Dr. Mariela Glandt - 'Reawakening the pancreas in Type 2 Diabetes'

so I started actually with the conflict of interest I am a co-founder of a1 seafoods which is uh it was a company that was started by a father of a patient of mine that was looking to create delicious local food and this is really in its infancy and I used to do a lot of consulting way back then before I converted to low carb but now I have nothing to report so let's start so let's talk about the reawakening the pancreas and type-2 diabetes aka reversing diabetes and we're gonna talk about this more at a cellular level what does it really mean and before I dive into the Nitty Gritty because there is quite a bit of nitty-gritty I want you to just take home this message which is the sooner we treat the more likely we are to reverse disease so with that said let's start so usually when you go to a conference or wherever you read an article about diabetes it says diabetes is a one-way street things really just get worse over time and pretty much no matter what treatment we do we expect things to worsen but we're here because we really think that's not true so let's start with diabetes definition of type-2 essentially we need to have insulin resistance as well as the self failure in order to have diabetes and insulin resistance by itself is just metabolic syndrome beta cell failure by itself is actually type 1 diabetes but when you have it combined we have type 2 diabetes now beta cells are extremely specialized beautiful cells and they start off as stem cells and they go through this process this conversion from two intermediary cells that eventually become this very specialized cell that knows exactly how much glucose comes in and how much insulin needs to be secreted in order to function properly and this process is called differentiation now you need to have some kind of predisposition in order to get type 2 diabetes one is for example having a small pancreas as was discussed this morning if you are malnourished as a mother you may make an offspring with very just a small number of beta cells the more common scenario is having a normal number of beta cells but genetic defect or a normal number of beta cells with environmental injury or a slow autoimmune attack which is really a lotta a lot of latent autoimmune disease that gets misclassified as type 1 type 2 diabetes so why do these beta cells fail well first of all it might be that these beta cells die and we get this information from cadavers we look researchers looked at the pancreases of cadavers and they saw first of all in those people without diabetes when we compared the lean in compared to the obese we see the obese patients do a really good job at compensating for that increased demand in insulin so they're able to rev up those beta cells in contrast those people who get diabetes know their beta cell mass is greatly reduced and this is what we see under light microscopy so let's take a look here in the top left you see a slide of a islet of Langerhans under the light microscopy you see the that brown is actually insulin we're staining for insulin and it Stanley very nicely in comparison to the the slide underneath the the this slide is basically missing the brown staining because there is no insulin it's it's not lighting up but if we look with a much more powerful microscope the electron microscope we see that hey it looks like there's something there it may not have been staining for insulin but it's not actually dead there are some beta cells there that are hanging out in a dormant state so this dormant state is called D differentiation remember that we looked at how is stem cell became a beta cell through a process of differentiation this is going backwards Ferengi Asian and sometimes actually these beta cells get converted to alpha cells which are glucagon producing cells and these alpha said this is called transdifferentiation and we know the alpha cells secrete glucagon and there is a paradoxical increase in glucagon and diabetes which we target when we treat diabetes as clinicians with dpp-4 inhibitors and glp-1 agonists in order to try to reduce this glucagon because glucagon increases the sugar in the blood what do we need that for when we already have high sugars so this might be in part because of this trans differentiation of beta cells to alpha cells alright so here's a schematic view of a beta cell and glucose comes in and it has to be metabolized in order for it to be coupled to insulin secretion so it has to go through the mitochondria a lot of things happen there and in the end a calcium has to rush into the cell insulin is produced through a process of first being pre pro insulin then pro insulin and finally insulin is released under the appropriate stimulus now when a cell gets D differentiated all of the special enzymes and transcription factors that make a beta cell special they go away they start to be the expression that gene expression goes down and these are you can see in pink on the slide on the other hand all those boring cells that are not doing anything special they have enzymes that are not expressed in beta cells and those are in green but when a beta cell gets D differentiated what happens is that those special enzymes go away and the non special enzymes go up so beta cell is kind of like Superman Superman is mister differentiated he's super super powerful and can do things that nobody else can do but then when he takes the Kryptonite he becomes weak and powerless so we want to know what is the kryptonite of beta cells so there are three causes that are debated that lead to deep differentiation gluco toxicity lipo toxicity and inflammation so let's take a look at this all right let's start with glucose oxidase city a little bit of sugar or sugar at a physiological level a good thing it makes beta cells secrete very nicely makes them work the way they should work but too much glucose is actually damaging so I was actually involved in a study in this study that I think actually shows this quite nicely this was way back like almost 20 years ago at the Joslin with Gordon Weir and Ross Levi and this this study involved put do something called pancreatectomy a partial pancreatectomy were they the rats underwent surgery a little bit of this the pancreas was removed and this made them hyperglycemic if how hyperglycemic depended on how much