We don't know that, but looking further into the mechanisms, one, it is clear that this is not a primary testicular problem, it is central problem; and number two, the association of low testosterone with diabetes had nothing to do with glycemia. The hemoglobin A1C and testosterone in these men were not related. The duration of diabetes, the complications of diabetes had no relation to that, and it was strictly related to their BMI, their obesity, and inversely so, so the higher their BMI, the lower their testosterone concentrations.

And neither was age a big impact factor in these conditions, so then we started looking deeper into that. We looked at young men with type 2 diabetes and we compared them with young men with type 1 diabetes. Low testosterone is not present in type 1 diabetes since it is not a glycemia-based issue. It is an issue based on the obesity status largely. But even young men below the age of 35 years had one-third prevalence of low free testosterone, so that makes you wonder as to why at such a young age it is happening and when does it start, because people have always thought of testosterone and obesity linked as a bidirectional association. So you have obesity that causes low testosterone probably, and then you have testosterone that makes people lose some fat and reverses the situation. But I would like to say is that rather than this chicken-and-egg circle, another way of thinking about it is clearer in my mind, and it depends on the particular patient population that you are talking about. So let’s talk about a simple aspect, prostate cancer, and we give them long-acting GnRH agonist and we make them totally hypogonadal. What happens to these men? Here you have clear evidence that you cause low testosterone and that leads to more fat mass, loss of muscle mass, and increase in the incidence of metabolic syndrome as well as diabetes, so clearly low testosterone causing obesity and that. But what about the other aspect that I started talking about, obesity causing low testosterone? So one very informative study we did about that was in boys completing their puberty. So a pre-pubertal boy, whether he is lean or obese, they have low testosterone levels. Then Tanner Stage 1 comes, then Tanner Stage 2, and their testosterone starts to rise. Around Tanner Stage 4 or so, the obese boys start lagging behind in their free testosterone – and I again specify we’re talking of free, not of total, so we are not talking of the binding protein problem – and by Tanner Stage 5, the difference in the testosterone level of an obese boy and a lean boy is around 40%, so obese boy is 40% lower. So you can argue now that very early on, obesity has impacted their gonadal access, and this is the peak testosterone of their life, right? Usually men achieve their peak at puberty, their peak remains for 10 to 15 years, and then there is a 1% or 2% decline in testosterone throughout their life, so they are starting low. As to whether this will cause them to have more fat accumulation in the long term, more diabetes, other ill effects, we don't know, but that's something. Their fertility may be impacted for all we know, of having such hypogonadotropic hypogonadism at an early age.

So that brings me to the next point as to why would obesity cause that, and people have often said in the past, “Well, that's easy, you have more fat tissue so you have more aromatase enzymes so you’re going to convert more testosterone into estrogen, estrogen will go back up to the brain, suppress the access.” It is not true, or let’s say partially true. When you have obesity, yes, you do have more aromatase enzyme, and you will form more estradiol if testosterone is present. So in a hypogonadal man, if the substrate testosterone is low, then you may not have the elevated estrogen that you were expecting, so we looked at that. We looked at obese boys, we looked at obese middle-aged men with type 2 diabetes, we compared them with eugonadal type 2 diabetes men and the lean boys and so on, and what we found was that if an obese man has low testosterone he also has low estrogen. When an obese man has normal testosterone, he does have elevated estrogen as compared to a lean man, but the hypogonadal man still has low estrogen, so you cannot blame estrogen as the cause of hypogonadotropic axis. No, estrogen is mainly following the testosterone and something else is causing the suppression. As to what that something else is, we do not know yet. We believe insulin resistance at the neuronal level plays a role, perhaps leptin resistance at the neuronal level plays a role, or it may be something else. We know that they may not have enough kisspeptin, and you give them kisspeptin and that works, but again then what is keeping the kisspeptin low then in the neuron, so we don't know the cause underlying that, and that would be so interesting to find out. But I would say that it has been an under-recognized complication of obesity metabolic syndrome in type 2 diabetes, and we may be missing out on an important aspect of the male health in 20% to 30% of these men because they have low testosterone.

