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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: Twitter: Dereklowe

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July 17, 2014

Reversal of Type II Diabetes May Be Possible

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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


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."

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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".

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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).

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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"

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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.

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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. :(

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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: (ignore the silly title, as that's just the publisher trying to sell books; do read it, however).

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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.

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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.

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

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

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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.

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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!

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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)."

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

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

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


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

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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.

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


"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.

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


FGFR1 kinase kinase inhiitor

(assuming there is a kinase that activates FGR1 kinase)

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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 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.

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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.....

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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:

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


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

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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.

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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.

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