Showing posts from July, 2010

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes Obesity is associated with increased storage of lipids in nonadipose tissues like skeletal muscle, liver, and pancreatic b cells. These lipids constitute a continuous source of long-chain fatty acyl CoA (LC-CoA) and derived metabolites like diacylglycerol and ceramide, acting as signalling molecules on protein kinases activities (in particular, the family of PKCs), ion channel, gene expression, and protein acylation. In skeletal muscle, the increase in LC-CoA and diacylglycerol translocates and activates specific protein kinase C (PKC) isoforms, which will phosphorylate IRS-1 on serine, preventing its phosphorylation on tyrosine and association with PI3 kinase. This interrupts the insulin signalling pathway leading to the stimulation of glucose transport. In pancreatic b cells, short-term excess of fatty acids or LC-CoA activates PKC and also directly stimulates insulin exocytosis. Longterm ex
I was a bit taken aback by the title on a recent blog post by Dr. William Davis at his Heart Scan Blog Why doesn't your doctor try to CURE diabetes? Dr. Davis paints the medical profession with a rather broad unflattering brush.   Are there docs out there who are more concerned about profit over your health?  Yes.  Are there doctor-drones who reflexively reach for the prescription pad?  Again, yes.   But I believe that most doctors -- and I know several since before they became docs -- do care about their patients and dole out advice based on what they believe to be the best course of action. Certainly the statement that " Adult diabetes is the one chronic disease that nobody cares to cure " goes more than a bit over the top! Davis goes on to say that most docs don't think it can be cured, and that is probably true.  The old school re: type 2 would be based on when the disease was more rare and probably not detected until progressed significantly to the point o

The Progression of Insulin Resistance

Vascular function, insulin resistance and fatty acids   (I'll blog on the vascular focus of this paper shortly, but this post is focusing on the bolded statements in the abstract). Abstract Over the past 10 years it has become clear that intact vascular function, especially at the level of the endothelium {cells lining the blood vessels}, is paramount in the prevention or delay of cardiovascular disease. It has also become clear that insulin itself, in addition to its metabolic actions, directly effects vascular endothelium and smooth muscle.  Insulin, at normal physiologic concentrations, causes changes in skeletal muscle blood flow in healthy, insulin-sensitive subjects. Insulin’s effect on the endothelium is mediated through its own receptor and insulin signalling pathways, resulting in the increased release of nitric oxide. Insulin’s vascular actions are impaired in insulin-resistant conditions such as obesity, Type II (non-insulin-dependent) diabetes mellitus and hypertens

Atkins Autopsy

Every now and then I'm reminded of something that kind of bugs me about LC diet promoters.  There simply aren't many long term low carbers in our general population (as a percent).  So when I see these long term meta studies looking at correlations between various biomarkers and CVD, for example, I wonder how this translates to someone who follows a low carb diet for the long run.  Real life examples ... people who may have yo-yo'd a bit with LC as well.  Do the low fasting trigs of a low carber correlate with reduced CVD?  But I hold no illusions that some meta study will be done following thousands of low carbers.  (Still, I can dream) In the absence of that, the next best thing would be for prominent "leaders" in the field to share their personal experience/results.  So it's always bothered me a little bit that Dr. Atkins didn't leave instructions for an autopsy to be made public.  After all, what better vindication of low carbing can one imagine than

Exercise to lose weight and reduce lipotoxicity!

Thanks to reader Cody for finding a study I had come across previously regarding IMCL/IMTG.  Actually the study linked to was an update, but there's a secondary lesson, I believe, to be had from the results.  Since this was a study in older folks, there's a sub-message here:  it's never too late! Study:   Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete’s paradox revisited We previously reported an “athlete’s paradox” in which endurance-trained athletes, who possess a high oxidative capacity and enhanced insulin sensitivity, also have higher intramyocellular lipid (IMCL) content. The purpose of this study was to determine whether moderate exercise training would increase IMCL, oxidative capacity of muscle, and insulin sensitivity in previously sedentary overweight to obese, insulin- resistant, older subjects. Twenty-five older (66.4 0.8 yr) obese (BMI 30.3 0.7 kg/m2) men (n 9) and women (n 16) completed a 16-wk moderate

Insulin and Glucose Transport

A shout-out to LynMarie over at Adipo Insights. I encourage all of my readers to go check out: How the "Black Age" of Endocrinology May Be Affecting Your Understanding of Insulin Resistance & Obesity I'm still mulling over the ramifications of, in particular, her second link that applies more specifically to insulin.  A major point of the article is that insulin's inhibitory actions are likely more important than it's stimulatory actions.  This ties in with my research on NEFA's and concerns over the impact of VLC/HF diets on NEFA levels and whether or not this is potentially detrimental.  I'll blog on that in the near future.