is removed but in the end the mice the rats ended up moving into two groups a group that became very hyperglycemic and a group that became mildly hypoglycemic so then after a while after 14 weeks the rats were sacrificed and we checked all of the expression of their gene expression of all their specialized enzymes and what we saw let's take a look here at insulin for example is that after 14 weeks of being exposed to really high sugars those beta cells had lost the expression of insulin now there was another group that wasn't sacrificed immediately and were instead had their glucose corrected completely they were given a drug that's the predecessor to the sglt2 s that are now in the market today inhibitors that are in our market today so it's called fluorescein and fluorescein makes you pee out the sugar in the urine and this is what happened to the rats and they had normal sugars after being exposed to very high sugars and what's nice is that actually they were able to improve their markers or their the insulin for example you could see that the expression of insulin goes up again now in the case of these that had 14 weeks of high sugars first it didn't normalize completely it still it came back but not all the way we know from a prior experiment that after four weeks of high sugar instead of fourteen ignore alized completely so the duration and the severity of hyperglycemia matters on how much you can correct this this defect so let's look at lipo toxicity to my surprise actually I didn't know that beta cells had a receptor to fat but they do and a little fat actually causes insulin secretion a lot of fat actually causes beta cell damage if you take fat and you pour it on a petri dish on top of beta cells it really damages them and causes them to differentiate now let's take a look at the this is called the super diabetic rat and this rat first accumulates a lot a lot of fat and then it becomes diabetic so you can see that what happens here is that first the fat changes the morphology of the of the beta cell and only then after this rapid accumulation it becomes diabetic so this is a very commonly used model of animals in humans we think that that it's it's the fatty acids that are coming from the liver that end up being deposited in the pancreas and causing and wreaking a little bit of havoc so what about inflammation again a little inflammation might be a good thing for example in pregnancy a little hyperglycemia causes a little bit of inflammation in this inflammation leads to beta cell expansion and this is something that we want in pregnancy but a lot of inflammation not a good thing and leads to D differentiation so we know the being obese or having type 2 diabetes leads to systemic state of inflammation where we have low-grade cytokines in the blood and that might be contributing to beta cell failure but we also have inflammation going on at the local level in the in the eyelid so what are the things that contribute to inflammation well first of all having high glucose levels high glucose levels leads to first of all we said before activating the mitochondria but too much activation of the mitochondria leads to a lot of reactive oxygen species advanced glycation products do the same free fatty acids do the same an LDL modified LDL does the same now the glucose and these and these factors also activate something called the nlrp3 inflammasome and what this does is it activates for the secretion of interleukins and all sorts of cytokines into the Miller calling attracting all of those macrophages to come and live in the eyelid now what the problem is that these macrophages they're angry and they are secreting all sorts of nasty things that are making us de-differentiate our beta cells what's interesting is if in in rats if you actually are able to deplete the microphages you see that the beta cells re differentiate so inflammation might be playing a role here as well so in conclusion to this first part we have glucose oxy city we have lipo toxicity and we have inflammation as possible causes of d differentiation and it's debated in the literature is it this more than this or what is the real culprit but I think what's important is that we don't just have beta cell death the fact that they just see differentiate gives us a lot of hope because there's something we can do here and how much is dead versus how much is D differentiated depends on how long a person has been with hyperglycemia so what can we do about this how can we wake up these beta cells here Superman is being woken up and he becomes a super beta so let's look at some strategies for reawakening these one of them is anti-inflammatory agents that since I just mentioned inflammation we would have thought that treating patients with anti-inflammatory agents especially the interleukin 1 B which is the most prominent interleukin would revert diabetes but that actually turned out to be quite disappointing and did not pan out the way we expected it to and many trials have been done actually many more than you see on the slide but none of them have really been as beneficial as we thought and of course we have side-effects when you suppress the immune system that are not so desirable another strategy is treating the glucose toxicity with intensive insulin therapy you know the best tool to bring down sugar is just insulin we know that for a fact but here's the study that was done on recently diagnosed type 2 diabetics and they randomized them to two groups of people those that received intensive insulin therapy at the beginning using a pump and insulin pump and the others were just controlled and they follow them for two years and what they found after the two to three weeks their patients were followed with just diet and what they found is that there was a at 24 months 42% of patients were still diabetes free after just having received 3 weeks of intensive insulin therapy 2 years prior so that's really interesting and what they did is they looked back and saw who were those that actually responded and it was those that had the lowest sugars during that time so they divided it into Turtles and here's a proportion of patients on the y-axis and remission and you can see that the top line out of those three is the one that had the lowest mean blood glucose during those two to three weeks so you have to get down to really really good glucose