Flipping the Switch: From Insulin Resistance to Type 2 Diabetes.

I could be there to do this in person but this will be I think an acceptable substitution that I wanted to speak to was to speak to you about was this idea of someone transitioning or the body making this transition from insulin resistance to type 2 diabetes known to as T2D.

and so we'll look at what goes on in the body to flip that switch if you will and then in moving from one disease state to a more exaggerated disease state.

now my disclosures I used to have none but it just goes to show how relevant things are getting in the realm of metabolic health.

From Insulin Resistance to Type 2 Diabetes.

I have a book that I will receive royalties from that is released later this year about insulin resistance which is a topic I'll speak about today.

I'm a scientific adviser for a health insurance group that's United health insurance company United Health Group.

and the supplement company called unicity and then I'm a co-owner in the company called our co-founder and a company called health code and we make a low carb high-fat high protein.

shakes and not too to facilitate optimal metabolic health having said all this I obviously have a Prairie preference that I adhere to which is a low carb diet and that should be considered in my disclosure

now with that let's get into the science diabetes is one of the most common disorders within the US and one of the most lethal accounting or taking the seventh spot with regards to mortality.

now I believe this is somewhat deceiving because diabetes has its hand in many other diseases that both go down or up on this list diabetes.

is the leading cause of kidney disease, of course, most many I'll say instances of heart disease are derived from
diabetes certain cancers are significantly greater unlikelihood.

and the mortality goes up with diabetes like breast and prostate cancers stroke and even Alzheimer's disease sometimes.

referred to as type 3 diabetes are also related so I think that the true statistics highlighting the lethality of diabetes are much more compelling than perhaps at face value.

so if this is a disease that is so relevant it is lethal and as I make the case causing so many other disorders we need to understand it and to understand type 2 diabetes.

we have to appreciate the foundation upon which it is built and that is insulin resistance type 2 diabetes is essentially a prolonged state of insulin resistance.

and I'll define that in a little more detail but just to set the stage here and I regret that my little video insert is going to cut some of this off this was a study published at the end of last year.

that found that 88% of adults in the US are considered metabolically unfit and to come to this classification they looked at the 5 metrics of metabolic health being as indicated here waist circumference.

so an ideal waist circumference and ideal blood pressure HDL and triglycerides and then as well as blood glucose.

these are the five metrics they looked at now only 12%, in other words, to present their findings in another way of adults only 12% of adults were good or considered healthy in all five of these outcomes.

this constellation of good health in this case however in this with these five things in mind a lack of these five not even all five of them is what constitutes the metabolic syndrome.

and that's what they were doing they were looking at the constellation of disorders that are connected to the metabolic syndrome and then using that as a gauge of metabolic health.

now what is so relevant about this is that metabolic syndrome is the current name of a disease that used to be called the insulin resistance syndrome and rightly.

so insofar as each of these disorders can in some way be connected or derivative from insulin resistance and I won't take the time to go into that.

that's not the purpose of my talk I'm just simply establishing the relevance of insulin resistance and when it comes to the metabolic syndrome.

what is insulin resistance and diabetes

insulin resistance is profoundly relevant in fact I would argue it's the most relevant a variable but insulin resistance has its hand and many more disorders here are some of the big ones body fat levels body fat regulation.

diabetes as I've already indicated heart disease which is an umbrella term for numerous disorders of the cardiovascular.

system certain cancers and fatty liver disease but there are more like in certain forms of infertility polycystic
ovarian syndrome and women at its core.

is a disease of insulin and insulin altering the production of sex hormones from the ovaries erectile dysfunction
there's a study to suggest that it's the most one of the earliest symptoms of insulin resistance in men and then some neurological disorders like migraines and Alzheimer's disease and then some other disorders like stroke and arthritis and indeed there are many more.

that I just don't have the room to include here so insulin resistance has its hand in essentially every non-infectious chronic disease.

so we want to understand it in order to truly understand the etiology of these disorders now to put things in

the perspective here along the x-axis.

I have time and by that I mean the lifetime of an individual I'm not talking minutes or hours here I mean I mean
years and then glucose is in yellow and insulin in green and over the course of someone's life what would happen.

is this spike in insulin or the steady climb in insulin or well steady but earlier so this earlier rise in insulin and then an eventual rise in glucose and is so important to appreciate.

that these two molecules insulin and glucose do not move hand-in-hand over the lifetime of an individual too often.

we think they do and so we look at glucose and we think we're getting an understanding of insulin but that is not necessarily.

the case not at all now there's two important points that I want to draw here the first point the first hash line is
really and everything encompassed in, it from line 1 to line 2 that is what I want us to look at as an incident as
insulin resistance that is on the body.

is insulin resistant and you'll notice that this is a state of fairly normal glucose and yet not normal insulin so insulin resistance is defined as a state.

that is hyperinsulinemic but normal glycemic in contrast beyond that line we now move into the realm of type 2
diabetes and this is now finally when the body is so resistant to its own insulin indeed even.

when insulin is elevated which it is throughout the life of the type 2 diabetic even when it starts to come down and we'll come to.

that later it still gets it is still higher than what it is in a normal individual it's just lower than it used to be and so commonly this reduction in insulin um the scientific literature will say insulin is insufficient to.

control glucose but that shouldn't be mistaken for insulin as absent it just means the body is and though isn't
making as much as it was before potentially and even if it is on this front end of the insulin drop.

it's just not enough to control the glucose and thus we see that rise in glucose and then we identified the disease as type 2 diabetes.

