This post is prompted by a new German study:
"Diabetes and the Prostate: Elevated Fasting Glucose, Insulin Resistance and Higher Levels of Adrenal Steroids in Prostate Cancer" [1]
[It has been 20 years since a nodule was detected on my prostate. I have been spending the past few months of self-exile writing an account of those years. I have used testosterone for the latter 17 years, but the picture is complex. I have been spending a lot of time reconstructing the first few years and digging out ancient PubMed studies. Hence the references to 16 years ago, etc.]
It has been 16+ years since I asked my regular doctor for Metformin. Of course, he refused. My fasting blood sugar was only 99 mg/dL. Perfectly normal. At 100 mg/dL, I would have been prediabetic, but he would still have turned me down. I went to my integrative medicine doctor & he gave me 1,000 mg/day. I now use 2,000 mg/day. Metformin is the standard drug for new diabetics. It inhibits glucose production and thereby helps to restore insulin sensitivity.
So, at least16 years ago, I had come across studies that associated diabetes with reduced risk for PCa. Which is odd, since diabetics have an increased risk for all other forms of cancer. Perhaps there was a clue there?
I already knew that PCa cells continued to prefer fatty acids over glucose. (At a late stage, cells might switch to glycolysis.) As Dr. Myers said in one of his vlog posts: "Good luck getting insurance to pay" for an FDG PET scan.
So it wasn't about the glucose spikes - had to be about insulin.
The different stages leading up to diabetes:
- chronic glucose spikes cause chronic insulin spikes and, ultimately, insulin resistance
- eventually, pancreatic beta cells produce more insulin in a vain attempt to overcome resistance
- beta cells start to burn out, so less insulin is ultimately produced
- when fasting glucose reaches 126 mg/dL, it is officially diabetes.
PCa risk doesn't immediately drop - that takes about 12 months.
The diabetic has found the hard way to solve his insulin resistance problem. I don't view him as being protected, but, rather, that the greater number of prediabetics (who mostly do not progress) have excess risk of PCa. And that pre-diabetes must be common in those at risk. I began to view PCa as perhaps, a symptom of the metabolic syndrome [MetS]. It has long been recognized that men with PCa have a higher risk of cardiovascular mortality, even if not on ADT. The MetS is a risk factor for cardiovascular events.
Over the years there have been attempts to explain away the apparent diabetic protection, and no great effort to explain how a protection mechanism might operate.
Unlike prior studies, the new German study measured estradiol, cortisol, progesterone, DHEAS & androstenedione.
"Here, we report that patients with prostate cancer display higher fasting blood glucose levels and insulin resistance (consistent with MetS), without changes in insulin secretion."
Interestingly, "serum triglyceride levels were {much!} lower in patients with prostate cancer". (95.4 mg/dL versus 130.6 mg/dL.) "... the metabolic pattern of hyperglycemia in the context of low circulating triglycerides was associated with poor prognosis and increased risk of PCa death in a previous study [4]. The role of triglycerides in PCa is not fully understood yet. However, lipid metabolism seems essential for prostate cancer cells, while they do not depend on increased aerobic glycolysis [15]. As we detected lower triglycerides in PCa patients, while liver fat content was comparable to healthy controls, triglyceride uptake might be higher in prostate cancer cells."
"In addition, we report increased adrenal steroid biosynthesis in these patients. Our results indicate that higher fasting glucose levels in patients with prostate cancer may be explained at least in part by insulin resistance, due to the enhanced synthesis of adrenal steroids." ("... we found elevated levels of cortisol, androstenedione, DHEA-Sulfate, progesterone and estradiol in PCa.")
Estradiol.
Going back 18 years, I remember the literature as claiming that the newly-diagnosed man invariable has "wild type" (i.e. normal) androgen receptor [AR]. (ADT was responsible for treatment-emergent changes to AR.) In contrast, the estrogen receptor [ER] situation had already changed by the time of diagnosis. The protective ERbeta had become down-regulated, whereas growth-promoting ERalpha was up-regulated.
In the new study, estradiol was higher in cases (126.4 ... pmol/L versus 115.5 ... pmol/L. [34 versus 31 pg/mL]
"... our results are supported by a previous report showing higher levels of estradiol in PCa [22]"
" Several reports exist suggesting a proliferative role of estradiol in PCa ... [23]"
Insulin.
Insulin is a mitogen. See: "Mechanism of the mitogenic influence of hyperinsulinemia" [2].
There are currently 557 hits on PubMed for . IGF-I is insulin-like growth factor I.
IGF-I is present in human milk, and boidentical IGF-I is found in cow's milk. Milk is the only food that comes with a growth promoter. Why are their so many PCa IGF-I studies? And why do men drink milk? LOL
The basic story is that IGF-I tends to be higher in PCa, while the IGF binding proteins tend to be reduced. Together, that means there is elevated free IGF-I.
But what is the connection between insulin & IGF-I?
"Insulin increases the bioactivity of IGF-I by enhancing hepatic IGF-I synthesis and by reducing hepatic protein production of the insulin-like growth factor binding proteins 1 (IGFBP-1) and 2 (IGFBP-2) [10, 11]. Therefore, although insulin can directly induce tumour growth, many of its mitogenic and antiapoptotic effects are operating through the IGF-I system, as reported in individuals with high levels of circulating IGF-I, in which an increased risk of developing certain types of tumours, in particular breast and prostate cancers, has been documented" [3]
[1] mdpi.com/2077-0383/11/22/6762
[2] ncbi.nlm.nih.gov/pmc/articl...
[3] hindawi.com/journals/jdr/20...
[4] onlinelibrary.wiley.com/doi...
[15] sciencedirect.com/science/a...
as it makes the place a bit more informative!
