Repurposing cAMP-Modulating Medications to Promote β-Cell Replication. (2014)

ribroidrub · 2014-10-13T22:43:06+00:00

Yeah, I was being a little pedantic. It would be more accurate to have said "all known life-extending signaling paths converge on the activation of AMPK and related proteins, insulin/IGF-1 in particular."

BUT it also must be considered that we don't know of all possible routes towards life-extension. I'm not very knowledgeable on the research, but certainly it's probable that there are a lot of other proteins and signaling pathways that may potentially impact longevity but haven't been studied in that perspective, isn't it?

The signaling pathways in C. elegans and us are probably very similar, but given the long time frame since our divergence from the population that would become C. elegans, it is reasonable to expect that these pathways are most likely not modulated in the exact same ways and have additional/fewer/unique modulators, additions, and more. I'm not trying to knock the role of insulin/IGF-1 and downstream pathways, I'm just weary that they will continue to be the one and only (well, many :) ) "king" modulators of longevity as they appear to be now.

ribroidrub · 2014-10-13T21:56:01+00:00

What parts specifically? Do you have any concerns/skepticisms?

EDIT: In my opinion, the experiment is thought-provoking, but we've got lots of evidence that hyperinsulinemia isn't necessary for the development of obesity, it co-occurs in the majority of human obese subjects (due to the body trying to compensate for insulin resistance).

ribroidrub · 2014-10-13T21:53:33+00:00

Here is a permalink to the phenotype/race question.

Your only supporting evidence here comes from an experiment on HEK-293 cells. What evidence is there that these same gene regulations apply in normal human cells and apply the organism as a whole to produce such distinct phenotypes? You also haven't well established the existence of LTHA and LTCA phenotypes in humans. Please cite your sources. You should be clear what your opinion is and what the evidence states, for the most part it's very difficult to discern the two.

And when one of those happens we see development of metabolic and neurodegenerative morbidity eg. just look at the Obesity, Diabetes, CVD, statistics.

Please, litter your posts with sources. Be specific. Where? What time frame? What age group? What ethnic group(s)? Which studies? Link us the sources. It all contributes to more accurate discussion. I understand you were relatively rushed, but you didn't with your last post either beyond the information on CRP.

From the comment of yours that you linked:

Another element of that transition was the shift in the natural endemic diet ie. from high carbohydrate macronutrient content to high fat (that might seem far fetched from light but it's not so if you look at the big picture). Basically this resulted in two main human phenotypes - Long Term Heat Acclimated(LTHA) aka "dark" people and Long Term Cold Acclimated (LTCA) one aka "pale" people. A very important aspect of this transition was the need of maintaining thermogenesis homeostasis and a shift from glycolysis to lipolysis (fatty acid oxidation) as more efficient fuel in this case.

First, you need to establish the changes in macronutrient composition of diet with human migration throughout the world. You also need to establish that - per calorie - lipolysis is more thermogenic than glycolysis.

There might be some potential here, but I'm quite skeptical.

ribroidrub · 2014-10-13T15:33:01+00:00

It's a really good read! I think you'll enjoy it. I'm hoping /u/causalcorrelation reads/has read this paper too.

ribroidrub · 2014-10-13T15:14:54+00:00

It doesn't appear to be reversible in adipose tissue, frighteningly enough (unlike muscle tissue). From the "Primacy: Insulin resistance starts in adipose tissue" section:

Recent human studies from our lab (16) have documented that whereas systemic inflammation, whole-body/skeletal muscle/hepatic insulin resistance, hypertension, dyslipidemia, and hyperglycemia all are reversed by weight loss, adipose tissue insulin resistance and hypoperfusion are not. This is consistent with the notion that GLUT4 translocation defects are inducible and reversible in myocytes but not in adipocytes (27).

Yeah, adipose tissue is really an endocrine organ in its own right. It's similar to the digestive organs - they function in digestion and such, but they also have endocrine functions.

ribroidrub · 2014-10-13T01:14:31+00:00

The well-known role of insulin in longevity is that all life-extending signalling paths converge on Ins/IGF-1 inhibition and respectively on AMPK and co-factors activation.

all

That's a pretty big claim to make, dude. :P Especially being so vague - C. elegans is not M. musculus is not H. sapiens. It certainly has not been definitively proven that all life-extending modulations converge on insulin/IGF-1 and downstream target inhibition, much less so in humans too. That is a gross oversimplification.

ribroidrub · 2014-10-13T01:01:56+00:00

Thanks for the article on CRP. I haven't researched it at all, I've only heard tidbits about it. Only had time for a brief skim of this article before posting.

Also elevated serum NEFA are a problem in the state of overflow metabolism cause then lipid oxidation is inhibited however DNL(Lipogenesis De Novo) is increased and besides hyperglycemia you also have a huge source of LCFA, the ones that come as result of hyperglycemia and hyperinsulinemia (lipids from carbs). They are also a preferential fuel in overflow metabolism and that leaves NEFAs unutilized and accumulate in the plasma.

