Advanced Nutrition and Human Metabolism

[reefedjib]

Is the book I am currently reading. It's heavy right out of the gate. I love it! I was reading last night briefly about glycolysis and how the enzymes "line up" (glycolysis is the metabolic pathway to convert glucose to ATP without oxygen, I believe):

Furthermore, if enzymes that catalyze the reactions of a metabolic pathway are oriented sequentially, so that the product of one reaction is released in very close proximity to the next enzyme for which it is a substrate, the velocity of the overall pathway will be greatly enhanced. Evidence indicates that such an arrangement does in fact exist among the enzymes that participate in glycolysis.

I wonder how that gets coordinated? I was also reading about the citric acid cycle, or the Krebs cycle, that takes place in the mitochondria (citric acid cycle is the metabolic pathway to convert glucose, and fatty acids, to ATP with oxygen, I believe). Very cool.

Anyway, it's a great book and I am just in Chapter 1. Later chapters will go into detail about glycolysis, citric acid cycle and other metabolic processes.

Cheers!

[reefedjib]

Ok, now I am confused. I just read:

Glycolysis gives rise to pyruvate, which is decarboxylated and oxidized to acetyl CoA and enters the TCA cycle [citric acid cycle, Krebs cycle] by combination with oxaloacetate to form citrate.

So it is glycolysis -> citric acid cycle -> respiratory chain (electron transport chain), where glycolysis produces acetyl CoA, citric acid cycle produces free Hydrogens, and the respiratory chain takes the Hydrogens, pumps ADP to ATP and combines with ocygen to produce H2O. It depends on Oxygen!

The problem I am having is that I wrote earlier (read it somewhere) that "glycolysis is the metabolic pathway to convert glucose to ATP without oxygen, I believe". This seems to require Oxygen. Can someone explain?

Thanks!

[reefedjib]

Promising field of research...

Nutritional genomics - Wikipedia, the free encyclopedia (http://en.wikipedia.org/wiki/Nutritional_genomics#Nutrigenetics_and_Type_2_Diab etes_mellitus)

[reefedjib]

Oligosaccharides
Raffinose, stachyose, and verbascose are made up of glucose, galactose, and fructose and are found in beans, peas, bran, and whole grains. Human digestive enzymes do not hydrolyze them, but the bacteria within the intestine can digest them. This is the basis for flatulence that occurs after eating these foods.

Knowledge is a powerful thing. ;););)

[reefedjib]

This is interesting. GLUT stands for glucose transporters.

...glucose is passively admitted to nearly all cells in the body by a carrier-mediated transport mechanism that does not require energy. The family of protein carriers involved in this process are called GLUTs

It goes on to list all 12 known GLUTs, whether they are regulated by insulin, and the tissues they correspond too:

Transporter Protein | Insulin Regulatable | Major Sites of Expression

GLUT1 | No | Erythrocytes, blood brain barrier, placenta, fetal tissues
GLUT2 | No | Liver, beta-cells of pancreas, kidney, small intestine
GLUT3 | No | Brains (neurons)
GLUT4 | Yes | Muscle, heart, brown and white adipocytes (fat cells)
GLUT5 | No | Intestine, testis, kidney
GLUT6 | No | Spleen, leukocytes, brain
GLUT7 | No | Unknown
GLUT8 | No | Testis, blastocyst, brain
GLUT9 | No | Liver, kidney
GLUT10 | No | Liver, pancreas
GLUT11 | No | Heart, muscle
GLUT12 | No | Heart, prostrate

So, only GLUT4 is regulated by insulin and feeds the Muscle and fat of the body.

GLUT4 ... is quite sensitive to insulin, and its concetration on the plasma membrane increases dramatically in response to the hormone. The increase in the membrane transporter population is accompanied by an accelerated increase in the uptake of glucose by the insulin-stimulated cells.

I just thought this was interesting.

More to come... ;););)

[ShottleBop]

Nutrition and Metabolism for Dummies (http://www.youtube.com/watch?v=mNYlIcXynwE)

[Real4]

The problem I am having is that I wrote earlier (read it somewhere) that "glycolysis is the metabolic pathway to convert glucose to ATP without oxygen, I believe". This seems to require Oxygen. Can someone explain?

Yes, without oxygen, the process stops at that point. There is a a net release of energy, but not near as much as if the process continued with oxygen.

Anaerobic bacteria, which at one time (the first billion years or so) were the only type of life on earth can process glucose only that far. There was big time climate change when chlorophyll containing bacteria came around and started producing the "poisonous" oxygen.

I hope this helps.

[reefedjib]

Yes, without oxygen, the process stops at that point. There is a a net release of energy, but not near as much as if the process continued with oxygen.

Anaerobic bacteria, which at one time (the first billion years or so) were the only type of life on earth can process glucose only that far. There was big time climate change when chlorophyll containing bacteria came around and started producing the "poisonous" oxygen.

I hope this helps.

Thanks for posting. This is a good starting point, but you say "There is a net release of energy, but near as much as if the process continued with oxygen.".

I know we can operate in anaerobic mode. That's what anaerobic exercize is all about (lifting weights).

I presume we need the same amount of energy.

So whatever metabolic process is providing energy anaerobically (without oxygen), it must be as efficient as the aerobic process (with oxygen: glycolysis -> citric acid cycle -> respiratory chain).

Is it the same pathway, just slightly changed to not use oxygen, or is it a completely new pathway?

[reefedjib]

Insulin is complicated. This brief discussion confuses me and I am trying to untangle it.

In general, insulin increases the expression or activity of enzymes that catalyze the synthesis of glycogen, lipids, and proteins. It also inhibits the expression or activity of enzymes that catalyze the catabolism of glycogen, lipids, and amino acids.

So insulin, through increasing active enzymes, produces more glycogen, lipids and protein.

And insulin, through decreasing active enzymes, prevents destroying glycogen, lipids and amino acids.

It is like for each one of glycogen, lipids and protein/amino acids there are two processes: one to create and one to destroy. Insulin promotes creation and suppresses destruction. In Frank's terminology, this is Fat-Storage Mode. Likewise, the absence of Insulin suppresses creation and promotes destruction. In Frank's terminology, this is Fat-Burning Mode.

Ok, this brain dump is helping me sort it out. The thing that was really tricky was the discussion of the enzymes that activate those metabolic processes. Thanks for listening!

[reefedjib]

Insulin also promotes the uptake of insulin, through GLUT4, into muscle and fat cells. I have read elsewhere that the mechanism of Insulin Resistence is that glucose is not uptaken (by GLUT4).

The question in my mind, related to the previous post, is whether the production of proteins and lipids is also impacted by diabetes?

Presumably, the production of glycogen is impacted since it needs glucose. Well, likewise, the production of lipids (triglycerides) would be impacted because of no glucose (for glycerol). But the production of proteins should be ok, unless the amino acid pump, in the cell membrane, is also impacted by IR.

Ruminations...

[reefedjib]

Thanks for posting. This is a good starting point, but you say "There is a net release of energy, but near as much as if the process continued with oxygen.".

I know we can operate in anaerobic mode. That's what anaerobic exercize is all about (lifting weights).

I presume we need the same amount of energy.

So whatever metabolic process is providing energy anaerobically (without oxygen), it must be as efficient as the aerobic process (with oxygen: glycolysis -> citric acid cycle -> respiratory chain).

Is it the same pathway, just slightly changed to not use oxygen, or is it a completely new pathway?

I did a search on Wikipedia on glycolysis (http://en.wikipedia.org/wiki/Glycolysis).

Glycolysis is thought to be the archetype of a universal metabolic pathway. It occurs, with variations, in nearly all organisms, both aerobic and anaerobic.

Furthermore, there is a wikipedia entry for Anaerobic Respiration (http://en.wikipedia.org/wiki/Anaerobic_respiration).

