Sugar and the beating heart: the conundrum of heart failure in diabetes

Sugar and the beating heart: the conundrum of heart failure in diabetes


>>GOOD AFTERNOON, EVERYONE. WELCOME TO A SPECIAL WEDNESDAY AFTERNOON LECTURE. THIS ONE, THE ASTUTE CLINICIAN LECTURE, WHERE WE SEEK TO BRING INDIVIDUALS WHO ARE COMBINING SCIENTIFIC EXPERTISE WITH CLINICAL EXPERTISE AND MAKING OBSERVATIONS THAT TRANSFORM OUR UNDERSTANDING OF HEALTH AND DISEASE, AND TODAY’S SPEAKER, DALE ABEL, AS A GREAT EXAMPLE OF SOMEONE WHO SPENT HIS CAREER DOING THAT. SOME OF YOU ARE HERE ANXIOUS ABOUT WHETHER THE GOVERNMENT IS GOING TO SHUT DOWN TOMORROW NIGHT, BUT FOR THE NEXT HOUR PUT THAT ALL ASIDE. IT LOOKS AS IF WE MIGHT SQUEAK BY THIS TIME WITH A FEW STEPS BETWEEN NOW AND TOMORROW. SOME OF YOU ARE DREAMING VALENTINE’S DAY, IT IS A WEEK FROM TODAY. THE FACT WE’RE TALKING ABOUT THE HEART, NOT SUCH A BAD THING. THE FACT THAT SOME OF YOU ARE MAYBE PLANNING TO GIVE CHOCOLATES TO YOUR LOVED ONES, WELL, LOTS OF SUGAR. THINK HARDER AFTER THIS PRESENTATION WHETHER THAT’S A GOOD GIFT OR NOT. WE’LL ALL LEARN SOMETHING ALONG THE WAY. OUR SPEAKER HAS A REMARKABLE TRAJECTORY IN TERMS OF HIS TRAINING AND HIS CONTRIBUTIONS AND VARIOUS ACADEMIC INSTITUTIONS. HE RECEIVED HIS MBBS AT THE UNIVERSITY OF THE WEST INDIES IN KINGSTON, JAMAICA, Ph.D. FROM OXFORD UNIVERSITY, HE WAS A CHIEF RESIDENT IN INTERNAL MEDICINE AT NORTHWESTERN, SPENT TIME IN BOSTON AT A PLACE CALLED HARVARD, AND THEN MOVED TO THE UNIVERSITY OF UTAH FOR 13 YEARS, WHERE HE MOVED THROUGH THE RANKS FROM ASSISTANT TO FULL PROFESSOR AND MEDICAL DIRECTOR OF THE DIABETES ENDOCRINOLOGY CENTER. BUT SINCE 2013, HE’S BEEN AT THE UNIVERSITY OF IOWA, INITIALLY AS DIRECTOR OF THE DIVISION OF ENDOCRINOLOGY AND METABOLISM, AND NOW AS THE FRANCOIS ABBOUD CHAIR IN INTERNAL MEDICINE, AS WELL AS DEPARTMENT EXECUTIVE OFFICER WHICH MEANS HE RUNS THE PLACE. SO HE OBVIOUSLY MUST HAVE SKILLS NOT ONLY IN RESEARCH, WHICH IS WHAT HE’S GOING TO TELL US ABOUT, BUT ALSO IN A WAY OF MANAGING A COMPLEX AND CRITICALLY IMPORTANT PART OF A VERY IMPORTANT INSTITUTION, RIGHT THERE AT THE UNIVERSITY OF IOWA. HE’S A FORMER RHODES SCHOLAR, RECEIVED A NUMBER OF IMPORTANT AWARDS, I MENTIONED THE GERALD AURBACH AWARD. HE’S BEEN ELECTED AS THE PRESIDENT OF THE ENDOCRINE SOCIETY, WE’RE GRATEFUL TO HIM BECAUSE OF HIS CONTRIBUTIONS TO NIH BECAUSE HE HAS SERVED PREVIOUSLY AS THE CHAIR OF THE BOARD OF SCIENTIFIC COUNSELORS FOR NIDDK, AND IS CURRENTLY A MEMBER OF AN ADVISORY COMMITTEE TO NHLBI, AND A LONG-TERM GRANTEE. HE’S BEEN ELECTED TO THE ASCI, AAP, AND NATIONAL ACADEMY OF MEDICINE. AND CURRENT RESEARCH INTERESTS WHICH HE WILL TALK TO US ABOUT VERY MUCH PLAY OUT IN THIS UNDERSTANDING OF THE ROLE OF SUGAR AND INSULIN, AND THEIR DYSFNCTION IN THE HEART THAT HAPPENS IN DIABETES. JOIN ME IN WELCOMING DR. DALE ABEL. [APPLAUSE]>>THANK YOU VERY MUCH FOR TURNING UP IN THIS TREMENDOUS STORM THAT HAS CLOSED DOWN MONTGOMERY COUNTY. [LAUGHTER] AND HAVING COME FROM TWO PLACES THERE’S REAL SNOW, I ALWAYS FIND IT VERY INTERESTING HOW THE REST OF THE WORLD REACTS TO THE THREAT OF SNOW. NEVERTHELESS I WANT TO SPEND FOUR TO FIVE MINUTES SPEAKING ABOUT WHAT WE’VE BEEN DOING OVER THE YEARS TRYING TO UNDERSTAND THE MECHANISMS THAT RELATE TO CARDIOVASCULAR COMPLICATIONS OF DIABETES. NOW, IT SHOULDN’T BE MORE PLAIN THAN IN THIS ROOM WE’VE SEEN A TREMENDOUS INCREASE IN THE PREFERENCE OF OBESITY AND DIABETES OVER THE LAST TWO OR THREE DECADES. AND IN FACT, THIS IS A SLIDE THAT IS USED OF USED QUITE A BIT, INCREASE IN NUMBER OF PERCENTAGE OF PEOPLE WITH DIABETES IN THE U.S. IT’S IMPORTANT TO EMPHASIZE DIABETES IS A GLOBAL EPIDEMIC, AND EVEN THOUGH WE THINK ABOUT THE NUMBERS IN THE U.S., JUST NOTE IN THE DEVELOPING WORLD, SUB-SAHARAN AFRICA, FOR EXAMPLE, AND IN THE MIDDLE EAST, WE’RE SEEING DOUBLE AND TRIPLE DIGIT INCREASES IN THE PREVALANCY OF DIABETES. IT’S SOMETHING WE NEED TO WORRY ABOUT, ITS COMPLICATIONS. WHEN I WAS IN MEDICAL SCHOOL WE LEARNED ABOUT MICROVASCULAR, RHETT KNOP RATE, NEPHROPATHY, NEUROPATHY, BUT THE ELEPHANT IN THE ROOM IS CARDIOVASCULAR COMPLICATIONS. WHEN WE THINK ABOUT THAT, WE THINK ABOUT ATHEROSCLEROSIS, MIs AND STROKE. BUT I WILL SUGGEST AS ANOTHER DIABETIC COMPLIATION, WHICH IS HEART FAILURE. I THINK THAT’S LARGELY UNRECOGNIZED, I HOPE TO SHOW WHY THAT NEEDS TO BE CHANGED. THIS IS THE FACT THAT A STUDY TWO DECADES AGO LOOKING AL CELLS IN INDIVIDUALS, AND LOOKING AT PREVALENCE AND INCIDENCE OF HEARTFAILURE ACROSS THE LIFESPAN OF INDIVIDUALS WITH TYPE 2 DIABETES, SIGNIFICANT INCREASE IN HEART FAILURE INCIDENCE IN INDIVIDUALS WITH DIABETES, TWO-FOLD TO THREE-FOLD INCREASE IN INCIDENCE OR PREVALENCE IN INDIVIDUALS WITH DIABETES. THEY LOOKED FOR POTENTIAL PREDICTORS OF HEART FAILURE IN THIS POPULATION, SOME WERE NOT UNEXPECTED SUCH AS ISCHEMIC HEART DISEASE, HYPERTENSION, RENAL FAILURE. IF YOU’RE DIABETIC AND YOU’RE A WOMAN, THEN YOUR RISK FOR HEART IS TWICE AS