in order to get an effect but we know and I learn from many of you guys here in the audience the giving insulin to a patient with type 2 diabetes is not exactly logical they these patients have too much insulin to start off with and we don't want to make the situation worse than other ways yes we might clear the gluco toxicity but insulin is not what we want to give and also these patients had hypoglycemia so let's look at other strategies well we know that bariatric surgery is the most clear case of beta cell recovery these patients do really really well and after two years 72 percent of them are diabetes free and after 10 years over a third of them are still without diabetes now I think it's very interesting that when we look at this a little bit closer and we break it down by how long the duration of the diabetes was before the surgery we can see the duration is critical on the left you see that the light blue bars is those patients that were diabetes under one year so if you have diabetes for under one year you're gonna be told the chances of you being cured are very very high even after 15 years 50% of these patients are doing great but if you had diabetes for just four years that's not a lot and most of these patients have actually 15 years of diabetes before they go for surgery just four years decreases your chances of recovery after two years look less than 50% recover so how long you've had diabetes again impacts how well we are able to revive those beta cells now these beta cells actually if you are gonna recover they recover very fast and most people think or the the there is an increase in in Cretan hormones the glp-1 for example hormone that goes up immediately after the surgery so they attributed to the response to this hormone but a professor by the name of Roy Taylor in England and Newcastle actually tested this and it turns out to not be true and he argues that it's actually the melting of the ectopic fat in the liver and in the pancreas that's more responsible for this and I'll get into this in a second but it is important to know that before we see a change on the scale we see that that the fat content in the liver goes down and it will in any in any type of diet and this decrease you you're not gonna see it's my cream it's its grams this we're not gonna see that on the scale but the melting away of the fat at the liver level and at the pancreatic level seems to be a very interesting thing and so he argued at the end the timing of the melting away that he noted by checking this with very sophisticated MRI techniques said wow there's something to look into here this looks very interesting say well if it is about the melting of the fat then let's just not do the surgery and give these people very very low calorie diet and see if we get the same effect so he said let's check if weight-loss no hypocaloric diet will reverse diabetes and he did a study at first there was eight weeks long and he looked at this in a great amount of detail by doing these MRIs on the patients who took diabetic patients and compared them to obese patients with the same weight but without heavy teas and what he noted was that the amount of liver fat the hepatic triglyceride went down I need a pointer but you see the the circle there on the left that represents the people without diabetes that's that's the control group so the fat goes down and as soon as it hits the fat level of the control group which happens to be one week after the the surgery or after the diet started we see that the fasting insulin corrects because what's happening here is that the liver is suddenly freed up of this fat and it's able to respond now to insulin it is sensitive to insulin and hence it's able to stop cranking out the glucose which is what a liver does when it's not insulin sensitive right when I liver has a lot of insulin resistance it doesn't it doesn't listen to the signal to stop cranking out sugar and just makes that fasting glucose really high so in a winded way what we're seeing is that we decreased the hepatic fat we correct the fasting glucose and the same thing happened here with the pancreas he was able to do an MRI on these patients and follow them over time and see that as the the fatty pancreas went away and reached the same level as fat as the control group then the face the first phase insulin response improved what does that mean it means that when when we eat we secrete insulin and now and when we have diabetes that doesn't happen and in this case it it started to happen again the insulin started to be released appropriately with meals all right so then he said let's do a write a big trial and prove that this is really this is true in a bigger in a bigger longer-term trial and this trial really made headlines all around the world and what they did is they fed people 825 calorie kilocalories a day for a year okay well if they first gave you meal replacements and then they slowly started to introduce food but these patients had diabetes for only six years at a maximum and everybody that responded lost a lot of weight that was a participated lost a lot of weight the average weight loss with 10 kilos after a year but not everybody was able to reverse her diabetes only 46% so when he looked carefully through these sophisticated MRIs he compared the liver fat and the pancreatic fat and he saw that both of these groups the responders and the non-responders both lost the fat so what was the problem the problem was in the beta cell the beta cells of the responders had been hyperglycemic for less time they apparently their duration of diabetes was only 2 point 7 years versus the non-responders there were three point years three point eight years in duration so again in this case we see that even though the fat corrected in the liver and the fat corrected in the pancreas in both of them and everybody in everybody in the responders and non-responders only the responders had a shorter duration of diabetes so moving on to my favorite strategy which is a very low carb diet because yes we can decrease the ectopic fat with a very low carb diet and it's much more fun to do we get to eat steak and we get to eat strawberries and cream and it is much easier and reluctant and and it's just feasible and fun and the thing is that there's so much more benefit to the beta cells when we eat this way because not only are we