Anaerobic respiration is oxidation without oxygen which might well sound like a contradiction in terms. However, oxidation has come to mean any reaction like the oxidation of, say, carbon by oxygen - that is to say a reaction involving a transfer of electrons.

So the answer to my question is that it is the same pathway, glycolysis, which feeds the citric acid cycle (Krebs cycle, TCA cycle) and then the electron transport chain.

[reefedjib]

Here is my model so far:

Metabolic processes

glycogenesis: glucose -> glycogen
glycogenolysis: glycogen -> glucose
gluconeogenesis: amino acids -> glucose
lipogenesis: glucose, dietary fat -> triglycerides
glycolysis (aerobic and anaerobic): glucose -> acetyl coenzyme A
beta oxidation: fatty acids -> acetyl coenzyme A
deamination: amino acids -> acetyl coenzyme A
citric acid cycle, electron transport chain:acetyl coenzyme A, ADP -> ATP (stored energy)

Insulin

- Stimulates glucose uptake (GLUT4 transport)
- Stimulates tyrosine kinase system
-- General gene expression
-- Cell growth
-- Cell differentiation
-- Specific gene expression
-- Glucose metabolism
--- Glycogen
---- Stimulates enzyme for glycogen production (glycogenesis)
---- Inhibits enzyme (glucagon) for glycogen catabolism (glycogenolysis)
--- Lipids
---- Stimulates enzyme for lipid production (lipogenesis)
---- Inhibits enzyme for lipid catabolism (beta oxidation)
--- Proteins
---- Stimulates enzyme for protein production
---- Inhibits enzyme for protein catabolism (gluconeogenesis)

YMMV!! :D:D:D

[Dis-N-Dat]

Nutrition and Metabolism for Dummies (http://www.youtube.com/watch?v=mNYlIcXynwE)

Thank you! Even though they're ignoring us, I can't tell you how much I appreciate your post. My head was starting to hurt! :D

[reefedjib]

Yes, without oxygen, the process stops at that point. There is a a net release of energy, but not near as much as if the process continued with oxygen.

I have found that the glycolysis process continues anaerobically past pyruvate. I see what you mean about there being a reduced level of energy released and captured. Anaerobically, 1 glucose results in 2 ATP. Aerobically, 1 glucose results in 6 ATP.

I'm glad I caught up to what you were telling me! Thanks!

[reefedjib]

Thank you! Even though they're ignoring us, I can't tell you how much I appreciate your post. My head was starting to hurt! :D

Nutrition and Metabolism for Dummies sounds like a great title for another thread! :D You'll definitely have more traffic than this one. I feel like I am talking to myself, for the most part, but that's ok. It is helping me think about this stuff. If there is one person intrigued by this then all the better. You should read the stuff I am not posting about! Wow! I am skimming! ;)

[reefedjib]

Anaerobically, 1 glucose results in 2 ATP. Aerobically, 1 glucose results in 6 ATP.

Let me correct myself:

Aerobically, 1 glucose results in 34 ATP!

[reefedjib]

A few quotes on lipids:

Because triglycerides can be formed from glucose, hepatic triglyceride production is accelerated when the diet is rich in carbohydrate. The additional triglycerides results in VLDL overproduction and may account for the occasional transient hypertriacylglycerolemia in normal people when they consume diets rich in simple sugars.

Contrary to widespread belief, changing the amount of cholesterol in the diet has only a minor influence on blood cholesterol concentration in most people. This is because compensatory mechanisms are engaged, such as HDL activity in scavenging excess cholesterol and the down-regulation of cholesterol synthesis by dietary cholesterol. It is well known, however, that certain individuals respond strongly, and others weakly, to dietary cholesterol. This phenomenon, which may have a genetic basis, is further complicated by the observation that considerable within-person variability exists independent of diet, a fact that clearly confounds the results of intersubject studies.

Several mechanisms may be considered when trying to account for differences in individual responses to dietary cholesterol, including differences in:
- absorbtion or biosynthesis
- formation of LDL and its receptor-mediated clearance
- rates of LDL removal and excretion

More tomorrow...goodnight.

[reefedjib]

"Fatty acids are a very rich source of energy, and on an equal-weight basis they surpass carbohydrates in this property. This occurs because fatty acids exist in a more reduced state than that of carbohydrate and therefore undergo a greater extent of oxidation en route to CO2 and H2O."

[reefedjib]

"Ketone body formation is actually an “overflow” pathway for acetyl CoA use, providing another way for the liver to distribute fuel to peripheral cells. Normally, the concentration of the ketone bodies in the blood is very low, but it may reach very high levels in situations of accelerated fatty acid oxidation [beta oxidation] combined with low carbohydrate intake or impaired carbohydrate use.

Such a situation would occur in diabetes mellitus, starvation, or simply a very low carbohydrate diet. Recall from Chapter 3 that for the TCA cycle to function, the supply of four-carbon units must be adequate. These intermediates are formed mainly from pyruvate (formed during glycolysis). Without the oxidation of glucose, the supply of carbohydrate is inadequate and thus, the pool of oxaloacetate, with which the acetyl CoA normally combines for oxidation in the TCA cycle, is reduced. As carbohydrate use diminishes, oxidation of fatty acids accelerates to provide energy through the production of TCA cycle substrates (acetyl CoA). This shift to fat catabolism, coupled with reduced oxaloacetate availability, results in an accumulation of acetyl CoA. As would be expected, a sharp increase in ketone body formation follows, resulting in a condition known as ketosis. Ketosis can be dangerous because it can disturb the body’s acid-base balance (two of the ketone bodies are, in fact, organic acids). However, the liver’s ability to deliver ketone bodies to peripheral tissues such as the brain and muscle is an important mechanism for providing fuel in periods of starvation. In short, it is the lesser of two evils.
"

[reefedjib]

"Nearly all tissues in the body are capable of synthesizing cholesterol from acetyl CoA. The liver accounts for about 20% of endogenous cholesterol. Among the extrahepatic tissues, which are responsible for the remaining 80% of synthesized cholesterol, the intestine is probably the most active. The cholesterol production rate, which includes both absorbed cholesterol and endogenously synthesized cholesterol, approximates 1 g/day. Compare this with the recommended dietary intake of about 300 mg/day. The average cholesterol intake is considered to be about 600 mg/day, only about half of which is absorbed. Endogenous synthesis therefore accounts for more than two-thirds of the daily total."

[reefedjib]

"The regulation of fatty acid oxidation is closely linked to carbohydrate status. Fatty acids formed in the cytoplast of liver cells can either be converted into [triglycerides] or be transported via carnitine into the mitochondrion for oxidation. The enzyme carnitine acyl transferase I, which catalyzes the transfer of fatty acyl groups to carnitine, is specifically inhibited by malonyl CoA. Recall that malonyl CoA is the first intermediate in the synthesis of fatty acids. Therefore, it is logical that an increase in the concentration of malonyl CoA would promote fatty acid synthesis while inhibiting fatty acid oxidation. Malonyl CoA concentration increases whenever a person is well supplied with carbohydrate. Excess glucose that cannot be oxidized through the glycolytic pathway or stored as glycogen is converted to [triglycerides] for storage, using the available malonyl CoA. Therefore, glucose-rich cells do not actively oxidize fatty acids for energy. Instead, a switch to lipogenesis is stimulated, accomplished in part by inhibition of the entry of fatty acids into the mitochondrion.

Blood glucose levels can affect lipolysis and fatty acid oxidation by other mechanisms as well. Hyperglycemia triggers the release of insulin, which promotes glucose transport into the adipose cell [fat cell] and therefore promotes lipogenesis. Insulin also exerts a pronounced antilipolytic effect. Hypoglycemia, on the other hand, results in a reduced intracellular supply of glucose, thereby suppressing lipogenesis. Furthermore, the low level of insulin accompanying the hypoglycemic state would favor lipolysis, with a flow of free fatty acids into the bloodstream. Low glucose levels also stimulate the rate of fatty acid oxidation in the manner described in the section dealing with ketone bodies. In this case, accelerated oxidation of fatty acids follows the reduction in TCA cycle activity, which in turn results from inadequate oxaloacetate availability."