I believe there's power in this paradigm because if we can acknowledge this early rise in insulin we can detect
the progression towards type 2 diabetes potentially much much sooner.

so what is it that flips the switch

what is it that makes that glucose start to climb when the insulin has been elevated for so long fighting this quiet war.

well, let's get into it in fact I'm going to present it to you in the context of different tissues insulin resistance starting with a disorder of the adipose tissue.

and then type 2 diabetes or the glucose spike really settling and when we have disorders of muscle and liver and pancreas and will go in that order but let's start with a really a common background or understanding that

in each instance of these tissues failing or contributing to this progression towards type 2 diabetes.

insulin resistance is the underlying disorder

each of these tissues becomes insulin resistant and that's part of its pathology and we'll get into that in more detail now very briefly because I'm not the purpose of this.

talk is not to define insulin resistance it's to identify the transition from insulin resistance to type 2 diabetes.

but I just wanted to briefly show my perspective here in how we are driving the insulin resistance in these tissues hyperinsulinemia as much as this is debated is very well documented to directly drive insulin resistance in
adipose and muscle and by mass on the person.

insulin resistance of these to tissues really matters and I'll come back to the relevance of this and the muscle and the progression towards type 2 diabetes in just a moment but the little the references;

I have here those are the PubMed IDs and of course, anyone can look this up I just want us to have a mutual
understanding that despite the debate.

there is direct evidence this shouldn't be debated the evidence is very very clear hyperinsulinemia can drive insulin resistance now there are other causes that have little to do with insulin at least directly cortisol can directly cause or a glucocorticoid the cortisol like a drug like a dexamethasone.

that can directly drive insulin resistance and so too can inflammation now these are not related hyperinsulinemia is not the same as cortisol and neither of those is the same as inflammation.

these are all distinct at least in their origins however there is nevertheless once again a common territory here and that is that each of these molecules high insulin cortisol and inflammation drives the accumulation or facilitate the accumulation of a molecule called ceramides and ceramides.

is one of the types of lipids that are made within a cell now so I'm just introducing ceramides as a common root or touchstone for each of these distinct origins when it comes to insulin resistance.

so let's look at those three tissues on the muscle the liver and the pancreas and see how they drive the hyperglycemia but let's start with the muscle because the muscle is the elephant in the room.

it is the main the consumer of glucose and indeed it consumes up to 80 percent of the glucose in the body so we need the muscle to be working for that glucose ink to be at our disposal to clear the glucose from the blood and thus mitigate the progression towards type 2 diabetes.

what's interesting of course with the muscle is that it is it generally requires insulin for glucose uptake now
there's an exception to that which is.

when the muscle is contracting but I won't get into that right now insulin facilitates glucose uptake certainly when the muscle is at rest which let's admit it people spend most of the day doing even active people however with insulin resistance.

this insulin facilitated glucose uptake is compromised and then we have a reduction up to 50% reduction in glucose uptake in an insulin-resistant muscle again.

is matters when we're talking about a tissue that accounts for up to eighty percent of all glucose uptake if we lose half of that ability we now have glucose in the blood that is well lingering it's struggling to find a place to be used and naturally.

of course, this results in an increase in blood glucose and so if we look at this paradigm again of this insulin resistance progressing towards type 2 diabetes.

we shift the line a bit moving closer into the realm of type 2 diabetes now the liver I believe is one of the unsung heroes.

or unappreciated heroes when it comes to human metabolism there are two processes I want to highlight and that is the liver's ability to both make lipids and to make glycogen.

the storage form of glucose so it's the livers one of the tricks the liver has to once in Seleucus has been pulled in it will store it so it's just a way to help buffer the glucose levels in the blood.

if glucose levels are high the liver can pull in some of that more than what it needs for its own energy demands then when glucose goes low the liver can break that glycogen down and share it with the blood or with the body.

so that's the definitions there the production of fat in the production of glycogen insulin of course as it has its
hand in so many things also has.

its hand in these events as well, in particular, it stimulates both of them insulin will both stimulate the production of lipid and the production of glycogen with insulin resistance in the liver.

there's an interesting phenomenon and it is reflective of the fact that insulin resistance is not just a global effect within the cell.

it is not that every event that insulin used to do is not happening and let me get into that just to make that clear. 

when the liver is insulin resistant.

lipogenesis is still activated when insulin comes knocking at the door so to speak when insulin binds its insulin
receptor so to make that clear even if the liver is insulin resistant insulin can still stimulate lipid Genesis in contrast in the insulin-resistant liver.