HIGH AND WE DON’T FULLY UNDERSTAND WHY THAT IS. IF YOU’RE AN INSULIN USER YOU’RE AT CLOSER RISK OF HEART FAILURE IN BUY DIABETES. THIS IS AN INTERESTING ASSOCIATION. IT RAISES THE QUESTION IS INSULIN A PROXY FOR DURATION OR SEVERITY OF DIABETES OR IS INSULIN USED MAYBE GIVING US ANOTHER CLUE POTENTIALLY ABOUT THE UNDERLYING PATHOPHYSIOLOGY. I HOPE DURING THE TALK TO SHOW YOU DATA THAT SUGGESTS THAT IT MIGHT CONTRIBUTE TO INCREASED RISK OF HEART FAILURE IN THE CONTEXT OF DIABETES. HERE IS A RECENT STUDY THAT WAS RECENTLY PUBLISHED FROM BRIGHAM AND WOMEN’S HOSPITAL, LOOKING AT HOSPITALIZATION FOR HEART FAILURE AND ASKING HOW MANY, WHAT PERCENTAGE OF PEOPLE WITH HEART FAILURE DIAGNOSIS ARE DIABETIC. REMEMBER IN THE POPULATION IT’S 10 TO 15%. BUT IN THE HEART FAILURE POPULATION IT’S ABOUT 50% OF INDIVIDUALS WITH HEART FAILURE ARE DIABETIC. IN FACT IF YOU LOOK AT THE FLAVOR OF HEART FAILURE, HEART FAILURE WITH REDUCED INFRACTION, OR PRESERVED EJECTION FRACTION THERE’S SIGNIFICANT ENRICHMENT FOR INDIVIDUALS WHO ARE DIABETIC. HEART FAILURE, WE NEED A MOONSHOT. IF YOU LOOK AT THE SLIDE, CANCER, CANCER, CANCER, HEART FAILURE. THE MORTALITY OF HEART FAILURE IS SIGNIFICANTLY WORSE THAN MANY CANCERS. IF YOU ARE DIABETIC, YOUR PROGNOSIS IS EVEN WORSE THAN IF YOU ARE NOT. LET ME GIVE YOU WHO EXAMPLES. THIS IS ANOTHER PAPER FROM JUSTIN’S GROUP, LOOKING AT PAPER WITH ADVANCED HEART FAILURE WHO REQUIRED RESYNCHRONIZATION, IN BLUE, YOUR CHANCE IS SURVIVAL IS SIGNIFICANTLY WORSE THAN NON-DIABETIC. SO IT RAISES THE QUESTION WHY IS THIS? SO CLEARLY ONE OF THE OBVIOUS THINGS TO LOOK AT IS GLYCEMIC CONTROL. IF GLYCEMIC CONTROL IS LESS ROBUSTER, ARE YOU AT GREATER RISK OF HEART FAILURE? THIS META-ANALYSIS WOULD SUGGEST IN FACT THIS IS THE CASE, IF YOU HAVE AN INCREASE IN HEMOGLOBIN A1c, ONE STUDY, IN FACT YOUR RISK FOR HEART FAILURE IS AMPLIFIED. SO IF GLYCEMIC CONTROL EMPHASIZES RISK FOR HEART FAILURE THE QUESTION BECOMES DOES IMPROVED GLYCEMIC CONTROL REDUCE RISK FOR HEART FAILURE? SO THE QUESTION, WHAT IS IMPACT OF GLYCEMIC CONTROL ON THE OUTCOME? BEFORE I SHOW DATA, LET ME REMIND YOU OF LANDMARK TRIALS THAT SOME OF WHICH WERE FUNDED BY THE NIH THAT LOOKED AT THE IMPACT OF TIGHT GLYCEMIC CONTROL ON A A NUMBER OF CARDIOVASCULAR END POINTS. THIS IS A WAKEUP CALL FOR MANY OF US IN THE FIELDS. IN ALL THESE TRIALS THAT LOOKED AT VARIETY OF WAYS OF ACHIEVING CONTROL IN INDIVIDUALS WITH TYPE 2 DIABETES, A COUPLE INTERESTING MESSAGES. ONE, PEOPLE WEREN’T NECESSARILY LIVING LONGER, SECONDLY IN SOME STUDIES, NOT ALL, IT APPEARS MAYBE THERE’S AN INCREASED RISK OF CARDIOVASCULAR EVENTS. IF ONE LOOKS AT RELATIONSHIP BETWEEN DIABETES THERAPIES AND HEART FAILURE THE PICTURE IS SOMEWHAT MIXED, THAT SOME MEDICATIONS LOOKING ACROSS A BROAD SWATH OF EPIDEMIOLOGIC LITERATURE WOULD SUGGEST IF YOU ARE ON THESE MEDICINES, THAT THEY EITHER COULD POTENTIALLY EXACERBATE OR INCREASE RISK FOR HEART FAILURE, WHEREAS A FEW OTHERS INCLUDING NEW AGENTS SUCH AS SGLT2 INHIBITORS AND STANDBY METFORMIN MAY BE BENEFICIAL IN THE CONTEXT OF HEART FAILURE. LET ME GIVE YOU A COUPLE EXAMPLES FROM THE LITERATURE. SO THIS IS AN ANALYSIS OF THOSE SAME TYPE CONTROL TRIALS I JUST MENTIONED EARLIER, LOOKING AT IMPACT OF ANY OF THESE TRIALS ON THE RISK FOR HEART FAILURE. THE WAY YOU LOOK AT THESE DATA IS THAT IF IN FACT TIGHT CONTROL WAS BENEFICIAL, THEN YOU WOULD BE ON THIS SIDE. IF TIGHT CONTROL WAS LESS BENEFICIAL, YOU WOULD BE ON THIS SIDE. MOST STUDIES ARE KIND OF TO THE LEFT OF THIS LINE. AGAIN, SUGGESTING THAT THERE’S SOMETHING ABOUT INTENSIVE CONTROL THAT MAY NOT NECESSARILY BE GOOD FOR THE FAILING HEART. HERE’S ANOTHER EXAMPLE, THE SAVIOR-TIMI TRIAL, IN GREEN WERE PATIENTS RANDOMIZED, PLACEBO, LOOKING AT HOSPITALIZATION FOR HEART FAILURE, YOU CAN SEE THERE’S SIGNIFICANT INCREASE IN HEART FAILURE HOSPITALIZATIONS IN THOSE PEOPLE WHO WERE RANDOMIZED TO THE DP4 INHIBITOR. THEY DRUG NEVER MADE IT TO MARKET. ACTIVES A ALPHA PPAR GAMMA AGONIST, TREATING DYSLIPIDEMIA, THE TRIAL WAS STOPPED BECAUSE PEOPLE WERE ACTUALLY HAVING ADVERSE EVENTS, INCLUDING INCREASED HOSPITALIZATION FOR HEART FAILURE. AND THEN THIS IS ANOTHER INTERESTING STUDY WHICH IS DONE A DIFFERENT WAY. HE TOOK PEOPLE WITH HEART FAILURES, STAGE 3 OR STAGE 4, AMERICAN HEART ASSOCIATION HEART FAILURE, AND RANDOMIZED THEM TO BE TREATED WITH A GLP 1 RECEPTOR AGONIST, OR NOT, LIRAGLUTIDE, ANTI-HYPERGLYCEMIC MEDICATIONS, IN SOME RANDOMIZED TRIALS REDUCED CARDIOVASCULAR OUTCOMES BUT IN THIS VERY SPECIFIC PUBLISH IN PATIENTS WITH HEART FAILURE, ER VISITS WAS STATISTICALLY HIGHER IN THE LIRAGLUTIDE GROUP RELATIVE TO PLACEBO GROUP. LOOKING AT WHO WERE THE ONES DRIVING THIS ASSOCIATION, IN FACT IT WAS THE PATIENTS WITH DIABETES BUT NOT THE PATIENTS WITHOUT DIABETES. I’M PAINTING YOU THIS PICTURE THAT THINGS WHICH LOWER BLOOD GLUCOSE VERY WELL MIGHT NOT NECESSARILY HAVE A PROPORTIONATE BENEFIT IN TERMS OF HEART FAILURE OUTCOMES. AND THEN THIS STUDY