[fgummett]

Blood glucose levels can affect lipolysis and fatty acid oxidation by other mechanisms as well. Hyperglycemia triggers the release of insulin, which promotes glucose transport into the adipose cell [fat cell] and therefore promotes lipogenesis. Insulin also exerts a pronounced antilipolytic effect. Hypoglycemia, on the other hand, results in a reduced intracellular supply of glucose, thereby suppressing lipogenesis. Furthermore, the low level of insulin accompanying the hypoglycemic state would favor lipolysis, with a flow of free fatty acids into the bloodstream. Low glucose levels also stimulate the rate of fatty acid oxidation in the manner described in the section dealing with ketone bodies. In this case, accelerated oxidation of fatty acids follows the reduction in TCA cycle activity, which in turn results from inadequate oxaloacetate availability."Translation:

High BG drives high insulin which not only increases the storage of fat but also prevents the burning of fat for energy... AKA "Fat Storage mode".

Low BG leads to lower insulin levels, slows down fat storage and allows fat burning for energy... AKA "Fat Burning mode".

So what causes the high or low BG..?

[reefedjib]

Translation:

High BG drives high insulin which not only increases the storage of fat but also prevents the burning of fat for energy... AKA "Fat Storage mode".

Low BG leads to lower insulin levels, slows down fat storage and allows fat burning for energy... AKA "Fat Burning mode".

So what causes the high or low BG..?

I think it would mainly be diet. High carbohydrates equals high BG. Secondarily, insufficient insulin would leave you with high BG longer. [Edit - oops, I think we missed something. In your translation you say high BG/low BG. It is actually the intracellular glucose that is important here. So low insulin or high IR may still mean low intracellular glucose].

Insulin resistence I have questions about. If you have a high insulin concentration, but it is ineffective in pumping glucose into cells, you would have a high BG longer. My question with IR is what other activities of insulin are affected by IR?

After the next Chapter on Protein, there are chapters on Regulation of Metabolism and Energy Balance. I know those are supposed to get into diabetes issues.

[reefedjib]

Translation:

High BG drives high insulin which not only increases the storage of fat but also prevents the burning of fat for energy... AKA "Fat Storage mode".

Low BG leads to lower insulin levels, slows down fat storage and allows fat burning for energy... AKA "Fat Burning mode".

So what causes the high or low BG..?

So, let's try again:

One mechanism (malonyl CoA) applies to intracellular glucose levels...

Therefore, glucose-rich cells do not actively oxidize fatty acids for energy. Instead, a switch to lipogenesis is stimulated, accomplished in part by inhibition of the entry of fatty acids into the mitochondrion.

Another mechanism is based of blood glucose and insulin...

Insulin also exerts a pronounced antilipolytic effect.

Lot's of moving parts to this puzzle. Here is a stab at summarizing:

High BG, High Insulin, Normal IR, High intracellular G: lipogenesis on, lipolysis off "Fat Storage Mode"
Low BG, Low Insulin, Normal IR, Low intracellular G: lipogenesis off, lipolysis on "Fat Burning Mode"

High BG, Low Insulin, Normal IR, Low intracellular G: lipogenesis off, lipolysis on "Type 1 Diabetes - Fat Burning Mode???"

High BG, High Insulin, High IR, Low intracellular G: lipogenesis off, lipolysis off "Type 2 Diabetes - Fat Homeostasis???"

Low BG, High Insulin, Normal/High IR, Low intracellular G: lipogenesis off, lipolysis off "Hypoglycemia - out of fuel"

[reefedjib]

Metabolic pathways

glycogenesis: glucose -> glycogen
glycogenolysis: glycogen -> glucose
gluconeogenesis: amino acids -> glucose
lipogenesis: glucose, amino acids, dietary fat -> triglycerides
lipolysis: triglycerides -> glycerol, fatty acids
glycolysis (aerobic): glucose -> pyruvate
glycolysis (anaerobic): glucose, ADP -> ATP
beta oxidation (mitochondrial): fatty acids, ADP -> acetyl coenzyme A, ATP
deamination: amino acids -> acetyl coenzyme A
pyruvate decarboxylation (mitochondrial): pyruvate -> acetyl coenzyme A
TCA cycle, citric acid cycle (aerobic - mitochondrial): acetyl coenzyme A, ADP -> ATP (stored energy)

Insulin

- Stimulates glucose uptake (GLUT4 transport)
- Stimulates tyrosine kinase system
-- General gene expression
-- Cell growth
-- Cell differentiation
-- Specific gene expression
-- Metabolism
--- Glycogen
---- promotes enzyme (glucokinase) for glycogen production (glycogenesis)
---- inhibits enzyme (glucagon, epinephrine) for glycogen catabolism (glycogenolysis)
--- Lipids
---- promotes enzyme (lipoprotein lipase) for lipid production (lipogenesis)
---- inhibits enzyme (intracellular lipase) for lipid catabolism (lipolysis)
--- Proteins
---- promotes enzyme for protein production (glycolysis)
---- inhibits enzyme for protein catabolism (gluconeogenesis)

Blood glucose

Hypoglycemia
- promotes growth hormone
Hyperglycemia
- inhibits growth hormone

Hormones

insulin: transports glucose into cells and stimulates/inhibits enzymes
glucokinase: promotes glycogenesis
glucagon: promotes glycogenolysis
epinephrine: promotes glycogenolysis
amylin: inhibits glucagon and produces satiety
growth hormone: promotes lipolysis, gluconeogenesis; inhibits glycogenesis
lipoprotein lipase: promotes lipogenesis

[reefedjib]

Primary structure – covalent bonding into a polypeptide chain
Secondary structure – weak (hydrogen) bonding into alpha-helixes and beta-pleated sheets
Tertiary structure – 3D folding due to bonding within the side chains
Quaternary structure (optional) – bonding between polypeptide chains.

"Some heat shock proteins are thought to facilitate protein folding (that is the formation of the secondary and tertiary protein structures) as the proteins are synthesized in cells."

[reefedjib]

"The liver is the primary site for the uptake of most amino acids (about 50%-65%) following ingestion of a meal. The liver is thought to monitor the absorbed amino acids and to adjust the rate of their metabolism (including catabolism, or breakdown of amino acids, and anabolism, or use of amino acids for synthesis) according to the needs of the body. Typically, of the amino acids entering the liver after a meal, about 20% are used to synthesize proteins and nitrogen-containing compounds; of this 20% of amino acids used for synthesis, most of what is synthesized remains in the liver, and the rest is released into the plasma."

[reefedjib]

"Use of amino acids for anabolism occurs throughout the day, but especially following meal ingestion (foods containing carbohydrate, fat, and protein). The amino acids from the diet as well as those generated from degradation of body proteins are metabolized for various roles in various tissues and are used for the synthesis of various body proteins. Insulin secreted in response to carbohydrate (and protein) ingestion promotes cellular uptake and use of the amino acids for protein synthesis. For example, insulin affects (generally stimulates) the transcellular movement of amino acid transporters to the membrane and the activity of several amino acid transporters including, for example, system A, ASC, and N in the liver, muscle, and other tissues. Insulin also antagonizes the activation of some enzymes responsible for amino acid oxidation. [] However, should blood glucagon concentrations predominate over insulin as may occur in fasting situations and with untreated diabetes, some amino acids are preferentially used for glucose synthesis (gluconeogenesis). Thus, typically in a healthy person, with eating, protein synthesis increases in the body and degradation of body proteins decreases.