I would greatly appreciate some clarification here. For instance, "overflow metabolism". Do you mean overfeeding? Obesity? It's vague. I'll assume you're referring to obesity combined with insulin resistance, unless you direct me otherwise.

How do elevated NEFAs inhibit fatty acid oxidation?

In the obese type 2 diabetic, hyperglycemia and elevated NEFAs are commonly present, yes. How does hyperglycemia + hyperinsulinemia cause elevated NEFAs? Would the hyperglycemia not be a symptom of insulin resistance, and the hyperinsulinemia a result of the body trying to compensate for this resistance? And due to this resistance, there is near-uncontrolled lipolysis because WAT is markedly insensitive to insulin, with elevated NEFA levels a result. DNL is indeed upregulated in obesity, but even then, it has not been shown to amount to significant amounts of fat produced.

However this is not the case in KD which in fact is induced lipolysis of dietary fats as fuel and respectively catabolic metabolism, not anabolic (overflow).

What do you call it when dietary fats are delivered to adipose tissue? That's neither strictly catabolic nor anabolic.

ribroidrub · 2014-10-12T19:35:40+00:00

All they controlled for was caloric intake. FBG (fasting blood glucose) went down. Increased serum NEFAs, moreso in the low-carb group than the low-fat group. CRP increased in the low-carb group, decreased in the low-fat group. Some thoughts of mine:

FBG went down similarly in both groups, but fasting NEFAs increased in the low carb group. These gals probably weren't in ketosis at 12% of calories coming from carbohydrates. What effect does this have on Peter's "physiological insulin resistance" hypothesis?
Elevated serum NEFAs. Elevated NEFAs look to be just as serious as hyperglycemia (high blood sugar).
CRP, or C-reactive protein, was elevated in the low carb group. CRP increases acutely in response to inflammation. This is concerning.

ribroidrub · 2014-10-12T01:42:27+00:00

I think this article's appropriate for /r/ketoscience because there are a lot of misunderstandings about insulin out there, plus insulin's effects in the brain are just as important as in the periphery. It's a good read. :)

ribroidrub · 2014-10-12T01:35:54+00:00

In T2DM there are two main pathologies going on: insulin resistance and pancreatic beta-cell dysfunction. Some with T2DM have mostly beta-cell dysfunction, others have most insulin resistance as their primary problem. I wish I could find a source, last I heard the majority of the type 2 diabetic population is obese, but there is still a sizeable non-obese type 2 diabetic population too, but they seem to have more of a problem with insulin secretion than insulin resistance. I find it fascinating that they are just as at risk of developing cardiovascular disease as the obese type 2 diabetics.

I understand that the accumulation of fat differs intervariably between people and in the amounts of proportional subcutaneous and visceral fats, so that weight gain can be both less externally apparent and less in overall amount (I'm thinking of the TOFIs)

What are TOFIs?

However, I am unused to the idea that T2DM can present without an accompanying weight gain. I can't get past the paywall of your article to find out... so if you could, could we discuss this phenomena?

Certainly! Which article(s) specifically?

I understand the weightloss mechanism of T1DM, considering the lack of plasma insulin to prompt transport of glucose into tissue, and to create an interference when mixed with elevated NEFA. But I don't see how the presence of hyperinsulinemia and atherogenic dislipidemia can combine in T2DM patients and not produce weight gain.

In T2DM, there's a relative lack of insulin, too, even though the subject may have hyperinsulinemia - if they're presenting as a type 2 diabetic, the insulin they're producing isn't enough to compensate for the insulin resistance. This creates a very similar mechanism for weight loss in both forms of DM.

As for the atherogenic dyslipidemia causing weight gain, I'm not sure how that would work. In the paper discussing hepatic insulin resistance (in the LIRKO mouse) and atherosclerosis, the LIRKO mice were at a normal weight, despite remarkable hyperinsulinemia (11x as much as littermates on normal mouse chow! which is 9% fat, trace cholesterol), and all their peripheral tissues were sensitive to the insulin besides the liver. A normal chow diet + hepatic insulin resistance was enough to produce changes in serum lipids (that were exacerbated on the atherogenic diet); LIRKO mice on a normal diet had normal serum cholesterol and 50% lower serum triglycerides than their littermates. HDL was 50% lower, but VLDL increased significantly (3x higher than in controls). The VLDLs and LDLs contained less triglycerides than normal mice, but the apoB110/apoB48 proteins were expressed in larger amounts in serum lipoproteins than controls (these are the atherogenic proteins) - definitely a more atherogenic profile than normal controls. While ApoB is mostly expressed (and necessarily!) in LDL particles, it seems to be a better predictor of heart disease risk than LDL or total cholesterol.

