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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Insulin Resistance ~ Part I: A condition in dire need of diagnostic clarity

I've written many times about how we need some new disease classifications, names or something for the various conditions that are currently termed "diabetes".  This is because hyperglycemia -- the predominant symptom that garners a diabetes diagnosis -- can have many underlying physiological bases.   In this post I'm going to make the same case for the pathologies lumped together under the term "insulin resistance" (from hereon, IR).   The problem with discussions of IR are similar to those of diabetes.  In a nutshell, hyperglycemia is to diabetes as glucose transport/disposal is to IR.  Just as blood glucose is the myopic focus of many discussions of diabetes, so, too, insulin's role in glucose transport is the myopic focus of many discussions of IR.   

Let's begin with a diagnosis of insulin resistance.  The most commonly used single diagnostic parameter for this is something called the HOMA-IR.  This ratio is determined from fasting plasma levels of insulin and glucose.  From the link

HOMA-IR = (Glucose x Insulin)/22.5

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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 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".  

Adipocyte Size & Adipokine Secretion

Relationship between Adipocyte Size and Adipokine Expression and Secretion

Context: Adipocytes are known to release a variety of factors that may contribute to the proinflammatory state characteristic for obesity. This secretory function is considered to providethe basis for obesity-related complications such as type 2 diabetes and atherosclerosis.

Objective: To get a better insight into possible underlying mechanisms, we investigated the effect of adipocyte size on adipokine production and secretion.

Design, Patients, and Main Outcome Measures: Protein secretion and mRNA expression in cultured adipocytes separated according to cell size from 30 individuals undergoing elective plastic surgery were investigated.

Results: The mean adipocyte volume of the four fractions ranged from 205 ± 146 to 1.077 ± 471 pl. There were stronglinear correlations for the secretion of adipokines over time. Secretion of leptin, IL-6, IL-8, TNF-, monocyte chemoattractant protein-1, interferon--inducible protein 10, macrophage inflammatory protein-1ß, granulocyte colony stimulating factor, IL-1ra, and adiponectin was positively correlated with cell size. After correction for cell surface, there was still a significant difference between fraction IV (very large) and fraction I (small cells), for leptin, IL-6, IL-8, monocyte chemoattractant protein-1, and granulocyte colony-stimulating factor. In contrast, antiinflammatory factors such as IL-1ra and adiponectin lost their association after correction for cell surface area comparing fraction I and IV. In addition, there was a decrease of IL-10 secretion with increasing cell size.

Conclusions: The results clearly suggest that adipocyte size is an important determinant of adipokine secretion. There seems to be a differential expression of pro- and antiinflammatory factors with increasing adipocyte size resulting in a shift toward dominance of proinflammatory adipokines largely as a result of a dysregulation of hypertrophic, very large cells.

Fat cells were removed from participants and isolated.  They were then separated into four fractions for each individual.  Fraction I (very small) to Fraction IV (very large).  Plots of the various parameters measured are shown below (see the article for more clarity) comparing the smallest (I) and largest (IV) fractions.

Some excerpts from the discussion:

The results of our study clearly indicate that adipocyte size is an important determinant for the secretion of several adipokines. In particular, the secretion of proinflammatory adipokines is significantly elevated in very large adipocytes compared with small or medium-sized adipocytes, even after correcting for cell volume and surface....

...In contrast to the published studies, which demonstrated associations between average adipocyte size and serum levels or secretion, our study is unique because it investigated the secretory capacity of adipocyte fractions from the same individual separated by cell size. The results obtained by the technique clearly suggest that only the very large adipocytes are dysregulated. Adipocyte hypertrophy appears to cause a differentially impaired secretion between pro- and antiinflammatory adipokines shifting the immunological balance toward the expression of proinflammatory proteins. Thisabnormal function of adipocytes may play an important role in the development of a chronic low-grade proinflammatory state in obesity, which is considered to build the common soil for the development of insulin resistance, type 2 diabetes, and atherosclerosis (5, 68)....

...In conclusion, the results of this study clearly indicate that adipocytes per se are an important production site for manyadipokines, although the relative contribution to the overall secretion from adipose tissue remains to be elucidated.

In the whole chicken-egg debate over obesity and inflammation, it seems that perhaps a certain degree of accumulated fat (large fat cells) sets off the inflammatory environment.   

The discussion in this paper contains quite a lot of background information on both the anti-inflammatory and pro-inflammatory components manufactured in and secreted by adipocytes.  I plan to revisit some of that.

