Question
Asked 7th Mar, 2013

An Explanation of Insulin Resistance

According to the medical literature, type 2 diabetes is a disease characterized by chronic hyperglycemia, i.e., abnormally high concentrations of blood sugar (serum glucose), in the presence of adequate amounts of insulin. This hyperglycemia is attributed to insulin resistance, a faulty condition in which serum insulin cannot act on insulin receptors in the walls of cells. This condition prevents the receptors from allowing glucose to pass from the blood into the cells.
According to the biochemical literature, an insulin receptor is a protein molecule located in the wall of a cell. The structure of the molecule is such that a smaller molecule called a ligand may attach to it. There are two kinds of ligands: an agonist, which causes the receptor to function, and an antagonist, which does nothing but prevent the agonist from attaching to the receptor.
Without an attached ligand, an insulin receptor cannot allow glucose molecules to pass from the blood into a cell. An insulin molecule is an agonist, and when one becomes a ligand, an insulin receptor can allow glucose molecules to pass into a cell. But the hormone cortisol is an insulin antagonist, and when a cortisol molecule becomes a ligand, it prevents an insulin molecule from becoming a ligand, which prevents glucose from passing from the blood into the cell involved.
I believe that the action of cortisol as an insulin antagonist is a reasonable explanation of the condition that we call insulin resistance, in which case there is nothing wrong with the insulin receptors or the insulin. Insulin resistance, then, would be part of the natural functioning of an insulin receptor.
There are reasons to believe that the brain is responsible for the production of excess cortisol for the purpose of preventing the loss of serum glucose that the brain needs under special circumstances. Firstly, the brain has no insulin receptors (per Gerald Reaven); the brain cells have unrestricted access to all the glucose in the blood. Secondly, at least half of all the glucose in the blood is consumed by the brain, and when it is under stress, the brain can consume two-thirds of the glucose or even more (per Achim Peters). These facts suggest that the role of the insulin receptor is to help regulate the concentration of glucose in the blood for the benefit of the brain.

Most recent answer

15th Oct, 2017
Nalini Deshpande
University of Wollongong
I am a newly enrolled PhD student and researching the literature on insulin resistance and the basic steps in the biochemical and physiological pathways of this condition. Your discussions have been extremely valuable. I am actually trying to locate studies that have elucidated insulin resistance in multi-hormonal and related enzymatic cascade in lipid metabolism .

Popular Answers (1)

8th Mar, 2013
Marcello Casaccia Bertoluci
Universidade Federal do Rio Grande do Sul
This is a very interesting topic. Indeed hypercortisolemia can generate insulin resistance. However the most common mechanism of insulin resistance in type 2 diabetes is due to post-receptor signalling cascate changes after insulin binds to its receptor. These changes occur at the liver, adipocyte and muscle cells and are characterized by a change in the phosphorilation pathway after the insulin post receptor substrate IRS-1 is activated. Normally the physiological cascate is the phosphorilation of the IRS in tyrosine directing the action through the Akt pathway leading to GLUT-1 translocation to membrane in order to promote glucose entry to the cell. On the contrary, if the IRS is phosphorilated in serine the pathway is skewed to the MAPK cascade which leads to nfkb production as well as to insulin resistance, inflammation and cell proliferation. The beggining of this process is still debated and it has been considered that abdominal fat can trigger this mechanism by producing inflammatory citokines to adipocyte. It also has been claimed that genetic predisposition to muscle cell insulin resistance could be the first mechanism. The reality is that this is a multifatorial process where genetic and environment play important roles.
4 Recommendations

All Answers (8)

