Wednesday, November 6, 2013

The Carbohydrate Monster Under your Bed Part 5

Carbohydrates weight gain, Insulin resistance, Paleo carbohydrates, low carb Diets, Insulin paleo, Glycogen, LIRKO, MIRKO, Knockout Mice, Nutrition, Carbohydrate Nutrition, Carbohydrate health, Blood sugar control, ketosis Carbohydrates
Flying Spaghetti Monster
"Fear is the enemy of logic" - FRANK SINATRA, quoted in The Way You Wear Your Hat

In this section we will again just look at very small slice of evidence: Understanding the mechanisms of insulin resistance and how it relates to glucose intolerance, high fasting glucose, and fatty acid disruption. 

-->The Actions of Insulin and Insulin resistance

Lets first begin this discussion with a quick history lesson. Insulin appears to be have been first discovered back in 1916 by Sir Edward Schafer. He wrote in his book, The Endocrine Organs :

"The results of pancreas extirpation and pancreas grafting are best explained by supposing that the islet tissue produce an Autacoid which passes into the blood stream and effects carbohydrate metabolism and carbohydrate storage in such a manner that there is no undue accumulation of glucose in the blood. provisionally it will be convient to refer to this hypothetical substance as insuline."-(41)

Insulin was officially discovered 8 years later in 1921 and Schafer also hypothesized that insulin was created by an inactive precursor which was also discovered 50 years later and is known today as??/ that's right.. Pro- Insulin. Schafer was truly a man ahead of his time...


In addition to its discovery, Schafer also pointed out that insulin acted as an Autacoid with excitatory actions while also acting as a Chalone with Inhibitory actions.

Excitatory Actions:
+ Enhanced uptake of Glucose into Muscle, fat, Brain,Liver, etc
+ increases Glycogenesis, Protein synthesis and lipid synthesis (fat making)

Inhibitory Actions: Inhibits the following:
+ Lipolysis (fat release)
+ Proteolysis (protein release)
+ Glycogenolysis (breakdown of glycogen)
+ Gluconeogenesis ( New glucose making)
+ Ketogenesis (New Ketone making)

We will discuss the importance of the inhibitory actions in a second...

 Here is where some of the confusion comes into play, so pay close attention. To start with, review the below statement:

Without insulin, you can eat lots of food and actually be in a state of starvation since many of our cells cannot access the calories contained in the glucose very well without the action of insulin."-(42)

Essentially the argument that I am refuting goes like this: when muscle cells become "insulin resistant" the glucose can not get "into the cells", thus resulting in high glucose levels i.e hyperglycemia and the glucose is then packed away in the adipose tissue overtime resulting in obesity.

Contrary to popular belief, the above statement is false... Insulin is not required for cells to take up Glucose. What? Read that bold red statement once more. The reason that the above quote is still taught in class rooms is because of some in vitro studies that were done on rats about 30 years ago that were applied to in vivo studies in humans and then published in textbooks. It turns out that this flaw has lead to some shaky conclusions in the alternative health and nutrition spheres.

"These actions of insulin in vitro were discovered in the late 1950s when it was also shown that insulin stimulated glucose uptake by rat muscle. It was extrapolation of this last observation in rat muscle to explain the path-physiology of diabetes that was erroneous. The consequence of this error was the (fallacious) concept of insulin being 'required' for glucose entry into cells rather then just accelerating glucose uptake. The Hyperglycemia of diabetes was interpreted as a damning back of glucose in the blood stream as a consequence of a lack of insulin. This became established teaching and although the concept was shown to be erroneous in the mid -1970's, the teaching has not changed. Consequently  therapy has been based on a flawed concept."(41)

Remember in the last section how we talked about Glut Transporters? In the muscle and fat tissue there are also glucose transporters that are called Glut-4 Transporter proteins and they assist in bringing glucose by coming to the surface of the membrane and transversing glucose from a high concentration out side the cell to a low concentration inside the Skeletal muscle and fat cells  (see picture below) Once inside the cells, glucose can be either used to synthesize ATP and/or to be stored as Glycogen in muscle cells or it can be stored as triglycerides in fat cells ( we will discuss fat cells in another section). It is true that fat cells and muscle cells have many glut transporters (Glut-1, 5, 8,12 etc) but Glut-4 displays the unique characteristic of a large intracellular disposition in the un stimulated state that is then redistributed to the plasma membrane when stimulated by insulin and other stimuli.


