so i actually think about wehave a series at hopkins called telling stories about science. and so, that's sort of whati want to do in the next 15 minutes or so, is sort of tell you how aconversation i had with a mentor
early in my career led toa whole field of research. so, the title of my talk iswhy depression and diabetes are associated, connectingthe brain to the pancreas. and so, i sorta hope to takesome of the basic science that
you've heard this morning and sort of tie that in to sometranslational work that we've done in the area ofpopulation science. so i like to show this slide. and you may wonder why i'mshowing you a slide with the hard rock cafe and a little babythat looks somewhat like me. and so the reason isbecause right before i started my facultyposition at hopkins in 2000, i went to the american diabetesassociation meeting with my
mentor, fred brancati, and itwas held in san antonio texas. and it was memorable fora variety of reasons. one is that it was the firsttime i actually left my son, who was about nine months old,with my family, and actually leftthe state of maryland. but the other memorablething is that fred and i went to eat at thishard rock cafe in san antonio. and it started to storm terriblywhile we were in there and neither of us had umbrellas, sowe were forced to sit there for
about 2 hours and i rememberduring the conversation fred asked me he said you knowi’ve been preparing all this literature about a linkbetween diabetes and depression like why wouldthey be associated? why do you thinkthis might happen? and sort of the neuro endocrinetraining that i had just had in my endocrine fellowship kindof got the wheels spinning and that's what i'm goingto talk to you about. so we probably all recognizethis very famous painting
by edvard munch,called the scream. and i know that many of us haveoften felt this way in various scenarios. so if you add the bleach to your color by accidentwhen you're doing laundry you woke up at the time you weresupposed to be leaving for work. i don't know if that's everhappened, but you wake up and realize the room isway to bright for the time it's suppose to be.
and interestinglyit's kind of fun for me to be at the national pressclub cuz my son who's now a junior in high school wantsto be a print journalist. he's been very frustrated thatmany of his writers have not submitted their articles intime for the pending deadline. cuz he's the deputy editorof the school newspaper. but on a more serious note. sir william osler wassort of the founder of medicine as we know it.
today and the first chairman ofthe department of medicine at john's hopkins university. and he wrote a very famous bookcalled, osler principles and practices of medicine, that iactually got a copy of when i graduated from medical school. and he wrote that bookback in 19, sorry in 1892. and had a chapteron risk factors for type two diabetes and obesity. and so, what's interesting isif you actually look at the left
side of the column you recognizethat many of these are what we consider traditional riskfactors for type two diabetes. but what's interestingis on the right column, he was a bit visionary,he recognizes nervous strain or worry as risk factor fordiabetes. and actually beforehe recognized it, so did doctor willis, who actually,there's a circle of vessels in the back of the brain namedfor him the circle of willis. he also had recognized this and
it was even calledthe diabetogenic personality. so, but moving forward to the,sorta the turn of this century, there had beena lot of work showing that there was an association betweendiabetes and depression. and about a year after ibecame interested in the work. there was a meta analysisshowing that individuals with diabetes are about twice aslikely to have depression as individuals without diabetes. and the lifetime prevalence ofmajor depression is higher in
those with diabetes comparedto those without diabetes. this is actually alsoa common association in type i diabetes as well, soit's relevant to adolescence. so 15% to 20% of adolescentswith type i diabetes will have elevated depressive of symptoms. about 23% have sub clinicaldepressive symptoms, and there's a study called a searchstudy which is the largest us based epidemiological studyof diabetes in children and adolescents and actually thereare similar rates of depression
and type one and type twodiabetes in children and adolescents maybe slightlyhigher in type 2. and so, one of the questions ismost of those studies were cross sectional so it sort of beggedthe question of the chicken and the egg which one came first. so this is kind of trickybecause if you think about the natural history ofthe one set of type one diabetes is typically in latechildhood to early adolescence. and then type 2 diabetes tendsto be a disease of middle age.
but then depression'sinteresting. it has its onset between towardthe end of adolescent and young adulthood. and then there's a second waveof depression that occurs in mid life as well. so you could see that one mightactually predict the development of the other. and back at the turnof the century, we were really unclear whichdirection was the primary.
