"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.
- 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]
Welcome back Patrick! So delightful to see your post on FPC. I have found this particular forum to be a great place for interacting. Many sharp minds and very friendly here. Hope you make a home here. We are self monitoring with kindness, respect and intellectual curiosity surrounding topics, both central and peripheral, to living well while dealing with PC.
Perfectly expressed as usual Paul. Now all websites and human relations should be governed by the three principles you've noted. You've been a wonderful addition too at FPC.
Appreciate the prayers and support. It goes well..He is moving better...ate breakfast...once, he gets a shower then I'll head home and his wife and daughter will care for him.
Just got back from Cleveland, but yeah....Everything good....surgery went well...prostate only involvement, no extensions... we are happy....how could we not be??
Welcome back from your self-exile Patrick. Great post. So to minimise IGF-1 we can avoid dairy, reduce sugar, take metformin or berberine (if we cannot get metformin). Is there anything else we can do?
It now seems that Christmas has come early to all those reading at FPC. Fantastic to see you once again finding those important research papers and connection dots that few outside of a well-funded research lab can do. I was just trying to get someone to do a post on PCa metabolics . . . and you present one to start the conversation. (You even got in a trademark "LOL".)
Hope you had a nice T'Day and are now working on a fine end of the year. I spoke with your seasonal lunch companion yesterday and he says he will stick around this winter and forego the warm-water fishing. Maybe that means an extra lunch session or two, so get out you wine list now.
Really is nice to see pjoshea13 in the headers at FPC! Looking froward to seeing you around the "campus".
Absolutely brilliant to see you posting here. It has made my day. I have really missed your deep research posts. Thanks for such an interesting post. Great that you have done so well for 17 years but you deserve it for all the effort you have put in to trying to outwit this clever, complex and ever adapting foe we all face
It is a paradox to see less PCa in the presence of DM. However, have you considered PTEN status and the role of PTEN? As a tumor suppressor, PTEN lowers the activity of Akt/PI3K/mTOR. These are all mediators of enhanced insulin sensitivity. So intact PTEN with lower Akt/PI3K/mTOR helps suppress tumor growth but compromises insulin sensitivity, potentially allowing insulin resistance, metabolic syndrome, and ultimately DM to arise in susceptible individuals.
Otoh, PTEN mutation/inactivation with elevated Akt/PI3K/mTOR activity will encourage tumor growth in vulnerable individuals, all the while enhancing insulin sensitivity and lowering the risk of metabolic syndrome and DM.
Apologies for the delayed response. I rarely think of PTEN, since it is commonly lost by the time of diagnosis (70%), & presumably increasingly so over time. & probably very much so in my case.
The old cell studies commonly used the LNCaP & PC3 cell lines, which do not have functional PTEN, I suppose that researchers weren't thinking of PTEN very much, either. lol
But when I began reading about epigenetics & learned that PTEN was often not mutated, but only epigenetically silenced, I did become interested for a while. Surely, we would soon see drugs that would reverse epigenetic silencing? Back when I asked my doctor for Metformin & was turned down, I jokingly asked him for Valproic Acid. How dangerous could it be? - it's prescribed for migraines. Importantly, for me, it is a histone deacetylase [HDAC} inhibitor & might restore my PTEN. It is also an AR antagonist and an aromatase inhibitor.
He made it clear that he would never give me that drug. There were a few trials around then, but nothing came of them. I gave up on epigenics way back, but it still crops up. From last month:
"PTEN tumor suppressor is frequently inactivated in endometrium and prostate carcinomas, and also in glioblastoma, illustrating the contribution of elevated PIP3 levels for cancer development. PTEN biological activity can be modulated by heterozygous gene loss, gene mutation, and epigenetic or transcriptional alterations. In addition, PTEN can also be regulated by post-translational modifications. Acetylation, oxidation, phosphorylation, sumoylation, and ubiquitination can alter PTEN stability, cellular localization, or activity, highlighting the complexity of PTEN regulation. While current strategies to treat tumors exhibiting a deregulated PI3-kinase/PTEN axis have focused on PI3-kinase inhibition, a better understanding of PTEN post-translational modifications could provide new therapeutic strategies to restore PTEN action in PIP3-dependent tumors." [1]
Thank you for the reference. Two paper by authors from Beth Israel Deaconess may be of interest:
N Engl J Med . 2020 May 28;382(22):2103-2116. doi: 10.1056/NEJMoa1914919. WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition
Background: Patients with PTEN hamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (PTEN). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative for PTEN mutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN.
