A very interesting exchange. I refer you all to a new review i had written on how hyper-insulinemia can cause insulin resistance (Najjar and Perdomo, Physiology, May issue-2019).

Hyperinsulinemia can cause insulin resistance via several mechanisms, including down regulation of the insulin receptor and lipogenesis, which in turn can cause insulin resistance. 

I see insulin resistance from a different perspective.  Of course, as Sonia says, down regulation may happen with any excess of any hormone. However, I see the hyperinsulinemia of insulin resistance as a compensatory elevation of insulin to the hyperglycemic effect of another hormone that we may know or we may not know. Glucagon, Ghrelin and many others may increase gluconeogenesis and/ or glucogenolysis in obesity making the pancreas to produce more insulin. When the capacity of the pancreas fail to compensate for the insulin needs then we develop type 2 diabetes mellitus (DM2). Why we do not know this? Probably because there are no studies for this. However, absence of evidence is not evidence of absence.

While hyperinsulinemia often reflects elevated insulin release to compensate for insulin resistance, it can also cause insulin resistance. For instance, if the liver fails to clear insulin, chronic hyperinsulinemia develops, which in turn, activates the lipogenic effect of chronically elevated levels of insulin and leads to insulin resistance. I  refer you to several of our published papers on the subject. We are currently submitting a manuscript describing how hyperinsulinemia can cause insulin resistance, and not just a marker of it, in the context of diet-induced obesity.  This question is a very important one. 

How insulin resistance disappears after a bariatric surgery that reduces or bypasses the stomach?. Probably a hormone in the stomach plays an important role. Of course hyperinsulinemia causes insulin resistance. The term insulin resistance was coined in the 1940's and confirmed after the studies of Yallow and Berson in the late 1950's. Congratulation for your paper!

How one can define hyperinsulinemia ?? There is no universal standard set as it is for glucose. Also, there is huge variability among non-diabetic and diabetic insulin levels based upon which its difficult to separate two groups. Any opinion on this ?

Thanks,

Rashmi

There is a method accepted universally to measure insulin sensitivity. The hyperinsulinemic euglycemic clamp. Ralph DeFronzo was pioneering on this (IN THE1970's).

But basal hyperinsulinemia may be consider when insulin levels are above normal range.  It is usually less than 20 in most labs. You may wish to look for postprandial values too and do not forget C-peptide and proinsulin.

Hi Ally

Hyperinsulinemia have many causes like: insulinoma, obesity, insulin resistance, among others. And indeed, as Sonia said, high plasma insulin levels can produce a down-regulation of insulin receptors on the cells and resulting resistance of the cells to act in the presence of insulin. However, the causes of insulin resistance are unclear, it is hypothesized that the beta cells produce high levels of proinsulin which is only between 10 and 20% of comparable effectiveness to insulin but comparable effect in the adipogenic activity (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192645/#b11). In other words, high insulin levels that do not regulate plasma glucose levels but may be involved in the production of adipose tissue.

"Why we do not know this? Probably because there are no studies for this. However, absence of evidence is not evidence of absence."

I am not sure Carlos what in your note are you referring to that we do not know about - we actually know fairly well about all that you have mentioned through peer-reviewed published work.

Erika, given a known chain of events, some times it is interesting to note that how interpretations of causes and affects vary. Of course beta cells make proinsulin; after all, it is precursor of insulin. The reason they end up secreting proinsulin before the processing and maturation of fully functional insulin is complete, is perceived high demand of insulin which is not met by pre made mature insulin stored in secretory granules. When for any number of reasons, normal amount of insulin secretion does not result in euglycemia, increasingly larger amount of insulin is secreted. Chronic hyperglycemia, in the beginning, causes beta cell mass to increase (hyperplasia and hypertrophy) but even if that is not successful in achieving euglycemia, partially processed and unprocessed insulin gets pushed out as part of compensatory effort of beta cells. It seems that in this chicken and egg story, insulin resistance (or need for considerably larger than normal insulin) comes first.

