My Sump-Pump Analogy for the ß-Cell

I'm going to try to make this as short and to the point as possible.  It's just me thinking out loud a bit, drawing on the massive amount of peer review research I've read on the topic -- a mere fraction of which I've formally blogged on -- but without any references so that I can just get this out there.  No ... this is not some manifesto grand theory on diabetes and all that to be analyzed and picked apart as if I'm presenting this as fact.  It's just a plausible analogy for what I think happens when metabolic mahem turns to "diabetes".  I'm also going to simplify things and deal with only glucose and fatty acids here.

Our ß-cells metabolize glucose and fatty acids the same way our other cells like muscle cells do for energy.  Essentially this metabolism is part of the mechanism by which the ß-cell senses the circulating levels of these energy substrates.  This metabolism also produces ROS -- reactive oxidative species.  While ROS are often seen as detrimental, due to the fact that they are in inappropriate amounts, the ROS molecules also play key signaling roles.  The metabolism of glucose and fatty acids produce a different redox state and ROS so this is roughly how the cells can tell what's being metabolized, etc.  

Insulin is secreted by ß-cells in response to both glucose and fatty acids.  In response to a sharp rise in glucose (e.g. eating a carby meal), an insulin "spike" is mounted -- an acute secretion of insulin -- the GSIS = glucose stimulated insulin secretion.  However we always have some basal level of circulating insulin (and it isn't as simple as some constant slow secretion) that is regulated to a significant degree by the levels of circulating free fatty acids, NEFA. The production of insulin can be simplified to modification of a precursor protein (proinsulin) to form insulin granules packaged in vesicles which eventually are released into circulation by the process of exocytosis.  There is some evidence that high demand for basal insulin depletes the proinsulin stores so that the cell can no longer produce the larger amounts of insulin required for an appropriate GSIS.

The ß-cell takes up glucose via GLUT transporters -- proteins that allow glucose to pass through the membrane.  While most are familiar with the insulin-stimulated GLUT4, the major transporters in ß-cells are GLUT2.   Fatty acids do not require transporters, but there is evidence that NEFA uptake is a combination of both passive diffusion and membrane-protein (FA transporter) mediated.  While it may be a bit of an oversimplification, since glucose requires transporters (though not necessarily insulin) for uptake while NEFA do not, the ß-cells, like other non-adipose cells, cannot refuse the delivery of fatty acids.  Once inside the cell, that which is not oxidized is esterified -- converted to triglycerides -- for local storage.  These local storage depots are called lipid droplets, and are perfectly normal.   However once esterified, the NEFA concentration inside the cell is kept low, and if the circulating level is high, thanks to diffusion the cells keep taking up fatty acids and fatty lipid droplets grow.

We can think of the ß-cell as having a well that fills with fatty acids and glucose that are metabolized for energy or pumped out temporarily with a sump-pump and used in timely fashion.  The level of the "float" on that automatic pump regulates how much insulin is produced in the basal state to try to suppress NEFA release from adipose tissue in the fasted state and keep glucose production in the liver in check to effectively lower the level in the well.  Float up = hyperinsulinemia, float down = low basal insulin production.  It's like that pump in a leaky basement.  Slight trickles, the pump goes on a couple times a day.  Big rain storm and the pump is going on every hour.  

Now this analogy is tricky, because the ß-cells are not pumping out glucose and fatty acids, but rather insulin.  So let's think of the insulin as a current requirement to power the pump.  The more the pump is required to run, the greater the continual current requirement.  A semi-renewable power source will work for this analogy -- e.g. a rechargeable battery with a slow recharge rate, so that if you run the pump on battery too long it can't keep up.  In the normal pancreas, the battery charge rarely goes below, say, 75% in response to a surge in flow of glucose, and is recharged to 100% in between.  But in the over-nourished state, the pump is working 24/7 to keep the well level down while still working well enough to deal with the intermittent deluges.   Perhaps the well level gets closer to the overflow and the pump has to work for longer to get the level back down, but the ß-cells manage.  Indeed in many "pre-diabetics", the pancreas compensates by putting more pumps (increased ß-cell mass) into the well.  Still with the increased running times, the battery charge now barely makes it to 75% before it's drained again, and now the charge goes down below 50% or even lower when the surges come.  The pump is still working. 