CAME UP, SGLT2 INHIBITORS, CONTINUES TO ROCK THE WORLD. NOBODY KNOWS WHY OR HOW IT HAPPENED. BUT THIS IS WHAT HAPPENED. YOU GIVE A DRUG THAT MAKES YOU ACTUALLY PEE OUT MORE GLUCOSE, INHIBITS SODIUM TRANSPORTERS IN YOUR KIDNEY, AND YOU HAD SIGNIFICANT REDUCTION IN MORTALITY, SIGNIFICANT REDUCTION IN THE HEART FAILURE HOSPITALIZATION, AND THIS IN FACT MIGHT BE CLASSIC, ANOTHER STUDY USING ANOTHER DRUG PRETTY MUCH SHOWED SIMILAR RESULTS. YOU HAVE A SCENARIO WHERE CLEARLY LOWERING BLOOD GLUCOSE MAY NOT BE ENOUGH AND THERE MIGHT BE SOME OTHER ATTRIBUTES OF OUR THERAPIES THAT MIGHT BE IMPORTANT IF ONE WANTS TO THEN TACKLE THIS ISSUEOF HEART FAILURE. SO WHY HAVE WE BEEN MISSING THE MARK IS THE QUESTION. I THINK ONE OF THE REASONS FOR THAT WHICH IS ATTEMPTED TO BE SUMMARIZED HERE IN THIS CARTOON WAS THAT, WELL, MAYBE IF YOU LOOK AT ANTI-HYPERGLYCEMIC THERAPIES, IN PEOPLE WITH HEART FAILURE IT IS POSSIBLE IT HAS NOTHING TO DO WITH THE THERAPY. IT’S JUST CHANCE, IT’S A RANDOMIZED TRIAL, IT’S THE LUCK OF THE DRAW. AND MAYBE IT’S JUST BAD. IT HAPPENS SO MUCH IF CLASSES OF AGENTS, IT MAKES IT LESS LIKELY THAT’S WHAT’S HAPPENING, OR IT COULD BE SOMETHING AS SIMPLE THAT THE AGENT IS PUTTING MORE VOLUME ON IT. THAT’S CERTAINLY TRUE FOR TZDs BUT NOT NECESSARILY ALL
CLASSES,& OR POTENTIALLY THERE MIGHT BE DIRECT MYOCARDIAL DEFECTS OF THESE AGENTS, I POSIT THERE MAY BE SOMETHING ELSE. THERE MIGHT BE A CARDIOMYOPATHY OF OBESITY AND DIABETES. THE WAY WE DEFINED THIS OVER THE YEARS IT REPRESENTS AN INTRINSIC DEFECT IN CARDIAC MUSCLE THAT INCREASES THE LIKELIHOOD THAT CARDIAC DYSFUNCTION WILL DEVELOP IN THE CONTEXT OF ADDITIONAL STRESSORS SUCH AS ISCHEMIA OR CARDIAC HYPERTROPHY. THIS IS A WONDERFUL STUDY DONE BY ELIZABETH SELDEN AND COLLEAGUES AT HOPKINS WHERE THEY HAVE FOR MANY YEARS BEEN STUDYING THIS COHORT IN THE ARIC STUDY LOOKING AT PEOPLE IN THE COMMUNITY AND RISK FACTORS FOR ATHEROSCLEROSIS AND CARDIOVASCULAR DISEASE. WHEN YOU HAVE SAMPLES IN THE FREEZER AS TECHNOLOGIES ADVANCES CAN YOU GO BACK TO THE FREEZER AND LEARN NEW THINGS. IN THIS CASE THEY APPLIED A VERY HIGHLY SENSITIVE TROPONIN ASSAY TO INDIVIDUALS STRATIFIED, NON-DIABETIC, PRE-DIABETIC, DIAGNOSED DIABETES. YOU CAN SEE CLEARLY THAT THERE WAS A SIGNIFICANT ALMOST LINEAR TROPONIN. THAT’S NOT THE LEVEL OF A HEART ATTACK, BUT SAYING THERE IS EVIDENCE OF SUBCLINICAL MUSCLE DAMAGE THAT’S OCCURRING. THIS IS THE ARBITRARY CUTOFF 1.4, BELOW OR ABOVE, AND EVEN WITH THAT CUTOFF THERE WAS STILL THIS LINEAR RELATIONSHIP IN TERMS OF ANY CARDIOVASCULAR EVENT OR DEATH OR RISK OF HEART FAILURE THAT WAS VERY PROPORTIONAL TO THE LEVEL OF SUBCLINICAL MYOCARDIAL DAMAGE OCCURRING IN THESE INDIVIDUALS WITH DIABETES, OF COURSE AMPLIFIED IN THOSE ON THE RIGHT SIDE OF THIS CUTOFF. SO, IT REALLY COMES TO THIS NOTION, WHAT IS HAPPENING IN THE HEART IN THE CONTEXT OF DIABETES? AND SO I PUT UP THIS CARTOON FROM A REVIEW WE PUBLISHED A FEW YEARS AGO THAT ATTEMPTED TO CAPTURE WHAT WAS KNOWN OR BEING STUDIED. YOU CAN SEE EVERYTHING IS BEING STUDIED. IT’S LIKE INSULIN RESISTANCE, RIGHT? THERE WAS 50 DIFFERENT PARTNERS THAT MIGHT NEED INSULIN RESISTANCE, UNFORTUNATELY IN THE CONTEXT OF DIABETES IT REALLY IS A THOUSAND SLOGS ON THE HEART, EVIDENCE IMPLICATING PATHWAYS IN THE PATHOPHYSIOLOGY OF DIABETIC CARDIOMYOPATHY. I’M GOING TO PICK A COUPLE FROM OUR OWN LAB TO GIVE YOU INSIGHT INTO SOME MECHANISMS THAT WE AND OTHERS HAVE IDENTIFIED. SO, WE FIRST TALK ABOUT WORK IN THE MITOCHONDRIA AND CONCEPT OF LIPO TOXICITY AND INCREASED FA UTILIZATION IN THE HEART AND DIABETES. THE HEADLINE IS THIS. THAT THE HEART IS A SUBSTRATE HUNGRY MUSCLE, DOESN’T HAVE THE OPTION TO FATIGUE OR REST, AND IT REALLY NEEDS TO GENERATE ANYWHERE FROM 6 TO 9 KILL OH GRAMS OF ATP PER DAY TO MAINTAIN FUNCTION, AND AS A RESULT OF THAT IS AN AVID USER OF MULTIPLE SUBSTRATES. WHAT HAPPENS IN THE CONTEXT OF DIABETES IS THAT THERE’S A SWITCH OF THE HEART WHICH TENDS TO LIKE TO BURN FAT BUT TENDS ACTUALLY TO BURN MORE FAT, IN THE CONTEXT OF DIABETES, SOMEWHAT AT THE EXPENSE OF USING GLUCOSE, THIS OCCURS IN CONCERT WITH MITOCHONDRIAL DYSFUNCTION. LET ME SHOW YOU SOME DATA FROM A HUMAN STUDY THAT WAS DONE BY ETHAN ANDERSON AT EAST CAROLINA UNIVERSITY. THIS IS A NICE EXAMPLE OF TRANSLATION OF RESEARCH. HE TOLD CARDIOTHORACIC SURGEONS, RATHER THAN SEND TO PATHOLOGY, SEND IT TO ME. IF YOU LOOK AT DIABETICS, THEY HAD MORE TRIGLYCERIDES IN APPENDAGES WHICH CORRELATED WITH HEMOGLOBIN A1c AND MITOCHONDRIA RESPIREOMETKY, IN BLACK IMIMPAIRED MITOCHONDRIAL FUNCTION WHICH CORRELATES TO A1c, THE MORE DIABETIC, LOWER MITOCHONDRIAL RESPIRATION. YOU CAN AGAIN SEE CLEARLY THE DIABETIC INDIVIDUAL MADE FOR HYDROGEN PEROXIDE, SHOWN HERE WITH DIFFERENT SUBSTRATES, AND IF YOU LOOKED AT MARKERS OF OXIDATIVE DAMAGE IN THESE TISSUES, AGAIN THIS WAS INCREASED IN THE DIABETIC. HERE IS A WESTERN BLOT SHOWING HYDROXY ANENOL, HERE IS A WESTERN BLOT SHOWING THAT WAS INCREASED IN DIABETICS. WORK