Although protein synthesis typically predominates over protein degradation after eating, the opposite becomes true when food is not eaten. During prolonged periods in which food is not eaten, such as during the overnight hours or a fast, protein synthesis still occurs but at a much lower rate, and protein degradation increases. The tissue that experiences the most protein degradation during these postabsorbtive periods is the skeletal muscle. The degradative process is stimulated by cortisol release and by the higher glucagon to insulin ratio in the blood. Amino acids generated from the degradation of protein can be further catabolized for various uses by the body[.]"

[reefedjib]

"The secretion of insulin, glucagon, growth hormone, and glucocorticoids increases in response to elevated concentrations of selected amino acids. In general, increased protein synthesis, decreased protein degradation, and positive nitrogen balance are promoted by insulin, whereas the counterregulatory hormones, glucagon, epinephrine, and glucocorticoids have an opposite effect, promoting overall protein degradation and a negative nitrogen balance. Growth hormone, though counterregulatory, is anabolic, like insulin."

Counterregulatory hormone - Wikipedia, the free encyclopedia (http://en.wikipedia.org/wiki/Counterregulatory_hormone)

[reefedjib]

Just read the wikipedia.... (I don't want to type it in ;) )

Insulin resistance - Wikipedia, the free encyclopedia (http://en.wikipedia.org/wiki/Insulin_resistance)

[reefedjib]

Type 2 diabetes accounts for 80% to 90% of all reported cases of the disease. The cause of type 2 diabetes has not been completely resolved, but it appears to be associated with insulin resistance in adipose [fat] tissue and muscle. This condition is caused not by a failure of target cells to bind insulin but by a postbinding abnormality, arising somewhere in the sequence of events that follows the binding of insulin to its receptor []. Experimental evidence suggests that a primary cause for the interrupted signal may be compromised synthesis or mobilization of the cell’s glucose transporters [(GLUT4)].
…
In summary, type 2 diabetes is characterized by insulin resistance in peripheral target tissues because of a diminished population of functional glucose transporters [(GLUT4)]. In muscle cells, the defect appears to arise from a failure, on insulin stimulation, of vesicle-bound transporters to translocate to the plasma membrane. In adipocytes [fat cells], translocation is also compromised, but the major mechanism for insulin resistance in these cells, in both type 2 diabetes and obesity, is a pretranslational depletion of GLUT4 mRNA. In the latter stages of type 2 diabetes, the pancreas loses its ability to produce insulin.

[reefedjib]

Well folks, those of you still with me, I have read all I am going to read out of my book. The rest is Body Composition, and the Metabolism of Vitamins and Minerals. I just don't care about that stuff.

Thanks for listening. :)

[reefedjib]

Fed state
Insulin
- Stimulates glucose uptake (GLUT4 transport – promotes glucose transporter, glucokinase)
- Stimulates tyrosine kinase system
-- General gene expression
-- Cell growth
-- Cell differentiation
-- Specific gene expression
-- Metabolism
--- Glycogen
---- promotes glucogen synthase for glycogen production (glycogenesis)
---- inhibits glucogen phosphorylase for glycogen catabolism (glycogenolysis)
--- Lipids
---- promotes lipoprotein lipase for lipid production (lipogenesis)
---- inhibits intracellular lipase for lipid catabolism (lipolysis)
--- Proteins
---- promotes enzyme for protein production (glycolysis)
---- inhibits enzyme for protein catabolism (gluconeogenesis)


Early fasting, fasting, starvation states
Glucagon
- promotes glucogen phosphorylase for glyceride catabolism (glycogenolysis)
- promotes enzyme for glucose production (gluconeogenesis)
- promotes enzyme for triglyceride catabolism (lipolysis)
- promotes enzyme for fatty acid catabolism (beta oxidation)

Epinephrine (Adrenaline)
- promotes enzyme for glucose production (glycogenolysis)
- promotes enzyme for glucose production (gluconeogenesis)

Norepinephrine


Blood glucose
Hypoglycemia
- promotes growth hormone
Hyperglycemia
- inhibits growth hormone

Metabolic pathways
glycogenesis: glucose -> glycogen
glycogenolysis: glycogen -> glucose
gluconeogenesis: amino acids, glycerol -> glucose
cholesterogenesis: acetyl coenzyme A -> cholesterol
lipogenesis: fatty acids -> triglycerides
fatty acid synthesis: acetyl coenzyme A -> fatty acids
lipolysis: triglycerides -> glycerol, fatty acids
cholesterogenesis: acetyl coenzyme A -> cholesterol
glycolysis (aerobic): glucose -> pyruvate
glycolysis (anaerobic): glucose, ADP -> ATP
beta oxidation (mitochondrial): fatty acids, ADP -> acetyl coenzyme A, ATP
deamination: amino acids -> acetyl coenzyme A
pyruvate decarboxylation (mitochondrial): pyruvate -> acetyl coenzyme A
TCA cycle, citric acid cycle (aerobic - mitochondrial): acetyl coenzyme A, ADP -> ATP (stored energy)

Enzymes
glucose transporter: promotes glucose uptake
glucokinase: promotes glucose uptake
glucogen synthase: promotes glycogenesis
glucogen phosphorylase: promotes glycogenolysis
phosphofructokinase-1: promotes glycolysis
pyruvate dehydrogenase complex: promotes glycolysis
acetyl CoA carboxylase: promotes lipogenesis
growth hormone: promotes lipolysis, gluconeogenesis; inhibits glycogenesis
lipoprotein lipase: promotes lipogenesis
intracellular lipase: promotes lipolysis, beta oxidation

:)

[butterflykisses]

Thanks Rob, you had at least one person in the back seat along for the ride. :D

[reefedjib]

Let's try again, with all the information I think I have.

Normal Fat Storage Mode
High BG, High Insulin, Normal IR, High intracellular G: lipogenesis on, lipolysis off "Fat Storage Mode"
High BG, High Insulin, Normal IR, High intracellular G
- GLUT4 glucose uptake on
- glycogenesis on
- glycogenolysis off
- lipogenesis on (Store Fat)
- lipolysis off
- beta oxidation off
- amino acid synthesis on
- protein synthesis on
- gluconeogenesis off


Normal Fat Burning Mode
Low BG, Low Insulin, Normal IR, Low intracellular G: lipogenesis off, lipolysis on "Fat Burning Mode"
Low BG, Low Insulin, Normal IR, Low intracellular G
- GLUT4 glucose uptake off
- glycogenesis off
- glycogenolysis on
- lipogenesis off
- lipolysis on (Burn Fat)
- beta oxidation on
- amino acid synthesis off
- protein synthesis off
- gluconeogenesis on


Type 1 Diabetes Fat Burning Mode
High BG, Low Insulin, Normal IR, Low intracellular G: lipogenesis off, lipolysis on "Type 1 Diabetes - Fat Burning Mode???"
High BG, Low Insulin, Normal IR, Low intracellular G
- GLUT4 glucose uptake off
- glycogenesis off
- glycogenolysis on (Synthesize Glucose)
- lipogenesis off
- lipolysis on (Burn Fat)
- beta oxidation on
- amino acid synthesis off
- protein synthesis off
- gluconeogenesis on (Synthesize Glucose)

So here, you have a high BG which gets even higher because of glycogenolysis and gluconeogenesis. Does this pass the sanity test? Is this what happens?


Type 2 Diabetes Fat Homeostasis Mode
High BG, High Insulin, High IR, Low intracellular G: lipogenesis off, lipolysis off "Type 2 Diabetes - Fat Homeostasis???"
High BG, High Insulin, High IR, Low intracellular G
- GLUT4 glucose uptake off (Insulin Resistence - Faulty Uptake)
- glycogenesis starved (Low cellular glucose)
- glycogenolysis off
- lipogenesis starved (Low cellular glucose???)
- lipolysis off
- beta oxidation off
- amino acid synthesis starved (Low cellular glucose)
- protein synthesis starved (Low cellular glucose)
- gluconeogenesis off

I have no idea if this is right. What mechanism causes obesity? Lipogenesis must be occuring...