Something else that caught my eye:  Recently, adipocyte size in the sc abdominal depot was identified to be a significant predictor for the future development of diabetes mellitus type 2 (5).  Note:  sc = subcutaneous, not visceral.  Must check this out.

Insulin Resistance and Inflammation

Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance

This is yet another paper demonstrating that the evidence strongly points to the fat cells being the origin of the sequences of events leading to peripheral insulin resistance.  This paper looked at inflammation.

Abstract:

Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues. Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. However, the underlying molecular pathways are largely unknown. In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO). The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level. Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated. Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells. These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance. We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.

This group used several models of obesity in mice -- both genetic and diet induced.  Yes, it's a mouse study with all the inherent problems in applying results to humans.  The results:

Expression levels of genes in inflammatory pathways are significantly upregulated in WAT of obese mice. To study obesity and obesity-induced insulin resistance, we performed global transcriptional profiling studies with various tissues (WAT {note:  WAT = white adipose tissue}, brown adipose tissue, muscle, liver, stomach, hypothalamus, small intestine, and pancreas) taken from genetically obese mice, including ob/ob,db/db, tubby, agouti, and DIO {note: DIO = diet induced obesity} mice. Notably, we found that many of the most significantly upregulated genes in WAT were not known to be involved in adipocyte biology; instead, they could be broadly categorized as macrophage- or inflammation-related genes. Of the genes upregulated more than twofold in at least four of these five models, 59% (50/85) could be counted as inflammation genes, as determined by their known functions. The remaining genes were involved in diverse molecular pathways, including fat storage, cholesterol metabolism, DNA modification, transcription, cell division, signal transduction, and unknown functions  

In plain English, almost 3 out of 5 genes that were expressed in greater amounts in WAT are not associated with fat metabolism, but rather can be considered inflammation genes.

... with multiple models of genetic and diet-induced obesity, our data suggest that the inflammatory response is a general phenomenon of the obese state, independent of the availability of the leptin protein. We also noticed that this phenomenon was WAT-specific and was not observed in any other tissues we profiled. 

Inflammation is associated with the state of WAT adiposity irrespective of the various metabolic paths altered in the genetically obese mice or if adiposity was induced through diet.   The discussion does go on to mention that the same genes are not upregulated the same amount comparing various models, but there is consistency in the genes that are upregulated to some extent.

To determine whether the upregulation of these genes occurs prior to the development of systematic insulin resistance, which is characterized by hyperinsulinemia, we tracked the expression levels of these genes in WAT of mice with high-fat diet–induced obesity at multiple time points for 26 weeks. The body weight increased steadily over this period, as did the fasting blood glucose level, although the latter remained within the normal range (<120 mg/dl) until sometime after 16 weeks (Figure 2a). Meanwhile, we observed an increase in expression of some of these inflammation genes as early as 3 weeks on high-fat diet (Figure2b). Around 16 weeks on high-fat diet, a much more dramatic upregulation of these transcripts occurred, which correlated closely with a marked increase in fasting blood insulin levels (Figure 2). It appears that the adipose inflammatory response increases with an increase of adiposity, prior to the increase of fasting insulin level, but intensifies at the onset of hyperinsulinemia.

Lower level inflammation (dysfunction?) in WAT preceded an acute inflammation which seems to trigger insulin resistance (measured by fasting insulin).  This may have a snowball effect as hyperinsulinemia associated with IR may trigger more inflammation may trigger greater IR and so on and so on.  Other tissues (skeletal muscle, liver, spleen, lung) were studied and the inflammation genes were not significantly upregulated compared to lean controls except for the DIO after lengthy exposure (26 weeks) although the effect was still smaller than that seen in WAT.  It seems to me that this liver inflammation doesn't occur until the fat inflammation and IR has long since been established.  

Other conclusions of the study:

• Inflammation is associated with macrophages in WAT that increase in the obese state.
• Macrophage infiltration is a likely explanation for increased macrophages in the WAT of the obese.
• Macrophage accumulation in WAT is highly correlated and perhaps causative of IR.
• Macrophage activities increase after a certain degree of adiposity is achieved but before the onset of insulin resistance.
• Obesity induced insulin resistance begins in WAT but spreads systemically as adiposity increases further.