All the while, some of the excesses from the well have been moved to overflow tanks and now these are full-up.  Now the well fills and despite the pump going all the time, it can't keep the level down.  The pump runs and runs, it can't recharge fast enough.  The glucose flood comes and it tries to make enough insulin, but the battery is fully discharged by the attempt.  Perhaps this is also analogous to a sump pump in the well where the flow in exceeds the pump's ability to pump out -- once the well is overflowed into the basement, the pump "float" no longer sees gushes.  It just keeps running and running trying to get the level down but it doesn't "see" the periodic influx from the downpours any differently from the constant ground water trickle because the level is too high.  At some point, this is your ß-cells.  They are now malfunctioning.  You are officially diabetic with chronic hyperglycemia.

If it's your basement, perhaps you do whatever it is you do (pray? an anti-rain dance?) to get the water flow to stop so your pump can eventually get rid of all the water.  Otherwise you call in the fire department and the pump has long since been shut off to avoid burning out the motor.  The FD comes in with their mega pumps and removes the water.  You turn the pump back on and it's able to function again.  

Over the past year I've blogged on *reversal* of the diabetic state by gastric bypass surgery (GBP), the "crash" diets (very low calorie VLCD) and early insulin therapy.  All of these are generally poo-pooed in the low carb community because basically they are fixated on (a) lowering insulin and (b) reducing dietary carbohydrate contributions to blood glucose levels.    Certainly there's utility in the latter for controlling hyperglycemia to a degree, but in my opinion, the insulin lowering strategy is ill-conceived as it is implemented.  Let's look at the reversal strategies using our analogy.

1.  Early Insulin Therapy, EIT:  The progression of ß-cell malfunction seems to start with excessive fatty acids (lipotoxicity) and snowball with the combination of fatty acid and glucose excess (lipotoxicity + glucotoxicity = glucolipotoxicity).  Although the majority of T2 diabetics have "functioning" ß-cells, once this function is insufficient to maintain glycemic control (the end of the line) and a diabetes diagnosis is made, it seems that the hyperglycemia per se makes matters even worse.    EIT is analogous to calling in the fire department.  The exogenous insulin is like bringing in the super pumps to bring down the flood waters of nutrients.  EIT is also a bit like getting the prayer or whatever answered as well because the insulin will help trap the fatty acids in the fat cells (where they belong) and stem the incessant flow of glucose from the liver.  

2. Crash Diets:  The crash diets stop the inflow of BOTH fatty acids and glucose into the well and the significant calorie deficit allows the pancreas to drain the filled-to-the-gills overflow tanks -- e.g. pancreatic fat.  In the recent study, we see that even without changes in the basal state, the acute response was already improved.   The combination of virtually eliminating the added nutrients and draining the local overflow tanks seems to be enough to allow the ß-cell to resume functioning.

3.  GBP Surgery:  It may well be that this works largely by means of #2.  There is additional (and perhaps longer term) evidence that improved incretin (GLP-1 specifically) responses that stimulate insulin secretion and other things, plays a role.

So what of low carb successes?  Well, I submit that in the short term, the *normal* Atkins-induction style diet is successful largely by means of #2.   Folks going on a low carb diet, especially VLC for the very first time (sung to the tune of Madonna) spontaneously reduce intake dramatically and don't "up the fat".  But the results -- even with legit VLC like the touted Westman study -- are largely attained in the first few months with no further improvements, and seem to be mostly in the area of reducing insulin dosage.  In other words, lower dietary carb = lower pp insulin dose needed.  But even Wheat Belly describes his diabetes as in remission.  One tiny carb dose sends his blood glucose soaring.  Fat Head, who didn't have BG issues before going low carb, now describes similar if he were to eat starches.  This is because those eating maintenance low carb high fat likely have their ß-cell fatty acid wells all full up and they've adapted their metabolisms to a lower insulin response.  For those who have reversed their diabetes, many will never even know, I'm afraid, because they are slaves to their glucometers and hysteria over glucose "spikes" so they'll never know if they can be *normal*.   Eating energy balance calories, with high levels of fats and low dietary carb only stops the periodic rain showers.  It does nothing for the ground trickle and perhaps even increases it.  Why?  Because if VLC is effective in lowering basal insulin without improving hepatic/adipose sensitivity to insulin, the trickle may even increase due to (a) improper suppression of NEFA release from adipose tissue and/or (b) improper suppression of endogenous glucose production by the liver. 