Hypoglycemia Mode
Low BG, High Insulin, Normal/High IR, Low intracellular G: lipogenesis off, lipolysis off "Hypoglycemia - out of fuel"
Low BG, High Insulin, Normal/High IR, Low intracellular G
- GLUT4 glucose uptake on
- glycogenesis on
- glycogenolysis off (No glucose production)
- lipogenesis on
- lipolysis off (No fatty acid production)
- amino acid synthesis on
- protein synthesis on
- gluconeogenesis off (No glucose production)

BG drops lower and lower as GLUT4 uptakes. Energy drops as glucose is starved and lipolysis is off, so fatty acids are starved.

[reefedjib]

Thanks Rob, you had at least one person in the back seat along for the ride. :D

Sweet! I hope you have enjoyed it, Katherine. It was a little bumpy. :)

[yannah]

holy cr ap rob. we all know I cannot possibly hang with this.

all I know is that when bllod sugar is high. your insulin is running all the time and you get fat. and as your get fat IR gets worse and as it gets worse, blood sugar is higher, which then drives insulin and you are diabetic.

so........

nope thats it.

the idea then is to lower bs, lower insulin, loose wieght and try to keep bad stuff from happening.

thats all I got.

[reefedjib]

Hey thanks for reading! I have no idea what the mechanism is for type 2 getting fat. I'll keep trying to figure it out.

Cheers!

[reefedjib]

I reworked the metabolic pathways and ensured they were correct. I also reworked the insulin metabolic effect and I have a few questions about some of the pathways they may or may not affect (promotes fatty acid synthesis, amino acid synthesis. inhibits beta oxidation).

Metabolic pathways
glycogenesis: glucose -> glycogen
glycogenolysis: glycogen -> glucose
lipogenesis: fatty acids -> triglycerides
lipogenesis: fatty acids -> triglycerides
fatty acid synthesis: acetyl coenzyme A -> fatty acids
lipolysis: triglycerides -> glycerol, fatty acids
cholesterogenesis: acetyl coenzyme A -> cholesterol
gluconeogenesis: glucogenic amino acids, glycerol -> glucose
transamidation: amino acids -> keto acid (enters TCA cycle)
protein synthesis (translation): amino acids -> proteins
proteolysis: proteins -> fatty acids
amino acid synthesis: glucose, fatty acids -> amino acids
glycolysis (aerobic): glucose -> pyruvate
glycolysis (anaerobic): glucose, ADP -> ATP
pyruvate decarboxylation (mitochondrial): pyruvate -> acetyl coenzyme A
beta oxidation (mitochondrial): fatty acids -> acetyl coenzyme A
deamination (mitochondrial): amino acids -> acetyl coenzyme A
TCA cycle, citric acid cycle, Krebs cycle (mitochondrial): acetyl coenzyme A -> NADH, succinate
TCA cycle, citric acid cycle, Krebs cycle (mitochondrial): keto acid -> NADH, succinate
electron transport chain (mitochondrial): NADH, ADP -> NAD+, ATP (stored energy)
electron transport chain (mitochondrial): succinate, ADP -> fumarate, ATP (stored energy)

Insulin
- Stimulates glucose uptake (GLUT4 transport – promotes glucose transporter, glucokinase)
- Stimulates amino acid uptake
- Stimulates tyrosine kinase system
-- General gene expression
-- Cell growth
-- Cell differentiation
-- Specific gene expression
-- Metabolism
--- Glycogen
---- promotes glycogenesis
---- inhibits glycogenolysis
--- Lipids
---- promotes lipogenesis
---- promotes fatty acid synthesis ???
---- inhibits lipolysis
---- inhibits beta oxidation ???
--- Proteins
---- promotes protein synthesis
---- promotes amino acid synthesis ???
---- inhibits gluconeogenesis
---- inhibits proteolysis

[reefedjib]

Given the previous post, I reworked the situation with Type 2 Diabetes, here. From earlier, I showed Normal Fat Burning Mode and Normal Fat Storage Mode as well as Type 1 High BG, Low Insulin Mode and Hypoglycemia Mode. Those all made sense. Type 2 does not. Hopefully, someone will decide to comment on this and we can have a conversation, Frank, Doug, anyone...

What we know about Type 2
- High blood glucose
- Fat storage
- High blood triglycerides
- High blood VLDL
- High blood LDL
- High blood cholesterol
- Low energy - lethargic

Type 2 Diabetes Fat Homeostasis Mode
High BG, High Insulin, High IR, Low intracellular G
- glucose uptake off (GLUT4) (Insulin Resistence - Faulty Uptake)
- amino acid uptake on
- glycogenesis starved (Low cellular glucose)
- glycogenolysis off
- lipogenesis starved (Low cellular glucose???)
- fatty acid synthesis starved ??? (Low cellular glucose???)
- lipolysis off
- beta oxidation off ???
- protein synthesis starved (Low cellular glucose)
- amino acid synthesis starved ??? (Low cellular glucose???)
- gluconeogenesis off
- proteolysis off

I have no idea if this is right. What mechanism causes obesity? Lipogenesis must be occuring. Could it be that the liver, the adipose tissue and the muscles are reacting differently? If the GLUT4 in the liver were working, then lipogenesis and fatty acid synthesis could be working. The mechanism for storing fat into adipose tissue will be working as they uptake triglycerides, LDL, and VLDL.

[reefedjib]

And another thing to add to the list of Type 2 conditions:

What we know about Type 2
- High blood glucose
- Fat storage
- High blood triglycerides
- High blood VLDL
- High blood LDL
- High blood cholesterol
- Low energy - lethargic
- Increasing concentration of insulin required to uptake glucose

At first, Type 2 can control blood sugar through diet and exercise. But then we need meds, and ultimately insulin to overcome IR. I read somewhere that they think the insulin is getting to the receptors, but that the response is impaired. I don't see how increasing the concentration of insulin through exogenous insulin injections can make the response occur.

[fgummett]

It's like shouting in the ear of a person with impaired hearing...

[reefedjib]

It's like shouting in the ear of a person with impaired hearing...

I'm here trying to learn and, if I can, help others learn. If you aren't willing to help me do that, or help me get past my own disabilities, then shut the f uck up!

[fgummett]

Big misunderstanding... :eek: At first, Type 2 can control blood sugar through diet and exercise. But then we need meds, and ultimately insulin to overcome IR. I read somewhere that they think the insulin is getting to the receptors, but that the response is impaired. I don't see how increasing the concentration of insulin through exogenous insulin injections can make the response occur. It's like shouting in the ear of a person with impaired hearing...Increase the stimulus to elicit the previous response... :D

[Granny Shanny]

I'm here trying to learn and, if I can, help others learn. If you aren't willing to help me do that, or help me get past my own disabilities, then shut the **** up!

Simmer down, big fella - I think he's agreeing with you . . .

[foxl]

It's like shouting in the ear of a person with impaired hearing...

This is great analogy for using insulin in a T2D with a high C-peptide!

[slipperyelm]

I don't see how increasing the concentration of insulin through exogenous insulin injections can make the response occur.

Do you have a science background, by chance? It's has been about twenty years since I had classes in chemistry, microbiology, cell biology, etc. I, too, keep wishing someone would turn up in these forums who understands this question about insulin. But I do vaguely remember that hormone mediated reactions can sometimes be classified according to rate law. Remember zero order equations, first order equations, second order equations? Those factor concentrations.

However, with insulin, there are multiple reactions taking place. Over time we see increasing levels of insulin building greater insulin resistance, leading to more need of insulin. So the puzzle continues, I agree.

