Bump: The Diabetes "Crash" Cure & Pancreatic Fat

Today's 8/15/13 bump was inspired by a comment by Tsimblist (thanks!) alerting me to this paper:  Type 2 Diabetes Etiology and reversibility

Reversal of type 2 diabetes to normal metabolic control by either bariatric surgery or hypocaloric diet allows for the time sequence of underlying pathophysiologic mechanisms to be observed. In reverse order, the same mechanisms are likely to determine the events leading to the onset of hyperglycemia and permit insight into the etiology of type 2 diabetes. Within 7 days of instituting a substantial negative calorie balance by either dietary intervention or bariatric surgery, fasting plasma glucose levels can normalize. This rapid change relates to a substantial fall in liver fat content and return of normal hepatic insulin sensitivity. Over 8 weeks, first phase and maximal rates of insulin secretion steadily return to normal, and this change is in step with steadily decreasing pancreatic fat content.

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Aug. 1 Over the Hump Bump: Baby your Pancreas? Part I: The Tired Pancreas

Another two-fer for the Thursday post bumps again this week.  More explanation for why this set in the next bump.

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Original Publish Date:  7/26/11

In the comments on a recent post on beta cell lipotoxicity, Ned Kock (of Health Correlator blog) posted a link to a post he made a while back entitled:  Lipotoxicity or tired pancreas? Abnormal fat metabolism as a possible precondition for type 2 diabetes.  This article deals with the concept of the "tired pancreas" in the development of diabetes.  It seems that (and hopefully he corrects me if I'm wrong here) Ned and I agree that this is not a likely explanation for diabetes.   Ned summarizes the progression of obesity induced T2 diabetes from Unger & Zhou, 2001.  It is worth mentioning that Unger is often summarily dismissed from the "scientific discussion roundtable" by low carbers because of the unfortunately titled "Gluttony and Sloth" paper, that, even more unfortunately also included a biblical verse.   Unger's hypothesis is very leptin-centric, but not at all incompatible with other lipotoxicity based theories.  Basically, lipotoxicity is the result of dysfunctional adipocytes leading to excessive "spill-over" of fatty acids into circulation and accumulation in ectopic tissues.   Unger & Zhou identify dysfunction in leptin secretion and/or signaling as the initiating factor in this process.  One thing that doesn't quite add up for me here is that I keep finding citations indicating leptin action increases free fatty acids which would seem counterintuitive.  In any case ...

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Why We Get (Sick) Fat (and Sick Livers) - Lessons from a Cafeteria Rat

Since we're talking about fructose and the liver of late, I thought I'd bump this post.  In this study groups of rats were fed one of four diets.  The "low fat" diet is better described as a high sucrose diet as 35% of the diet was sucrose.  This replaced 35% of the fat in the 45% "high fat" diet.  While the LF and HF rats gained a little more weight than the standard (also LF at 12%) chow rats, it is clear that the high fat has rather more negative metabolic effects.  I don't think the 35% sucrose diet was beneficial, rather the contrary, but that level of sucrose consumption, every single day for 10-15 weeks (which is a very long time for a human) is also hardly indicative of even SAD consumption.

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Original Posting:  3/8/11

It seems fairly generally accepted that whatever the cause or progression, the so-called Metabolic Syndrome, Syndrome X and Type 2 Diabetes are associated with a dysregulation of adipose tissue metabolism, and fat tissue that is infiltrated with macrophages and secretes excessive amounts of inflammatory molecules called adipokines (e.g. TNF-α, IL-6).   A term has been coined, adisopathy, to describe this "sick fat".  

I've recently discussed the "Cafeteria Rat" study  as pertains weight gain in general.  But the other thing about this study is that it looked at the fat tissue with the different dietary interventions.  To recap, four groups of rats were fed ad libitum different diets:

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Lessons from LIRKO

The LIRKO mouse has no insulin receptors in its liver.  It's one pretty sickly mouse.  In most studies it becomes hyperglycemic and hyperinsulinemic very early in life, but by six months or so of age is either normoglycemic or hypoglycemic.  Despite the concurrent hyperglycemia and hyperinsulinemia, the LIRKO remains normal weight, it is even a bit underweight if anything.  This is despite the fact that  circulating free fatty acids (FFA, or my preferred acronym, NEFA)  are suppressed by 40%.  {Here are the two papers I've discussed in previous blog posts: Loss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic Dysfunction , High Circulating Leptin Receptors with Normal Leptin Sensitivity in Liver-specific Insulin Receptor Knock-out (LIRKO) Mice both links are to free full texts}

LIRKO presents two problems for the TWICHOOB:

1.  Chronic hyperinsulinemia does not cause rampant fat accumulation 

2.  Insulin "locking away" fats does not lead to hyperphagia (overeating)

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Physician Phollies ~ II: Dr. William "Wheat Belly" Davis

Next up in our "how can he/she even say that?" series of blatantly erroneous things said by practicing physicians in furtherance of the carbophobic agenda ...