So there you have it.  The ardent low carbers are trying to deal with flooded basements by putting an umbrella over their ß-cells and diverting the intermittent glucose downpours.  Little do they realize that fatty acids permeate their umbrellas.  They do nothing, absent substantial and sustained weight loss, about that ground flow, and may even increase it.  The "crasher" or EIT'er has either called in the fire department or stemmed the downpours sufficiently to allow their sump-pumps the opportunity to return to "functioning".   Perhaps this is analogous to the pump being reset a little higher up in the well after emergency measures get it within operating range.  As things improve, the pump can be repositioned back where it belongs.


Craig said…
I guess you lost me a bit on that very last comment...

I had the impression that you had already lost weight and were now in maintenance mode. But the post suggests VLC is beneficial mainly to the extent it helps produce calorie deficit and weight reduction? So maybe you meant hypothetically, if you were still overweight, and then were diagnosed?

And once you got to an acceptable weight/degree of leanness, I assume you'd slowly begin to add back carbs to exercise your pancreas?
bentleyj74 said…
If my primary goal was short term calorie restriction I'd hit whatever got me there like it owed me money. Probably I'd do basically an extended fast using the bland goop through a straw to meet my absolute basic nutrient needs without having to set foot in a kitchen or make any meal decisions.
Sue said…
I think Evelyn meant she would go on a VLCD - very low calorie diet to improve beta cell function if she was ever diagnosed with diabetes. Maybe she would also go VLC - very low carb if it helped her keep the calories low. Saying that, on VLCD you will probably be low on all macros. This post has nothing to do with her weight.
Sue said…
Me too but it would be hard. Or I'm sure I could do 2 tasty meals per day about 300-400 calories each and take some supps to decrease appetite/cravings if needed and exercise a bit.
@bentleyj74 for "fun" you could also install that weird-looking "futuristic" device in your house that Stephan included in that post about that extremely low-reward diet which dispensed that bland goop whereof you speak & started spontaneously consuming under 500 calories. :)
Sanjeev said…
some other words that may make sense to a lot of people here are "duty cycle"


_______A duty cycle is the time that an entity spends in an active state as a fraction of the total time under consideration.[1][2] The term is often used pertaining to electrical devices, e.g., switching power supplies. It is also sometimes used pertaining to living systems such as the firing of action potentials by neurons.

Motors with a short, high-power duty cycle (a car starter motor) may be run continuously but this considerably shortens their overall life.
Sanjeev said…
by your description above, beta cells, like some human designed systems, can operate in several modes but operate optimally in one of them.

Adding modes usually degrades the optimal mode (relative to special-purpose devices without the general-purpose modes)
Morris said…
@ Evelyn
Nice analogy and interesting. I have a couple of questions. You say “The metabolism of glucose and fatty acids produce a different re-dox state and ROS so this is roughly how the cells can tell what's being metabolized” Redox state = redox potential? of what? The cytosol? How do the redox states differ to distinguish glucose (pyruvate?) from FFAs?
You say “he NEFA concentration inside the cell is (normally?) kept low, and if the circulating level is high, thanks to diffusion the cells keep taking up fatty acids”. Is there an implication that since FFA uptake is less regulated than glucose that FFA’s excess is less harmful? Thanks. I could not find answers in my bio text.
CarbSane said…
Sue is right about what I meant. Yes I've lost a lot of weight and maintained that. I still have more to lose. When I lost fast on VLC back in 2007, it was also very low calorie -- not by design, but for a good long time I just wasn't eating a lot to satiety.
CarbSane said…
Hi Morris. One example of the "redox state" I'm talking about is that glucose metabolism produces H2O2 (or more than fatty acids) which appears to be a signalling molecule for how beta cells sense glucose levels. I guess what I'm trying to say is that the beta cells sense nutrient levels by metabolizing them themselves. And the ROS concentration signals insulin. As to the uptake of FFA's, they seem actually to be most harmful which is why cells esterify them to store as triglycerides. The fact that FA's can be taken up w/o active transport is simply because of their physicochemical properties. In this regard, esterifying FA inside the cells may keep the internal cellular environment "safe", but it also allows the cells to keep sopping up NEFA from circulation as the concentration gradient is there.