Methods: In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned for WWP1 germline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representative WWP1 variants.
Results: The existence of germline WWP1 variants was first established in a family with wild-type PTEN who had oligopolyposis and early-onset colon cancers. A validation series indicated that WWP1 germline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germline WWP1 variants, particularly the WWP1 K740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including PTEN-related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritized WWP1 variants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models.
Conclusions: In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms without PTEN germline mutations, we confirmed the function of WWP1 as a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).
Science . 2019 May 17;364(6441):eaau0159. doi: 10.1126/science.aau0159. Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway
Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain-containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either genetic ablation or pharmacological inhibition of WWP1 triggered PTEN reactivation and unleashed tumor suppressive activity. WWP1 appears to be a direct MYC (MYC proto-oncogene) target gene and was critical for MYC-driven tumorigenesis. We identified indole-3-carbinol, a compound found in cruciferous vegetables, as a natural and potent WWP1 inhibitor. Thus, our findings unravel a potential therapeutic strategy for cancer prevention and treatment through PTEN reactivation.
Awesome food for thought and thank you for posting!!! Definitely many thanks as well for lifting your exile as it makes the place a bit more informative!
Perhaps another reason to use metformin when you have aPC, is to potentially stave off dementia, which some people are concerned about as a possible side effect of long term ADT.
The Garvan Institute in Australia is currently conducting a Phase 3 trial to examine the effects of metformin on cognitive decline.
Will be very interesting to see how this trial progresses Gail...make sure you keep us updated. There's so much incidental information around this medication and it's such a temptation for a whole lot of reasons apart from diabetes...even Normal Swan mentions it in his new book!!
Good to see interesting new information. My husband used metformin to prevent diabetes for several years prior to his prostate cancer diagnose. We do not beleive it helped re prostate cancer but thankfully he is still sharp in mind.
Dear Patrick, I really missed your and Nal’s contributions in the last months. I probably have to read your post several times until I understand it. Up to now I was under the impression that the glucose peaks may lead to PC development…
Welcome back , Patrick ! You’ve been a great resource for me since way back in the yahoo group !
My urologist prescribes Metformin transdermal cream which I push up into my body through the back door with a device called aneros ( I think ). He says pills are less effective .
My A1 c goes to 6.5 if I eat carbs . I can get it down to 5.6 with Metformin and a very low carb diet .
Just got home a bit ago...My regular MD would not Rx metformin, so I take Berberine a couple times a day... the path of least resistance.... not equivalent, but not chopped liver either...
I remember reading the FDA almost classified Berberine as a drug due to it's efficacy being almost as good as Metformin in regard to Glucose. I was taking it for a while too, using Milk Thistle along with it, something about the absorbtion of Berberine and MT helping increase the bioavailability...
Coconut Oil or Milk Thistle (Isosilybin B especially) was what I found to couple with it.
Unfortunately, I worry too about the CYP3A4 interactions as well. I stopped Berberine when my PCa became active again for a while, wanting clean blood tests. And there were a few pieces of information I came across that indicated Berberine was problematic with PCa as well... via AMPK & ATP pathways if I recall correctly... My brain spins when I jump down these rabbit holes, lol
There is sooooo much information... Good that Patrick is here... Everyone brings information that is valuable... Today, I learned from you.... thanks for the info... will look at it a bit later.... It is good to go down the rabbit hole, bold adventurer... on the horn with some of the NoLa Syndicate....
Denmeade's protocol is to continue ADT, but that's only for convenience and to keep things simple. (He could have switched to daily/oral ADT. I'm using oral DES, so can easily stop for a week or so.)
Seems to me the situation would be similar with Zytiga. Continuous is easier. Tcyp trumps it while in the body.
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as it makes the place a bit more informative!
Any tips for lowering AST (liver enzyme score)