Stimulation of Insulin Secretion by Long-Chain Free Fatty Acids ~ A Direct Pancreatic Effect

Stimulation of Insulin Secretion by Long-Chain Free Fatty Acids, A Direct Pancreatic Effect These studies indicate that long-chain FFA, in physiological concentrations, can markedly stimulate insulin secretion by a direct effect on the pancreas. The results lend support to the concept of insulin as a hormone that is importantly involved in regulating the metabolism of all three principal classes of metabolic substrates and whose release is in turn regulated by all of them. So why almost no insulin response to just a fat meal?  Because most of the ingested fats are transported as triglycerides in chylomicrons.  But NEFA release from adipose tissue with fat ingestion may be responsible for the slight response seen early on.   This may well be the mechanism for elevated basal insulin in the obese.  It's our body's attempt to keep circulating NEFA levels in check. This would be consistent with a direction of causality that fat accumulation (due to chronic positive energy bala

Nutrient Fates after Absorption

Nutrient effects: post-absorptive interactions BY ERIC JEQUIER    (1995) After a meal, the metabolic fuel selection at the whole-body level depends on the plasma concentrations of nutrients such as glucose, non-esterified fatty acids (NEFA) , amino acids, and on hormonal responses. Over the last 10 years, there has been great interest in studying the metabolic effects following the ingestion or the intravenous (i.v.) infusion of the three macronutrients, carbohydrate (CHO), fat, and protein (or amino acids for i.v. infusion). The aim of the present brief review  {I'm thinking it's not so brief!}  is to summarize the main mechanisms which determine the post-absorptive interactions between the nutrients. This is an older paper, but still recent enough to provide some good info on the basics.  I'm going to do something a bit different with this one and I otherwise would be quoting huge chunks.  So I'll do bullet point summaries with select summary quotes from the pap

High-fat diet, muscular lipotoxicity and insulin resistance

High-fat diet, muscular lipotoxicity and insulin resistance A high dietary fat intake and low physical activity characterize the current Western lifestyle.  Dietary fatty acids do not stimulate their own oxidation and a surplus of fat is stored in white adipose tissue, liver, heart and muscle. In these organs intracellular lipids serve as a rapidly available energy source during, for example, physical activity. However, under conditions of elevated plasma fatty acid levels and high dietary fat intake, conditions implicated in the development of modern diseases such as obesity and type 2 diabetes mellitus, fat accumulation in liver and muscle (intramyocellular lipids; IMCL) is associated with the development of insulin resistance. Recent data suggest that IMCL are specifically harmful when combined with reduced mitochondrial function, both conditions that characterize type 2 diabetes. In the (pre)diabetic state reduced expression of the transcription factor PPARg co-activator-1a (PGC

Mechanism of Free Fatty Acid–induced Insulin Resistance in Humans

Mechanism of Free Fatty Acid–induced Insulin Resistance in Humans   (PDF) these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an ~50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation. The introduction section discusses the history and controversy over how NEFA/FFA induce insulin resistance.   In conclusion, contrary to the classical mechanism of free fatty acid–induced insulin resistance as proposed by Randle et al. (2, 27, 28) in which free fatty acids exert their effect through initial inhibition of pyruvate dehydrogenase, we found that elevation in plasma free fatty acid concentration causes insulin resistance by inhibition of glucose transport and/or phosphorylation with a subsequent reduction in rates of glucose oxidation and muscle glycogen synthesis. This reduction in insulin inducible glucose transport/phosphorylation is similar t

Mechanisms linking obesity to insulin resistance and type 2 diabetes

Mechanisms linking obesity to insulin resistance and type 2 diabetes   (PDF) There is a LOT of info here (and references) as this is a fairly recent (2006) review paper.   A personal aside:  I'm often accused of bashing low carb diets.  Many times I'll get the "why are you here" if I don't agree with dogma or dare suggest that certain versions of LC may well not be as healthy for certain people as they think they are.   I started researching when my weight loss plateaued out to ensure myself that this WOE was indeed not unhealthy.  If you're interested in more details on that, I've posted some thoughts here at my non-science blog.   Basically I've come across a lot of information on free fatty acids (NEFA/FFA) that does at least give me pause regarding especially the more extreme versions of LC.  This is one review paper that got me started.  I'll quote a few excerpts, but encourage even the less technically minded to give this a read.     Bo

Ad libitum

Atkins described his diet in his first book as "high calorie".  Taubes describes low carb diets as unrestricted calories.  While unrestricted is not an incorrect interpretation of ad libitum, it is misleading.  Most people will equate unrestricted with higher intake when that plan is compared to a calorie restricted plan.  The implication is that those on an unrestricted plan are eating more than those on a restricted plan and therefore are losing the same amount of weight (or more weight) eating more calories on LC vs. other plans. If I had a dollar for every time I've read something along the lines of "just imagine how much more weight the LC group would have lost if they were allowed to eat more", I'd be rich!  Clearly too many interpret ad libitum  incorrectly. This study   I've previously blogged on  is but one of many examples in the literature of spontaneous reductions in intake when allowed to eat as much as one wanted.  In this study carboh