so one of the first questionsi was interested in and looking at is does diabetespredict the development of depression. and so you might sort ofhypothesize they would be linked because perhaps is thepsychological burden impose by diabetes that can increasethe risk for depression. so we know that diabetes inthe setting of new complications particularly if thereare complications that are associated withfunctional impairment and
in a setting of a lackof social support and passive coping skills, certainlycan lead to depression. but as an endocrinologistwith a biological background, it turns out thathypergylcemia itself, which is associatedwith diabetes. tends to actually adverselyeffect the parts of the brain that control mood and cognition. so, specifically, thehippocampus, where there can be atrophy of neurons andalso neuronal apoptosis.
so, that's why it's not uncommonin diabetes that we can not only see depressed mood but we canalso see cognitive impairment. so, one study i was interestedin looking at does diabetes predict depression was inthe multi-ethnic study of atherosclerosis, so this isa very large population based study of cardiovascular disease. but a lot of the populationalso has diabetes and these individuals were recruitedfrom six centers throughout the us andthey were truly multi ethnic, so
they were 45 to 85 atthe time of recruitment. they represented africanamerican, hispanic americans, chinese americans and whites. and they had no clinicalcardiovascular disease at baseline, so they were fairlyhealthy cohort in our turfs. and so, what we were able to dobecause masa had several follow up visits was to actually lookat the presence of diabetes on the first visit. and then subsequently and
we defined them according totheir glucose tolerance status. so, at that first visit,do they have diabetes, do they have impairedglucose tolerance, or do they have normalglucose tolerance. and then, we follow them,and at visit three, there was a depression measure. and we were actually able todetermine whether or not they had depression based on theiranswers on a questionnaire and whether or not they were usingmedications to treat depression.
we also had that informationon them at that first visit. so we were able to excludepeople that had depression at baseline to sort ofremove the confounding. and so, what we found is thatindividuals with diabetes at baseline had about a 50% higherrisk of developing depression during followup compared tothose without diabetes and that it was independentof differences and complications, socioeconomicstatus, and obesity. so it looked like that diabetesdid predict depression, but
about depressionpredicting diabetes? and so this actually willsort of answer a little bit the question that was asked atthe end of the last session. so here again we had severalplausible biological mechanisms. so one again, the depression and the psychologicalburden of the disease my lead through obesity througha variety of mechanisms. there are also the behavioralaspects, so typically individuals who are depressed,don't like to exercise.
they may tend to over eat, maybeless inherent with the doctors and weight loss recommendations,that can lead to obesity and insulin resistance. in addition, some ofthe treatments that we use for depression can actuallyinduce obesity. so particularly some of theatypical antipsychotics are now used as booster therapy alongwith the serotonin reuptake inhibitors to induce obesity andinsulin resistance. finally, what i wasmost interested in
as an endocrinologist. was the impact ofchronic stress and depression onthe neuroendocrine system, so specifically elevationsin cortisol, your catecholamines hormones andinflammatory markers. so we, and again, went back tothe mesa study and this time we looked at individuals atbaseline who had depression who did not have diabetes. so we excludedprevalent diabetes.
defined the same way as theywere in the other half of our analysis. and again we followed them fortwo years to look for the development ofincident diabetes. and what's interesting, individuals with depressionhad a lot of risk factors for type ii diabetes. they were lessphysically active, they consumed morecalories during the day.
they were also more likelyto be current smokers. and smoking, even though you may lose weight,be less obese as a smoker, smoking's still an independentrisk factor for diabetes. they also had higherbody mass index and higher inflammatory markers. but the question was,if we control for all of those factors,do we see an increased risk for type 2 diabetes andin fact we did.
individuals who had depressionat baseline had about a 21% higher risk of developingtype 2 diabetes. but it wasn't all explained bythose factors we adjusted for. which, sort of, made me to thinkthat there was still a missing link and like what is themissing link between the brain and the pancreasthat we may make. and that's what i wanna spendthe last few minutes talking to you about. so this is a body stress system.
so dr. hussein andi didn't really plan to have talks that were somewhatcomplimentary, but it actually was veryhelpful to set the stage. so in his example, the gazelle was being chasedby a pack of cheetahs. so that does activate ourfight or flight response, and so what typically happens isthat, what happens is that you have any type of stress, here,activates the hypothalamus and that stimulates the releaseof hormones that femulate
the pituitary gland--it'sa little small gland sitting at the base of your brain--tosecrete additional hormones that ultimately stimulate youradrenal glands over here. hold on. i think it's this one. i'm a little it challenged, solet me go back to where i was. sorry about that. [laugh] hold on. i need to stop using the laserpointer that's always a thing.