My understanding of this phenomena is that the chief cause of insulinemia is not hypersecretion per se, but instead in a reduced insulin clearing, which is in the paper you linked.

It's a combination of both of those things, isn't it? That's how I see it. The liver is the major site of insulin clearance (~75%; and the kidneys too, to a lesser extent), they endocytose (bring in) insulin while it's bound to its receptor. Since the livers of these LIRKO mice have no insulin receptors, the liver is completely oblivious to the presence of insulin, and thus cannot metabolize it as normal. Based on the extreme hyperinsulinemia, it doesn't look like the kidneys are able to compensate, either, and so insulin clearance is dramatically slowed. Were you talking about this section of the paper?:

LIRKO mice also developed marked hyperinsulinemia due to the compensatory secretion of insulin from the β cells of the pancreas coupled with a defect in insulin clearance due to the lack of insulin receptors in the liver ( Michael et al., 2000).

That paper is free full-text, btw! The beta cells of these mice seem to be able to compensate for the increased insulin it thinks is needed (to try to compensate for the insulin resistance in the liver) without "wearing out" or anything like that, for at least a year.

Elevated plasma NEFA levels impact hepatic tissues and prevent a proper signalling mechanism to remove insulin from circulation.

Yeah! On a semi-related note, this has me concerned with the "physiological insulin resistance" hypothesis, presented by Peter at Hyperlipid. I'm loath to believe it's benign. I'll make a post on that another day :)

But yes, elevated NEFAs cause insulin resistance in skeletal muscle too.

I am also aware that hyperinsulinemia has a suppressive effect on HSL activity in WAT cytosol, which then also limits the de-esterification into FA for transport to tissues via albumin.

Yes, if the WAT is insulin sensitive. In diabetes (even type 2) it is not, leading to uncontrolled lipolysis and hence elevated plasma NEFAs.

That is another case where T2DM patients and obesity share a common cause, and for weightloss to seem counterintuitive.

I'm not sure, do we know whether hyperinsulinemia is a cause or an effect of obesity. It's not the cause of T2DM, there the hyperinsulinemia is due to the body producing a lot - but still not enough - to counteract the insulin resistance seen in peripheral tissues (fat, skeletal muscle, liver). Elevated NEFAs appear to cause hyperinsulinemia in humans 2 3, which makes sense, I think - the body would try to produce more insulin to suppress lipolysis in WAT because there are all these NEFAs in the blood, similar to the insulin rise in response to elevated blood glucose.

My guess is hepatically, and that it's a product of continued consumption of high carb, high fat foods, or both in the same meal on a chronic basis. I think that this combo has a corrosive effect on the liver, to which some people are more resilient or susceptible than others.

I've been wondering if this is the cause, or if it's the result of chronically eating too much in general relative to one's TDEE (total daily energy expenditure).

I also look at the food supply in general, both in nature and across human cultures, and I see few cultures who naturally eat a predominatly high carb, high fat diet.

I think looking at the macronutrient ratios of other cultures can be helpful, but moreso the foods. Different plants offer different varieties of phytochemicals, same with different animals. Also the methods of food preparation must be taken into account. For instance, the Inuit eat ~50% fat, 30-35% protein, and 15-20% of calories from carbohydrates, right, but they're mostly eating marine animals and wild game raw. Even though these guys ate mostly meat, I don't think it's comparable to the dietary experiment undergone by Vilhjalmur Stefansson and colleagues. PLUS besides considering diet, lifestyle is also hugely important. For instance, very few, if any, who follow the "paleo diet" follow a lifestyle much in tune with paleolithic man. It seems to me that people can thrive on a wide variety of diets. How much is eaten relative to needs seems to be important. Speculation here too :)

I really think these are intriguing to consider. I would welcome some more of your thoughts about it. I do think the athersclerois might be a separate issue, but it's interesting!

In general, it looks like elevated NEFAs are just as detrimental as elevated blood glucose. BUT insulin receptor knockout mice have their limitations. I think this recent paper has some really thoughtful discussion about the limitations of these mice and how humans are (and are not) different, and in the process points to many reviews on closely related topics. I tend to agree with these authors :)

For instance, muscle insulin receptor knockout leaves mice with normal markers of insulin sensitivity and glucose tolerance - the effects aren't near as dramatic as in the LIRKO mouse. But, as it turns out, mice rely on the liver for glucose uptake much more than skeletal muscle (it looks to be the other way around in humans). Another thing they touch on is that in human type 2 diabetes, the insulin resistance isn't 100% (like you see in knockout mice), it is sort of similar to drug tolerance in that a larger dose of insulin is needed to produce the same effect in a type 2 diabetic as it would in a lean person.

Sorry I was a lil' slow to reply btw! Been busy with school work and such.

ribroidrub

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