So how do we know that Insulin is not required for glucose uptake? What evidence is there to justify this claim?

To start of with, we need to remember that energy homeostasis is achieved when energy in equals energy out right? well it turns out that Blood sugar homeostasis is achieved when Rate of disposal ( which is combination of cell utilization and urinary loss) is equal to the rate of production (i.e production of sugar in the liver from glycogenolysis and gluconeogenesis ).

So to put it simply, Blood sugar homeostasis is achieved when Ra (rate of production) = Rd (rate of disposal which is equal to Rut (rate of utilization) + Ru (rate of urine excretion)) . This balance remains relatively stable for minutes, hours, days, months, and even years suggesting that this balance is largely genetically determined.


So the way we figured out that insulin is not required for glucose uptake was by measuring Rd vs Ra in  patients with hyperglycemia; Hyperglycemia being the hallmark of diabetes.

"By collecting urine and measuring looses directly, tissue glucose can be calculated readily. Such calculations show that, in the face of hyperglycemia, tissue glucose uptake is usually increased above normal even when insulin deficiency is severe. this cannot be reconciled with the concept that insulin is required for glucose uptake by insulin sensitive tissues. Indeed it proves beyond question that insulin is not required."(41)

 Insulin resistance, Nutrtion insulin, carbhydrate tolerance, carbohydrate weight gain, carbohydrate fat loss, Starch Fat loss
Ruh- Roh!!
"....even in the fasted state or in a state of absolute insulin deficiency  there are sufficient glucose transporters already in place in the cell membrane to allow glucose uptake to exceed that of a normal individual when the gradient of glucose concentration across the cell membrane is sufficiently high...This 'mass action' effect accounts for the observations which show unequivocally that tissue glucose uptake can exceed normal even in the face of severe insulin deficiency."(41)

"As hepatic glucose output is ‘switched off’ by the chalonic action of insulin, glucose concentration falls and glucose uptake actually decreases. Contrary to most textbooks and previous teaching, glucose uptake is therefore actually increased in uncontrolled diabetes and decreased by insulin administration! The explanation for this is that because, even in the face of insulin de´Čüciency, there are plenty of glucose transporters in the cell membranes. The factor determining glucose uptake under these conditions is the concentration gradient across the cell membrane;this is highest in uncontrolled diabetes and falls as insulin lowers blood glucose concentration primarily (at physiological insulin concentrations) through reducing hepatic glucose production" -(43)

The error in logic that is committed is for us to think that insulin is required for glucose to transverse the membranes of muscle and fat cells, when in fact there are already plenty of Glut-4 transporters already located on the surface of these cell membranes. This is because the main factor driving glucose uptake is the mass action effect through Facilitated diffusion, the rate of which is determined by the concentration gradient between extracellular and intracellular glucose concentrations.(41)

What exactly is Facilitated Diffusion and how does it differ from active transport? Well lets look at a quick example: In the Gut, glucose is transported through the epithelial cells by active transport because no matter what the concentration gradient, the job of the the transporter protein is to transport the glucose to the bloodstream and keep it from flooding back into the gut. Imagine if these transporters acted by facilitated diffusion, the glucose would just flood back out into our gut once the concentration is low. Not only is this inefficient it could potentially be lethal.