IN ANIMAL MODELS, WE LOOKED AT THESE VERY DRAMATIC GENETIC MODELS OF OBESITY AND TYPE 2 DIABETES AND BEGAN TO LOOK AT MITOCHONDRIA. AGAIN, WE SAW THAT THE MITOCHONDRIA WERE QUITE DYSMORPHIC, AND THERE’S LIPID ACCUMULATION IN THE HEARTS OF THESE ANIMALS. TO SUMMARIZE WHAT HAPPENS TO CARDIAC METABOLISM IN HEARTS WHEN WE PERFUSE THEM, THERE’S A SWITCH IN SUBSTRATE USE THE HEARTS WERE USING MUCH MORE FATTY ACIDS, SHOWN HERE IN BLACK FOR THE DIABETIC ANIMALS, AND WHY OXIDIZING LESS GLUCOSE AND HAVING LESS GLYCOLYSIS. NOW, ONE OF THE THINGS THAT HAPPENS WHEN YOU BURN MORE FAT, YOU USE MORE OXYGEN TO MAKE ATP, WE SAW AN INCREASE IN THOSE 02 CONSUMPTION, IF YOU THINK OF A MARATHON RUNNER, IF YOU’RE A MARATHON RUNNER, I’M SURE THIS ROOM IS FULL OF MARATHON RUNNERS AND YOU’RE NOT LOOKING AT ONE HERE, I COULD BE THE CONTROL, THAT IF YOU ACTUALLY PUT ME IN A BOX AND MEASURED MY O2 CONSUMPTION AFTER I RAN TWO OR THREE MILES COMPARED TO THE MARATHON RUNNER, HE OR SHE WOULD USE SIGNIFICANTLY LESS OXYGEN THEN I WOULD. THAT PERSON IS VERY EFFICIENT. THE DIABETIC HEART IS THE ANTI-MARATHON HEART. IN A SENSE, THEY ARE RATHER INEFFICINT. WE ASKED IS IT BECAUSE THEY ARE BURNING MORE FAT? THE ANSWER IS NO BECAUSE IN FACT IN ADDITION TO USING MORE FAT, WHAT HAPPENS AT THE LEVEL OF MITOCHONDRIA, MITOCHONDRIA HAS SIGNIFICANT IMPAIRMENT IN THE MACHINERY OF THE ELECTRON TRANSPORT CHAIN, AND AS A CONSEQUENCE OF THAT THERE IS A PROPENSITY TO OVERGENERATE REACTIVE OXYGEN SPECIES OR SUPEROXIDE. AND AN IMPORTANT CONSEQUENCE OF SUPEROXIDE OVER A GENERATION, SUPEROXIDES DON’T ACTUAL — THEN ACTUALLY LEAD TO THIS. THIS IS A SCHEMATIZED MITOCHONDRIA, ELECTRONS ARE ACROSS THE CHAIN. I APOLOGIZE TO DR. BALABAN IN THE AUDIENCE, HE KNOWS THE CHAIN LOOKS NOTHING LIKE THAT IN REALITY BUT FROM THE STANDPOINT OF CARTOON IT WORKS FOR ME. ESSENTIALLY, AS THE ELECTRONS ARE BEING PUMPED ACROSS THE ELECTRON TRANSPORT CHAIN, THEY DO GENERATE SUPEROXIDE. AND IT TURNS OUT THAT SUPEROXIDE ACTIVATES PROTEINS WITHIN MITOCHONDRIAL MEMBRANE, UNCOUPLING PROTEIN THAT CAUSE PROTEINS TO LEAK BACK IN THE MATRIX, WHEN THEY ENTER, THEY INTERACT WITH MOLECULAR OXYGEN TO PRODUCE WATER. SO IF YOUR MITOCHONDRIA IS UNCOUPLED, YOU CAN HAVE A HIGH OXYGEN CONSUMPTION RATE AND THEY ARE NOT MAKING ATP. SO WHAT WE’VE SHOWN IN DIABETES, THIS DRIVES THIS INCREASE IN OXYGEN CONSUMPTION RATES AND REDUCES THE AMOUNT OF ATP ENERGY THAT MITOCHONDRIA ARE GENERATING, WHICH WE THINK IS AN IMPORTANT MECHANISM FOR DECREASED INEFFICIENCY IN THE HEART IN THE CONTEXT OF DIABETES. NOW, THIS IS ALSO TRUE OF PEOPLE. I’M GOING TO GO BACK AND FORTH BETWEEN HUMANS AND MICE, IT’S IMPORTANT TO REALLY VALIDATE SOME OF THESE OBSERVATIONS. THIS IS WORK FROM LINDA PETERSON AT WASH U, COHORT OF WOMEN WITH TYPE 2 DIABETES, A PET APPROACH TO MEASURE UPTAKE OR OXIDATION OF FATTY ACIDS IN RELATIONSHIP TO GLUCOSE TOLERANCE. AS YOU BECOME MORE DIABETIC THE HEART USES MORE FATTY ACIDS, AND A NICE RELATIONSHIP BETWEEN OBESITY AS PROXY FOR INSULIN RECESS TANS AND MYOCARDIAL OXYGEN RATES AND INSUFFICIENCY. IF YOU’RE DIABETIC, HEART IS USING MORE FAT, MORE OXYGEN, LESS EFFICIENT. THEREFORE IF YOU THEN START TO GET ISCHEMIC, THEN YOU’RE MUCH MORE LIKELY TO GET TO THE POINT OF INJURY EARLIER BECAUSE YOUR OXYGEN REQUIREMENTS ARE THAT MUCH MORE HIGH. NOW, THE OTHER THING I WANT TO GIVE YOU A FLAVOR OF, WHAT ELSE IS THIS ROS DOING TO MITOCHONDRIA BESIDES UNCOUPLING? I’M GOING TO SHARE A SNIPPET OF A RECENT PUBLICATION FROM OUR LAB WHERE WE REALLY SHOWED THAT ROS ALSO WAS AFFECTING MITOCHONDRIAL FORM AND FUNCTION. SO FOR THOSE WHO DON’T THINK ABOUT THIS A LOT, MITOCHONDRIA, YOU KNOW, WERE PERHAPS AT ONE POINT BACTERIA, AND STILL DO THINGS THAT BACTERIA LIKE TO DO, FUSE AND SHARE DNA, AND TO DIVIDE AND TO FUSE AND SHARE DNA, IN A SENSE THAT’S WHAT ALL OF LIFE DOES FROM TIME TO TIME. AND SO THIS PROCESS IS CALLED MITOCHONDRIAL DYNAMICS, WHERE THE MITOCHONDRIA EITHER UNDERGO PROCESS OF FISSION OR FUSION, A NUMBER OF MOLECULES WELL ESTABLISHED TO DRIVE THAT PROCESS. WE MADE AN ANIMAL MODEL INCREASED FATTY ACID, THIS IS A PET SCAN OF A MOUSE, YOU CAN SEE INCREASED FATTY ACID UPTAKE IN THE HEART RELATIVE TO CONTROL, THIS IS ABOUT AT THE LEVEL OF WHAT WE’D SEE IN DIABETES. WHAT WAS VERY INTERESTING IN THESE ANIMALS WAS THAT WHEN WE LOOK AT MITOCHONDRIA OF THESE ANIMALS, THERE WAS A REALLY VERY DRAMATIC KIND OF CHANGE IN THE MITOCHONDRIAL MORPHOLOGY AS SHOWN HERE. NOW, FOR THOSE WHO LOOK AT EMs, WE MAKE A SECTION, AND YOU LOOK DOWN ON YOUR IMAGE AND SEE WHAT THE MITOCHONDRIA LOOK LIKE. SO INITIALLY WE SAID OH MY GOSH, THESE MITOCHONDRIA ARE COMPLETELY FRAGMENTED. WE SUBMIT THE PAPER, THE REVIEWER SAID WE WANT MORE. I’M SHOWING THIS IS AS SOMETHING THAT IS FAMILIAR TO MANY OF YOU IN THIS ROOM. SO THEY WEREN’T CONVINCED THAT THEY WERE FRAGMENTED AND FORCED US TO PUT ON A VIRTUAL REALITY HEAD SET AND LOOK AT 3D RECONSTRUCTION OF WHAT WAS HAPPENING TO THE