I bring you, an Asylum favorite, Dr. William "Wheat Belly" Davis.  In the most recent post on his WB blog, Wheat Belly trips over himself trying to implicate wheat, specifically, in the diabetes epidemic.  

But can we blame diabetes on wheat?
Yes, absolutely, as much as you can blame poor oral hygience for toothlessness in West Virginia.

Wow!  Gratuitous slam on WVa's aside, Dr. Wee Bee goes on  to list all the ways wheat causes diabetes:

–Any food that increases blood sugar to high levels (i.e., high glycemic index) also increases insulin to high levels. Repetitive high insulin leads to insulin resistance, which leads to visceral fat deposition, more insulin resistance, inflammation, etc., eventuating in diabetes.
–High blood sugar, such as that resulting from eating two slices of whole wheat bread, is toxic to pancreatic beta cells, the cells that produce insulin: glucotoxicity.
–Triglyceride-containing lipoproteins, such as chylomicrons and its remnants, are toxic to pancreatic beta cells: lipotoxicity.

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You're as Hyperinsulinemic as You Need to Be †

Recent comments by Todd Becker (Getting Stronger blog) have prompted me to write yet another post on the (infamous on this blog) Grey & Kipnis study.  Perhaps, part of the problem in discussing these issues is a failure to define what it is we're talking about.  For instance with IR, we have chronic/pathologic IR, glucose-sparing IR (physiologic, fasting/carb restriction), and postprandial IR (usually impaired glucose clearance following a high fat meal or large fructose load).  With hyperinsulinemia we can talk about basal insulin levels vs. postprandial insulin levels.  It appears to me, that if we combine the observations in G&K with those of the long term fasting study, with the hypothesis of G&K -- that diet can play a role in basal hyperinsulinemia and therefore contribute to obesity -- perhaps basal insulin levels are comprised of both a chronic component (I would suggest related to NEFA) and a more transient component due to the diet of the previous day(s).  

So, Todd wrote:   Forgive me if I oversimplify the argument in your above post:

1. Obesity leads to spilling of excess fat as NEFA.
2. Excess NEFA leads to insulin resistance in the tissues, including the adipocytes

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Intracellular Fatty Acid Metabolism ~ Background Discussion

Before some of the recent commotion around here, a blog post entitled Let's Play Concentration caught the eye of Paul Jaminet over at Perfect Health.  His commentary then inspired me to write Glucose and NEFA: From Dysfunctional Metabolism to Toxicity.  

In the comments section Paul and I got into a discussion about free fatty acid (NEFA) clearance from circulation.  It seems that this is a subject of a lot of uncertainty.  Indeed when I first started looking into this stuff, way back when, I kept coming across statements like that insulin was required for fatty acids to be taken up by fat cells (three guesses where that traced to and the first two don't count ...).  My inner geek was prompted to look back into this.   This topic is of interest to me as my regular readers are well aware of my near-obsession with NEFA.  {grin}

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Glucose and NEFA: From Dysfunctional Metabolism to Toxicity

This post started out as a comment in response to Paul Jaminet's mention of a post on this blog in his Around the Web post yesterday.  It got rather long so I decided to move it here.  In the interest of more rapid publication, I'm not going to be doing a whole lot of referencing in my discussion here, but if you're interested in a particular statement please indicate so in the comments section and I'll try to track down the reference(s) I have in mind.  Paul writes:

Every once in a while someone writes to ask me if they should fear a high-fat diet because of CarbSane’s writings on lipotoxicity. I reply that lipotoxicity only appears after metabolic syndrome has developed and, while it may drive the transition from obesity to diabetes, it is not a cause of obesity, and not a danger to people who don’t have metabolic syndrome. Also, the implications for diet are not obvious, since carb intake suppresses NEFA clearance from the blood and enhances glucotoxicity. The literature commonly speaks of “glucolipotoxicity” to describe this compounded toxicity problem. CarbSane hasn’t always been clear on these points, so it’s good to see an excellent post from her covering the basics.