In contract to active transport, most of the cells in our body move glucose by facilitated diffusion carriers. This makes sense because the environment is different in the blood then in the gut . In contrast to the gut which constantly experience various high and low concentration of glucose, the glucose in the blood is heavily regulated so that the intracellular concentrations are lower then the blood concentrations. This ensures that a steady stream of glucose is entering the cells at all times.



This way the cells are never truly dependent on insulin to sustain their energy needs. Glucose can get into the cell just fine. These results in turn suggest that the high blood glucose levels seen in diabetes is a result of the unregulated activity in the liver more so then the inability of glucose to get into the cells of peripheral tissue in both type 1 and type 2 Diabetics. (44)

Nutrition carbohydrates, insulin weight gain, insulin fat loss, insulin fat storage, insulin diabetes, insulin resistance muscle, insulin resistance liver, Blood glucose insulin
http://ajpendo.physiology.org/content/284/4/E716.full.pdf
Notice in the graph to the right, when glucose from a meal goes up in normal healthy individuals, endogenous glucose production is significantly lowered. By the end of the meal, the endogenous glucose has risen back up and total Glucose RA is back down at the original level 6 hours later after meal ingestion... keeping glucose production and utilization constant through out the day.

Now read the below quotes from a study where they measured the different effects of insulin on six insulin dependent diabetic men. The results of the study further support the above evidence.

"These results suggest that a low-dose infusion of insulin can lower plasma glucose entirely by reducing glucose production. Since at least 8O°O of glucose production in the fasting state is hepatic'- this strongly suggests that low concentrations of insulin act primarily on the liver by reducing either glycogenolysis or gluconeogenesis or both. Only when insulin was administered at rates producing high physiological concentrations (about 100 mUJ did an increase in peripheral uptake of glucose by fat and muscle tissue contribute to lowering the plasma glucose concentration. These results confirm in man the results obtained by Issekutz on alloxan-diabetic dogs.'" We believe that the concentration-dependent effect of insulin on hepatic glucose production and uptake by peripheral tissues has important implications for insulin-treated diabetics." (45)

"In normal people endogenously secreted insulin is likely to affect mainly the liver because insulin secreted into the portal tract reaches the liver in concentrations many times greater than those reaching the periphery.' The importance of the liver in normal glucose homoeostasis is emphasised by the results of the experiments of Felig et al,2') which showed that only 15",, of ingested glucose leaves the liver over three hours. In diabetics, who are insulin deficient, the restraining effect of insulin on hepatic glucose production is impaired and increased glucose production causes hyperglycemia. The peripheral utilisation of glucose in diabetes is similar to that of normal subjects."(45)


The reason insulin lowers blood glucose in diabetic patients is mainly because it lowers the amount of glucose production in the liver. It has a less pronounced effect on the uptake of glucose by the peripheral tissue..is this all starting to make sense now?


 I also would like to point out that one of insulin's main function is to halt the production of ketones in the presence of excess glucose. If ketones production is not regulated then ketone bodies will rise and we will be in a state known as ketosis. In Ketosis, The metabolism of glucose can be inhibited by the increasing ketone bodies in the plasma which then enter the kreb's cycle and can supply most of the cells energy needs. (Glucose. ketones, and fatty acids are constantly competing in the body) This results in a damning back of Glycolysis from glucose as the substrate becomes "clogged". Thus, glucose transport and uptake into cells is dependent on the degree of ketones present in the blood... not insulin. One other big difference between Glucose and ketones being that ketone bodies must be metabolized and are not significantly excreted through urine which can then possibly produce ketoacidosis.  In Type 2 Diabetics it is not uncommon to see ketoacidosis because insulin is not regulating gluconeogenesis or ketogensis. The result then being high levels of ketone bodies and glucose (As shown in figure 5,the picture above and to the right) because remember with out insulin, the breaks on the liver are essentially gone, which can then lead to the metabolic mayhem that is seen in type 1 diabetic patients.