Sorry, not an answer. I share your puzzlement

Rate equation - Wikipedia, the free encyclopedia (http://en.wikipedia.org/wiki/Rate_equation)

[Dis-N-Dat]

Rob this was great. I was trying to be funny, not flipant before, but I really did find this fascinating.

Now my question is on the role of genetics in all of this, where/when is the intersection? If it were only possible to not just turn off the problematic genetic interaction, but to fundamentaly transform it... hmmm.

[yannah]

RRRRRRRRRRRRRRoooooooooooooooooBBBBBBBBBBBB!


(((((((((((((((((((((((YOU))))))))))))))))))))).

[reefedjib]

Big misunderstanding... :eek:

Very big! I am so embarrassed. :o:o:o I thought that you weren't going to bother talking to me, as it must be exacerbating. Please excuse the misunderstanding and the language, Frank. Give me some context next time. That would have helped a lot!

Seems that I'll have to start taking my meds again... :(

[fgummett]

No worries Rob... you're not the first to take my posts the wrong way... I think it must be my upper-class British accent :whistling

It's hard to strike a balance sometimes... if I'm referring back to an earlier post I'll usually quote it but if it's the one just above I don't always... as it can just make the thread longer and longer.

[reefedjib]

Good deal. :beer:

I would like to point out that electrons are cheaper than misunderstandings... DF seems to have the disk space.

[reefedjib]

It's like shouting in the ear of a person with impaired hearing...

So why is the "hearing" impaired?

I mean I am not so concerned with beta-cell burnout from high BG. They recover when rested.

Evidently, the "hearing" or IR can get better too. Nonetheless, it starts out small and gets worse over time. I read somewhere that in Type 2, the insulin is getting to the GLUT4 receptor and presumable tripping the tyrosine kinase to signal secondary hormones to affect enzymes and thus the metabolic pathways.

If it is tripping the receptor, then it is a problem within the cell. It makes me wonder if only some of the activity is impaired or all of it. Evidently the glucose uptake is impaired. Don't know whether the other metabolic stuff is impaired.

Another thing is that this is a systemic problem. It isn't as if the transcription of proteins in one cell is faulty. Whatever the problem is, it is affecting all cells of certain types (adipose and muscle). The liver seems to be happily creating fatty acids and triglycerides.

Here is a good link:
Physiologic Effects of Insulin (http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_phys.html)

[reefedjib]

Do you have a science background, by chance? It's has been about twenty years since I had classes in chemistry, microbiology, cell biology, etc. I, too, keep wishing someone would turn up in these forums who understands this question about insulin. But I do vaguely remember that hormone mediated reactions can sometimes be classified according to rate law. Remember zero order equations, first order equations, second order equations? Those factor concentrations.

However, with insulin, there are multiple reactions taking place. Over time we see increasing levels of insulin building greater insulin resistance, leading to more need of insulin. So the puzzle continues, I agree.

Sorry, not an answer. I share your puzzlement

Rate equation - Wikipedia, the free encyclopedia (http://en.wikipedia.org/wiki/Rate_equation)

I do have a science background, but not in biology or chemistry, although I took physical chemistry in college. I am into physics. I start my phd program, in physics, on Wednesday. It should take about 8 years...

I want to specialize in biophysics. I thought it would be about protein folding, in the ribosomes of the endoplasmic reticulum. I got this hunch that some of the non-essential nucleotides (that don't specify amino acids for the polypeptide chain) are used to specify folding instructions. Now I want to understand Insulin Resistence. Maybe I could combine the two, if IR is found to be a protein synthesis problem?

Never seen a rate law governing a reaction before. Thanks for the link. If k is dependent on BG levels and free fatty acid/LDL/VLDL levels, then perhaps that is a way to specify the IR effect of a reaction.

The puzzle continues... :)

[fgummett]

So why is the "hearing" impaired? I'll be Frank that some of the science you're discussing is over my head but my simple understanding of IR is -- at least initially -- a down-regulation mechanism resulting from many years (perhaps as many as 20) of frequent/constant high insulin levels working to control the potential high BGs that occur from our Western diet being so abundant in refined/concentrated carbohydrates.

Simply put: we are not adapted to eat so much sugar and after years of trying to manage our BGs the system starts to fail.

My favourite analogy for "down-regulation" is people living close to a busy road... after a while they don't even notice the noise of the traffic... and they may even have trouble sleeping when on holiday somewhere quiet.

I further understand that IR is related to excess fat mass in that more stored fat seems to make IR worse, while less seems to lessen the IR.

Another point I have read about IR is that it can affect different cells differently... so if (as may well be the case) our muscle cells are more affected by IR than our fat cells... then the amount of insulin we need to secrete to allow glucose into our muscles will have that much more effect on fat storage.

[reefedjib]

Rob this was great. I was trying to be funny, not flipant before, but I really did find this fascinating.

I know you were being funny! The thing is, is that I had my head buried in that book, trying to come up to speed on this stuff. I only got 3 hours of sleep Sturday night - I couldn't stop thinking about it!

Now my question is on the role of genetics in all of this, where/when is the intersection? If it were only possible to not just turn off the problematic genetic interaction, but to fundamentaly transform it... hmmm.

My thoughts on this are that IR is a phenotype problem and not a genotype problem. In other words, it is environmental/metabolic problem and not a DNA coding problem.
- it is systemic: it affects many, many cells and not just a few. I haven't ever heard of a genetic mutation spreading through the phenotype.
- it is onset: there isn't a problem with IR for many years, then it starts happening and it grows. I have heard that with rest (diet/exercise/insulin/low BG), not only does the beta cells recover, but IR lessens.
- it can be overcome: a higher dose of exogenous insulin will clear the vascular system of glucose and kickstart any metabolic pathways that were not working.

Now, the affected metabolic pathways could be involved in protein synthesis but this would have to be highly specific to one or a few proteins. Everything else seems to work fine in the cell.

Don't know where that leaves us.

[reefedjib]

Another point I have read about IR is that it can affect different cells differently... so if (as may well be the case) our muscle cells are more affected by IR than our fat cells... then the amount of insulin we need to secrete to allow glucose into our muscles will have that much more effect on fat storage.

That is something I have been wondering about. Muscle is a high percentage of our body mass and a significant consumer of glucose. The liver has a GLUT2 glucose transporter, which isn't insulin dependent, so glucose (spice) can flow. (The Spice must flow! ;) ) Insulin can trip the liver's receptors and the liver can do the whole fatty acid synthesis and lipogenesis thing and produce triglycerides. Fat and muscle both use GLUT4 glucose transporters so maybe they are both affected, but fat, though it may be blocking glucose, can uptake triglycerides that the liver has produced. Get fat.

[reefedjib]

Thanks Kelli. Right back at you!

I tried to do it back to you, but all my uppercase were turned to lowercase! :(

[Dis-N-Dat]

Good deal. :beer:

I would like to point out that electrons are cheaper than misunderstandings... DF seems to have the disk space.


ROFLOL Rob! :D :D :D

[reefedjib]

How does this sound? (it's a bit involved, but I'll try to do it orderly)

Thesis: the body, or most of it, is burning fat when the person is Type 2 and there is high BG.

Muscle and adipose tissue (fat cells) make up a large percentage of our body mass (75%???).

The liver is what makes fatty acids (called elongation) from glucose. "VLDL's carry lipids synthesized by the liver to body cells"

Now, there are two glucose transporters in question: GLUT2 and GLUT4. GLUT2 is always working when there is a high BG. GLUT4 only works when there is Insulin, but IR limits this.

- The liver cell has GLUT2, so with high BG, there is lots of glucose in the cell.
- The muscle and fat cells have GLUT4, and it isn't working because of IR, so with high BG, there is little glucose in the cells.

Next, insulin turns on fatty acid synthesis in the liver.

