Up for debate: Diabetes Mellitus or Diabetes Lipidus
In light of recent comments suggesting I'm barking up the wrong tree with my concerns over free fatty acids, I decided to bump this July 2010 post. I think it is an excellent review. The rest of the post remains unchanged.
Introduction
Since ancient times the search for causes of diabetes was related to the sweetness of urine and other body fluids. In England, Thomas Willis (1621–1675) was among the first to taste the urine of diabetic patients and declare that “its sweet taste was imbued with honey sugar” with the supposition that it was derived from blood. This finding led to the addition of “mellitus” to the word diabetes.
We should reconsider whether the definition of diabetes as mellitus is justified. The traditional emphasis on the insulin-glucose axis with respect to examining glucose tolerance, although diagnostically useful does not explain the basic pathophysiological mechanisms operating in diabetes. The glucose-insulin axis has been overemphasised, while alterations in the insulin to non-esterified fatty acid (NEFA) ratio and metabolism received much less attention both as diabetes derangement and as diagnostic potential. Perhaps this is partly due to the fact that the techniques for glucose measurements have been considerably simplified for home use, whereas the measurement of NEFA and triglycerides is still encumbered with relative difficulties, being more expensive and time consuming.
This article discusses what happens to post prandial (after eating) NEFA levels in normal, insulin resistant, obese and diabetic people. My research seems to point to the conclusion that elevated circulating NEFA precedes the development of IR and diabetes and is therefore likely the cause of these. Hyperinsulinemia may well be protective in that insulin controls the release of NEFA from adipose tissue, and VLC diets have been shown to blunt insulin's protective role and increase NEFA levels. I think this should give pause to those on VLC diets who are obese, insulin resistant and or diabetic.
Comments
That is a logical non-sequiter. Post hoc, ergo propter hoc. If one follows the other, this does not establish causality. Basal insulin also rises before diabetes develops. Does insulin cause diabetes? Of course not.
And what exactly is it you think we should all do to avoid the elevated NEFA that is, as you say, causing diabetes? Everyone on the SAD is already avoiding VLC aren't they?
What is the cause of all this elevated NEFA causing Type II DM, as there is clearly not an outbreak of VLC dieting going on over the past 30 years, is there?
Is is eat less, move more? A Calculator and scale deficit is the cause of the diabetes epidemic?
An you keep saying "my research" when I think you mean "my reading"...
I discussed the article by Drs Shafrir and Raz four years ago. They are hopelessly lost in cause, effect and treatment advice.
http://high-fat-nutrition.blogspot.com/2007/11/getting-fat-is-bad-when-you-stop.html
I have only modified my views very slightly in the last four years and nothing suggests that the low fat approach suggested by Shafrir and Raz is valid. Millions are suffering by trying it.
VLC diets provide immediate protection against both hyperglycaemia and hyperinsulinaemia. Spontaneous calorie reduction then tailors NEFA to metabolic needs. I fully agree that to blame the current diabetes epidemic on fat intake requires that we are eating more fat. Duh.
Peter
Upon close reading Raz article seems to have zero bearing on TG intake or FFA metabolism in low carb diets. For instance:
“The lack of restraint of NEFA mobilisation in hypoinsulinaemia leads to a marked plasma NEFA increase, ectopic deposition of triglycerides, insulin resistance and defect in glucose uptake by muscles. The latter fact stresses the effect of excessive availability of NEFA on the reduction of the insulin-mediated muscle glucose utilisation as shown in the classic experiments of Randle et al. [7, 8]. It involves a reduction of muscle glycolysis by inhibiting phosphofructokinase by rising cytosolic concentrations of citrate and consequent accumulation of glucose 6-phosphate. Pyruvate dehydrogenase is also inhibited by rising mitochondrial concentrations of acetylCoA and the NADH:NAD ratio. In the liver, the same changes in redox ratio and activation of pyruvate carboxylase by acetylCoA result in stimulation of gluconeogenesis. This is a further instance of the effect of NEFA oversupply as a contribution to hyperglycaemia in diabetes.”