Essentially, this "damning back" of glucose phenomenon that people will often refer to is not stemming from a lack of insulin's effect on glucose uptake into peripheral tissue but because the lower substrate (i.e  The krebs cycle) is being dominated by an overload of free fatty acid and ketone oxidation in insulin resistant individuals. It is abnormal to have Free Fatty Acids, Glucose and Ketones all at high levels at the same time...

When this happens we have a disputation in the glucose fatty acid cycle as described in part 2 of this series. This "disruption" takes place at the prep step of cellular respiration stemming from the enzyme complex pyruvate dehydrogenase (PDH) as shown below:




So what exactly does PDH do? Well it has a very important job in regulating what substrates enter into the krebs cycle i.e pyruvate, amino acids, keto acids, fatty acids as seen in the above. It is regulated by PDH Kinases and Phosphatases which are affected by the amount of Acetyle COA and NADH entering the prep step. See the below

Product inhibition by NADH and acetyl CoA: NADH competes with NAD+ for binding to E3. Acetyl CoA competes with Coenzyme A for binding to E2.

Regulation by phosphorylation/dephosphorylation of E1: Specific regulatory Kinases and Phosphatases are associated with the Pyruvate Dehydrogenase complex within the mitochondrial matrix.
Pyruvate Dehydrogenase Kinases catalyze phosphorylation of serine residues of E1, inhibiting the complex.
Pyruvate Dehydrogenase Phosphatases reverse this inhibition.

"Pyruvate Dehydrogenase Kinases are activated by NADH and acetyl-CoA, providing another way the two major products of the Pyruvate Dehydrogenase reaction inhibit the complex. Pyruvate Dehydrogenase Kinase activation involves interaction with E2 subunits to sense changes in oxidation state and acetylation of lipoamide caused by NADH and acetyl-CoA." (46)

"During starvation, Pyruvate Dehydrogenase Kinase increases in amount in most tissues, including skeletal muscle, via increased gene transcription. Under the same conditions, the amount of Pyruvate Dehydrogenase Phosphatase decreases. The resulting inhibition of Pyruvate Dehydrogenase prevents muscle and other tissues from catabolizing glucose and gluconeogenesis precursors. Metabolism shifts toward fat utilization, while muscle protein breakdown to supply gluconeogenesis precursors is minimized, and available glucose is spared for use by the brain." - (46)

This seem's quite obvious to me as elevated Free fatty acids or ketone bodies can lead to some serious metabolic damage so your body will shift to a "starvation mode" to get these fatty acids oxidized as soon as possible. Thus, PDH will be switched off for pyruvate and glucose and instead be switched on for Fatty acids. The problem is that because free fatty acids, lactate and ketones are constantly elevated in glucose impaired scenarios, PDH is always inactive and the bodies primary fuel, glucose, is not able to be oxidized as efficiently. (47)

The On/Off switch in PDH is normally not a problem but in the case of diabetes it can lead disastrous results as seen in the below excerpt discussing the impaired blood glucose seen in thyroid conditions.


"Thyrotoxic subjects frequently show impaired glucose tolerance. This is a result of increased glucose turnover with increased glucose absorption through the gastrointestinal tract, postabsorptive hyperglycemia, elevated hepatic glucose output, with elevated fasting and/or postprandial insulin and proinsulin levels, elevated free fatty acid concentrations and elevated peripheral glucose transport and utilization." (48)


Diabetes Summarized:
  • Unregulated and elevated Glucose in the liver, resulting in Hyperlgycemia
  • Down regulated and elevated Free Fatty Acid Concentrations
  • Increased Glucose absorption through the intestinal tract ( possibly explaining decreased satiety and increased hunger)
  • Post Absorptive HyperGlycemia
  • Elevated Fasting or postprandial Insulin as well as Pro Insulin Levels (Indicating some degree of Beta Cell Dysfunction)
  • Elevated peripheral transport and utilization 