Thanks for the shout out Paul!

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Free Fatty Acids and Cytokines Induce Pancreatic ß-Cell Apoptosis by Different Mechanisms

Free Fatty Acids and Cytokines Induce Pancreatic ß-Cell Apoptosis by Different Mechanisms

(I've scrubbed the distracting reference numbers from some excerpts of the introduction and I'm also going to try to cite only the information pertinent to T2)

Hypercaloric diets containing large amounts of fat, also called the Western diet, contribute to a major extent to the increasing prevalence of obesity and type 2 diabetes mellitus (T2DM). T2DM is characterized by peripheral insulin resistance, pancreatic ß-cell dysfunction, and decreased ß-cell mass associated with increased rates of ß-cell apoptosis. Elevated levels of circulating free fatty acids (FFAs) contribute to the pathogenesis of T2DM. High concentrations of FFAs lead to both impairment of insulin action and ß-cell dysfunction.  Moreover, FFAs have been shown to cause ß -cell death, mainly by apoptosis. 

Of note, increased adiposity is associated not only with increased FFA release but also with adipocyte secretion of a variety of cytokines and cytokine-like adipokines, such as TNF -α, IL-6, leptin, resistin, and adiponectin. TNF-α has direct cytotoxic effects on pancreatic ß -cells, especially in combination with other cytokines.

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β-Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: Impairment in adipocyte-β-cell relationships

β-Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: Impairment in adipocyte-β-cell relationships

Yes, this is a rat study, but it seems applicable in light of the recent Diabetes "Crash Diet" Cure and the reductions in pancreatic fat seen in the study.  The study and the pancreatic fat issue were discussed here.  Summary:  11 diabetics followed a 600 cal/day diet for 8 weeks and regained normal insulin secretion and glycemic control.  The restored glucose induced insulin secretion (GSIS) was attributed to reduction in pancreatic fat content.

The investigators in the current study had this to say in the introduction:

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Join a discussion on: Saturated fatty acids and insulin resistance

Hi gang!  I'm going to try something a little different here with my blog.  Mirrorball had the idea to start a Scientific Discussion Group of sorts over at the Meeting Rooms, but we're not getting much in the way of takers.    So I thought I'd try a few things.

The first is this post per se, because I know far more people read feeds, etc., to see if we can't snag a few more interested takers for such a thing.

The second is that the really cool thing about my discussion board system is that I can embed a topic right here in this blog post for everyone to talk amongst themselves without going anywhere, yet this thread will be over in the Scientific Discussion sub-forum at the Meeting Rooms.  This should also give those who have trouble logging into blogger the ability to join in as well.  The default is a flat style display, but this should also allow for greater ease in following discussions that have, at times, become very difficult to follow in the comments here.  With the discussion you can view things in list and threaded form to navigate a reply thread and reply inline.  You can even reply by email if you select the "Email replies" option.  How cool is that!

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Elevated Free Fatty Acids Further Impair Glucose Tolerance in IGT but not NGT

Elevated plasma nonesterified fatty acids are associated with deterioration of acute insulin response in IGT but not NGT

High concentrations of nonesterified fatty acids (NEFA) are a risk factor for developing type 2 diabetes in Pima Indians. In vitro and in vivo, chronic elevation of NEFA decreases glucose-stimulated insulin secretion. We hypothesized that high fasting plasma NEFA would increase the risk of type 2 diabetes by inducing a worsening of glucose-stimulated insulin secretion in Pima Indians.

The subjects were 151 Pima - 107 with normal glucose tolerance (NGT) and 44 with impaired glucose tolerance (IGT) at the outset of the study.  At the outset none of the subjects had been diagnosed with frank diabetes.  These subjects were part of a study on pathogenesis of diabetes in the Pima and returned for annual visits to have various tests performed.  Of note, offspring of diabetic mothers were excluded from the analysis, thus the NGT group did not include this "at risk" group. 

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Fatty Acid Trafficking

Here's an interesting recent study that LynMarie Daye of Adipo-Insights blog brought to my attention a while ago.  The link below is to the full text I'm sharing through GoogleDocs.

Downregulation of Adipose Tissue Fatty Acid Trafficking in Obesity, A Driver for Ectopic Fat Deposition?