The body ‘needs’ to be insulin resistant during periods of carbohydrate restriction or it faces the prospect of severe hypoglycemia since insulin increases rates of glycogenesis and because gluconeogenesis is an energy-intensive (and during starvation, catabolic) process. Decreases in rate-limiting steps of glycolysis aren’t worrisome since glucose isn’t in large supply to begin with, not to mention Krebs cycle flux has decreased (and ketogenesis has increased) since oxaloacetate is now being used and depleted for gluconeogenesis. And NEFA oversupply isn’t contributing to hyperglycemia in VLC since there is typically no hyperglycemia to begin with (unless you are already franky diabetic). But oh no, what about ketones? Raz says:
“In pronounced hypoinsulinaemia, when the NEFA supply from adipose tissue escapes control, not only total body glucose homeostasis is disrupted, but the resultant ketosis and acidosis become life-threatening.”
Blurring the lines between benign dietary ketosis and diabetic ketoacidosis…ok.
CarbSane- why are you trying to use this paper as evidence of NEFA effects in VLC when logically, this paper is meant to disparage the detrimental effects of high fat intake concomitant with high carb intake and its associated hyperglycemia?
Look into what is counseled for low carbers going in for a "diabetes test", aka OGTT. They are told to "carb up" and consume 150g+/day for several days ahead of time. Why? Because low carbing makes you insulin resistant.
I'm not using this "as evidence of NEFA effects in VLC when logically" whatever that means ... I could give a crap about the bias of the authors when I look at the evidence they present. Too many read one line in an abstract, conclude the authors are biased, and go in biased themselves to anything the authors might have to say. I think this is going on here.
I have read literally hundreds of well conducted peer review articles discussing DIRECT effects of NEFA on insulin signalling, vascular endothelial function, etc.
So I would ask the detractors this: If you are so willing to accept the causal relationship between hyperglycemia and certain clinical results (e.g. neuropathy), why so reticent to accept the same for NEFA and certain clinical results (e.g. impaired acute beta cell function)?
If elevated BG can be deleterious, who cares how it gets that way - only the levels, and for how long. Apply the SAME standard to NEFA. Because who cares what elevates them, they have the same effect ... only now we note that elevated NEFA is a far more chronic issue than BG (even in the most deranged metabolisms) in ways that can be produced by short term dietary changes.
Could someone knowledgable please critique Insulin Resistance: Solutions to problems?
I think that it's the answer to life, the universe and everything. Unfortunately, self-praise is no recommendation.
We know from multiple studies that insulin sensitivity improves with carbohydrate restriction even as percentage of fat in the macronutrient ratio (but not necessarily absolute total amount of fat) goes up.
http://www.jacn.org/cgi/content/full/23/2/177
“Fasting oxidized LDL was unchanged by either diet. Fasting glucose, insulin, and insulin resistance HOMA were significantly lower after the very low-carbohydrate diet (Table 2).
…
There is concern that very low carbohydrate diets, especially diets high in saturated fat, might lead to insulin resistance; however we observed a significant reduction in insulin resistance after the very low-carbohydrate diet as measured by the homeostatic model assessment technique [16], which uses fasting levels of glucose and insulin. Adaptation to a three-week very low carbohydrate diet (8% carbohydrate, 75% fat) in healthy subjects resulted in no change in resting or insulin-stimulated total glucose disposal [36]. There was however a significant decrease in insulin-stimulated glucose oxidation and a proportional increase in nonoxidative glucose metabolism, presumably glycogen formation [36]. This study also showed that insulin-stimulated suppression of lipid oxidation was nearly prevented (i.e., insulin was ineffective at inhibiting oxidation of fat) after a low carbohydrate diet compared to an 80% reduction after a standard diet [36]. Similar results were obtained in healthy men who consumed 3 isoenergetic liquid diets equal in protein (15% of energy) but different in carbohydrate (2%, 44% and 85% of energy) [37]. Glucose disposal was similar between all three diets but the low carbohydrate diet resulted in lower rates of insulin-stimulated glucose oxidation and increased nonoxidative glucose disposal. The low carbohydrate diet also prevented insulin-stimulated inhibition of lipid oxidation. Collectively, these findings do not support the notion that very low carbohydrate diets exacerbate risk of type II diabetes mellitus and insulin resistance.”