-- What Can we Learn from Knockout Mice??? --

A "knockout" mouse is a laboratory mouse in which researchers have inactivated or 'knocked out" a gene by either replacing it or disrupting it with an artificial piece of DNA. The purpose behind this? When scientists knockout a gene in a mouse they can then observe the behavior, appearance, and  physical and biomedical characteristics of the mouse which can then hopefully give us clues about what the gene does. The logic being that because mice share many characteristics with humans we can develop models to test on the knock mouse to help us study the formation of disease in mice which we can then apply to ourselves. There are obvious drawbacks to these experiments but none the less knockout mice offer one of the most powerful means available for studying gene formation in organism similar to ourselves.

1) Lirko Mice

LIRKO short for Liver-specific insulin receptor knockout was an experiment where, as the name suggests, the insulin receptor was "knockouted" in the livers of these mice. The theory being that a dis function of the liver, more specifically insulin resistance of the liver, would lead to impaired glucose homeostasis.

"Liver-specific insulin receptor knockout (LIRKO) mice exhibit dramatic insulin resistance, severe glucose intolerance, and a failure of insulin to suppress hepatic glucose production and to regulate hepatic gene expression. These alterations are paralleled by marked hyperinsulinemia due to a combination of increased insulin secretion and decreased insulin clearance." -(49)

"The physiological effects of the disruption of insulin signaling in liver were apparent in young LIRKO mice. By 2 months of age, male LIRKO mice displayed markedly elevated blood glucose in the fed state (Figure 2a, left graph). This occurred despite the presence of insulin levels that were 20-fold higher than normal (Figure 2a, right graph)."-(49)

"Since we have previously demonstrated that mice with tissue-specific knockout of the insulin receptor in muscle still showed normal insulin tolerance (Bru ̈ ning et al., 1998), it is unlikely that the modest downregulation of insulin receptors in muscle could account for this finding. To test this proposal directly, we analyzed glucose transport in vitro in isolated soleus muscles from control and LIRKO mice. Basal glucose transport was not different between control and LIRKO mice (1.07 +/- 0.14 mol/ g/hr in controls versus 0.98 +/- 0.11 mol/g/hr in LIRKO). Furthermore, stimulation of glucose transport by incu- bating the muscles in the presence of 33 nM insulin resulted in a 3.4-fold increase in glucose transport in muscles from both the controls and the LIRKO mice (3.64 +/- 0.47 mol/g/hr in controls versus 3.26 +/- 0.36 mol/g/hr in LIRKO). Taken together, these data suggest that a considerable portion of the decrease in blood glucose following intraperitoneal administration of insulin in mice is due to suppression of hepatic glucose output rather than an increase in muscle glucose disposal."-(49)

"The present study of LIRKO mice suggests that despite extreme insulin resistance and hyperglycemia, the B cells from these animals are capable of prolonged hypersecretion of insulin for more than one year without suffering failure. These results bring into question the notion that continuous hypersecretion itself can induce islet failure, even in the presence of impaired glucose tolerance. This sug- gests that B cell failure requires either an additional genetic or acquired component." (49)

Despite having impaired insulin sensitivity in the liver which then lead to glucose dis-regulation, the Pancreas in the LIRKO mice did not "tire out" and was pumping out insulin just fine. The Lirko mice was indistinguishable from the controls, essentially they were not overweight as one may expect but were actually underweight later in their lives.  

Please also see the LID mouse(50)

2) Mirko Mice

Mirko short for Muscle specific Insulin receptor Knock out was an experiment where researchers knocked out the insulin receptors in the skeletal muscle. The experiment resulted in the mice becoming quite fat however the typical biomarkers of type 2 diabets were not observed. These reason this study is important is because some individuals have stated that insulin resistance in the muscle is the main reason we (humans) get fat and have high fasting blood glucose...only problem is these mice don't have any of the markers of whole body insulin resistance despite being quite large.

