Tuesday, 15 January 2013

JJ's Insulin Paper and beta-cell expansion

Wow I havent made a post on this paper yet.

By now it seems pointless, everything that could of been discussed has already been discussed about it elsewhere. However the points about beta cell mass expansion in obesity were interesting.

Pancreas and beta cell is an area that I am under-researched in ( I have been focusing alot on the morphology of the adipose tissue ), so I was a bit surprised that learn that beta cell mass increases in obesity. Its worse than I could ever have imagined, one study reports as much 10-30% increase in beta cell mass for each 10kg in weight gain.

One of the best lines in JJ's paper is this...

Together, many lines of evidence from multiple groups support the concept that insulin acts via insulin receptors to mediate the compensatory increase in b cell mass and basal insulin release in the context of high-fat diet

Ignore the bolded part for now. What JJ says in the paper is that there appears to be some kind of positive feedback mechanism between insulin secretion and beta cell expansion. I.E. insulin acts via receptors locally on the pancreas to promote beta cell expansion. Insulin hyper-secretion feeds back positively to the beta cells telling them to increase mass, presumably so that you can become a better insulin hyper-secreter in the future.

more insulin leads to more insulin leads to more insulin.

Yeh something like that.

Ofcourse the beta cells probably dont have any idea in the meantime that all this insulin its learning to pump out is rapidly expanding your fat tissue.

In addition there is this excerpt from the 2004 paper linked above...

In conclusion, obesity is a condition of predominantly β-cell functional upregulation rather than β-cell expansion. This upregulation involves the static responses (i.e., basal and total secretion) much more than the dynamic responses (i.e., glucose sensitivity and potentiation), at least as long as glucose-tolerant subjects are concerned. The insulin hypersecretion of obesity has a primary component, which cannot be explained by adaptation to insulin resistance and can be tracked through the period of weight loss (induced by calorie reduction or restrictive bariatric surgery). The residual insulin hypersecretion of the postobese (or weight-reduced) state may be the equivalent of an inherent insulin hypersecretion of the preobese condition.

So what im getting at is this, did you become obese because your pancreas learned to become an insulin-hypersecreter? All the fucked up stuff that happens with the morphology of your adipose tissue is likely just the result of this insulin-hypersecretion.

But, what provided the positive feedback of insulin hypersecretion to get the snowball rolling in the first place? I think this is a good point to go back to the Jenkins study . Insulin-hypersecretion BEGINS in response to blood sugar spikes.

But what causes blood sugar spikes? Again as shown in the Jenkins study, it is fast absorption of lots of glucose. Jenkins shows that fast absorption of glucose alone is not enough to spike blood sugar, you must also have significant amounts for it to build up in the blood ( I suppose thats obvious really, a single glucose molecule is not going to spike your blood sugar ) . Also we have to consider the degree of hepatic insulin resistance you have and how well you can activate glucokinase in the liver in response to carb ingestion.

All in all, the physiology remains complex, but the cause remains simple. Its the fast digesting, glucose dense foods spiking your blood sugar that is making you fat.

Also what happens with weight loss? Does beta cell mass shrink along with your BMI? Even after youve lost weight, it doesnt change the fact you were an insulin-hypersecreter in the past. And you can be one again in the future. You just need to get the snowball rolling again with some potato.


  1. Epic.

    And yes, your last paragraph is crucial because for all the health benefits of glucose restriction, it only really side-steps the problem. Obesity cannot be cured, it's an intractable illness. You can eat LC for a long time and normalise all your parameters but you are not cured; all it takes is just one meal of pizza or baked potato to send you spiking your BG and insulin again.

  2. Maybe that’s why some diabetics put on insulin therapy early seem to recover some of their own insulin production.

    1. imo that is backwards thinking, is the case of diabesity, they got IR in the first place because they got fat, and they got fat because insulin production started snowballing upwards. And this started to happen because of hepatic insulin resistance + high GI/carb dense foods allowing blood sugar to spike progressively more aggressively.

      These people do not need insulin therapy, they need to stop spiking their blood sugar so that the requirements for insulin go down and the bodies homeostatic systems can normalize.

  3. Hi Kindke,

    Thanks for your insightful post on the paper. It turned up when I was Googling something else. Anyway, I think you have noticed what I personally think is one of the most interesting aspects of the results. The study of the effects of insulin on beta-cell survival and proliferation is something I have written a large number of papers on in the past (e.g. Johnson et al PNAS 2006; Beith et al Endocrinology 2008; Alejandro et al Endocrinology 2010) and it was actually the original motivation for the study - the analysis of obesity and fat reprogramming was actually a secondary endpoint.

    The long-term effects of diets on beta-cell mass is an area that needs lots more investigation. Although beta-cell mass increases with obesity in humans, no one has any idea whether some diets have more significant or durable effects. We are planning to do exactly that study in mice. As you probably know, the Cell Metabolism paper was not designed with diets in mind - we just used a diet we knew would increase insulin in male mice. We (or some other group) needs to redo the study with better matched and controlled diets in order to get answers on carbs vs fat.



  4. And, the reversibility of the changes in beta-cell mass are very poorly understood. I think there are data from the Weir group at Joslin that indicate that if you transplant islets into a rat, the rat's own islets will shrink. I believe they attribute this to glucose rather than insulin though. The debate between the effects of glucose and insulin on beta-cell proliferation and mass is a very testy one in diabetes research circles. For a long time I was on the unpopular side of this debate, but I think the pendulum is swinging.

  5. Oh hi JJ!

    Part of my motivation for making this post is because those of us who have lost weight following a lowcarb/ketogenic diet are all to aware that in a weight-reduced state we remain incredibly vulnerable to weight regain as soon as we start to add back carbohydrates. Particularly those that spike blood sugar like potato/rice.

    Theres lots of possible reasons for this, with the leading contender being leptin insufficiency. After reading your paper I had the idea that a pancreas that is aggressive for beta-cell expansion and insulin hyper-secretion may be another reason for the increased susceptibility for weight regain in response to carbs.

    Anyway, Big thanks for your comment. I read your comments on the other blogs and certainly learned alot :)

  6. It has been enjoyable for me to interact with so many interested and interesting people in the blogs. It gets me thinking outside the classroom, which I think is good.

    The beta-cell mass issue is a big one, and I hope to get some more answers in this area in the coming years (science is slow).

    As far as leptin, I'm not a 'world-leading' expert in this area, but I do know that it is a lot more complicated than even most scientists and MDs appreciate. My friend and colleague Dr. Kieffer has some great stuff on its roles in glucose homeostasis, which appear to be at least partially distinct from its roles in food intake. Interestingly, he and others have identified links between leptin-deficiency and hyperinsulinemia.

  7. I wonder, how does the higher fasting blood sugar as a result of adaptation to the low-carb diet fits the picture. Could it be the sign of diminishing insulin production, because higher insulin will probably inhibit glyconeogenesis? After 5 years of LCarbing, I am not so hungry as before after eating carbs, just experience a post-meal lethargy.

  8. Just a spelling correction.
    By now it seems pointless, everything that could have been discussed...
    In comments I don't mind, in a blog entry it's a more serious thing.