I hope to get to blogging on this but there's a whole NEFA/TAG cycle going on INSIDE the cells too that seems to be quite regulated.
CarbSane said…
He said duty (snickers, just saw a Friends rerun where Chandler went for an interview and the guy was talking about his duties ...).

The LIRKO mouse shows us that running the beta cell in overdrive doesn't seem to wear it out, instead the liver wears out when it can no longer keep up with gluconeogenesis. Food for thought for all of those folks who "baby their pancreas" and try to put the burden of glucose homeostasis entirely on the liver.
CarbSane said…
I know you're mostly kidding FTD, but there are quite a lot of very obese people in the LC community who are largely housebound -- IOW they have pretty limited mobility and rarely leave the house. Thus if someone else doesn't bring food in the house, they couldn't eat it. Rather than hurling hateful rants at Stephan, if I were them, I might just learn from that study. I'd buy myself some sort of stirring apparatus, make up a honking batch of bland protein shake, stick it in a dorm fridge with a tube coming out. Being home all the time compliance would be easier, more like it would be in a "metabolic ward".
MM said…
"...the ß-cells, like other non-adipose cells, cannot refuse the delivery of fatty acids."

Wow, I had no idea this was the case. No wonder the high-fatters are having blood sugar issues after a while.

For me, after being a high-fatter for too long it took me a lot longer than 3 days to carb-up. It was probably about 2 weeks before I started seeing normal bg on a regular basis.
bentleyj74 said…
Don't they have some sort of single serving device by now? Like the squashy juice box things? Ideally, I'd have a completely bare kitchen and no dishes or mixing...nada. I'd want food as far down my list of things I have to actively participate in or think about as I can get it.
Kindke said…
What I would say is, people should do whatever is working for them, take the science in stride as it comes.

Indeed if I was diagnosed with T2DM I would fast myself, probably 1-2 weeks. I would probably throw in some HIIT style exercise sessions aswell, provided my health wasnt too damaged.
@Evelyn - OMG it was totally not my intention at all to to make fun of anyone housebound because of their weight. I just got such a kick out of the pic that Stephan posted with that blog.

I definitely agree with you that instead of being so nasty to Stephan (um, a certain woo comes to mind) they should consider, I dunno, trying out his suggestions. It's funny, I had already read the Kessler book about End of Overeating & then Stephan's food reward stuff, and I've been applying it when I get these full-on protein-craving attacks (a lingering leftover thing from my whole stupid VLC thyroid-shutdown episode). When I'm craving serious amounts of protein, I go for the Whole Foods "naked" roast chicken precisely because it's roasted without any specialty spices and to me, it tastes quite bland - meaning I find it very low-reward. However, I eat it just until I'm physically satiated which is not the case when I have one of their elaborately-spiced roast chickens which taste good to me but do take active willpower on my part to stop with my 3-4 oz portion allotment for that meal.
bentleyj74 said…
@ Evelyn

What do you think is behind the emotional out bursting?
CarbSane said…
@FTD, I didn't take your comment as poking fun at anyone. I was just pointing out that such a strategy might actually work quite well for someone who is housebound.

@Bentley: I think it's a reaction to the gluttony & sloth thing. It is unfortunate that every time some mentions eating too much or overeating that this is equated with accusing someone of greed in biblical terms, and sedentary behavior is equated with laziness. While many obese are not lazy gluttons, I do think there's at least enough of a partial truth to this to hit a nerve. Nobody gets to be 300 lbs without eating a lot of food and/or being rather sedentary. When you read a lot of these people's writings you discover that they readily admit to having overeaten in the past -- they were starving all the time which drove them to eat uncontrollably at times. Gary Taubes tells the obese it is not only not their fault they are obese, but that it's the government's fault, BigPharma's, Big Corn, Big Sugar, Big Grain, etc.etc. What I find odd is that those who are successful at LC still don't take credit for taking control of their own behaviors and would rather credit Atkins or Taubes for saving their lives and somesuch. It takes discipline to adhere to an LC diet too.