Fats are continually being cycled in and out of our fat cells.  In the obese, circulating free fatty acids (or non-esterified fatty acids), NEFA, are often elevated.  These are often accompanied by deposition of fat in non-adipose tissues, aka ectopic fat deposition.  This ectopic fat is implicated in various impairments of cell function and even cell death (apoptosis) that result in insulin resistance, beta-cell dysfunction, etc.  This is often referred to as lipotoxicity.  

This study sought to determine if this lipotoxicity is due to excessive release of NEFA from adipose tissue or from impaired trapping by adipose tissue of the NEFA released from dietary fat.  This work is from Keith Frayn's group.  It might be worthwhile to read my blog post on Frayn's paper on adipose tissue as lipid buffer.

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Adiposopathy

Presented without comment on the content per se:

Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus

This is probably the most exhaustively referenced review article I've ever come across on the etiology of MetS and T2 Diabetes and the role of adipose tissue.  Too extensive to quote w/o copying the whole darned thing, although I may revisit it at some point to do a bullet point summary type post.  

Does eating carbohydrates cause diabetes?

Type II that is ...

I've made some posts on this topic about the net, and been taken to task over them by some.  In a nutshell, my answer to this question is:  No.  So I thought I would post a little treatise here for future reference.  

I think it is important to define what we mean by Type II Diabetes, aka NIDDM (non-insulin dependent diabetes mellitus).  A T2 diabetic differs dramatically from a T1 diabetic in many ways, however the correlation with obesity aside, the two conditions lead to much the same metabolic derangement:  high triglycerides, NEFA and LDL, hyperglycemia, CVD risk, etc.  Much of the focus in diabetes is profoundly glucocentric,  moreso in avid low carb circles.  Thus in a word association game if I say diabetes, most would respond with hyperglycemia, or blood sugar problems or something like that.  Essentially diabetes = hyperglycemia.

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Adipose tissue as a buffer for daily lipid flux ~ Keith Frayn 2002

Adipose tissue as a buffer for daily lipid flux

Insulin resistance occurs in obesity and Type II (noninsulin-dependent) diabetes mellitus, but it is also a prominent feature of lipodystrophy. Adipose tissue could play a crucial part in buffering the flux of fatty acids in the circulation in the postprandial period, analogous to the roles of the liver and skeletal muscle in buffering postprandial glucose fluxes. Adipose tissue provides its buffering action by suppressing the release of non-esterified fatty acids into the circulation and by increasing triacylglycerol clearance. In particular, the pathway of ‘fatty acid trapping’ (adipocyte uptake of fatty acids liberated from plasma triacylglycerol by lipoprotein lipase) could play a key part in the buffering process. If this buffering action is impaired, then extra-adipose tissues are exposed to excessive fluxes of lipid fuels and could accumulate these in the form of triacylglycerol, leading to insulin resistance.  These tissues will include liver, skeletal muscle and the pancreatic beta cell, where the long term effect is to impair insulin secretion. Adipose tissue buffering of lipid fluxes is impaired in obesity through defects in the ability of adipose tissue to respond rapidly to the dynamic situation that occurs after meals. It is also impaired in lipodystrophy because there is not sufficient adipose tissue to provide the necessary buffering capacity. Thus, the phenotype, at least with regard to insulin resistance, is similar with both excess and deficiency of adipose tissue.

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Adipose Tissue Characteristics in Obese Teens & Insulin Resistance

Cellularity and Adipogenic Profile of the Abdominal Subcutaneous Adipose Tissue From Obese Adolescents: Association With Insulin Resistance and Hepatic Steatosis

Yes ... I'm going to be on a bit of a bookmarking post spree here :-)

This study looked at fat cell size and proliferation in obese teens and compared this to IR and fatty liver.  This study seems to be consistent with the whole "critical threshold" or "normal fat capacity" theories on why some obese are relatively "metabolically healthy" while others are not.  I've not, however, had a chance to read thoroughly.

Conclusions:  A reduced lipo-/adipogenic capacity, fraction, and estimated number of large subcutaneous adipocytes may contribute to the abnormal distribution of abdominal fat and hepatic steatosis, as well as to insulin resistance in obese adolescents.

Thinking out loud:  It seems more and more to me these days that abdominal fat - visceral in particular - is our short term buffer as Frayn describes the behavior of fat tissue in the postprandial period (recently fed state).  Overages go into our subcutaneous "overflow tank".  If we have insufficient capacity in that tank, our fat gets "sick".  