MITOCHONDRIA, THAT’S HERE. THIS IS NORMAL. LOOK HERE, YOU SEE THIS IS WHAT THE LIPIDS ARE DOING TO THE MITOCHONDRIA IN THE ANIMAL MODEL. IT’S REALLY BECOMING LIKE SPAGHETTI OR NOODLES, GOING IN AND OUT OF THE PLANE. WE NEEDED A SECTION, SAW WHAT APPEARED TO BE MITOCHONDRIAL FRAGMENTS, IN FACT YOU WERE SEEING A MITOCHONDRIA THAT WAS REALLY STRETCHED AND TWISTED AND TORTUROUS. AND NOT FUNCTIONING VERY WELL. AND SO IT TURNS OUT THAT WHAT IS DRIVING THIS MORPHOLOGICAL CHANGE IS SUPEROXIDE. IN THE SAME PAPER WE LOOKED AT ANIMALS THAT OVEREXPRESSED SUPEROXIDE DISMETASE, CROSSED WITH TRANSGENIC MICE AND HAD SOME COMPOUND MUTANTS. THE KEY POINT I WANT TO MAKE HERE IS THIS, THAT IF YOU SCAVENGE ROS AGGRESSIVELY IN OVEREXPRESSING, YOU GET LARGE MITOCHONDRIA. WHICH IS AN OPPOSITE TO WHAT WE SAW WHEN WE WERE OVERPRODUCING ROS BY INCREASING FATTY ACID USE, SHOWN HERE IN TERMS OF MITOCHONDRIAL SIZE IN THE TRANSGENIC ANIMAL COMPARING WITH ACS MOUSE THAT HAS INCREASED ROS AND WHEN YOU PUT THE TWO TOGETHER WITH YOU NORMALIZE MITOCHONDRIA SIZE. MITOCHONDRIA ARE NOT THESE STATIC ORGANELLES ON EMs BUT REALLY DYNAMICALLY BEING REGULATED BY THE ENERGY THAT IT’S RECEIVING IN A SUPEROXIDE-DEPENDENT MANNER. WE SHOWED ROS WAS DRIVING THIS PROCESS BY VARIOUS MODIFICATIONS ON CRITICAL MOLECULES THAT WERE INVOLVED IN THIS MITOCHONDRIAL DYNAMICS PROCESS. SO, THIS HAS BEEN PICKED UP BY VARIOUS PEOPLE. I GOT THIS OFF THE INTERNET BECAUSE ELIZABETH DOUGHMAN HAD THIS NICE CARTOON WITH THE TAG LINE INCREASED MYOCARDIAL FATTY ACID UTILIZATION AMPLIFIES THE RISK OF HEART FAILURE ASSOCIATED WITH DIABETES, INCLUDING ALTERATIONS IN MITOCHONDRIA STRUCTURE AND MITOCHONDRIAL FUNCTION. OKAY. SO THAT’S A LITTLE BIT ON MITOCHONDRIA AND LIPIDS. I’M GOING TO GIVE YOU A LITTLE BIT ON INSULIN SIGNALING. SO, I’M GOING TO GIVE YOU SOME EVIDENCE THAT WE THINK HYPERINSULINEMIA MAY CONTRIBUTE TO HEART FAILURE IN DIABETES. I APOLOGIZE FOR EVERYONE WHO STUDIES INSULIN ACTION, THIS IS A SIMPLE. INSULIN IS A TYROSINE KINASE, WHEN BINDS WITH LIGAND ACTIVATES INTRACELLULAR MOLECULES AND TRANSMITS SIGNAL INTO MULTIPLE PATHWAYS SUMMARIZED HERE INCLUDING METABOLIC PATHWAYS, CELL SURVIVAL AND CELL GROWTH PATHWAYS AS SHOWN HERE. I’M GOING TO SHOW YOU DATA ON SOME IMPORTANT INTERMEDIATE, AKT, IRS PROTEIN, AND GLUCOSE TRANSPORTER 4. WHEN YOU THINK ABOUT INSULIN RESISTANCE, WE THINK ABOUT A HORMONE THAT NORMALLY ARISES AND RESPONDS TO FEEDING WITH THE PRIMARY GOAL OF MAINTAINING HOMEOSTASIS TO PUSH GLUCOSE BACK INTO MULL, SUPPRESS HEPATIC GLUCOSE PRODUCTION AND GLYCOLYSIS, THESE PATHWAYS ARE IMPAIRED LEADING TO METABOLIC MILIEU CHARACTERIZED BY HYPER INSULEMIA, INCREASED LEVELS OF GLUCOSE ULTIMATELY. TURNS OUT IF YOU MEASURE THESE SAME THINGS IN PEOPLE WITH HEART FAILURE, YOU ALSO SEE THAT HEART FAILURE ITSELF IS AN INSULIN RESISTANT STATE, WITH MECHANISMS SIMILAR TO DIABETES SUCH AS INCREASED ECTOPIC ACCUMULATION OF LIPIDS IN MUSCLE AND LEVEL, INCREASED INFLAMMATION IN SKELETAL MUSCLE AND ADIPOSE TISSUE FOR EXAMPLE. SO THE QUESTION THEN IS WHAT HAPPENS TO INSULIN SIGNALING IN THE HEART IN THE CONTEXT OF DIABETES OR CONTEXT OF HEART FAILURE? THE ENDOCRINE STUDIERS IN THE ROOM KNOW IF YOU MEASURE INSULIN ACTION IN SKELETAL MUSCLE OR ADIPOSE TISSUE OR LIVER YOU’LL IT IMPAIRED. WE NEEDED TO KNOW WHETHER THAT WAS TRUE IN THE HEART. THIS IS AN INTERESTING STUDY DONE BY STUART COOK AT THE HAMMERSMITH IN LONDON, TOOK PATIENTS IN THE CARDIOLOGY CLINIC AND SAID SIGN CONSENT FORM FOR YOUR TREATMENT AND INTENSIVE CRITICAL PROTOCOL. PEOPLE WERE COMING THROUGH THE CLINIC, UNDERGOING ANGIOGRAPHY, BECAUSE THEY HAD STRESS TEST THAT THEY FAILED, OR THEY WERE PATIENTS WITH HEART FAILURE, SECONDARY DISEASE COMING FOR SURGERY. AND BASICALLY HE CONVINCED THEM TO HAVE A GLUCOSE CLAMP, SKELETAL MUSCLE BIOPSY, PET SCAN AND THEN WHEN THEY WENT TO THE O.R. FOR CORONARY ARTERY BYPASS SURGERY HAD A (INDISCERNIBLE) BIOPSY AT WELL. THE IRB APPROVED THE STUDY, AT LEAST WHAT I COULD TELL. UNFORTUNATELY, IT IS VERY INFORMATIVE. LET ME TELL YOU WHO THE PATIENTS WERE, THESE ARE THE CONTROLS, THESE ARE THE HEART FAILURE PATIENTS, TYPE 2 DIABETICS HERE. YOU CAN SEE TYPE 2 DIABETICS ARE NORMAL LD FUNCTION BY EJECTION FRACTION, HEART FAILURE WITH REDUCED EJECTION FRACTION, YOUR THREE COHORTS. AND IMPORTANTLY FOR THE COMMISSIONS IN THE — CLINICIANS IN THE AUDIENCE, A1cs WERE 6.6, IMAGES AT WORK, RIGHT? SO WHEN THEY DID SKELETAL MUSCLE BIOPSIES OF THESE INDIVIDUALS, WHAT THEY ACTUALLY — BEFORE THEY DO THAT LET ME MENTION THE GLUCOSE CLAMPS. THIS IS A GLUCOSE CLAMP LOOKING AT WHOLE BODY GLUCOSE UTILIZATION, HEART FAILURE PATIENTS OR BUY DIABETIC SUBJECTS WERE INSULIN RESISTANCE, DECREASED WHOLE BODY USE OF GLUCOSE, ALSO TRUE IN THE HEART. THIS IS THE SKELETAL MUSCLE BIOPSY RESULT, NOT UNEXPECTED, WHETHER IN HEART FAILURE PATIENTS OR PATIENTS WITH TYPE 2 DIABETES THERE WAS SIGNIFICANT IMPAIRMENT IN THE PHOSPHORYLATION OF IRS 1 FOR INSULIN RESISTANCE