"Muscle-specific insulin receptor knockout (MIRKO) mice do not develop insulin resistance or diabetes under physiological conditions despite a marked in- crease in adiposity and plasma FFA. On the contrary, WAT of MIRKO is sensitized to insulin action during a euglycemic clamp, and WAT glucose utilization is dramatically increased." -(51)

"MIRKO mice show a severe resistance to insulin action in skeletal muscle both in vitro and in vivo (1, 2), a dramatic increase in total body fat mass, and elevated serum triglyceride and FFA levels. This phenotype is similar to the metabolic syndrome described in humans. However, despite these features typical of type 2 diabetes, these mice do not develop hyperinsulinemia or glucose intolerance (1)." -(51)

"Diet-induced obesity usually results from a hypertrophy of pre-existing adipocytes followed, when cell size reaches a pecific threshold, by a phase of cellular expansion during which new fat cells are recruited from the preadipocyte pop- ulation (11, 12). Here, we show that the increased adiposity in MIRKO mice results from adipocyte hyperplasia, with individual adipocytes reaching the same size as in control mice and without increase in expression of the major lipo- genic genes, i.e. leading to de novo triglyceride synthesis from glucose: PPAR��, SREBP-1c, and FAS. Thus, unlike in the case of diet-induced obesity, the increased adiposity observed in MIRKO mice does not result from hypertrophy of pre- existing adipocytes leading to enlarged insulin-resistant cells, but rather to the recruitment/differentiation of new small insulin-sensitive adipocytes. This is consistent with the finding that insulin sensitivity is increased in WAT from MIRKO mice during euglycemic hyperinsulinemic clamp conditions (2), and this explains why WAT glucose uptake is increased in the postprandial period (3). "(51)

This is where a big difference between humans and mice comes into play. Mice have a very large capacity to increase fat making in the presences of excess glucose, nearly 40-50% of glucose can be converted to triglycerides(52535455)

"We know that if you look at comparative physiological studies, animals metabolize carbohydrates differently than do humans. In animals on a high-carbohydrate diet not providing excess energy, you find that de novo lipogenesis [conversion by the liver to fatty acids] is anywhere from 50 percent or higher. They basically make fatty acids for at least 50 percent of the carbohydrate [consumed]. De novo lipogenesis accounts for at least 50 percent carbohydrate. In humans, it is very, very hard under isocaloric (neutral energy) conditions, let alone in overfeeding conditions, to push that beyond 10 percent or even 20 percent. " -(56)

 This would in part explain how the Mirko Mice increased the number of adipocytes. Note in this study that muscle insulin resistance did not lead to increased circulating insulin levels or hyperglycemia in these mice but they did became increasingly fat.

"Although a defect in mitochondrial function is associated with extremes of insulin resistance in skeletal muscle (30), this does not appear to be relevant to the etiology of type 2 diabetes. " - (57)

3) Firko Mice

Firko short for adipose/fat insulin resistant knock out was an experiment where the researchers knocked out the insulin receptors in the adipose tissue of these mice.

"Insulin signaling in adipose tissue plays an important role in lipid storage and regulation of glucose homeostasis. Using the Cre-loxP system, we created mice with fat-specific disruption of the insulin receptor gene (FIRKO mice). These mice have low fat mass, loss of the normal relationship between plasma leptin and body weight, and are protected against age-related and hypothalamic lesion-induced obesity, and obesity-related glucose intolerance." -(58)

To state once more: "...We find that FIRKO mice have markedly reduced fat mass and whole-body triglyceride stores, and are protected from gold thioglucose-induced and age-related obesity, as well as the associated glucose intolerance." -(58)

4) Glucose Transporter Knockout Mice

In this first study the scientists either enhanced or down-regulated the expression of Glut-4 in the adipocytes, so they did not completely knockout the Glut-4 in the mice but none the less the results were quite the opposite of what many people would expect..