http://archinte.ama-assn.org/cgi/content/full/170/2/136#IOI90145T3
“Within the LCKD group, the following parameters decreased significantly from baseline to week 48: fasting glucose level (–9.7 mg/dL; 95% CI, –16.9 to –2.6), fasting insulin level (–7.3 µIU/mL; 95% CI, –13.5 to –1.2 [participants without diabetes only]), and hemoglobin A1c (–0.3%; 95% CI, –0.5 to –0.1).”
http://www.nejm.org/doi/full/10.1056/NEJMoa022207#t=articleResults
“The area under the glucose curve did not change significantly in either group throughout the study. The area under the insulin curve decreased in both groups, but there were no significant differences between groups (Table 2and Table 3). There were no significant differences between groups in insulin sensitivity (assessed by the quantitative insulin-sensitivity check index16) throughout the study period. Both groups had significant increases in insulin sensitivity at six months, but the values were not significantly different from base line at one year (Table 2 and Table 3).”
It’s good note that in the NEJM study they stopped seeing ketones in the LC group at 3 months…
In this study, both groups were put on 20-25% carb diets (CRD) for 6 weeks and then half the participants were switched to 55% carb for the next 6 weeks (CRD+AHA).
“After 12 wk, positive changes persisted for all participants, independent of diet. However, body weight and plasma TG and insulin were lower in the CRD (P < 0.05) group than in the CRD + AHA group.”
I read the Raz paper in its entirety, and it was really only after finishing that it became apparent how biased it was (a quick skim and I perhaps might’ve missed the boogeyman line about ketosis/acidosis). I used the phrase “when logically…” because the Raz paper is CLEARLY presenting the biochemistry from a perspective that only matters in the presence of the concomitant effects from hyperglycemia associated with carb overfeeding, but yet the paper pays no attention to this. You’re trying to use that same paper to support deleterious effects of NEFA during carb restriction and it simply doesn’t make any sense to do so. Not to mention, Raz specifically states “The mechanism of adipose tissue weight gain will not be elaborated here, although diabesity should definitely be looked upon as an aspect of fat metabolism aberration.” I’ve noticed these sorts of statements are very prevalent in the literature regarding lipotoxicity- everyone knows that being obese is a risk factor for insulin resistance but no one has wants to talk about initial causation of anything.
If you want to say that fat is an important factor in the pathogenesis of insulin resistance, then great- there is research to support the acute detrimental effects of lipotoxicity. But, if you want to claim that people who are low-carbing and who have low basal glucose levels need to watch their fat intake because it’s going make them insulin resistant, that’s a whole ‘nother ball game. I for one do care “how it got that way” whether we’re talking about elevated BG or elevated FFA. The causal relationship between glucotoxicity and neuropathy, nephropathy, and retinopathy is much stronger and is supported by much more evidence than the deleterious effects of elevated NEFA. For the time being, there is more evidence to support quality of fat (and absolute number of consumed calories) as being more important in the pathogenesis of diabetes than sheer quantity, and likewise, there is no evidence to support anyone developing full-blown insulin resistance or DM on HF/LC diet that maintains low fasting TG, insulin, and BG levels. Again, I'm not saying that fat intake is not crucial factor in the development of insulin resistance, but I think it should be made apparent that fat intake and insulin resistance needs to be treated as a difference beast in the carbohydrate-restricted state.
http://www.ncbi.nlm.nih.gov/pubmed/11382654
During 14 y of follow-up, 2507 incident cases of type 2 diabetes were documented. Total fat intake, compared with equivalent energy intake from carbohydrates, was not associated with risk of type 2 diabetes; for a 5% increase in total energy from fat, the relative risk (RR) was 0.98 (95% CI: 0.94, 1.02). Intakes of saturated or monounsaturated fatty acids were also not significantly associated with the risk of diabetes. However, for a 5% increase in energy from polyunsaturated fat, the RR was 0.63 (0.53, 0.76; P < 0.0001) and for a 2% increase in energy from trans fatty acids the RR was 1.39 (1.15, 1.67; P = 0.0006). We estimated that replacing 2% of energy from trans fatty acids isoenergetically with polyunsaturated fat would lead to a 40% lower risk (RR: 0.60; 95% CI: 0.48, 0.75).