Of Thermodynamics, Chemistry, Biology and Biochemistry ~ Feinman Reply

In response to, this post : Fred Hahn  said... I am posting this comment on behalf of Dr. Richard Feinman, professor of cellular biology at SUNY Downstate.  "I never had to go through steam tables but I still teach bioenergetics in biochemistry courses where we think thermodynamics has a lot to do with human metabolism.  Like most chemists and even some physicists, I would be willing to admit I don't understand the field that well but if you have a problem, feel free to write to me directly.  I think it is touching that people get excited about thermodynamics but I expect polite discourse.  Richard Feinman  Professor of Cell Biology  SUNY Downstate Medical Center Here's the discussion at Eades' blog that resulted in my steam table comment: Jim B, March 6, 2010 at 9:41 pm In the last year, or so, I have experienced a re-education on thermodynamics. In the last 20 years or so, there has been a mojor change in the way the subject has been taught.

Recommended Reading on Insulin

A shout-out to James Krieger who seems to think a lot like me (or me like him? or we just think alike??!).  I would like to encourage anyone reading this to go and take in an excellent post by James: Insulin…an Undeserved Bad Reputation Here's my bottom line on all this:  If the "alternate hypothesis" were true, then all cultures eating a higher carb diet would be obese and nobody could lose weight on a high carb calorie restricted diet.  We know neither is true.

Low Carb & Leptin

Lately there's been a lot of buzz around the internet about leptin and leptin resistance.  I've come across a few things over the past several months I wish to share, basically focusing on whether levels of this hormone can be manipulated by varying the macronutrient composition of one's diet. My general feeling on this is a cautiously stated:  no.  While some studies show differences in postprandrial leptin, fasting leptin, leptin AUC, there doesn't seem to be an overarching trend in this regard one way or the other.  It would appear that leptin has more of a chronic role in energy homeostasis rather than an acute one.  Insulin, OTOH, appears to have a somewhat dual role -- levels respond acutely to nutrient intake, while a basal insulin level generally correlates with one's degree of adiposity.  Indeed in many diet comparison studies, fasting insulin levels go down modestly (usually with weight loss) but to the surprise of low carbers everywhere, I've not se

Do other theories on obesity dispel Calorie Balance?

A little while back I listened to this interview with Stephan Guyenet from Whole Health Source blog did with Chris Kresser of The Healthy Skeptic.  I highly recommend listening to this, there's lots of info there.  Stephan discussed various theories on obesity such as Omega 6's, gut flora, inflammation/immune disorders, etc. Without trying to put words in Stephan's mouth, my overarching take-away message was that Stephan believes that our bodies have "set points" managed by an "adipostat" located in the hypothalamus.  The major hormone involved with the adipostat is leptin.  Leptin is secreted by fat cells and circulating levels are associated with one's level of fat mass.  The theory is that something throws off the adipostat, and that something leads to leptin resistance of the hypothalamus.  When leptin's "stop eating" signal fails to reach the brain, we overeat.  Basically each of the possible causes of the obesity epidemic trigg

What's a Healthy Diet?

Over at the GCBC post on , Fred Hahn weighed in with statements about low carb diets being the most healthy.  He also repeatedly mentioned speed of weight loss regarding the health of a weight loss diet.  He also seemingly mocks adherence as a factor to consider. I really believe that in the long run, a healthy diet is one that allows you to maintain a healthy weight.  That need not necessarily be super lean or buff either.   What REALLY gets lipids, blood sugar and hormones out of whack???  Being in chronic positive energy balance, OR being in chronic negative energy balance.  Catabolism is a stressful state, so a case could be made for taking expediency into account.  But the more extreme the caloric restriction (and LC works by creating this spontaneously in most people) the more stress. Blogger Jimmy Moore, having regained roughly 1/3rd of his 180 lb weight loss over the past couple of years recently went on an "eggfest" .  Actually if one looked

Of Thermodynamics, Chemistry, Biology and Biochemistry

The detractors of energy balance theory often say something along the lines that thermodynamics goes out the window in living organisms, the rules don't apply.  Nope.  The existence of the Second Law does not violate the First Law! This simply isn't true, and those who say similar must simply not understand these fields.  Humans are not bomb calorimeters or Carnot cycle/combustion engines .  When Dr. Eades tried to discredit Anthony Colpo a while back, he and his compadre Feinman waxed poetic and evoked nightmares of steam tables in their college thermo courses.