As for lipogenesis, normal amount of insulin (post-prandial level) causes conversion of excess energy into fat, which is used up during the time when we are not eating. After all, our heart runs primarily on fat; fat is not all bad - just too much of it causes issues!  ;)

Insulin resistance is seen NIDDM patients with irregular treatment. For them Insulin is best option to overcome resistance follwed by diet and excercise.

There is prevailing concept that hyperinsulinemia iteslf an contribute to insulin resistance via down regulation of IR. This might happen in type-1 diabetic patients treated with insulin. However, more importantly we are understanding that unoccupied insulin receptor is not silent. It also transducts signals. If these ordinarily unoccupied receptors are now liganded by extra available insulin, it can potentially counter normal transductive mechanisms. It appears that as Jesse Roth wisely opined -" it is all about receptor".

although cortisol has a great role in the regulation of insulin sensitivity ,its role is understimated as circulating cortisol is "normal" in metabolic diseases.It appears thatJesse Roth opinion-"it is al about receptor"is true for both insulin and cortisol.

The messenger (hormone), the receptor, downstream steps in signaling, translocation of transcription factors and consequent changes influencing the target cell, organ and the whole organism are all important and parts of the whole picture. To say that only one aspect of the entire chain is what it is all about seems a narrow view. But then we all have our tunnel universes... ;) 

to say that only one aspect of the entire chain is what"it is all about"may be a narrow view ,but the view  is also narrow  if  we do not take into accaunt that counter regulatory systems are part of the picture

Never meant to give the impression that counter-regulation isn't part of the bigger picture!

However, in the context of managing hyperglycemia, the most critical tool (some would say the only tool) our body possesses is insulin, which is unlike dealing with hypoglycemia where in addition to limiting insulin secretion, several other molecules and mechanisms are available to counteract a potentially life-threaning situation.

Insulin resistance means, that you need more Insulin in order to get glucose into the cells. Originally, insulin resistance was observed in persons with adipositas. At that time, the explanation was simple: in adipositas, insulin dependent cells incorporated more fat than usual. As a consequence, the cell volumes and cell surface increased. Since the numer of insulin-receptors in the cell surface stays constant, the number of insulin-receptors on the cell surface was diluted by fat incorporation. Therefore, you need more insulin in order to dock to the receptors for glucose transport into the cells.

Sighart Golf

As a critical component of countering hyperglycemia, insulin is no doubt crucial, but without a functioning receptor, it becomes practically useless. That is the whole point about key role of receptor. 

The primary role of body physiological adaptation is to find the energetically most efficient systems configuration to convey energy to the body and distribute energy to cells, tissues and organs when it is needed. Thus, pathways related to sensing and management of nutrients are part of the complex dynamic network system which includes the neuro, endocrine, immune systems. These pathways are evolutionary conserved . In this contest it is very difficult to establish what is the role of insulin in insulin resistance, because its activity  is the result of the interaction with other  systems.

For example, glucocorticoids ,with insulin the main metabolic hormone. have an important metabolic function as they provide substrate for oxidative metabolism by increasing hepatic glucose production , adipose tissues lypolisis and proteolysis . Modifications that impair  action from insulin can be triggered by increased  cortisol activity, nutrients and lipids. Thus research must be addressed to understand  the interactions among various components of the regulatory systems .  This is likely the way to find  new  issues for diagnosis and treatment  of  diabetes and other metabolic diseases .   

Romesh Khandori,  

"Countering hyperglycemia" (where insulin, insulin receptor and all the downstream cascade of events are part of establishing euglycemia) according to my understanding is different than what one conventionally calls "counter-regulation". In the context of glucose homeostasis, actions of insulin and glucagon would fit the description.  