so we were right here, so the little trianglesitting at the bottom, that's your adrenal gland. that is what ultimatelymakes your cortisol. and the other thing that happensis when that axis, that's called your hpa axis, whenthat's activated, it stimulates your sympathetic nervoussystem to be activated also. so you have an increasein cortisol, and you have an increasein catecholamines,
which you may referto adrenalin. so if you are that poor gazellebeing chased by the cheetah, this system is activated. but then,once the gazelle escapes, this should all turn off. so this is a tightlyregulated system. so then the cortisol feeds backto the pituitary gland and the hypothalamusjust shut this off. because we don't want thissystem activated all the time.
but then what we think happensin disorders like depression and chronic stress is that you havethis chronic activation of the hpa access. you also, this leads to activation of thesympathetic nervous system and they co-activate each other, andthat leads to an increase in the levels of cortisolthat i mentioned. and interestingly, when youactivate the sympathetic nervous system, it also activatesyour inflammatory system.
so you have an increaseinterleukin 6 levels. and so interleukin 6 issort of the beginning of a very progressivecytokine cascade. and all of those factorsare associated with insulin resistance. and so that can actuallylead to the development of type two diabetes. and specifically with cortisolnot only does it lead to insulin resistance directly, but
it can also lead tothe development of central fat. so we've heard about differentkinds of fat this morning, white fat, brown fat but there's subcutaneous fatthat was discussed earlier. there's also visceral fatwhich is the fat sitting, wrapping around the organs. and it turns out that cortisol,there are a lot of, cortisol receptors on thatfat and that it motivates and the development of morefat around the belly.
so that kind of central fatis also associated with so this is sort of my schematicof how the hormones might be linked to the developmentof diabetes and depression and stress. so again, one of the metabolicperils of having central fat, so what's shown on this particularslide, if you look to the left, you can see thatwhite on the ct scan. that's like central visceral fatthat's all wrapped around your organs.
that's the fat that's associatedwith poor metabolic outcomes. if you look to the right,you can see that there's sort of this panel of subcutaneousfat that's on the outside. the thought has been that thatfat is not as metabolically active as what's in the viscera. but i know that there's someemerging literature that it probably likely iscontributing as well, but it's really the visceral fat. so we know that that'sassociated with
higher glucose levels andinsulin resistance. it's associated withhigher blood pressure. more lipid disorders andalso are at-risk for developing type-ii diabetes. so what does it mean whenwe say insulin resistance, because we've used that terma lot this morning, and so this is just a reallysimple schematic. that our insulin receptor,we have normal insulin action. our insulin receptor basicallytakes the glucose that we
break down from food andbrings it into the cells, so our cells can have energy. and what happens in the settingof insulin resistance or abnormal insulin action is thatthere's a failure of glucose to enter those cells, and soour cells don't have energy, and they have to use othersources for energy. so is there any sort of datato support the cortisol hypothesis in relation todepression and diabetes? so this is where it's kind offun to go to the animal models,
and i always am jealous of mybasic science colleagues because they can knock outvarious things and you can't really do thatin human subjects research, because the irb doesn't reallylike that type of thing. [laugh] so but this is a verynice animal model of an enzyme called 11-beta-hydroxysteroiddehydrogenase. and what this enzyme does isit inactivates cortisol, so it keeps your body from beingoverexposed to cortisol. but what they did in this mouseis they made a mouse model that
overexpresses that enzyme, so this mouse fails to thenactivate its cortisol. so you can see in each of thesethe wild type mouse is shown on the left, andthen the transgenic mouse is shown on the right, and you cansee clearly that the transgenic mouse that's making toomuch cortisol is heavier. and then it's also more insulinresistant, is more obese, and actually has higher levelsof cortisol in it's liver circulation.
so then what evidencedo we have in humans? so we actually havetwo sets of evidence. so one is in ourclinical studying and. and so this is sort of the modeli thought about when dr. asked me what is the linkbetween depression and diabetes because whatwe see in clinical is there's a diseasecalled cushing syndrome. this is a picture ofa woman who has it. you get cushing syndrome frommaking too much cortisol from
either a pituitary tumor oran adrenal gland tumor. and so what happens is theseindividuals develop central obesity, so you can sortasee the central fat they actually develop musclewasting, insulin resistance and type two diabetes andinterestingly they can also develop mood disorderswhich is very fascinating. so that's one setting we see it,we also see the development of diabetes in insulin resistanceif we give patient high does steroids forinflammatory conditions.