IN SKELETAL MUSCLE. IN THE HEART, IT WAS ACTUALLY UNEXPECTED. IN CONTRAST TO SKELETAL MUSCLE, WHETHER EVERYTHING WAS REDUCED IN THE HEART, THESE DOTS ARE PI3 KINASE ACTIVITY, IN PATIENTS WITH HEART FAILURE OR TYPE 2 DIABETES THERE WAS ACTIVATION IN PI3 KINASE ASSOCIATED WITH ARIS 1, WHOLE BODY GLUCOSE DISPOSAL, THE LOWER THE NUMBER THE MORE INSULIN RESISTANT YOU ARE. PATIENTS WHO WERE MOST ARE THE HIGHEST ACTIVITY LEVELS OF PI3 KINASE IN THEIR HEARTS, TRUE IN THE MOST HYPER ANEMIC PATIENTS ARE HIGHEST LEVELS OF ACTIVITY AND DOWNSTREAM ANOTHER INTERMEDIATE GSK BETA, PHOSPHORYLATION HIGHER IN THE HEART OF INDIVIDUALS WITH DIABETES. SO WE HAVE PATIENTS WHO HAVE DECREASED GLUCOSE UPTAKE IN THE HEART, INCREASED PROXIMAL SIGNALING FROM RECEPTOR TO PI3 KINASE. WHY IS GLUCOSE INTAKE LOWER? THEY HAD LESS GLUT4 ON THE CELL SURFACE. IN CONDITIONS CHARACTERIZED BY GENERALIZED WHOLE BODY INSULIN RESISTANCE AND HYPER INSULINEMIA, THERE’S DECREASED INCREASED INSULIN UPTAKE, SIGNALING TO PI3 KINASE AND AKT. IS THIS TRUE IN MICE? SO WE DO A STUDY WHERE WE PUT ANIMALS ON A WESTERN DIET, WHICH MICE REALLY LIKE. ONE OF MY POSTDOCS CAME TO MY OFFICE WITH TWO PELLETS OF ANIMAL CHOW, ONE A WESTERN DIET, ONE WAS THE CARDBOARD PELLET THAT MICE ARE GIVEN THIS HARDSHIP TO EAT. THEY SAID THEY WILL ACTUALLY TASTE THIS. THESE ANIMALS PUT ON A WESTERN DIET WOULD CHOW DOWN AND WOULD GAIN WEIGHT AND BECOME INSULIN RESISTANT. WE WANTED TO KNOW VERY ON IN THE FIRST TWO WEEKS, AFTER TWO WEEKS ON THIS DIET THEY GOT A LITTLE HYPERANEMIC, LIPIDS WEREN’T SO ABNORMAL. THIS WORK WAS DONE BY JORDAN WRIGHT WHO WAS AN UNDERGRADUATE STUDENT, NOW A Ph.D. RESIDENT AT VANDERBILT. WE TALKED ABOUT THE PIPELINE, THIS IS A NICE EXAMPLE OF SOMEBODY WHO YOU CAUGHT VERY EARLY AS AN UNDERGRADUATE WHO IS NOW A PHYSICIAN-SCIENTIST. SO MEASURING GLUCOSE UPTAKE IN CARDIOMYOCYTES OF THESE ANIMALS AND IN FACT SAID, OH, INSULIN RESISTANT, AS YOU CAN SEE IN THE BLACK BARS THAT INCREASE IN GLUCOSE IS SIGNIFICANTLY LOWER OR IMPAIRED COMPARED TO THE WHITE BARS OF THE CONTROLS, WHEN WE EXPOSE THEM TO INSULIN. SO THEN HE DID THIS EXPERIMENT WHERE HE MEASURED PHOSPHORYLATION OF AKT AND GET PHONE CALLS, SOMETHING IS WRONG. I’VE DONE IT THREE TIMES MAKES KNOW SENSE, DIDN’T TRANSPORT GLUCOSE BUT WAY MORE AKT ACTIVATION. THIS IS A LITTLE FAST. ATK ACTIVATION MORE IN THE HEARTS RELATIVE TO CONTROL. OKAY, JORDAN, THIS IS INTERESTING. SO WHY ARE THEY NOT TRANSPORTING GLUCOSE? TURNS OUT THAT PEOPLE I TALKED TO, THEY ALSO DIDN’T HAVE ENOUGH GLUT4 ON THE MEMORIAL RAINS. — MEMBRANES. I CAN REMIND YOU IS THIS CONCEPT OF A CONDITION OF GENERALIZED INSULIN RESISTANCE WHERE THE HEART, HOWEVER, IS A LITTLE BIT SELECTIVE, DECREASED GLUCOSE UPTAKE, INCREASED SIGNALING TO PI3 KINASE TO AKT. CAN HYPERINSULINEMUA OR INCREASED INSULIN SIGNALING EXACERBATE HEART FAILURE? WE TOOK ADVANTAGE OF A MODEL THAT WE CAN USE IN MICE, TRANSVERSE AORTIC CONSTRUCTION, YOU NARROW THE LUMEN, THE HEART HYPERTROPHIES AND ULTIMATELY HEART FAILS. ONE OF THE VERY INTERESTING OBSERVATIONS THAT WE MADE IN THIS STUDY WAS THAT IF YOU DO TRANSVERSE AORTIC CONSTRICTION AFTER TWO WEEKS THERE’S INCREASED ACTIVATION OF INSULIN SIGNALING PATHWAYS. THERE’S INCREASED PHOSPHORYLATION OF IRS1, AKT, THAT’S QUANTIFIED HERE. MORE INTRIGUINGLY IF YOU TOOK A CARDIOMYOCYTE AND ISOLATED FROM HEART IN A DISH AND SIMPLY STRETCHED IT, THERE WAS ALSO INCREASED ACTIVATION OF IRS AND SIGNALING PATHWAYS, SOMETHING ABOUT CARDIAC MUSCLE AND STRETCH WHICH IS ACTIVATING SIGNALING PATHWAYS. WHEN THE ANIMALS DEVELOPED HEART FAILURE THEY DEVELOPED WHOLE BODY METABOLISM EVIDENCED BY HYPOGLYCEMIA, INSULIN SIGNALING IN A PERIPHERAL ORGAN, IN THIS CASE THE LIVES. INSULIN RESISTANCE IN THE PERIPHERY. WE ASKED WOULD REDUCING INSULIN SIGNALING AMELIORATE LV DYSFUNCTION IN THIS MODEL? WE HAVE OUR LAB SUMMARIZE WHERE WE HAD INACTIVE OR REDUCE INSULIN RECEPTORS IN CARDIOMYOCYTES. WE STUDIED HETEROZYGOTE, REPEATED THE EXPERIMENT. YOU CAN SEE THESE ANIMALS DID NOT HYPERACTIVATE IRS 1 NOR AKT QUANTIFIED HERE AND MORE IMPORTANTLY THEY DIDN’T HYPERTROPHY AS MUCH AND MAINTAINED FRACTION SHORTENING, MEASURE OF LEFT VENTRICULAR FUNCTION IN THE MOUSE BY ECHOCARDIO GRAPHY, IT’S PRESERVED IN THE ANIMALS IN WHICH WE REDUCED INSULIN SIGNALING. AND IN FACT THERE’S ALSO LESS APOPTOSIS SHOWN HERE. SO THIS SUGGESTED TO US IN THE CONTEXT OF THIS PARTICULAR MODEL OF HEART FAILURE, PRESSURE OVERLOAD IN THIS HEART, HYPERTROPHY IRS 1 CAN BE ACTIVATED, INCREASING SIGNALING THROUGH AKT AND CONTRIBUTE TO HARD FAILURE, INCREASING LEFT VENTRICULAR REMODELING. MANY THINGS COME IN PAIRS, THERE’S A NUMBER OF ISOFORMS, AND AKT EXPRESSED IN THE HEART. WE WERE WONDERING WHETHER BOTH IRS ISOFORMS WERE CONTRIBUTING TO THIS RELATIONSHIP BETWEEN HYPER ANEMIA AND HEART FAILURE. WE MADE ANIMAL MODELS WHERE WE SELECTIVELY DELETED IRS 1 OR 2 IN THE HEART, HYPERTROPHY, WE FOCUS ON THIS SLIDE, IF YOU GO COMPARING A SHAM HEART