"These mice show opposite phenotypes with regards to insulin sensitivity and glucose homeostasis. Adipose- GLUT4-Tg mice have enhanced glucose tolerance and insulin sensi- tivity4. Relatively increased insulin-sensitivity persists even in the diabetic state induced by pancreatic b-cell destruction6, and GLUT4 overexpression in adipocytes of mice lacking GLUT4 in muscle reverses their diabetes7. Thus, increasing GLUT4 expression selectively in adipocytes protects against whole-body insulin resist- ance. In contrast, mice with markedly reduced GLUT4 expression in adipose tissue, but normal GLUT4 expression in muscle, are insulin- resistant and have an increased risk of overt diabetes5. Adipose- specific deletion of Glut4 leads to secondary defects in insulin action in muscle and liver5. However, insulin action in muscle of adipose- Glut4 2 /2 mice ex vivo is normal5, indicating that a circulating factor(s) causes insulin resistance in these mice. " -(59)

"With the development of insulin resistance, GLUT4 expression is downregulated selectively in adipose tissue but not in skeletal muscle...Down-regulation of GLUT4 expression in adipose tissue is an almost universal feature of insulin-resistant states, including obesity, type 2 diabetes and the metabolic syndrome2." -(59) This applies to both humans and rodents (60)

Undoubtedly what this study shows is that adipose tissue plays a much more important role in insulin resistance where as the skeletal muscle does not. I highlighted that last quote because many people still believe that it is glucose's inability to get into muscle cells that is the issue but this study clearly shows that Glut-4 transport in muscle is not the issue but rather transport of glucose in the adipose increases insulin sensitivity the most and lowers risk for diabetes.

5) DGAT, ACC2, and UCP3 Knockout Mice

"FA oxidation and lipogenesis are highly integrated processes. For example, it has been previously shown in genetically modified mouse models with inhibition of FA storage in WAT there is upregulation of FA oxidation in skeletal muscle, demonstrating the interplay of energy fluxes between the two organs. One such model is the diacylglycerol acyltransferase (DGAT) knockout mice (DGAT is the enzyme that catalyses the final acylation step of triacylglyceride synthesis4). This shows reduced fat deposition and resistance to diet-induced obesity, due to the disruption in FA storage. In addition, DGAT knockout mice show elevated energy expenditure and increased activity, suggesting an increase in FA oxidation.5" (61)

"Similarly, deletion of acetyl-CoA carboxylase 2 (ACC2), a key enzyme for de novo FA synthesis, leads to a lean mouse showing an increase in FA oxidation.6 This is due to a fall in malonyl-CoA, the product of the ACC reaction. Malonyl-CoA is a potent inhibitor of carnitine-palmitoyl transferase 1 (CPT1), which transports FA moieties into the mitochondria for -oxidation.7 Thus, the absence of ACC2 reduces the cellular concentration of malonyl-CoA, removes the inhibition of CPT1 and allows FA oxidation to be maintained. A further model, the skeletal muscle-specific uncoupling protein 3 (UCP3) transgenic mouse also has increased FA oxidation, due to increased mitochondrial uncoupling.8 An interesting observation is that these mice remain lean despite hyperphagia, suggesting that elevations in FA oxidation capacity are powerful enough to overcome secondary effects on food intake.(61)

What to remember from this section:
  • Insulin is not required for glucose to transverse the cell membrane
  • The Inhibitory actions of insulin have been downplayed compared to the excitatory actions
  • Hyperglycemia is largely but not solely a result of unregulated glucose production, ketone production and glycogen breakdown in the liver, not a damning back of glucose by the peripheral tissue because insulin is not stimulating uptake
"Insulin resistance, most likely, is a development that takes place as an anti-starvation system in the body – preventing fat burning while also preventing energy from being packed into muscle cells where it would raise the metabolism and build calorically-expensive muscle tissue."(62)

Click Here for Part 6

To start from the beginning click Here