As for lack of insulin action without normal insulin receptor, same is true for any of the links in the long chain. For example, if the transporter Glut2 or the enzyme glucokinase is mutated, presence or absence of normal insulin receptor becomes nearly redundant - and that was my original point.

Often there are complex dynamic interactions in various aspects to maintain normal function. When everything is normal, one can assign as much significance to the aspect or a single link of the chain one is studying as one wishes, but when the links before or after the single link of choice falter, it becomes painfully obvious that the story is slightly more complex!   

GLUT2 role in pancrease is primarily linked to insulin release and in liver it helps facilitated glucose transport. It has similar role in kidney and small intestine. It nowhere participates in active glucose transport as insulin  does. Similarly Glukokinase has dominant role acting as glucose sensor on the beta cell with other assigned role in liver. Insulin resistance by definition implies degraded or absent response to circulating insulin levels. That is the whole point. In terms of countering hyperglycemia one could easily argue for the supremacy of glucagon since suppression of glucagon alone abrogates hyperglycemia and even ketoacidosis ( See Gerich J. NEJM 1975). Roger unger has been long pleading for acknowledging role of glucagon. We have experimental proof for it. Unfortunately safety issues cloud trials in humans at this time. For many of us interested in beta cell physiology - yes it is clear that we are still searching for the proverbial holly grail, but we certainly know how to define insulin resistance at least.

The fact that Glut2/Glucokinase are used as part of glucose sensing mechanism in liver and beta cells is well established. There is also no dispute about the important role insulin receptor plays in insulin action (and secretion) but at the same time other aspects are also quite important and cannot be ignored. For example, when other, supposedly not so critical, aspects falter, the end result is hyperglycemia and diabetes. Example: mutations in Glut4 result in diabetes.

[Roger Unger is a brilliant scientist, worthy of recognition by the Nobel Committee. He is my mentor who introduced me to diabetes and I am quite familiar with his work.]

well I am happy to see you were trained with Dr. Unger. I have enormous respect for him and his work. Now on to GLUT 4, GLUT 4 being downstream from IR depends on cues coming after insulin -IR interaction. Therefore, if the IR is non-operational, then I am afraid GLUT-4 is sunk. When one talks about GLUT-4 muation in essence we are talking about failure of signal emanating fron insulin-IR interaction to be transmitted further down (post IR resistance). However, I don't question importance of  transducers beyond IR. My stance is that if the IR is defective then down stream transducers matter very little. There is however, a twist (still being explored) that a fractured receptor may be occupied by other ligands and transduct signals. I just reviewed work submitted by an investigator, and it was just exhilirating. 

"My stance is that if the IR is defective then down stream transducers matter very little."

"Therefore, if the IR is non-operational, then I am afraid GLUT-4 is sunk."

That goes without saying, but the same is true for any link in the chain - one break destroys the entire chain of events (in the absence of alternate pathways), hence the example of Glut4 mutations with perfectly functional IR!  

Entire transduction system is a connected chain. It is like your TV that has so many parts but the initial step is to turn it on. If the power chord is not connected to electricity outlet, you will never be able to watch any pictures. Insulin and IR interaction is like the electricity that turns your TV on. GLUT 4 requires signal coming from above for its translocation . Without signal coming to it, it is practically useless. We have had a lively exchange and that the whole beauty. No point going in circles.

Interesting question... Enhancing lipogenic pathways, and increased fatty acid uptake  may be enhanced initially by increased insulin levels, however  at a certain point increased fat storage hinders insulin signalling pathways and GLUT transfer.

simple answer is no hyperinsulinemia per se does not cause insulin resistance at least for a long period of time , tumor secreting insulin will produce hypoglycemia for a long time . can the resulting increase in metabolic problems combined to have a secondary insulin resistance ? likely  yes .

A straight forward answer to your question would be, 'yes', hyperinsulinemia reduces the number of insulin receptors and cause further IR over the long run

The key point is "hyperinsulinemia", which does not happen under normal conditions. It begins for a reason- the secondary and compensatory roles played by other cells are important but obviously not sufficient without addressing the underlying cause of hyperinsulinemia. 