The last quotation I'll C&P follows:

Macrophage accumulation is likely a direct response to the abnormal fat metabolism caused by the increasing adiposity. The molecular signals that trigger the macrophage activity in obese WAT are not yet known, but several good candidates exist. Adipocytes are known to secrete hormones, cytokines, and FFAs, most of which have been shown to play some role in inflammation and systemic insulin resistance.

The discussion goes on to discuss these various factors, etc.  It's not too bad a read for those interested.

Adiposopathy v. Obesity ~ I

I just came across the following article, and haven't quite digested the whole thing just yet.  Still, it is interesting so I thought I would share it here.  This post will be about the most curious topic in this paper, but I hope to revisit this in a series of future blog posts (hence the "I" in the title).  

Adiposopathy Is a More Rational Treatment Target for Metabolic Disease than Obesity Alone

Near as I can tell, the lead author, Harold Bays, is the doctor who coined the term "adiposopathy" or "sick fat".  

Adiposopathy is pathologic adipose tissue dysfunction that may be initiated and/or exacerbated by fat accumulation (adiposity) in genetically susceptible patients [1••].  Adipocytes are metabolically active and adipose tissue is an important endocrine organ (Table 1) [2••]. Abnormalities of adipocyte factors contribute to dysmetabolism (Fig. 1), and adiposopathy [1••,3•] promotes some of the most common metabolic diseases encountered in clinical practice, including type 2 diabetes mellitus (T2DM), hypertension, and dyslipidemia.

This is a summary paper focusing on the fact that it is dysfunction of the adipose tissue rather than the amount of adipose tissue that is responsible for Metabolic Syndrome.  Thus explaining your "metabolically obese thin people" and "metabolically normal obese people", etc.   The focus, as the title implies, is MetS treatments that target the fat cell dysfunction rather than simply the person's fat mass.  

Sick fat appears to be related to adipocyte hypertrophy -- an enlarged fat cell:

It has been known since the 1970s that adipocyte hypertrophy increases the lipid/protein ratio of the adipocyte (through a relative consistency in protein content coupled with increased fat content) [13], decreases the responsiveness of adipose tissue to insulin [14], and increases the risk of metabolic diseases such as T2DM [15] and dyslipidemia, even if adipocyte hypertrophy is found in only slightly overweight individuals [16]. In fact, adipocyte hypertrophy is more closely linked to metabolic abnormalities, such as insulin resistance, than is an increase in total body fat [17].

An increase in fat cell size represents a failure of adipose tissue to adequately proliferate and differentiate [18] (as found with obesity and T2DM [19]) and, therefore, a failure to inadequately accommodate a further increase in energy influx [20]. Adipocyte hypertrophy may indicate a resistance or inability to store triglycerides beyond some maximal amount [21]. 

(This is consistent with the Critical Visceral Fat Theory I blogged on previously.)

For this post, I want to focus on the discussion of one of the pharmaceutical treatments:  PPAR-gamma agonists.  (Here's a LINK to general information on these drugs --  thiazolidinediones or “glitazones.” -- Actos and Avandia).  I'm not promoting pharmaceutical therapy, and Avandia has seen a lot of negative press of late, but nonetheless I find the mechanism of action of these drugs to be interesting.

These compounds appear to "cure" sick fat by stimulating the proliferation of new, small, young adipocytes and/or promote the death (apoptosis) of dysfunctional hypertrophied large fat cells.  Since SCAT has a greater ability to differentiate, and VAT cells are more metabolically active, this seems to have differential effects on the two types of adipose tissue.  These drugs tend to cause fat mass gain in SCAT, and loss in VAT, but appear to be most effective in the patients who are fatter to begin with and who gain more fat.  Yes, you read that right.  

From an adipose tissue metabolism standpoint, PPARγ agents have been shown to reduce free fatty acids [23••,91], increase adiponectin [92–94], and reduce leptin [93] (although not consistently so [95]), with unconfirmed effects upon resistin [95,96], IL-6 [97], and tumor necrosis factor-α [95,97]. Thus, it appears that many of the favorable effects of PPARγ agents upon glucose metabolism and adipocyte function may be most related to improvements in free fatty acid metabolism

I've seen diabetics list these meds in their treatment regimes and yet be on weight loss regimes.  In some ways this seems counter productive.  One way to try to cure sick fat is to try to reverse the dysfunction by emptying out the cells.  Another, it appears, would be to replace sick adipocytes with healthy ones.  While weight gain may be the last thing a person wants, I know I probably would resist it were I diabetic, it is interesting to consider.