http://www.springerlink.com/content/mvnfwche17mchgdc/fulltext.pdf (pg 806 last para)
“The Insulin Resistance and Atherosclerosis Study included the assessment of insulin sensitivity…in 1173 men and women. After multivariate adjustment…dietary fats (total, saturated, monounsaturated, or polyunsaturated fat) were not associated with insulin sensitivity despite the large power of the study.”
I NEVER SAID THAT EATING MORE FAT CAUSES ELEVATED NEFA CAUSES DIABETES Yes, I'm shouting.
@Kurt: I'll address your devolving comments shortly. But don't bother listening to old bunny ears here, read the papers I've cited in full regarding the development of diabetes. They simply do not support carbs -> insulin spikes -> hyperinsulinemia and IR progression as laid out by Taubes.
But who ever said they did?
You have a false dichotomy here. carbs > insulin spikes>diabetes is inaccurate, but none of us are defending that.
We are arguing with your supposed alternative of NEFA>daibetes.
We are pointing out that the papers you cite (you can quit telling me to read them - I have read them) do not support your claims, and that the claim that everyone should avoid VLC to avoid elevated NEFA because that will cause diabetes, when everyone getting diabetes is NOT on VLC and is eating plenty of carbohydrate is simply incoherent - not coherent - it does not hang together - it is internally inconsistent and at odds with all clinical observations.
So please explain what is causing all the NEFA elevation causing diabetes in population?
Or would it make more sense to say that elevated NEFA is an effect of metabolic dysregulation, and something else is causing the metabolic dyregulation? And that something, the thing that causes the met dysreg, is the cause of diabetes?
Hyperglycemia, obesity, hyperinsulinemia, inappropriately elevated NEFA, etc. -these are all EFFECTS of metabolic dysregulation.
Macro ratios in a normal person, whether CHO levels of Kitavan 70% or Inuit 3% level (the Inuits are not riddled with diabetes on VLC - but I'm sure you know that already) DO NOT CAUSE DIABETES.
And just like elevated glucose levels and elevated insulin levels do not CAUSE diabetes, elevated NEFA do not cause diabetes. All of these are effects.
DM II only occurs when there is metsyn, and longstanding hyerinsulinemia, and the pancreas is burned out or destroyed by the elevated BG and possibly elevated NEFA. But that does not mean blood glucose or NEFA are CAUSING diabetes and are therefore to be avoided at all costs. And it does not mean that elevated NEFA with fasting or dieting is dangerous or a pp BG of 120 after 3 baked potatoes is dangerous.
Perhaps you should start reading about linoleic acid, fructose, wheat, gut biome etc, instead of perseverating about NEFA and maybe you'll get somewhere with this.
Replacing your straw man hypothesis of CHO>Insulin>IR with an even more untenable one is not so good.
Okay, so if that is the pathogenesis you describe, then it seems that elevated NEFAs appear as a symptom of the insulin resistance of the fat cells which is caused by the hyperphagia. In a VLC carb diet, however, it appears that the elevated NEFAs are being produced not because fat cells have become insulin resistant but because the diet is designed to minimize insulin production and hence minimize inhibition of lipolysis.
Though in both cases NEFAs are elevated. I do not necessarily see the elevated NEFAs in the context of a VLC diet as being pathological versus the elevated NEFAs in the context of obesity. My question is why do you believe the elevated NEFAs in the context of VLC is pathological? Have I misunderstood something about the pathogenesis of diabetes?
Also, wouldn't the danger of elevated NEFAs only be a concern during rapid weight loss where a lot of lipolysis is happening? Assuming that hormones are working properly, wouldn't a relatively lean person on VLC have the lipolysis and storage of fats balanced?
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