TO HEART, FOUR WEEKS, YOU SEE EVIDENCE OF INCREASED FIBROSIS AND INJURY IN THE HEART. THIS IS TRUE IN ANIMALS THAT LACK IRS 2 BUT IMPORTANTLY ANIMALS LACKING IRS 1 IN THE HEART WERE COMPLETELY PROTECTED FROM THAT PHENOMENON. AND THE OTHER THING THAT WE THEN ALSO SHOWED WAS THAT THIS INJURED PATHWAY WAS ALSO SELECTED BY THE LEVEL OF AKT SPECIFICALLY FOR AKT 1 BUT NOT 2, A BUSY SLIDE BUT THIS IS THE QUANTIFICATION, IN THE CONTROLS, AKT IS HYPER PHOSPHORYLATED, IRS 2 KNOCKOUT IS THE SAME, IRS1 KNOCKOUT IS NOT, NO CHANGE IN AKT2. IS THIS TRUE IN HUMAN HEARTS? THE ANSWER IS YES. SO WE GOT SOME LEFT VENTRICULAR SAMPLES FROM CARDIAC SAMPLES AND LOOKED AT PHOSPHORYLATION IN THESE HUMAN HEARTS FROM HEART FAILURE AND AGAIN YOU CAN SEE SELECTIVE ACTIVATION OF IRS1 AND AKT1. SO HYPER INSULINEMIA IS EXACERBATING HEART FAILURE BY A SIGNALING PATHWAY INVOLVING IRS 1 BUT NOT IRS 2 AND AKT 1 BUT NOT AKT 2. MECHANISMS OF WHICH THERE ARE MANY I’M GOING TO SHOW YOU ONE MECHANISM, IRS1 DEFICIENT HEARTS HAVE INCREASED AMOUNT OF NUCLEOTIDE, CYCLIN GMP IN THEIR HEARTS, AND WE’RE NOW PURSUING THE MECHANISMS LINKING THE SIGNALING PATHWAYS. SO I WANT TO LEAVE UP WITH THE IDEA INCREASED INSULIN SIGNALING IN THE HEART WE THINK ACTUALLY IS GROWTH PROMOTING AND ACCELERATE LEFT VENTRICULAR REMODEL, AND REMEMBER TYPE 2 DIABETES IS A PROFOUNDLY HYPER INSULINEMIC STATE. THERE’S ANOTHER INSULIN RECEPTOR STORY WE RECENTLY DISCOVERED. IT’S THIS. SO, AGAIN, YOU HIGH FAT FEED THE ANIMALS. THEY GET DIABETIC. THEY GET HYPERINSULINEMIC, IF YOU DO IT LONG ENOUGH HEARTS WILL FAIL, HEARTS DILATE, FIBROSIS IN BLUE STAINS, EJECTION FRACTION FALLS. THIS IS A BETAD ADANERGIC RECEPTOR. AND WHEN THERE IS HYPERINSULINEMIA THIS FORMS, BECOMES STRONGER, ACTIVATES ANOTHER SIGNALING PATHWAY INVOLVES A KINASE CALLED GRK2, THROUGH BETA ARRESTIN, TO ERK, DEGRADING CYCLIC AMP. HERE IS EVIDENCE, YOU HAVE LESS PDE 4, IF YOU HIGH FAT FEED PDE 4 GOES UP, IF YOU HIGH FAT FEED INSULIN RESISTANT MOUSE DON’T SEE INCREASE IN PDE4. SO WHAT WE THEN DID IN THE STUDY WAS WE THEN ESSENTIALLY TRIED TO BLOCK THIS PROCESS BOTH PHARMACOLOGICALLY AND GENETICALLY TO SEE IF WE COULD PRESERVE CARDIAC STRUCTURE AND CARDIAC FUNCTION. SO WE HAD MUTANT MICE THAT WERE LACKING BETA2 RECEPTORS, OR WERE ABLE TO GENETICALLY OR PHARMACOLOGICALLY INHIBIT GRK 2 OR BETA ARRESTIN, IN THE CONTROL ANIMALS ON A HIGH FAT DIET THEY LOSE EJECTION FRACTION, BUT IN KNOCKOUTS THEY MAINTAIN EJECTION FRACTION. WE ALSO USED A COUPLE OF DRUGS, A BETA 1/BETA2 BLOCKER OR AN ANTI-DEPRESSANT, HIGHER DOSES THAT BLOCK AS PROOF-OF-CONCEPT, TOOK THE ANIMALS TO WHERE THEY DEVELOPED DYSFUNCTION, TREATED THEM, YOU CAN SEE ANIMALS TREATED WITH EITHER PREOSEINE IN RED OR BLUE, DESPITE NO REAL CHANGE IN HYPERGLYCEMIA OR HYPERINULINSEMIA, SUGGESTING TO US THAT TAKING BOTH SETS OF DATA TOGETHER EARLY ON IN THE INSULIN RESISTANT STATE WE THINK IT DRIVES SIGNALING PATHWAYS THAT DRIVE ABERRANT CARDIAC HYPERTROPHY AND PATHWAYS THAT INCREASE LEFT VENTRICULAR REMODELING AND FURTHER ON AS IT BECOMES MORE PROTRACTED THERE’S THIS GRK2 MECHANISM WHICH MAY CONTRIBUTE TO CARDIAC DECOMPENSATION. SO WE BELIEVE THE DATA WOULD SUGGEST IN THE CONTEXT OF HEART FAILURE, WE THINK IT’S IMPERATIVE TO IDENTIFY NOVEL WAYS TO MANAGE DIABETICS PARTICULARLY HYPERINSULINEMIC, MEASURE AT THE LOWEST POSSIBLE LEVEL OF SYSTEMIC INSULIN AND IT’S IMPERATIVE TO PURSUE MECHANISMS THAT WE MIGHT USE TO THERAPEUTICALLY LIMIT INDIRECT EFFECTS OF INSURE LANE RESISTANCE INSULIN RESISTANCE ON THE FAILING HEART. I’M GOING TO END WITH A COUPLE SUGAR SLIDES TO TELL YOU NEW WORK WE’RE DOING. WE’VE GOT ACCESS NOW TO VERY ROBUST HEART FAILURE TISSUE BANK. AND HAVE BEEN DOING SOME METABOLOMICS PROFILING ON THOSE SAMPLES, COLLABORATION WITH KEN MARGUILES AT THE UNIVERSITY OF PENNSYLVANIA, WE’RE PARTICULARLY INTERESTED IN LOOKING AT INDIVIDUALS WHO ARE STRATIFIED EITHER AS DONORS OR HEART FAILURE PATIENTS, EITHER OBESE OR DIABETIC OR NOT. AND SO THIS IS THEIR AGES, BETWEEN 40 AND 60. YOU CAN SEE IN THE NON-FAILING COHORT, THESE ARE DONOR HEARTS, WE HAVE INDIVIDUALS WHO ARE OBESE, INDIVIDUALS WHO ARE I GUESS LESS OBESE. AND THEN WE HAVE PATIENTS WITH HEART FAILURE. AND AGAIN THIS IS HEART FAILURE WITH REDUCED EJECTION FRACTION SHOWN HERE, AND AGAIN BY VIRTUE OF SAMPLES, WE HAVE CAN A PROXY OF GLYCEMIC CONTROL, AND OTHERS TEND TOWARD HIGHER FRUCTOSE LEVELS, INSIGHT INTO EARLY METABOLOMIC DATA WE’VE OBSERVED. SO A VERY STRIKING PHENOMENON THAT WE’VE SEEN IN THESE HEARTS IS A GLYCOLYTIC BACKUP, ACCUMULATION, MITOCHONDRIAL METABOLITES, IT APPEARS THINGS ARE BACKING UP IN GLYCOLYSIS, SPILLING INTO SOME SIDE PATHWAYS SHOWN HERE, SO GALACTOSE, MANNOSE, SORBITOL. THESE THINGS ACTIVATE TISSUE DAMAGING SIGNALING PATHWAYS, ATTEMPTING TO SUMMARIZE ON THIS SLIDE. MANNOSE WILL INCREASE, GLYCATION, AND INCREASE EXTRACELLULAR MATRIX REMODELING. SORBITOL WILL LEAD TO DEPLETION, OXIDATIVE STRESS, AND THEN THIS PATHWAYS WILL