insulin is less able to make glycogen so it's less able to tell the liver to store glucose in this loss of stimulating glycogen is meant.

we have a reduction we actually end up insulin loses its ability to prevent the breakdown of glycogen so now we have glycogenolysis this event is disrupted in insulin resistance and so now we have a liver.

that is supposed to be holding on to glucose it's actually letting it go but it's not supposed to remember that's the
pathology here insulin is trying to stimulate or it ought to be stimulating glucose uptake in storage it's not working anymore.

so the liver doesn't get the signal not to break down glycogen and so it does it's not being inhibited the glycogenolysis and this, of course, drives up blood glucose levels so once again if we look at this paradigm of the progression towards full-blown type 2 diabetes with the liver being insulin-resistant we've pushed that a little
further down the road, the patient has progressed a little further.

towards full-blown type 2 diabetes so they're getting this mounting hyperglycemia now in the paradigm or in the progression I'm presenting let's just say the pancreas is the last to fall and to talk about the pancreas.

we need to introduce two distinct characters or aspects of it and that is the pancreatic alpha cells and the
pancreatic beta cells now are so relevant because they each produce a pancreatic yin and yang in insulin. and

glucagon represent this really one of the many instances of a delicate orchestra within the body when it comes
especially endocrinology this urban flow of hormones that work together to maintain homeostasis and in one aspect of that although.

there is much more insulin and glucagon work together in this tug-of-war to control blood glucose levels glucagon attempting to increase blood glucose all the time.

and insulin, if it had its way of attempting to lower blood glucose all the time now in this relationship which maybe we could say, is somewhat abusive insulin is the dominant one here insulin is inhibiting glucagon release from the alpha cell.

so when the beta cell is making insulin it is depressing alpha cell glucagon secretion however well and that would act normally to lower blood glucose by suppressing glucagon helping insulin win that war of controlling blood glucose and ultimately reducing it.

however, with insulin resistance, this phenomenon is compromised insulins' ability to inhibit alpha cell glucagon release is compromised and that's because the alpha cell as I have indicated is what becomes insulin resistant.

when it experiences insulin resistance it doesn't get the signal to stop producing glucagon and thus the glucagon is if not normal it's beyond normal.

so when insulin is elevated to trying to lower blood glucose glucagon isn't listening anymore it's a naughty child here and it's just doing.

whatever it wants to so once again with this paradigm in mind the insulin resistance of the Alpha, cell pushes the person towards this mounting hyperglycemia and they're one step further to full-blown...

type 2 diabetes but the story is not done.

when it comes to the pancreas because there's more to say about the beta cell and in fact, it's appropriate to end this discussion of the problems.

and the tissues with the beta-cell because it appears to be so relevant here now with the beta-cell there is debate and there is no consensus with regards to what is it about the beta cell that is altered is it the number of
beta cells or is it the beta cells' ability to produce insulin itself.

so, in other words, the beta cells are there and they're just no longer attempting to control blood glucose and the production of insulin has gone down, and again there is a debate here so in this case.

whereas insulin is normally attempting to lower the blood glucose levels loss of either beta cell number or insulin
overall production resulting in a lower than previous insulin level means blood glucose levels start to climb but again.

the levels of blood insulin type 2 diabetic

let me emphasize that blood insulin levels don't go and they don't become deficient they are still elevated higher than what you'd see in a normal non-type type 2 diabetic it's just not enough to control.

the glucose in that person anymore because they're so insulin resistant now whether it was a beta cell problem or an insulin problem.

the deficiency relatively in either of them results in that increased glucose and pushing diabetes further it ultimately will say to the end, it's full-blown type-2 diabetes now I would slightly make the case that it is perhaps more a matter of just insulin production itself because there are and I have these studies length here instances of what is referred.

to as a beta cell reversal and just within a week, we see that there's a normalization of insulin production with
different lifestyle interventions and so but you could certainly say the beta cells themselves are bouncing back and they are proliferating within the course of a week but regardless of which one it.

is we can be quite comfortable that the beta cells are not irreversibly gone like we would have in type 1 diabetes and type 2 there appears to be some room for correction, in fact, ample room for correction to help reverse this trend and so with this proper intervention.

explained the blood glucose levels

can start to come down and we can start to reverse and push back the clock so to speak with regards to the mouthing hyperglycemia.

and the type 2 diabetes so to kind of sum it all up type 2 diabetes is built on a foundation of insulin resistance in
this insulin resistance manifests in key distinct tissues the adipose tissue first I would I submit and that's what
ultimately starts the insulin resistance typically although.

there it could happen elsewhere but in typical insulin resistance, I'd make the case that it starts in the adipose tissue and then this with the adipose being the first to fall.

tissues fall shortly after I'm so to speak and become insulin-resistant the muscle the liver and then the pancreas
and again a common mediator across all of these very distinct tissues is the accumulation of this lipid called
ceramides in every one of these whether.

it was the alpha cell or the beta cell in the pancreas whether its deliver muscle or adipose ceramides are a known inducer or antagonist of the insulin signal with regards to the biochemical pathway of insulin.