But I don't get why the bland liquid through a straw and FR in general elicit such an emotional response except that they seem to be equating subconscious brain (hypothalamus) signaling with conscious cognitive behavior.
@evelyn this is probably off-topic - but maybe not in light of what you point out about "the gluttony & sloth thing". That Colpo post you tweeted about Captain Girdle totally cracked me up - he further goes on to discuss the fact his pal Dom who was a chubby kid but decided to eat less & move more to lose his weight rather than decide his metabolism was broken & start an angry blog about "Livin' la Vida Lardass". He's brutal but funny.
CarbSane said…
LOL -- Yes, brutal but hilarious. I think AC has caused more almost meltdowns of my laptop due to spit-out coffee than anyone I read. Captain Girdle. Just too funny!

I think paleo and the likes are going to lose credibility before they gain it (widespread) if they're not careful. Jimmy's "gone paleo baybeee" schtick seems to be paying off for him as he'll be speaking at PaleoFX, he's doing Sean Croxton's online Paleo Summit (I have some things to say about that one!) in a couple weeks, and he'll probably be talking at AHS12 on something. Both of the former mentions are using his woefully outdated "After" success story pic, I think the FX'ers who meet him in person will be in for a surprise. Here's an image discussing Jimmy's talk for PS: IMAGE. Sorry, but Jimmy has only recently embraced the paleo way and it ain't working for him to alter the course of his regain back into the 280's. The man is still obese by any objective measure -- IOW, the number on the scale I'm borderline, but by size and measurements, I'm nowhere near -- by ANY measure, Jimmy is.
He also posted a video recently using a classic "before" trick many a fellow Weight Watcher has 'fessed up to: only being photographed from the collarbones up. The video had something to do with Quest Bars & a giveaway & they wanted people to video their goals. This video - once again - made me scratch my head as to why anyone would take diet or health advice from the Buddha'esque persona on screen. It's like he has one of author Douglas Adams's SEP fields around him or maybe a LC/paleo version of the King's new clothes. Something isn't adding up in Denmark.
CarbSane said…
Which reminds me I'm long overdue for writing about fatty acid transport. The whole fat burning thing is such a farce when you realize that obese people (women especially) already burn more fat than carbs vs. their lean counterparts. That's the PROBLEM with pathological obesity. Your fat cells are supposed to sequester excesses, when they can no longer do that, the fatty acids in circulation go up and they gotta go somewhere. If not back into your fat cells, then into the other cells -- no transporter or signaling necessary. And so long as the fatty acids are "taken away" (used or converted to triglycerides), more keep flowing in.
CarbSane said…
Near when I first found Jimmy I watched a number of YouTube vids he did with his wife sitting slightly up and behind him. He looked OK from the neck up head on b/c he doesn't have the classic double chin. But every time he craned his neck to look back at her you got a shot of his chineck and I thought he looked fat b/c of that. I note that YouTube videos starring him are hard to come by these days ;)
CarbSane said…
But don't ignore inconvenient science. For example folks have no problem worrying over fatty liver based on what happens when rats eat sucrose. But show them a fatty liver from a high fat diet? Oh no ... THAT can't be. And be honest with yourself about what's actually working and why. When low carbers start seeing their fasting glucose levels creep up they fashion all sorts of rationales for this and why it's either not detrimental or convince folks it's actually a good thing. These are purely speculative notions, and the timeline for permanent, discernible damage is long.
LeonRover said…
And as for whipped cream and sugar - Well, what can I say.
Sanjeev said…
thanks for the reminder
yes, I had forgotten the beta cell mass increased where the "overworked pancreas" idea suggests the beta cells should have all died from the strain of making so much insulin.
Woodey said…
@Carbsane...Jimmy needs to update his pics. It wasn't until I saw some pics you posted of him that I was like, "Holy s**t!". If I went to a seminar and saw what he really looked like for the first time I would not want to listen to him.

Reading this thread and some others I think I am starting to get a picture as to why stalls and weight gains on the lc diet plagued me. I found it discouraging and odd that even scheduling just a couple of cheat days and those cheat days where not gorge fest (a batch of popcorn and some licorice with a movie) would cause stalling and weight gain. Half a month of strict dieting would be undone in a single cheat moment. I had never had issues like that before on different diets.
CarbSane said…
It's worse than that Woodey, Jimmy REVERTED avatars to those old pics. For a while he had more updated pictures.

I found Jimmy either just after or not in enough time to go on the 2009 LC Cruise. When I saw pictures of it afterwards I was frankly horrified! I would have asked for my money back.