Brain insulin sensitivity: why is it important? |Ep.18

Join the insightful conversation in this episode with Dr. E.F. Rain and Dr. Stephanie Kullmann, Deputy Head of Metabolic Neuroimaging at the Institute for Diabetes Research and Metabolic Diseases (IDM), part of the Helmholtz Center Munich, University of Tübingen. Dr. Kullmann’s research is dedicated to exploring neurobiological mechanisms related to obesity and diabetes in humans. Leveraging neuroimaging methods, particularly functional magnetic resonance imaging, and employing measures of peripheral metabolism, she is keen on assessing brain insulin action through intranasal insulin application. This approach allows for the investigation of the metabolic and cognitive consequences of brain insulin resistance.

In this talk, we delve into the concept of brain insulin sensitivity and unravel why understanding this aspect opens a new window for further research. Dr. Kullmann sheds light on how this exploration could be beneficial for the development of innovative treatments for individuals grappling with metabolic syndrome and obesity. We discuss why reducing carbohydrates, sugar, weight loss, and exercise might not be universally effective in optimizing the reversal of insulin resistance.

This episode was based in the following articles:
Reference: Kullmann S, Goj T, Veit R, Fritsche L, Wagner L, Schneeweiss P, Hoene M, Hoffmann C, Machann J, Niess A, Preissl H, Birkenfeld AL, Peter A, Häring HU, Fritsche A, Moller A, Weigert C, Heni M. Exercise restores brain insulin sensitivity in sedentary adults who are overweight and obese. JCI Insight. 2022 Sep 22;7(18):e161498. doi: 10.1172/jci.insight.161498. PMID: 36134657; PMCID: PMC9675563.

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The content of this podcast is purely academic in nature and is intended for educational and informational purposes only. The material discussed does not represent or reflect the views, opinions, or policies of the Medical College of Georgia, and the information presented should not be construed as medical advice or guidance. Always consult with a qualified healthcare professional for any medical concerns or questions. I’d like to explicitly state that I have no endorsement from, affiliations with, or financial interests in any pharmaceutical companies or medical device manufacturers. Any mention of medications, devices, or treatments is made solely within the context of literature and academic discussion

Welcome to decoding Healthcare research a podcast by agara project join us as we delve into the behind the-scenes world of groundbreaking research and the dynamic healthcare industry interviewing top paper authors engaging experts on industry related topics and exploring medical subjects that affect our daily lives and now your host Dr EF

Rain welcome to the coding Healthcare research I’m host IFH riveros Dr E brain today we will continue exploring the different aspects of obesity specifically the role of insulin sensitivity this time in the central nervous system to discuss this particular topic we invited a very special guest Dr Stephanie colan she’s

The deputy head of metabolic neuroimaging at The Institute for diabetes research and metabolic diseases at University of toan in Germany welcome Dr comman thank you so much for having me as we started developing this this topic in depth we have focused mainly on the peripheral aspects related to

Metabolism and the action of insulin but I see that um that you have been focusing more on the effect of insulin on the central nervous system so I guess my first question to you is exactly that what was the the reason why you have this interest in in insulin in the brain

Um what uh what is the motivation and tell us a little bit about your research yeah so I come from the exact opposite side so I studied Neuroscience so for me the brain was always at the center and I’ve notice really quickly that you know each Community sort of has its main

Focus I was only focusing the brain but then really realized there’s this strong communication between brain and periphery and I was really interested to see how that sort of shapes the decisions we make with respect back to why do we decide what we eat and I was

Al curious about how you know the peripheral organs communicate with the brain about our current state you know do we have enough nutrients or glucose levels high enough so I was really always interested in this interaction brain body so that sort of I think from the very good go sparked my interest

From the neuroscience perspective and yeah I mean since diabetes and obesity is such a huge problem not just in the US but across the world I think yeah there’s a lot of research now going on to that direction you mentioned brain sensitivity to insulin what do you mean by that can you

Elaborate a little bit more about this concept yes so that’s that’s a really relevant question because of course from the basics we know I mean the brain does not need insulin to take up glucose it’s independent of that so it’s been sort of neglected right uh with this whole

Research of obesity and diabetes but it has a quite specific role that is very different from the rest of the body it’s very important for regul regulating how um our appetite control so in if insulin does its job right in the brain if it does it in a correct way then after we

Eat something we should feel satisfied and full it should give our brain a sort of feedback me mechanism of it’s been enough I’m satisfied and I can go now onto something else so a a sensitive brain region to insulin and that’s still very strong up to research so all the

Mechanisms are not known but it’s there are two aspects one is our recept in the brain so we have insulin receptors in the brain and which made a lot of researchers curious if it’s not we don’t need it for glucose uptech why do we have so many insulin receptors and we