Failure of LC/HF Diets to Suppress NEFA Release

Thanks to reader MM, I have procured a full text copy of the following study that I've discussed a bit previously:  Lack of suppression of circulating free fatty acids and hypercholesterolemia during weight loss on a high-fat, low-carbohydrate diet

A bullet pointed, sometimes paraphrased abstract/summary:

• This study compared a low carb (less than 20g/day, no fat content provided but "high fat") diet to a high carb diet (55% energy, 30% fat) 

• Fasting, 24 hour AUC (cumulative exposure) and time courses for metabolites were measured during weight loss.

• Subjects were healthy, obese adults (n = 32; 22 women, 10 men) - diabetics and those with a history of CVD were excluded.

• The study lasted six weeks. 

• A 24-h in-patient feeding study was performed at baseline and after 6 wk. Glucose, insulin, free fatty acids (FFAs), and triglycerides were measured hourly during meals, at regimented times. Remnant lipoprotein cholesterol was measured every 4 h.

• Results:

• Patients lost a similar amount of weight in both groups 

• There was no difference between groups on fasting triglycerides or on remnant lipoprotein cholesterol, which was the main outcome. 

• Fasting insulin decreased, and both fasting and 24-h FFAs  increased within the High Fat group. 

• Twenty-four-hour insulin decreased for both groups. 

• Fasting LDL cholesterol decreased in the High Carb group only.

• In both groups, the differences in fasting and 24-h FFAs at 6 wk were significantly correlated with the change in LDL cholesterol.

• Conclusions: Weight loss was similar between diets, but only the high-fat diet increased LDL-cholesterol concentrations. This effect was related to the lack of suppression of both fasting and 24-h FFAs.

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Deleterious Effects of NEFA II: Panceatic beta cell impairment

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

Progression from normal glucose tolerance to Type 2 diabetes results from a gradual deterioration in beta-cell function, in the presence of insulin resistance [1]. Over the past 10 years, the role of excess glucose in the alteration of beta-cell function has become increasingly clear and has led to the concept of glucotoxicity [2, 3].  At the same time, the deleterious effect of increased NEFA was suggested by studies on Zucker diabetic fatty (ZDF) rats, an animal model of Type 2 diabetes combined with obesity. The authors showed that altered beta-cell function was preceded by an important increase in the plasma concentration of NEFA and subsequent triglyceride (TG) accumulation in pancreatic islets [4, 5]. This hypothesis, also referred to as lipotoxicity, was confirmed by in vitro exposure of isolated islets to NEFA [6, 7, 8]. However, whether glucose and NEFA alter beta-cell function synergistically or separately, remains controversial.

...In this study, we examined the influence of NEFA on human islet function with or without concomitant increased glucose concentrations. Because lipid metabolism seems to have a crucial role in lipotoxicity [8], we also studied the expression of genes involved in this metabolism. 

NOTE:  GSIS = glucose stimulated insulin secretion  aka your acute or Phase I insulin response to carbs that is lacking in T2's.

With our model of in-vitro human islets, we showed that beta-cell alterations characteristic of clinical Type 2 diabetes, including loss of GSIS and decrease in insulin content, can be reproduced with either increased glucose or NEFA concentrations. The deleterious effect of high glucose is well established [2, 3], but increased NEFA at physiological glucose concentrations were also able to significantly alter GSIS and insulin content. These results are in accordance with previous studies [6, 10, 33], but argue against the hypothesis that increased glucose is a prerequisite for the deleterious effect of NEFA on betacell function [11, 12, 13, 14]. 

Bottom line:  NEFA alone can alter beta cell function.

Fat Futile Cycling ~ From Carb Excess??!!

This post may well make heads spin.  It sure did mine.

A common claim in LC circles is that we "waste" excess fats through futile cycling.  Although this has not been demonstrated in any significant amount in humans except in massive fat overfeeding, it is still incorporated into books and blog posts by the likes of Dr. Mike Eades (futile cycling to "blow off" low carb excesses is stated as if fact in The 6 Week Cure).

Inherent in these statements is the implication that this only happens for excess dietary fat when carbs are low ... insulin would be trapping the fats in the cells as the theories go.  Well ...

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity  (2004 Review Article,  PDF)

Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a ‘glucose–fatty acid cycle’ in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely:

(i) the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation (via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport),

(ii) the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation (via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recently

(iii) the stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose (via SREBP1c regulation of glycolytic and lipogenic enzymes).  