We have historically considered testosterone as playing an important role in the sexual health of a man. We have not known much about the role of testosterone in the metabolic health of a man as a direct contributor to improvement in glucose metabolism. We have known of its role in muscle growth but we have not tied the links towards let’s say origin of diabetes and the metabolic syndrome aspects of that. What we have tried to work in Buffalo, at University of Buffalo, is to detail the molecular aspects of testosterone therapy at the level of skeletal muscle and subcutaneous fat and overall insulin sensitivity of a person. We did hyperinsulinemic-euglycemic clamps to measure insulin sensitivity, and demonstrated that testosterone therapy in men with type 2 diabetes, in hypogonadal men with type 2 diabetes, increased their insulin sensitivity by approximately 30%. At the cellular in the fat tissue, we demonstrated an increase in the expression of insulin receptor, insulin receptor substrate 1, glucose transporter, and Akt; at a muscle level, there was an increase in AMP kinase activity; and to further study the mechanism underlying the increase in insulin sensitivity, we looked at the inflammation. The CRP went down, free fatty acids went down, TNF alpha in the serum went down at a cellular level in the circulating mononuclear cells which we considered as one of the hallmarks of inflammation. We were able to demonstrate a decrease in inflammatory genes that mediate insulin resistance, namely suppressors of cytokine signaling and IKK as well as beta.

So I would say that we are very excited and emboldened by learning about these mechanisms in which testosterone can enhance insulin sensitivity, and that is one aspect. As we learn more and more, we will know more about its effect on fatty liver for example. That is becoming a major problem, and specifically conversion of fatty liver into NASH. We know that testosterone decreases subcutaneous fat. In longer-term studies, there is some suggestion that it could lower visceral fat as well, and many people have shown direction and ways to circumference. Whether that translates into more clear cardiovascular benefits in the long term is not known. Apart from the metabolic aspects, we looked at bone and showed an increase osteoblastic activity after testosterone therapy, and also further evaluated the mechanisms that underlie the increase in hemoglobin after testosterone therapy. It turns out that testosterone increases hemoglobin by a number of mechanisms. There is a small increase in erythropoietin. There is a decrease in hepcidin which is the hormone that blocks the transfer of iron out of the macrophages by inhibiting the ferroportin, and we actually showed that ferroportin expression in mononuclear cells went up after testosterone therapy, so testosterone would increase iron delivery to the developing hematopoietic cells in that aspect, and our work in this field is still ongoing.

When a patient with type 2 diabetes presents to me, the man clearly has problems sometimes with glycemic control and they may have problems with lipids, but if you were to really ask about the patient important symptoms, the sexual function, erectile function is a major part of their symptomology. We have excellent therapies for diabetes nowadays, we have good drugs for erectile dysfunction, for libido testosterone aspect is there, and now we have some drugs that can help with obesity as well. However all these things are incremental, and if we do not think of testosterone as part of the treatment regime in a hypogonadal man with type 2 diabetes, we may be putting too much burden on each of our individual therapies to address these aspects, whereas with testosterone you may have an opportunity to address in a wide fashion many aspects of that man’s sexual health, so in that way I think of testosterone therapy as an essential part of the armamentarium of our pharmacotherapy.

I am glad that American Diabetes Association guidelines now include the measurement of testosterone as part of their recommendations for a man with type 2 diabetes. This I think will increase awareness and will also spur further investigation and interest in this area. I do know by anecdotal experience that the measurement of testosterone in men with type 2 diabetes is done very sporadically and rarely, so there is a lot of room for improvement in that aspect. There is also a general lack of awareness about the effects of testosterone therapy on metabolism, and often it is relegated only towards treatment of sexual symptoms, and as we learn about this more and more, I think the familiarity of practitioners in the population with testosterone therapy will increase and that will then feed back into them checking this on a more regular basis as well. So I look forward to growth in this area and a further increase in knowledge in this area.


 

Speakers

Prof. Dr. med. Marija Pfeifer

Prof. Dr. med. Marija Pfeifer
Medical Faculty
University of Ljubljana,
Slovenia

Sandeep Dhindsa, M.D.

Professor of Medicine
Chief, Division of Endocrinology, Diabetes and Metabolism

Saint Louis University School of Medicine, USA

 

Sandeep Dhindsa, M.D.

 

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