To elaborate on Joseph Fayad point, in case of inulinoma implanted in immunodeficient mice (NEDH), not only they become gradually severely hypoglycemic (

To my understanding, it's not easy to conclude that hyperglycemia is a cause or an effect. Beacuse they are both supported by adundant evidence. 

The preceding discussion was about hyperinsulinemia!

Hyperinsulinemia as a marker of insulin resistance happens after the signaling of absorption at the level of the portal system is disabled or dysfunctional that is totally different from hyperinsulinemia as a primary event .it is likely that hyperinsulinemia  like all endocrine system can cause some resistance to increase hormones levels ,but not enough in a healthy body to note it. It is only hyperinsulinemia that secondary to disruption of the l cells signaling in the portal space that precipitate the viscous cycle of increase resistance and increase pancreatic stimulation as a compensatory mechanism until pancreatic exhaustion and type 2 diabetes occurs. This is not to deny any secondary or membrane changes or affinity, like the glut, or intracellular intermediate, or RR receptor, but this is for an aerial view of what we can see as a major event happening on a more global level. This will also explain the reversal with gastric bypass and with re-stimulation of functioning L- cells orally

Understanding the role of insulin across a wide range of physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today.

The question we need to answer is this.  What causes Insulin Resistance?  From other biological systems, we can guess that a good place to start is with insulin itself.  Does insulin cause insulin resistance?  Let’s look at the evidence.

There are rare tumors called insulinomas that secrete abnormally large amounts of insulin.  In these cases, patients will have very large increases in insulin but very little else wrong with them.  In these cases, would the increase in insulin lead to insulin resistance?

If the body did not develop resistance to insulin, the high levels of insulin would rapidly lead to very, very low blood sugars.  This severe hypoglycemia would quickly lead to seizures and death.  Since we don’t want to die, the body protects itself by developing insulin resistance.  This is a good thing.

The blood sugar was kept stable by infusions of glucose.  At the end of the experiment, subjects were tested to see if insulin resistance had developed.  The subjects that had insulin infusion showed a significant 15% lower ability to use glucose compared to those that did not receive insulin.  Put another way, the insulin group developed 15% greater insulin resistance.

The implication is this – I can make you insulin resistant.  I can make anybody insulin resistant.  All I need to do is give them insulin.  Insulin causes insulin resistance.

Insulin causes both obesity and diabetes.  This is the new science of Diabesity.  With this new understanding, we are led to entirely new possibilities for the cure of diabesity.  If high insulin levels are the cause, then the cure is to lower insulin levels.  Cure type 2 diabetes?  Can it be true? Yes, but we still have some work before we get there.

Another approach is to identify insulin resistant patients, based on functional markers of insulin resistance. McLoughlin et al were able to identify insulin resistant individuals from an overweight-obese cohort by looking at plasma triglyceride concentration, ratio of triglyceride to high-density lipoprotein cholesterol concentrations and insulin concentration. Using cut points of 1.47 mmol/L for triglyceride, 1.8 mmol/L for the triglyceride-high-density lipoprotein cholesterol ratio and 109 pmol/L (16 mIU/L) for insulin, they achieved comparable sensitivity and specificity to the Adult Treatment Panel III to diagnose the metabolic syndrome.

A very interesting exchange. I refer you all to a new review i had written on how hyper-insulinemia can cause insulin resistance (Najjar and Perdomo, Physiology, May issue-2019).

Insulin is a ligand that binds to the trans membrane protein receptor to instigate signal transduction and associated biochemical activities which instructs glucose transporters to allow the sugar pass via the phospholipid bilayer. Inability of insulin to bind to the receptor is insulin resistance and pancreatic cell continues to produce more of the hormone resulting to hyperinsulinemia. Much glucose accumulates in blood since it can not be transported.