This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a ‘fine-tuning’ mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity.

The figure below describes the mechanisms by -- as the figure caption states -- nutrient OVERSUPPLY can lead to insulin resistance.

I like schematics like this because even though I'm scientifically-minded, sometimes reading about various reactions gets really confusing.  It helps to just see it.  The possible ways all three macronutrients can lead to IR in excess are described:

• The fatty acids are shown in the upper left, with the fats that are "burned" proceeding down the left arrow through ß-oxidation (this metabolic process is often referred to as the fatty-acid spiral).  An excess of FA's leads to accumulation of "lipid pools" in the cell:  that little cycle in the upper left including DG = diacylglycerol (2 FA's on a glycerol) and FA-CoA. In my posts on lipotoxicity and intramyocellular lipids (IMTG or IMCL), I've discussed the implications of this previously.  The metabolites DG and FA-CoA activate various enzymes that inhibit glucose uptake.  They also lead to cell dysfunction and/or death when they undergo conversion to ceramides and/or peroxidation (formation of ROS).
• Amino acids, surprisingly, can inhibit insulin mediated glucose uptake through the mTOR pathway.
• Glucose can inhibit its own uptake by glucosamine synthesis and its action.

There are two central molecules in the metabolic engines of the cells:  Pyruvate and Acetyl CoA.  Pyruvate is an intermediary coming from glycolysis (glucose breakdown) and some amino acids, whereas Acetyl CoA is the ultimate "end product" of the preliminary breakdown of many amino acids, glucose and lipids.  From Ac-CoA on, the rest of the "metabolic engine" is the same regardless of the source of this molecule.  

• The authors describe a state of gluco-lipotoxicity and/or proteo-lipotoxicity that could develop when excesses in either glucose or AA's or both stimulate the conversion of Acetyl CoA to Malonyl CoA that can suppress fatty acid oxidation leading to a vicious cycle of lipid accumulation in the cellular pools.

Malonyl CoA is usually considered a "commitment step" in de novo lipogenesis - fatty acid synthesis - but has previously been ignored in skeletal muscle as DNL wasn't thought to occur at any significant rate in these cells.  This is the groundbreaking revelation of this paper ... it DOES occur!   The discussion describes how there are two different enzymes, Acetyl CoA Carboxylases (ACC's) that convert Acetyl to Malonyl CoA.  ACC-1 expressed primarily in liver and adipose tissue, and ACC-2 in skeletal muscle and other "non-lipogenic" tissues.  The two ACC's are compartmentalized in cells so that:

• ACC-1:  Generates the cytoplasmic (cellular) pool of Malonyl CoA used for DNL
• ACC-2:  Associated with mitochondria and governs this pool of Malonyl CoA to control ß-oxidation

Excerpt:  

In skeletal muscle, the suppressive effect of an elevated concentration of glucose on fatty acid oxidation is now recognized to occur ... but the question of whether a cytoplasmic pool of malonyl-CoA might be utilized for fatty acid synthesis has rarely been invoked most probably because of the long-held assumption that skeletal muscle is not an organ where de novo lipogenesis occurs. ... Consequently, the importance of skeletal muscle substrate metabolism in the homeostatic control of blood glucose has been viewed entirely from the reciprocal nature of interactions between glucose and lipid metabolism.  Recent evidence, however, suggests otherwise. As discussed below, de novo lipogenesis can indeed be shown to occur in muscle cells and to be modulated by factors influencing nutritional status, thereby revealing another facet of interactions between glucose and lipid metabolism that shows dependency between these two fuel substrates in skeletal muscle.

Here's where this gets really interesting.  The discussion continues:

The recent recognition that de novo lipogenesis might have relevance for lipid homeostasis in skeletal muscle stems from the realization that Sterol regulatory element binding protein-1c (SREBP-1c), a member of the family of transcription factors that regulate the expression of genes involved in lipid storage in liver and adipose tissue, is also present in skeletal muscle at a level close to that observed in the liver,41,42 and that its dysregulation might lead to increased lipid storage, and hence contribute to the pathogenesis of insulin resistance. There is now evidence both in humans and in rodents that SREBP-1c mediates insulin upregulation of genes encoding glycolytic and lipogenic enzymes in skeletal muscle,42–46 but most fascinating are the very recent demonstrations that glucose alone (in the absence of insulin) can stimulate de novo lipogenesis in skeletal muscle cells. 