See that these insulin receptors are not as sensitive anymore to insulin and there there’s this hypothesis which has also been shown that there’s a sort of a a transport from uh of insulin getting into the brain that is sort of disturbed these are the two aspects what probably

It means insulin sensitivity and brain I was impressed by the methodology of the study you used very sophisticated methods can you H tell us a little bit more about how you conducted the study yes so since I’m really interested in in you know in Free Living people you know

How how a person who’s uh very strongly um fighting the Battle of of of trying to lose calories trying to lose weight trying to really go on a diet and stick with it we we investigate participants who are e either overweight or obese and

Then we want to do this of course in a non-invasive way so we use different kind of Imaging techniques that’s that’s the at the center of how we uh measure the brain activity to insulin and then we also think about of course what is the physiological setting that would be

You know after eating a meal our insulin levels go are are elevated in our body and that’s we could measure the brain response to that and we did this for a while but then of course we notice that we have now a mixture of all kinds of

Signals um all kinds of other gut hormones are activated by eating a meal not just insulin and then we have all kinds of peripheral signaling so we really wanted to just look at selectively how insulin acts in the brain and that’s why we sort of used the method also used by other researchers

Called the intranasal insulin approach so insulin is in a nasal spray and we use this as a as you would use as normal nasal spray when when you have a cold you apply this and it reaches the brain uh through what we call called the alory pathway so through the through the

Epithelia alator epithelia it gets into the brain and we know from different um research that around 30 minutes we have our Peak uh activation pattern and this has been shown also in animal research from colleagues and rodo models and we apply this basically in our human research so when you administer insulin

Intranasally do you expect to see any systemic effects or that insulin goes straight to the center nervous system yeah so on the one hand that’s I mean that’s a very uh relevant question on the one hand it Go does go directly to the brain but of course um there is a

Slight spill over also into the periphery we’ve been able to measure this we do see there are glucose level stay quite stable but there’s a slight spillover of insulin so we were interested if if there’s any systemic effect in a sense of that if once the brain is activated by this insulin

Stimulus through the nasal spray do we now see systemic effects that was actually a question that me and my colleagues were asking and that’s when we basically use a sort of we double design we use this internasal insulin approach but we use another approach used for uh peripheral measurements and

That is usually usually the hyper insul liic ug glycemic clamp technique so it’s a technique to measure whole body or peripheral insulin sensitivity and there we’ve actually been able to see that indeed if the the brain is sensitive to insulin and what we can see with this

Nasal spray approach we see with these uh gold standards for peripheral measurements that actually directly um Associates or directly activates Pathways in the periphery to enhance insulin sensitivity but also to enhance insulin secretion and also um hepatic processes I saw that in your paper you establish very clearly the effect of

Exercise and you separate it from the effect of insulin so let’s talk about that effect of exercise in the context of the administration of insulin how how does exercise affect the insulin sensitivity of the central nervous system so exercise of course is we know it’s it’s very health promoting so we

Have an increase in in blood flow in the brain and and overall also what has been reported in increased beneficial effect on cognition and we were now really trying to pinpoint but what is with the effect on insulin sensitivity in the brain so by using this design as just

Mentioned with the intranasal insulin and the Brain Imaging Technique fmri we then investigate participants before and after eight weeks uh8 weeks trial uh where they basically were obese and and overweight and have haven’t had a lot of experience with exercise and what we see is on the one hand side is that these

Individuals even though they’re very tightly controlled they don’t really lose a lot of weight but when we take a closer look at their brain function what we do see is that specific brain regions are quite sensitive um to exercise related changes specifically with respect to the insulin stimulus and that

Is parts of the so-called dopaminergic circuitry so regions in the brain that are dependent on dopamine so regions in the strium there seem to be very little responsive in these individuals prior to the intervention but once they’ve exercised for multiple weeks we see that these strid reg become more and more

Sensitive again to the insulin stimulus which is probably also from the mechanistic point of view linked to to dopamine function but we see that this region now becomes um responsive again similar to what a healthy normal weight person would be that is really also strongly linked that to the amount of

Visceral adpost tissue this unhealthy belly fat that they lose so on on a scale settings if they if they are on a scale their their weight is still quite the same maybe the loss a little bit but not much but actually their their belly fat that we also measure with MRI is

Already reducing so for me again this interesting link again between brain function and periphery so you saw those changes in the hippocampus and also in the striatum so how do you correlate those changes to the behavioral component as we all know H the appetite and the the behavior that is driven by

By those changes in appetite have to do with the metabolic components of this Cascade so what is the correlation exactly yes so of course I mean these are all correlative approaches and we need definite for example animal models to really go into this mechanistic

Findings so what we try to do is that we on one single measurement day we have multiple measurements we have different cognitive measurements so cognitive testings we have functional MRI and whole body MRI so that we sort of get this full picture um of the of the responsiveness but these are of

