Reversing beta cell dysfunction

Mostly a bookmarking post, but indicates the possibility of "curing" type 2 diabetes.

Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced β cell dysfunction in isolated pancreatic islets

  • Summary

  • Uncoupling protein 2 (UCP2) negatively regulates insulin secretion. UCP2 deficiency (by means of gene knockout) improves obesity- and high glucose-induced β cell dysfunction and consequently improves type 2 diabetes in mice. In the present study, we have discovered that the small molecule, genipin, rapidly inhibits UCP2-mediated proton leak. In isolated mitochondria, genipin inhibits UCP2-mediated proton leak. In pancreatic islet cells, genipin increases mitochondrial membrane potential, increases ATP levels, closes KATP channels, and stimulates insulin secretion. These actions of genipin occur in a UCP2-dependent manner. Importantly, acute addition of genipin to isolated islets reverses high glucose- and obesity-induced β cell dysfunction. Thus, genipin and/or chemically modified variants of genipin are useful research tools for studying biological processes thought to be controlled by UCP2. In addition, these agents represent lead compounds that comprise a starting point for the development of therapies aimed at treating β cell dysfunction.
On a related note, claims have been made by Dr. Eades and others, that on low carb diets a metabolic advantage is achieved at least in part by wasting fat calories because high fat diets increase uncoupling proteins in mitochondria.   If true, and this impacts UCP2 in beta cells, this would not be a good thing!  If I'm reading this summary correctly, excessive UCP2 "short circuits" the beta cells and keeps them from releasing insulin.  


Anonymous said…
I'm convinced Eades knows there's no metabolic advantage. He's making it up as he goes along. Gotta justify his paycheck somehow.

Lowcarb is mostly a game of smoke and mirrors. I think the only one who has got it right is Lyle McDonald with his RFL diet, and while that particular diet is lowcarb, it's also lowfat, and he categorically states that ketosis is irrelevant (even potentially dangerous, but that's a comment he made in an earlier book on ketogenic diets).

Anyway, hope you had a good Thanksgiving :)
CarbSane said…
Thanks dc, I had a great holiday. Lots of good food without overdoing it. Since I do all the prep work in our small kitchen for that holiday, I suspect I might have even lost an ounce or two :) Hope you enjoyed your's equally as much as I did.

I never read Protein Power, but from what I can gather from some discussions, he embraced calorie balance in that book. Nobody denies differences in TEF for the macronutrients either, although that would give the edge to carbs over fats for protein held constant. It seems somewhere along the line he needed an extra gimmick to sell books and products over more popular plans like Atkins. Give people a "magic" plan that involves less effort and voila!

The UCP angle is the most puzzling of the justifications IMO, because there would seem to be no survival benefit to running our mitochondria less efficiently, particularly to "waste" our most efficient molecular means of energy storage (lipid).

Lyle did an excellent piece on the energy balance a while back. It wasn't well received in LC circles ;)
Kindke said…
Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity
Karen said…
Read kindkes site and am not sure what I saw! Good or bad to eat high fat?
CarbSane said…
Interesting link Kindke (somehow I missed notice of your comment). Karen, I've not come across any research indicating that eating fat per se increases UCP's.

We do need to distinguish UCP levels and the endogenous metabolic state that raise them (e.g. energy surplus). UCP's do have all the benefits listed in Kindke's abstract there, but this is in reaction to a highly oxidative state. So elevated UCP's indicate an undesirable/damaging metabolic state requiring their action to alleviate it.

In Kindke's linked study, the mice were treated with something to raise UCP levels. They describe UCP's as a calorie restriction mimetic. The theory seems to be that calorie restriction prevents mitochondria from getting into the overloaded state that favors ROS formation. UCP's would do the same for eucaloric (energy balanced) or perhaps even mildly hypercaloric intakes.

But the UCP levels were elevated artificially by administration of protonophore 2,4-dinitrophenol. Notably the mice lost weight.

It seems to me that UCP's themselves are not inherently detrimental. And oddly enough, making mitochondria less efficient by "shorting them out" may be beneficial. But the metabolic state in which they are naturally elevated is another story. Not sure, but seems to make sense to me.
Sanjeev said…
The very first time I did Atkins, around 1994 I was measuring urine ketones. For the first 2 months or so I had zero readings.

Around that 2 month mark i started taking a little flax seed oil and started seeing pinkish readings (meaning "trace").

Summer came and I started riding my bike. After the first long ride of the summer (around 4 hours) the sticks turned deep purple for the better part of a week, with no further exercise for that week. I was losing something like 100mmol of fat with every liter of urine. (this is from memory, so likely very wrong ... but I'm doing my best)

>> I'm convinced Eades knows there's no metabolic advantage

I'm convinced there is, and I suppose some might call it "large"[1] but it's very VERY temporarily.

After about a year the sticks rarely got into the purple and most of the time were at trace, no matter what I did.

This makes complete sense to me now, having read about others' experiences - Lex Rooker, who has kept meticulous records of his near zero carb experience, found he could lose weight with caloric excess at the start, but later would gain weight unless he strictly controlled his calories.

Some of Lyle McDonald's research presented in his ketogenic diets book also supports this notion of diminishing ketosis. And of course Matt Stone maintains that one eventually adapts and one's body eventually rebounds to more than nullify any initial metabolic advantage.

So again, I think there is metabolic advantage, but it's tiny, temporary and may set up your body's systems in a vulnerable and unstable state, like a row of dominoes, for worse to come.

[1] 100mg, while tiny if one wants to lose 60 pounds, is huge compared to zero, and would be huge if it stayed that way for years, AND EVEN if it were a lifelong feature of low carb diets, one's body might take other compensatory actions, like increasing appetite after some time
CarbSane said…
Semantics, perhaps, but when one talks metabolic advantage, this denotes a significantly measureable difference in the amount of intake or weight loss. We become keto-adapted and spill fewer ketones over time. I also believe one's body will take compensatory actions to prolonged ketosis as this state is physiologically akin to starvation. Purely anecdotal, but my own metabolism seems to get super efficient on long stretches of low carb.
Sanjeev said…
> Semantics, perhaps, but when one talks metabolic
> advantage, this denotes a significantly measureable

Agree completely


there's also the temptation among those successful with low carb to credit those authors and their theories. Thus some vague, nonspecific "metabolic advantage" and "anti-insulin diet" gets the credit, but the specific, well documented "protein reduces appetite for most" gets lost in the popular discussion.
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