"Metabolism and homeostasis of fatty acid synthase is transcriptionally regulated by Upstream Stimulatory Factor (USFs) and sterol regulatory element binding protein-1c (SREBP-1c) in response to feeding/insulin in living animals"

So, the liver, with lots of glucose, is synthesizing fatty acids and through lipogenesis is building triglycerides and pumping them out into the bloodstream.

Now with the glucose starved muscle and fat cells, they can't burn glucose. However, they are getting a steady supply of Triglycerides. If lipolysis is on (???), then they will break the triglyceride into fatty acids and beta oxidation will burn the fatty acid as fuel. Fatty acids carries much more energy than glucose.

Fat cells will also be storing Triglycerides. So you get fat too.

So, the liver is building fatty acids and triglycerides and shipping them out.
Muscle and fat are starved for glucose and slurping in triglycerides and burning the fatty acids.
Fat is storing triglycerides.

Since only 25% of the body is consuming glucose (???), the high BG will last longer. The liver will make a lot of fatty acids.

Sound plausible? Comments?

This still doesn't explain why increased insulin can overcome IR. I am very curious about that.

[reefedjib]

Thesis: the body, or most of it, is burning fat when the person is Type 2 and there is high BG.

Partially wrong.



If lipolysis is on (???), then they will break the triglyceride into fatty acids and beta oxidation will burn the fatty acid as fuel.

Wrong. Lipolysis is off. There is no Glucagon being released by the alpha-cells of the pancreas because it is in a high BG environment. Glucagon turns on lipolysis. Plus the counterpart metabolic pathway, lipogenesis, is on. I believe this blocks lipolysis. So, in muscle and fat cells, there is no breakdown of triglycerides into fatty acids.

I do think the muscle and fat cells may be burning Free Fatty Acids through beta oxidation, but I don't know how many Free Fatty Acids are in the system.


Summary
So, the liver is building fatty acids and triglycerides and shipping them out.

Right on!

Muscle and fat are starved for glucose ...

Right on!

... and slurping in triglycerides [, breaking them down into fatty acids,] ...

No way, Jose!

... and burning the fatty acids.

Right on!

Fat is storing triglycerides.

Right on!

So, what are fat and muscle cells using for fuel?

[reefedjib]

I have two interests:

1) What is the metabolic homeostasis of a Type 2 Diabetic with high IR, after a meal, with high BG?

2) What is the mechanism of IR? (problems with the Insulin Signal Transduction)

[fgummett]

My basic understanding is simpler than the way you describe things:

over many years of eating too many refined/concentrated carbohydrates (sugar) with the resulting constant high levels of insulin... IR starts to manifest itself (a down-regulation mechanism, like living near a noisy road). This leads to increasingly higher insulin levels just to do the same work as before.

Insulin is a major fat storage hormone: while insulin levels are high we can only make fat, we cannot burn it. So we start to put on excess fat mass BUT at the same time the mechanisms to convert BG to fat are working overtime (high insulin levels and not so much IR in fat cells) so to answer you question about what the rest of the body is using for energy... nothing! It is starving in the midst of plenty... hence the phenomenon of someone eating a double-big mac, biggie fries and super-sized coke AND still being hungry... at the cellular level they actually are hungry!

I have experienced this myself and I have also experienced the degree of control which comes back to a person when they switch out of "fat storage mode" and into "fat burning mode" -- reducing the levels of insulin by avoiding the foods which drive insulin levels up... by cutting out the refined/concentrated carbohydrates. But, of course, YMMV... especially if you are Type 1 whose default position (low insulin levels) is to be constantly in "fat burning mode"

Have you read Gary Taubes "Good Calories Bad Calories" yet? I really think you should.

The move "Fat Head" is a light hearted way of expressing this same concept. YouTube - Why You Got Fat (http://www.youtube.com/watch?v=mNYlIcXynwE&feature=related)

[fgummett]

To clarify my statement above "over many years of eating too many refined/concentrated carbohydrates"... I'm not suggesting that we have been "stuffing our faces" or overeating but rather that the "Western" diet (especially since low-fat came into vogue) has too high a proportion of refined/concentrated carbohydrates which quickly break down to sugars and leads to the rest of the scenario I discussed above.

In other words: I'm suggesting that too much of the food on offer in our grocery stores and eateries is high GI index... I'm NOT saying that we start out eating too much food, although you may gather from my discussion how, over time, this kind of food can lead to increased hunger.

---

Look at what many are led to believe is a"healthy" breakfast: OJ, cereal with skimmed milk, toasted bagel with jam etc...

[reefedjib]

My basic understanding is simpler than the way you describe things:

over many years of eating too many refined/concentrated carbohydrates (sugar) with the resulting constant high levels of insulin... IR starts to manifest itself (a down-regulation mechanism, like living near a noisy road). This leads to increasingly higher insulin levels just to do the same work as before.

Ok.

Insulin is a major fat storage hormone: while insulin levels are high we can only make fat, we cannot burn it.

I am going to go back on what I said earlier...

Wrong. Lipolysis is off. There is no Glucagon being released by the alpha-cells of the pancreas because it is in a high BG environment. Glucagon turns on lipolysis. Plus the counterpart metabolic pathway, lipogenesis, is on. I believe this blocks lipolysis. So, in muscle and fat cells, there is no breakdown of triglycerides into fatty acids.

I think this is wrong. This article (http://www.biochemj.org/bj/imps_x/pdf/BJ20020708.pdf) states:

In this study, this compound increased tyrosine phosphorylation of the [Insulin Receptor] subunit and IR substrate-1 (IRS-1) in rat primary adipocytes, as well as induced phosphorylation of Akt kinase, p70 S6 kinase and glycogen synthase-3 (deactivation) in CHO.[Insulin Receptor] cells. Similar to insulin, compound 2 stimulated glucose uptake, glycogen synthesis, and inhibits isoproterenol-stimulated lipolysis in adipocytes.

So insulin turns on glucose uptake (GLUT4), turns on glycogen synthesis, and inhibits lipolysis. Since IR surppresses IRS-1, these things do not happen. With IR, glucose uptake is off (no glucose in the cell), glycogen synthesis is off, and lipolysis is on! The cells are burning fat!

So we start to put on excess fat mass BUT at the same time the mechanisms to convert BG to fat are working overtime (high insulin levels and not so much IR in fat cells) so to answer you question about what the rest of the body is using for energy... nothing! It is starving in the midst of plenty... hence the phenomenon of someone eating a double-big mac, biggie fries and super-sized coke AND still being hungry... at the cellular level they actually are hungry!

I totally disagree that cell energy starvation (which is not happening as I explained above - cells have to burn something!) causes hunger (http://en.wikipedia.org/wiki/Hunger). I do think that fat and protein satisfies hunger, by producing satiety, but carbohydrates do not - the wikipedia link does not mention this. It is a digestive phenomenon/hormonal phenomenon.

I do think that the symptoms of tiredness and fatigue can be caused by the system running at high speed. The liver is operating overtime producing fat.

I have experienced this myself and I have also experienced the degree of control which comes back to a person when they switch out of "fat storage mode" and into "fat burning mode" -- reducing the levels of insulin by avoiding the foods which drive insulin levels up... by cutting out the refined/concentrated carbohydrates. But, of course, YMMV... especially if you are Type 1 whose default position (low insulin levels) is to be constantly in "fat burning mode"

I totally believe you, here.

Have you read Gary Taubes "Good Calories Bad Calories" yet? I really think you should.

It is next up. I had actually started it but then I got this metabolism book in the mail and switched.

The move "Fat Head" is a light hearted way of expressing this same concept. YouTube - Why You Got Fat (http://www.youtube.com/watch?v=mNYlIcXynwE&feature=related)

It's in my NetFlix queue! :)

[reefedjib]

"In Type II diabetes, the mitochondria continue to use fat as an energy source and not glucose."