Naturally those are still associations and need to be shown that there’s a causal a causal link but from based on that study design what is really intriguing is that the motivation might have been different between these individuals yes but we basically controlled it that all their exercise sessions everything that they did was

Next to a sports medicine physician meaning we know exactly how much they exercised how many minutes and under what it was a very controlled setting and it was still very interesting to see that some individuals they’re very responsive also their skeletal muscle was quite responsive to exercise so

Meaning they improved um they improved in Fitness quite strongly and others were not as responsive even though they showed the same motivation in a sense they performed the exact same procedures as everyone else and we believe from our findings that one key element is actually how sensitive they already were

At Baseline to insulin in the brain and that those individuals who are quite insulin resistant and actually struggle more to have a beneficial effect what type of exercise do you use for your protocol so that was a a classical endurance exercise training so aerobic exercise so um basically walking and and

And cycling um and currently we’re now really wanting to know if that’s really specific to aerobic exercise so we’re doing also further research on that if that’s specific to this but that was uh endurance training aerobic exercise you anticipate that resistance training and isometric training may also have a

Significant effect yes I mean honestly we don’t know but I think it could also have beneficial effects since it’s known that also resistance training improves um insulin sensitivity or or I would say periperal metabolism how that is linked to the brain is currently uh is currently not

Known what do you think is the significance of uh of your findings and how how do your findings build on what is already published in in the literature patients and for the whole understanding of the pathophysiology of uh insulin and its different actions yeah so it definitely adds to the fact

That um this whole concept of response and non-response so that this whole con of individualized or personalized medicine that we have individuals who might benefit from another type of therapy because they are brain insulin resistant we have to figure out also what regions in the brain are insulin

Resistant in these individuals in this exercise study we see that the hippocampus and strial region can is adaptive or can change or improve its sensitivity with with some uh also benefit but we also know that other regions more is related to homeostasis the hypothalamus can become insulin resistant and their exercise might not

Necessarily be the exact right uh method to improve insulin sensitivity to brain there might be other pharmacological interventions for example so I think it adds to the fact uh that I think brain insulin resistance could be a key uh element in finding out why some people are just not responsive to the

Treatments that we have currently this is definitely opening new windows for for other researchers to continue exploring H these important aspects that you just mentioned so for your particular group what is coming next what is the next step in in the research that you are doing to try to to to

Elucidate the mechanisms involved in the insulin sensitivity in the brain and other aspects related to metabolic syndrome and Metabolism in general one large aspect is still missing um and I think we already talked about this in the beginning is that of course each researcher has sort of a focus based on

Their individual uh scientific background but now the community uh we’ve been really joining together seeing that in Alzheimer’s research they also see there’s a type of brain ins resistance related also to cognitive dysfunction even in persons who are in the periphery insulin sensitive so sort of opening this whole concept that

Peripheral and and and brain insulin resistance can correlate in some settings as some individuals but not necessarily to all so there’s a sort of Aging dependent insulin resistant that is not well explored currently so that’s one I think very important aspect because brain insul resistance is also

Sort of linked to uh poor cognition and another very important aspect that I’m not currently pursuing is also this differences uh between men and women um we also see that male males and females respond quite differently in certain brain regions to insulin and we’ been figuring out the certain sex hormones

Really contribute to this so that is another line of research is really interesting to us to see if there are any sex specific uh findings for right for a lay person what besides exercise what could be beneficial to try to restore insulin sensitivity in the brain so for those individuals um who are

Already in a pre-diabetes state so already very high risk to develop a diabetes we’ve seen that also using pharmacological interventions like sglt2 um inhibitor um actually improved the hypothalamus response to insulin so certain medications or pharmaceutical Med uh interventions could could help there and there’s also specific interventions looking to calorie

Restriction and of course regular dietary approaches but there of course we have again this this issue with a lot of our designs is that we we can help these individuals on a shortterm setting but then over long run they regain weight so it is it has been shown that

Insulin sensitivity also in the brain can be improved on a shortterm basis with uh weight loss independent of the method you use but currently we’re still lacking um this approach of how can this then translate into a long-term um weight maintenance um success for these individuals I think that’s a line of

Research is really strongly being pursued and I think also with these now new medications that came out really um with The gp1 Agonist where going to that direction that also targets very strongly the appetite center of the brain I think there’s a lot of work

Still to be done there how that can be facilitated so the the way you summarize all your findings is is very organized and uh um give us a a good idea about the findings and how the brain sensitivity to insulin is definitely a factor that we need to to factor in when

We talk about metabolic syndrome diabetes and all these metabolic consequences so I want to wrap up this conversation by thanking you and um again thank you for the for the honor of having you here for sharing your your knowledge with us and uh for our audience you will you will find the link

To the paper that we discuss today in the description of the video see you in the next episode thank you so much for having me thank you so much for tuning into this episode if you enjoyed it please don’t forget to give us a thumbs up and

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