8th Mar, 2013
Marcello Casaccia Bertoluci
Universidade Federal do Rio Grande do Sul
This is a very interesting topic. Indeed hypercortisolemia can generate insulin resistance. However the most common mechanism of insulin resistance in type 2 diabetes is due to post-receptor signalling cascate changes after insulin binds to its receptor. These changes occur at the liver, adipocyte and muscle cells and are characterized by a change in the phosphorilation pathway after the insulin post receptor substrate IRS-1 is activated. Normally the physiological cascate is the phosphorilation of the IRS in tyrosine directing the action through the Akt pathway leading to GLUT-1 translocation to membrane in order to promote glucose entry to the cell. On the contrary, if the IRS is phosphorilated in serine the pathway is skewed to the MAPK cascade which leads to nfkb production as well as to insulin resistance, inflammation and cell proliferation. The beggining of this process is still debated and it has been considered that abdominal fat can trigger this mechanism by producing inflammatory citokines to adipocyte. It also has been claimed that genetic predisposition to muscle cell insulin resistance could be the first mechanism. The reality is that this is a multifatorial process where genetic and environment play important roles.
4 Recommendations
10th Mar, 2013
Alexander V Vorotnikov
National Medical Research Centre of Cardiology
I doubt this hypothesis is consistent with basic principles in biochemistry and cell signaling. The term 'ligand' indeed means a substance that binds to a specific target molecule called receptor. 'Agonist' stands for an activating ligand (there may be few such ligands for a receptor). It induces conformational changes in the receptor that initiate signal transmission and evoke a response. 'Antagonist' also binds receptor, however it does not induce appropriate conformational changes and prevents binding of agonist. By this virtue, cortisol CAN NOT be a bona fide insulin antagonist as it acts on different type of receptors - glucocorticoid receptors located INSIDE cells. All the same, cortisol is a functional antagonist of insulin, as well as adrenalin and glucagon to some extent. This is provided by their opposite intracellular effects and post-receptor signal processing.
Secondly, in agreement with Marcello, pathophysiological resistance to insulin appears to come from post-receptor events in insulin signaling. It is thought to involve, as a critical point, phosphorylation of IRS, an immediate target of insulin receptor, at serine/threonine (S/T) residues. It is clearly distinct from the insulin-induced phosphorylation of IRS at tyrosine sites, which becomes somehow obstructed when certain S/T get phosphorylated on IRS. The enzymes that mediate S/T phosphorylation of IRS are not fully identified, but those that are appear to be distal targets of Akt, the critical member of insulin signaling. Thus it looks that an inhibitory feedback loop operates in the insulin signaling that interrupts IRS activation and leads to less Akt activation. As a result, the Akt-mediated translocation of the glucose transporter to plasma membrane is impaired. Note this is Glut4, not Glut-1, which is insulin-insensitive.
3 Recommendations
10th Mar, 2013
Claude Mayer
Université de Paris 1 Panthéon-Sorbonne
Marcello and Alexander seem to agree together. Does their interesting analysis lead to a potential treatment of insulin resistance ?
1 Recommendation
11th Mar, 2013
Marcello Casaccia Bertoluci
Universidade Federal do Rio Grande do Sul
Definitely yes, Dr Claude. Current treatment for type 2 diabetes is greately based in insulin-resistance, as well as in other mechanisms such as insulin secretion recovery and incretin based therapies. Insulin resistance is the key-stone of type 2 treatment because it is almost universal. The thiazolinendione drugs act as selective binders to the nuclear transcription factor gamma (PPAR-gama). These PPArs are a superfamily of nuclear receptors found in the adipocyte that can regulate the expression of inflammatory genes , but also can induce the glucose transporters ( GLUT-1 and GLUT-4) to move to the membrane of the cell to induce glucose transport. PPAR gamma agonist such as pioglitazone reduces insulin resistance and atenuates many other metabolic changes determined by insulin resistance such as dyslipidemia. Of course exercise and low saturated fat diet are also corner-stone of the therapy, as well as metformin. They all can reduce insuli resistance in different degrees and are the most used therapies to control glycemia in type 2 diabetes.
2 Recommendations
12th Mar, 2013
Alexander V Vorotnikov
National Medical Research Centre of Cardiology
I believe it does indeed. There are quite a few potential intracellular targets, though, in addition to PPARg. Because phosphorylation of IRS appears to be a central point in causing the insulin resistance, the most likely candidates are the kinases that mediate this event. They differ in insulin target tissues such as liver, muscle and fat. However they may have a common 'ancestor' - mTOR seem to function as the upstream activator. This makes mTOR a potential drug target to fight IR. As far as I know there is a huge number of clinical trials of mTOR inhibitors going on; rapamycin is the most known and being used as Sirolimus and its derivative/analogues. Ironically, it had been discovered first and then gave a name to its target mTOR, which stands for mammalian target of rapamycin. The mTOR signaling is probably most elaborate in the cells, so that other drugs directed at critical components of this network, such as metformin for example, may also have a potential against IR.
3 Recommendations
12th Mar, 2013
Claude Mayer
Université de Paris 1 Panthéon-Sorbonne
Thank you both. Strange etymology of mTOR. (Why not then MToR? lol)
1 Recommendation
13th Mar, 2013
Alexander V Vorotnikov
National Medical Research Centre of Cardiology
'Cause TOR comes first from the studies on yeast and other non-mammalian cells. Then mammalian counterpart has been described and corresponding prefix has been added. Now it is realized that mTOR is distributed widely and various cells use its signaling network to sense nutrients and their availability, as well as to respond accordingly by adjusting behavior and metabolism. In order to generalize the case, the 'mammalian' term is being suggested to be replaced by 'mechanistic'; this would also reflect that rapamycin physically interacts with a mTOR complex member. This approach is not new in science - everybody now refers to MAP-kinases as mitogen-activated protein kinases, but not everyone remember that formerly they were called microtubule-associated protein kinases. Same MAP, but different location... so to say :).
2 Recommendations

Similar questions and discussions

Related Publications

Got a technical question?
Get high-quality answers from experts.