[fgummett]

With IR, glucose uptake is off (no glucose in the cell), glycogen synthesis is off, and lipolysis is on!Are you assuming that IR means insulin action is completely blocked? Perhaps that is why you're struggling to see why adding more exogenous insulin is able to overcome this Insulin Resistance..?That has not been my personal experience... indeed if what you suggest is true, then someone with Type 2 after a high refined/concentrated meal, could expect to see ketones in their urine... not happening ;)

IR does not affect all cells equally but it does tend to lead to increased secretion of insulin (so long as the body can keep up with the demand) which is why you can have an increased insulin effect in some processes concurrent with a diminished effect in others.

Even that youtube clip from "Fat Head" posted above has quotes from an MD who seems to disagree with your assertion.

[reefedjib]

Now my question is on the role of genetics in all of this, where/when is the intersection? If it were only possible to not just turn off the problematic genetic interaction, but to fundamentaly transform it... hmmm.

My thoughts on this are that IR is a phenotype problem and not a genotype problem. In other words, it is environmental/metabolic problem and not a DNA coding problem.
- it is systemic: it affects many, many cells and not just a few. I haven't ever heard of a genetic mutation spreading through the phenotype.
- it is onset: there isn't a problem with IR for many years, then it starts happening and it grows. I have heard that with rest (diet/exercise/insulin/low BG), not only does the beta cells recover, but IR lessens.
- it can be overcome: a higher dose of exogenous insulin will clear the vascular system of glucose and kickstart any metabolic pathways that were not working.

Now, the affected metabolic pathways could be involved in protein synthesis but this would have to be highly specific to one or a few proteins. Everything else seems to work fine in the cell.

Don't know where that leaves us.


I am going to retract this hypothesis. In is still a systemic, metabolistic problem, but the underlying cause could be genetic. There are fat people who are not Type 2. It may take some time for the genetic problem to show up in hte metabolism.

In a normal person, digests, releases glucose into the blood stream, triggers the beta-cells of the pancreas to release insulin, insulin binds with the alpha-cells of the insulin receptors, which autophosphorlizes the beta-cells of the insulin receptor, which activates IRS-1, IRS-2, and IRS-3. IRS-1 turns on the enzymes that open glucose transport channels, start glycogenesis, and shut down lipolysis.

In Type 2, post meal, with high BG, glucose transport channels are closed, glyogenesis may not be happening, and lipolysis continues to operate. It is like the IRS-1 hormone is not turned on by the activated beta-cells of the receptor.

Could this be because the active sites for IRS-1 is blocked by another molecule that doesn't trigger it? Then the insulin receptor has to try really hard to get past the blockage (increase insulin). This could be the source of IR.

Now that other molecule could be transcripted from a corrupted gene making it a problem.

Who knows?

[reefedjib]

Are you assuming that IR means insulin action is completely blocked? Perhaps that is why you're struggling to see why adding more exogenous insulin is able to overcome this Insulin Resistance..?That has not been my personal experience... indeed if what you suggest is true, then someone with Type 2 after a high refined/concentrated meal, could expect to see ketones in their urine... not happening ;)

First, as I just wrote in the other post, I am saying that only some activities of insulin are blocked, specifically the ones associated with IRS-1:

In a normal person, digests, releases glucose into the blood stream, triggers the beta-cells of the pancreas to release insulin, insulin binds with the alpha-cells of the insulin receptors, which autophosphorlizes the beta-cells of the insulin receptor, which activates IRS-1, IRS-2, and IRS-3. IRS-1 turns on the enzymes that open glucose transport channels, start glycogenesis, and shut down lipolysis.

In Type 2, post meal, with high BG, glucose transport channels are closed, glyogenesis may not be happening, and lipolysis continues to operate. It is like the IRS-1 hormone is not turned on by the activated beta-cells of the receptor.

Secondly, there are no keyetones produced by the liver since it is rich with glucose and is NOT burning fat, like the muscle and fat cells are:

Ketone bodies are produced from acetyl-CoA (see ketogenesis) mainly in the mitochondrial matrix of hepatocytes [liver cells] when carbohydrates are so scarce that energy must be obtained from breaking down fatty acids. Such a state in humans is referred to as the fasted state.

YMMV! ;)

[yannah]

Thanks Kelli. Right back at you!

I tried to do it back to you, but all my uppercase were turned to lowercase! :(

...as long as you tried to do it back to me. its the thought that counts.

[reefedjib]

I was thinking...

How fast do these reactions occur? I tried searching for a rate equation for glycolysis, for instance, and didn't find anything that jumped out at me. I did some other poking around - found nothing.

But here is what I was thinking over lunch. We are talking molecular scales here, and these reactions are transforming electromagnetic fields that are quantum mechanical at those scales.

Did you know that a photon can travel faster than the speed of light? The speed of light is defined as the speed of light (sic) in a vacuum. When you have a certain solid (I think it is a field effect superconductor, but I am not sure) then a photon that hits it will come out the other side faster than the speed of light (in a vacuum). The deal is that it is not the same photon. The first photon excites the quantum mechanical state of the solid, and that state can travel very fast indeed, and out pops a new photon.

In a chemical reaction, there is probably no photons being produced. There are exchanges of energy and perhaps some increased molecular vibration (heat). I picture a very fast flow of substrates throught the metabolic pathway, from catalyst to catalyst, and out pops the result. It is a flow like a stream.

Hel.l, it may even be possible for this system to catalyze more than one substrate at a time. Since we are at the quantum level, Heisenberg's uncertainty principle applies. This means we can't know the precise time something happens. A corallary to this is that a quantum event can borrow energy or happen early.

These reactions are probably dependent on the substrates showing up in time so the concentration of substrates may be the limiting factor.

Just musing...

[reefedjib]

Type 2 Diabetes Fat Homeostasis Mode

Liver
High blood glucose, High insulin, High IR, High intracellular glucose
- IRS-1 is failing to be signalled (glycogenesis is off, lipolysis is on)
- glucose uptake on (GLUT2)
- glycogenesis off (IRS-1 failed)
- glycogenolysis off
- lipogenesis on (Synthesizing Fat!)
- lipolysis on (IRS-1 failed) (Burning Fat!)


Muscle
High blood glucose, High insulin, High IR, Low intracellular glucose
- IRS-1 is failing to be signalled (glucose uptake off, glycogenesis is off, lipolysis is on)
- glucose uptake off (GLUT4)
- glycogenesis off (IRS-1 failed)
- glycogenolysis off
- lipolysis on (IRS-1 failed) (Burning Fat!)


Fat (adipose)
High blood glucose, High insulin, High IR, Low intracellular glucose
- IRS-1 is failing to be signalled (glucose uptake off, glycogenesis is off, lipolysis is on)
- glucose uptake off (GLUT4)
- glycogenesis off (IRS-1 failed)
- glycogenolysis off
- lipolysis on (IRS-1 failed) (Burning Fat!)

[slipperyelm]

Rob, I've got to say, how cool it is to have you here! My son is in his senior year of physics and will also continue on to a PhD. I wrote a proud post about him in the Chat forum earlier in the summer as he was headed off to his REU at LIGO in Washington state.

I don't think many people realize how many of the medical advances we have, how many of the treatment and investigative devices we have were invented by physicists. :congrats: I wish I had the option to direct more of my taxes to your work...(won't even mention her what I'd take funding away from :cool: )

[reefedjib]

Thanks for the kind note! I hope you son rocks in his senior year. What is he focused on?

I just got back from my first class in grad school. I can say two things about it:

1) it totally rocks! I love learning this stuff!

2) I am in DEEP caca. It is WAY over my head right now and I have a lot of studying to do. That's what I get for picking the hardest class right out of the gate: Classical Electrodynamics. See #1! I AM doing this for the challenge.

Cheers!