getting rid of the ectopic fat but also we treat the gluco toxicity in the lipo toxicity we decrease the modified LDL and it elevates ketones which are anti-inflammatory so let's talk about this for just a second what I wanted to say before by the way about the about the low-calorie trial is that it was 825 kilocalories but that ended up being a hundred and twenty grams of fat a day which was very surprising because you would expect in such few calories it would be less carbs but it was actually well we would consider a little bit of carbee so the reason why we did we eat 20 grams of carbs in this diet for example between 20 and 50 so this really decreases the gluco toxicity because we're stopping from bringing in all of the sugar into the blood all the time so this relaxes the inflammation the reactive oxygen species we have less advanced glycation products the less complications that happen from the glucose binding to proteins in the blood we have less free fatty acids because we are decreasing the triglycerides significantly and the LDL improves in quality so all of this decreases the inflammation and besides that ketones are not just fuel sources they're actually also signaling metabolites they do other things which i think is really fascinating and they they are actually decreasing the mitochondrial reactive oxygen species and they're acting on this nlrp3 inflammasome directly they directly inhibit this so there is less inflammation so for many reasons it's very interesting now we know that in this trial the vertical trial took patients with diabetes fed them a very low well formulated ketogenic diet and after a year 60% of the patients achieved in a1c of less than 6.5 either with no meds at all or with metformin and here let's compare the continuous care intervention on the left to the usual care on the right and what you see is that I changed the units to a1c % because it's easier for me from the new way of the new units that were less familiar with we see that the the higher the a1c of course you're gonna have a greater response it usually in diabetes you know if you're starting from very high a1c the chances of seeing improvements are very high but the closer we get to a lower a1c the harder is to see improvement but in a continuous care intervention that received a low-carb diet you see that there was improvement no matter what your a1c was contrast that to the usual care and in the usual care that the high the group that started out with very high glucoses improved a little bit but we see worsening of diabetes in the lower a1c groups and this is what we see in practice diabetes gets worse this is why the slides at the beginning of the of every presentation we treat diabetes and yet it usually gets worse with a usual care also this very low carb diet leads to an energy expense and increase in energy expenditure in contrast to a very low calorie diet and I think this is beneficial because it allows us to maintain this diet we're not freezing and starving we actually are able to and enjoy the increased energy expenditure so this is another reason I prefer this strategy so in our clinic we are myself and two dietitians Adina is here joining me from Israel we have a nurse we have a psychotherapist and we've been treating this way for we opened about four years ago and it's been like a three and a half years since I really doable with the patient care and here's one of our patients his name is Nikolas and Nikolas came to me with an a1c of 10.8 and he was just recently diagnosed and he was you know feeling terrible I thought he was about to die and this is what he was told and I told him listen it's gonna be okay you're gonna eat a lot of fat and you're going to cut out all the stuff and it's all gonna be good and this is four months later and his a1c was four point eight four months later it was really unbelievable and this is he's one of many many many patients but he actually started writing a blog so it was it's it was easy to get his pictures there online and he continues to be at an a1c of four point eight after three and a half years he is without medications so this is what happens when we treat diabetes right away okay so his father actor who's also my patient he has had diabetes for thirty years and he you know I I was a doctor before I went through the low carb conversion so I had him on insulin and Actos sglt2 Victoza and him all the and all these medications and he was fairly well treated he had an a1c of seven and he was what we would consider controlled he was controlled and when I told him that I went through this conversion in that I I was gonna he almost died he was like you've got you've lost your marbles you've really gone crazy telling me now to eat fat but I that's what I did and he lost all the insulin he doesn't take any more insulin he doesn't take any any of most of the medications I took off the Actos I took off the st2 but still I can't get him off the glp-1 and the metformin even though his a1c is five point seven and the reason is because he's had diabetes for thirty years and too bad that we didn't start this thirty years ago but he's he's doing great but he's just it's just an example a living example of the the father and child of how important it is to reverse the diabetes right away so in conclusion beta cells are not all dead most are actually D differentiated and there's a lot we can do correcting the hyperglycemia the free fatty acids and the inflammation improved beta cell function if we decrease the ectopic fat in the liver and the pancreas this can correct the diabetes if your beta cells are still around diabetes is reversible but again the severity in the duration extremely important in determining how reversible and timing is of the essence which is why primary care doctors need to be involved in this so we can do this ASAP and not wait till we get to specialists so thank you very very much [Applause]

Channel: Low Carb Down Under

Views: 105,776

Keywords: Low Carb Down Under, LCDU, www.lowcarbdownunder.com.au, Low Carb Denver 2019, #LowCarbDenver, Type 2 Diabetes, Beta Cells, Insulin, Metformin, Mariela Glandt, Glandt Center for Diabetes, Bariatric Surgery, Low Calorie Diet, Ketogenic Diet, Low Carb High Fat, Endocrinology, intensive insulin therapy, Dr. Roy Taylor

Id: I6sYsQqnPS0

Length: 31min 29sec (1889 seconds)

Published: Sat Jun 01 2019