Corante

About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« An Easy Way to Make Cyclic Peptides | Main | TDP-43 and Alzheimer's »

July 17, 2014

Reversal of Type II Diabetes May Be Possible

Email This Entry

Posted by Derek

Here's some big news: Ron Evans and co-workers at Salk report that treatment with the growth factor FGF1 appears to reverse type II diabetes in mice. (Article in Science Daily on this study here). Evans has been working in this field (diabetes, insulin sensitivity, and related areas like growth factors and nuclear receptors) for a long time, and I would definitely take this work seriously.

They reported a couple of years ago that FGF1 seemed to be involved in insulin sensitivity. It's induced in adipose tissue under high-fat diet conditions. FGF1 knockout mice, for their part, have a seemingly normal phenotype, but when they're put on high-fat diets they respond very poorly indeed, quickly showing abnormal glucose control and other defects.

This new paper shows that in normal mice with metabolic problems brought on by a high-fat diet, a single injection of recombinant FGF1 is sufficient to normalize glucose for up to 48 hours. Interestingly (and importantly), this mechanism doesn't seem to overshoot - you don't swing over to hypoglycemia, which is always a worry in this field. And repeated FGF1 therapy leads to increased insulin sensitivity, suppression of hepatic glucose production - basically, everything you'd want in a Type II diabetes therapy. It's great stuff, and the best candidate I've yet seen for the Real Mechanism behind the disease.

Now, FGF1 is a cellular growth factor, so there's a possibility for trouble. But the glucose/insulin effects seem to be mediated by one particular FGF receptor (FGFR1), which makes one hopeful that this axis can be separated out. I would expect to see a great deal of work coming on variants of the protein with longer plasma half-life and greater selectivity. In vivo, the protein seems to be secreted and used locally in specific tissues - it's not in wide circulation. But perhaps it should be - you can be sure that someone's going to try to find out. Overall, this is excellent, exciting news, and we're poised to learn a huge amount about type II diabetes and how to treat it.

Comments (24) + TrackBacks (0) | Category: Diabetes and Obesity


COMMENTS

1. Vader on July 17, 2014 9:08 AM writes...

"Now, FGF1 is a cellular growth factor, so there's a possibility for trouble."

"Trouble." I suppose that's one spelling for "neoplasm."

Permalink to Comment

2. Teddy Z on July 17, 2014 9:11 AM writes...

If mice studies correlated well with humans, then I would get excited. What is the correlation rate? I would like to coin the phrase "Expectation Inflation".

Permalink to Comment

3. Derek Lowe on July 17, 2014 9:18 AM writes...

For diabetes, especially Type II, the mouse models are pretty good. One of the better therapeutic areas for that, I'd say (I used to work in it).

Permalink to Comment

4. Tuck on July 17, 2014 9:39 AM writes...

Reversing type II diabetes in humans is being done right now. However, it's done by putting them on a high-fat, low-carbohydrate diet.

There may, therefore, be a disconnect between the mouse model and the human model, although the type of fat used in the high-fat diet also appears to be important.

"The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus"

http://www.biomedcentral.com/content/pdf/1743-7075-5-36.pdf

Permalink to Comment

5. NMH on July 17, 2014 9:48 AM writes...

What a stupid waste of taxpayer money.

A lot of diabetes can be reversed on diet alone.

I wont say how, it will just piss off a lot of people.

But again, its easier to take a drug then to hold back on cheeseburgers, french fries and creamy milkshakes.

Permalink to Comment

6. In Vivo Veritas on July 17, 2014 10:00 AM writes...

Derek is right on this - the in vivo models work really well (comparatively) for obesity/diabetes. Plus they were smart enough to use 2 genetic and one diet induced model. I'd bet this one translates, at least partially.
Then again...... leptin. :(

Permalink to Comment

7. David Borhani on July 17, 2014 10:36 AM writes...

@4, @5: Yes indeed.

Pre-diabetic myself, at age 50, despite being thin as a rail (bad genes, I guess). So I started biking again (6 miles/day), and shifted my diet to much more protein& fat and much less carbohydrate. My BMI, which was "normal" at 20.8 (135 lbs *max*, 5'7"), dropped 19, the absolute bottom of the normal range. HbA1C and worrisome, prolonged elevated blood Glc after meals also normalized.

Unabashed pitch for my father-in-law, Dr. Richard K. Bernstein, whose low-carb approach seems to not get enough air play: http://www.diabetes-book.com/ (ignore the silly title, as that's just the publisher trying to sell books; do read it, however).

Permalink to Comment

8. SomeGuy on July 17, 2014 10:44 AM writes...

I saw Ron Evans present some of this data a year ago and we internally debated starting a program on this. But the big problem is FGF1 activates all FGF receptors and long term treatment with this just screams cancer with a capital C.

Very impressive glycemic data though.

Permalink to Comment

9. HT on July 17, 2014 10:56 AM writes...

@6: Actually leptin wasn't that bad ... the discovery did help some people. Let's just hope that FGF1 will eventually help a few more.

Permalink to Comment

10. MedChem on July 17, 2014 11:33 AM writes...

So in principle an FGFR1 kinase agonist would do the trick also?

Permalink to Comment

11. Harrison on July 17, 2014 12:08 PM writes...

@4 I always wonder why diet-induced obesity models use copious amounts of fat (60% of the diet) and a little sucrose. I think a far more accurate representation of the Western (aka American) diet would be copious amounts of high fructose corn syrup with some trans fats thrown in. At least that's what people ate throughout that 1980s and 1990s that led to today's T2D epidemic.