Translation:  Lipid storage pathways thought previously to only be active in significant levels in liver/adipose tissues have now been shown to be active in muscle cells.  What they are seeing is that the DNL stimulated by glucose in this manner is NOT accompanied by the expected suppression of ß-oxidation.  They speculate on possible explanations for this, but the bottom line is summarized:

Whatever the explanation, it is clear that de novo lipogenesis, although low in skeletal muscle, can be markedly stimulated in muscle cells, particularly under conditions of high glucose (and/or high insulin) concentrations.

Hmmmmmm.....  The discussion goes on to speculate on the physiological significance for DNL in muscles, and that it may contribute yet another "sink" for temporary glucose excesses (e.g. after a carby meal), particularly when glycogen depots are full.  However there's a "glitch" because lipid accumulation is associated with insulin resistance.  IOW, synthesizing more would seem counter-productive to glucose clearance/disposal  unless the synthesized lipids were also "disposed of".  Well here's where the observation that ß-oxidation is not suppressed comes into play.

... recent work from our laboratory investigating the mechanisms by which leptin ... may interact with insulin to stimulate thermogenesis in skeletal muscle, suggests the possible existence of a thermogenic pathway of substrate cycling in which lipids derived from glucose... are subsequently oxidized.

So the carbs are thermogenic, not the fats?  Looks like it!  The discussion gets a bit complicated because it names enzymes and pathways, etc.  I'll let the more scientifically inclined amongst you read that part for yourselves.  

My summary of "Substrate cycling between de novo lipogenesis and lipid oxidation"

One role of leptin has been demontrated to be it's regulation of thermogenesis.  This hormone is recognized as being involved, in conjunction with insulin, in glycemic control and in preventing excessive IMCL accumulation.  Leptin has been shown to stimulate both glucose utilization and lipid oxidation.   This research group demonstrated that leptin can stimulate thermogenesis by a pathway requiring an enzyme known as P13K, and P13K is stimulated by insulin (insulin is described as a "potent activator" of P13K).   Leptin apparently also stimulates AMPK, an enzyme involved in lipid oxidation.  Therefore, these researchers have demonstrated a concurrent stimulation of glucose and fatty acid oxidation resulting in thermogenesis, and that evidence is consistent with DNL involved in the thermogenesis - experiments with DNL suppressing agents and leptin demonstrate this as w/o DNL, thermogenesis was not observed.  As the authors summarize:

Taken together, these studies suggest that the direct effect of leptin in stimulating thermogenesis in skeletal muscle could be mediated by substrate cycling between de novo lipogenesis and lipid oxidation, and that the orchestration of this substrate cycling requires both PI3K and AMPK signaling.

The discussion continues on the possible control mechanisms for this proposed futile cycle of DNL/ß-oxidation that are likely initiated with Acetyl CoA produced by both glycolysis and fatty acid oxidation "backing up" as it overwhelms the Krebs Cycle.    This futile cycle is established in brown adipose tissue.  I was surprised to learn that this thermogenesis has pretty much been established to involve DNL from glucose:

... analogous to the relation between substrate metabolism and thermogenesis in brown adipose tissue. In this tissue, whose primary function is to produce heat for thermoregulation ... it has long been known that much of the fuel for thermogenesis also derives from glucose being first converted to lipids before being oxidized.70–73  {They go on to describe mouse studies demonstrating that suppressing DNL in BAT leads to hypothermia.} 

Furthermore, this ‘dependency’ interaction between these two substrates and thermogenesis is well recognized at the whole-body level, and is attributed to activation of a neuroendocrine network (comprising insulin, leptin and the sympathoadrenal system), which plays a pivotal role in several overlapping regulatory systems: that of blood glucose, body temperature, body weight and more recently intramyocellular lipids.56–58

... The energy-dissipating substrate cycle that links glucose and lipid metabolism to thermogenesis in skeletal muscle (depicted in Figure 3) provides a novel molecular mechanism of thermogenesis through which this abovementioned neuroendocrine network operating through insulin, leptin and catecholamines overlaps in the regulation of body weight, blood glucose and intramyocellular lipids, and hence in the protection against obesity, hyperglycemia and lipotoxicity. 

Take away message here?  Well, the futile cycle is lipids.  But what stimulates and/or is required for this futile cycle to "waste" energy?  Who'da thunk it.  CARBS!!!