so like rheumatoid arthritis orafter they've had some type of transplant, we'll oftengive high dose steroids. those patients are very prone todeveloping type ii diabetes and so, the thing that's beenreally interesting for me, and sort of several post-doctoralfellows that have worked with me is that we've actually beenable to look into multi-ethnic study of atherosclerosis, and we have a sub-study calledthe mesa stress study. and what we did is that we hadindividuals at two mesa exams
collect salivary cortisol. so you can actually measurecortisol in saliva by having your research participantschew on cotton swabs. and then you can actuallycentrifuge that saliva, and you can measure it. and one of the challenges withcortisol is that it's variable throughout the daylike many hormones, so it's highest in the morningwhen you first wake up, and then it drops downlower later in the day.
so we actually had to measurethe cortisol curves over the course of the day, andwe did this in about a thousand people and had them collect 6 to8 samples throughout the day so we could characterizethe whole curve. and what's been fascinating tous is that even independent of depression, we see evidence ofdysfunction of the cortisol excess in the setting of typetwo diabetes in obesity. so what we found is that in thesetting of type two diabetes, instead of having that robustcortisol response when you wake
up in the morning,is actually very blunted and we see that same cortisolprofile in depression. in addition, there's a loss of variability inthe cortisol throughout the day. so instead of itreaching a peak, it tends to be higherat the end of the day. so we see that in diabetes, andwe also see that in depression. so they actually share a verysimilar neuroendocrine profile. and then, the one questionthat we've been able to
sort of ask is okay,if you have diabetes, does it change yourcortisol access over time. or is it that your cortisolaccess predicts a development of diabetes, so this is the samequestion we asked earlier but without the depression. and so the jury is still out, so we have done one study showingthat if you have diabetes, it does not predict a change inyour cortisol curve over time. and now we're actually gonna askthe other question as soon as we
accumulate more diabetes cases. so you may say, so what whydo we care about how our hormones maybe relatedto metabolism sort of in thinking about everythingwe've talked about this morning. and i think it's because despitethe fact that we have a lot of known effective lifestyle andother interventions that help to prevent diabetes there is stilla large diabetes epidemic and we've really not beenable to fully implement everything into the environment,so it really begs the question,
are there other biologicaltargets that we should consider. so i would argue that it may be,because we see these neuroendocrine abnormalitiesin diabetes and obesity, that we may beable to actually modulate he neuroendocrine system as anovel way to complement existing strategies for preventing andtreating diabetes. and, in fact, there are sort of glucocorticoidreceptor antagonists, so those are the receptorsthat cortisol binds to.
there are agents thatantagonize that bonding. and we don't know yet howthey're related to obesity and diabetes risk, but i think that's an importantfuture area of investigation. and then from a clinicalperspective, because i'm sorta ending my story, i think it alsosays though, that in addition to understand the biology, thatit's important for us to sort of step back and think about how wecare for patients with diabetes. because it's not uncommon for
the mental health comorbiditiesto be a part of that. so we actually are gonna haveto change the way we deliver clear to these patients, so we have more ofa collaborative care approach. one of the very first patientsthat i saw when i was a young faculty member called me oneday on a snowy afternoon and said, i have been living withtype 1 diabetes for so long, i just can't take it anymore and i've just given myself 100units in my insulin pump.
this is a true story. i was actually able to call911 from my house and send, i said don't come to my house,go to hers, and intervene. but this is a reality that wheni'm not sort of doing molecules that i actually see inmy clinical practice. so ultimately we wanna moveour patients from feeling like this to looking more like this. >> [laugh]>> [laugh] so
Diabetes And Metabolism San Antonio,>> [laugh] so
i would just like to acknowledgeall of my collaborators over the years as well asmy funding sources. so thank you.
Since you now realize how to control your condition, you will be far better ready to create the right options and changes in your own life. Remember that these guidelines will only be appropriate if you utilize as the majority of them as you possibly can, and so you ought to commence right now to see timely results.
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