Permalink to Comment

12. In Vivo Veritas on July 17, 2014 1:16 PM writes...

@9 HT - believe me, I know that leptin in a godsend for those lipodystophy patients - I'm closer to that story than you might expect - but compared to the shock wave the discovery of leptin sent through met. disease, the global impact is relatively small.

@11 Harrison - we & others use use a high trans-fat, high fructose diet as a tool. It's good for modelling human obesity, but better at modelling NASH. Mouse livers hate that diet!

Permalink to Comment

13. Mr Nesidioblastosis on July 17, 2014 1:25 PM writes...

To add to comment #4, bariatric surgery (gastric band or bypass) appears almost implausibly effective at inducing remission from type 2 diabetes See, for example, Mingrone et al, N Engl J Med 2012; 366:1577-1585. Apparently, "At 2 years, diabetes remission had occurred in no patients in the medical-therapy group versus 75% in the gastric-bypass group and 95% in the biliopancreatic-diversion group (P less than 0.001 for both comparisons)."

Permalink to Comment

14. ESIMS on July 17, 2014 1:43 PM writes...

@8
I agree. If you make something circulating - which does not circulate in vivo - there will be consequences

Permalink to Comment

15. PMT on July 17, 2014 2:11 PM writes...

@10

According to his model yes, the N-terminal truncation still has glucose lowering effects has its affinity for several FGFRs is reduced blocking its mitogenic activity yet its ability to bind to FGFR1c is intact allowing for the glucose lowering effects.

The loss of activity of both recombinant forms of Fgf1 loose activity in the fat-Fgfr1 knockout so a selective agonist would be the best approach and mimic off target effects by circulating Fgf1

Permalink to Comment

16. steve on July 17, 2014 4:36 PM writes...

I beg to differ, the mouse models are not necessarily predictive. There was a big brouhaha when Doug Melton discovered a hormone, betatrophin, that reversed diabetes in mouse models. Problem was, it didn't do anything in humans. It's pretty unlikely that FGF alone will reverse diabetes in humans but one can always hope. As others have noted, the tumorigenic potential is something that will give FDA pause to say the least.

Permalink to Comment

17. SomeGuy on July 17, 2014 6:11 PM writes...

@16

"Betatrophin" does do something in humans, just not what Melton (and his postdoc) published. And it has nothing to do with beta cells. Said postdoc gave a very embarrassing talk at Keystone this year. I don't know if the results of that paper were faked or misinterpreted, but they were very, very wrong. Nothing to do with translatability there.

Permalink to Comment

18. anon on July 17, 2014 7:12 PM writes...

#10

FGFR1 kinase kinase inhiitor

(assuming there is a kinase that activates FGR1 kinase)

Permalink to Comment

19. cinc on July 17, 2014 8:33 PM writes...

Evans' approach is a new method to modulate FGFR1 signaling but it's not the first, and I'm skeptical this will end up being something that's useful for T2D in humans.

Scientists at Genentech have published data on an agonistic antibody against FGFR1b / FGFR1c (Wu et.al. SCi. Trans. Med. 2001, 3, 113ra1216) which appears to have similar effects in mouse models of T2D. However in a later publication they report seeing hypophosphatemia in bone cells with these antibodies. In addition, they suggest a (the?) major mediator of the antidiabetic effects in rodents is brown fat, which is clearly worrisome from a translational perspective. In addition, Lilly's FGF21 agonist, which signals through FGFR1 (and admittedly also through other FGFRs)was terminated in the clinic for T2D due to lack of efficacy and was rumored to have bone toxicity.

I'm afraid this may go the same way as Evans' 'marathon mouse' work on PPARdelta a few years back.

Permalink to Comment

20. Da Vinci on July 18, 2014 6:22 AM writes...

Having worked on FGF1, I'm sceptical about side effects. FGF1 is the floozy of the FGFs, binding to pretty much every receptor in all their isoforms. You'd have to work out which receptor is responsible (there seems to be a suggestion in the paper it's FGFR1c or 2c) and work on a specific agonist for that one. And good luck with that.....

Permalink to Comment

21. Martin Griffies on July 18, 2014 7:09 AM writes...

Reversal of diabetes by diet is now well-established, but it requires supervision and effort. Newcastle University (UK) has published on it:
http://www.ncl.ac.uk/magres/research/diabetes/reversal.htm

Permalink to Comment

22. anon-ymous(e) on July 18, 2014 7:47 AM writes...

Seriously....???

I can see the TV ad now -"Look Ma, no diabetes" (and the sign above his hospital bed says "Cancer Ward")

Permalink to Comment

23. anonymous on July 21, 2014 12:32 PM writes...

FGFR1c neutralizing antibodies cause significant hypophagia and weight loss, with no obvious signs of toxicity as MOA. These results have been reproduced in pharma in non-rodent species as well as rodent systems. It is hard to fully reconcile the possibility that adding FGF1 could cure diabetes via FGFR1c receptor signaling given these data.

http://www.ncbi.nlm.nih.gov/pubmed/17132826

Permalink to Comment

24. David on October 7, 2014 12:15 PM writes...

Another one just came up that also looks promising. It would be nice if someone who knows better could comment.
It is from Rutgers and the summary is:

Promising evidence that a modified form of the drug niclosamide – now used to eliminate intestinal parasites – may hold the key to battling type 2 diabetes at its source, scientists report.


http://www.sciencedaily.com/releases/2014/10/141005133656.htm?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+sciencedaily+%28Latest+Science+News+--+ScienceDaily%29

Permalink to Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
XKCD on Protein Folding
The 2014 Chemistry Nobel: Beating the Diffraction Limit
German Pharma, Or What's Left of It
Sunesis Fails with Vosaroxin
A New Way to Estimate a Compound's Chances?
Meinwald Honored
Molecular Biology Turns Into Chemistry
Speaking at Northeastern