ACTUALLY LEAD TO INCREASED ADVANCED GLYCATION, GIVEN WE HAVE NO EVIDENCE OF A BACKUP, CAN WE MODEL THE BACKUP IN A MOUSE HEART? WE DID THIS BY INACTIVATING A RECENTLY IDENTIFIED PYRUVATE CHANNEL, MITOCHONDRIAL PYRUVATE TRANSPORTER. WE PREDICTED THIS WOULD GIVE US A NICE MODEL OF BACKUP AND YOU’R WELCOME TO LEARN ABOUT THAT AND LEFT VENTRICULAR REMODEL. FOR THIS STORY, THESE ANIMALS ACTUALLY RECAPITULATE IN THE HEART, INCREASED CONSUMPTION, IF YOU FOLLOW OVER TIME THEY FAIL, WHICH IS NICE FOR THIS STORY, THEY GET DILATED, HAVE REDUCTION IN THEIR EJECTION FRACTURE. SO HAVE WE LEARNED IN CANCER METABOLITES, 2-HYDROXYGLUTARATE, CANCER METABOLISM, IT DRIVES A LOT OF ONCOGENESIS THROUGH MULTIPLE MECHANISMS INCLUDING FOR EXAMPLE STABILIZATION OF HIF1 ALPHA. THESE ANIMALS ACCUMULATE 2 HYDROXYGLUTARATE. I DON’T HAVE TIME TO TELL YOU HOW WE MANIPULATED THIS BUT ONE OF THE THINGS THAT HEINRICH HAS SHOWN NICELY RECENTLY IS THAT 2 HYDROXYGLUTARATE CAN IS PROFOUND EFFECT ON CARDIOVASCULAR METABOLISM, ULTIMATELY LEADING TO HISTONE MODIFICATION AND ALTERATIONS IN EPIGENETICS AND GENE EXPRESSION. SO I’M NOW BEGINNING TO THINK HEART FAILURE IS LIKENED TO CANCER OF THE HEART, TERRIBLE PROGNOSIS, BUT NOW CHANGING METABOLISM MIGHT BE DRIVING SOME OF THE ABERRANT SIGNALING PATHWAYS THAT WE SEE. SO GLUCOSE METABOLISM AND HEART FAILURE ARE NO LONGER SIMPLY A MATTER OF ENERGY PRODUCTION BUT I THINK RECENT WORK ON THOSE OF HEINRICH INTRODUCE A NEW FRONTIER OF METABOLITES AS MOLECULAR SIGNALS. AS WE UNDERSTAND WHAT’S HAPPENING AT THE LEVEL OF PATHOPHYSIOLOGY, WE BEGIN TO UNDERSTAND HOW THESE METABOLITES ARE LEADING TO ABERRANT SIGNALING PATHWAYS WHICH ULTIMATELY CAN BE THERAPEUTICALLY TARGETED. I’LL SHOW YOU WE’RE CONFUSED. WE DON’T KNOW ENOUGH ABOUT WHAT’S HAPPENING IN THE CONTEXT OF DIABETES WHICH IS WHY I HAD MADE THIS TITLE, SUGAR AND THE BEATING HEART, CONUNDRUM OF HEART FAILURE IN DIABETES, I HOPE THAT GIVES FLAVOR OF SOME COMPLEXITIES LINKING THIS VERY PREVALENT METABOLIC DISORDER WITH AN INCREASED RISK OF HEART FAILURE. SO I’M GOING TO — BECAUSE THEY ARE THERE, THIS IS A PICTURE OF MY LAB. (INDISCERNIBLE) DID THE WORK ON LIPIDS, JANG IS WORKING ON PYRUVATE, AND MANY HAVE NOW GONE ON TO RUN THEIR OWN LABS. IT TAKES A TEAM TO DO THIS WORK, AND MANY COLLABORATE CONTRIBUTED TO THESE STUDIES. I CONTINUE TO BE INDEBTED TO THE NIH FOR KEEPING US GOING THROUGH THICK AND THIN AND MANY A-1s AND MANY A-2s. WITH THAT I THANK YOU VERY MUCH FOR THE OPPORTUNITY TO SHARE THIS WITH YOU. [APPLAUSE] >>WELL, THANK YOU FOR A REALLY INTERESTING ROMP THROUGH A LOT OF DATA AND INTERESTING CONCLUSIONS THAT A YOU SAY OF THINGS WE MIGHT CONTINUE TO TALK ABOUT EVEN NOW. SO THERE ARE MICROPHONES IN THE AISLES FOR PEOPLE WHO MIGHT WANT TO POSE A QUESTION. PLEASE DO SO. WE CAN START RIGHT OVER HERE. YES, SIR.>>WHENEVER YOU SEE A TYPE 2 DIABETES, YOU DON’T THINK YOU’RE GOING TO HAVE OBESITY, METABOLIC SYNDROME AS WELL, CORRELATED, THE BIG BOY ON THE BLOCK, NOT ALCOHOLIC FATTY LIVER DISEASE, THERE’S A DRUG FOR NON-ALCOHOLIC, IS THERE ANY CORRELATION WITH THIS WITH YOUR HEART FAILURE, NUMBER ONE. NUMBER TWO, WOULD IT BE WORTHWHILE COMPARING TRIALS FOR THE DRUG NOW USED FOR NON-ALCOHOLIC FATTY LIVER DISEASE?>>RIGHT. SO I’M NOT SURE ABOUT TRIALS THAT’S LOOKING SPECIFICALLY AT THE LINK BETWEEN TREATING AND HEART FAILURE BUT I CAN SAY THERE ARE GROUPS THAT LOOKED AT MEASURING BOTH LIVER FAT AND HEART FAT IN PEOPLE AT RISK, AND CERTAINLY IF YOU HAVE NASH YOU’RE MORE LIKELY TO HAVE CHANGES IN YOUR HEART THAT MAY CONTRIBUTE TO THE INCREASED RISK OF HEART FAILURE BUT STUDIES LINK BOTH, AS FAR AS I’M AWARE, ARE YET TO BE DONE.>>OKAY. THANK YOU. OVER HERE.>>WELL, CONGRATULATIONS FOR COVERING COMPLEX ISSUES. I’M INTERESTED OF THE TOO MANY IMPLICATIONS OF TOO MANY PARTNERS, SO ONE OF THE ISSUES I THOUGHT I COULD DO WITHOUT TOO MUCH MEDICATION ABOUT THINGS IS EXERCISE. THIS IS MAJOR EFFECT AND YOU COULD PUT SOME OF THE MICE EVEN SOME OF THE PATIENTS AND SEE WHAT IS THE NET OUTCOME OF THE COMPLICATIONS THAT IS HAPPENING.>>YES, YOU MAKE A VERY IMPORTANT POINT. YES, EXERCISE IS IMPORTANT. THERE’S A PARTICULAR KIND OF HEART FAILURE CARD HEART FAILURE WITH PRESERVED EJECTION FRACTION THAT’S VERY PREVALENT IN INDIVIDUALS WITH TYPE 2 BUY DIABETES, AND YOU ONE OF THE MOST EFFICACIOUS THINGS WHERE THERE ARE NOT GOOD DRUGS IS EXERCISE. IF YOU HAVE HEART FAILURE YOUR ABILITY TO EXERCISE IS DIMINISHED, ULTIMATELY WE HAVE TO FIND OTHER TARGETS THAT WE CAN MIMIC EXERCISE WITH. YOU KNOW, IN ORDER TO SEE SOME BENEFIT.>>THE INTERVENTION IN THE EARLY STAGES IS CRITICAL. THANK YOU.>>YES, IT IS.>>OVER HERE ON THE RIGHT.>>THANK YOU VERY MUCH. VERY INTERESTING. ONE OF THE FIRST SLIDES THAT YOU PRESENTED SHOWED THAT THE RISK OF HEART FAILURE IS MUCH GREATER IN DIABETIC WOMEN COMPARED TO MEN.>>THAT’S CORRECT.>>I WONDER IF YOU CONDUCTED EXPERIMENTS IN MALES OR FEMALES AND IF BOTH DO YOU SEE DIFFERENCES IN MECHANISMS.>>YEAH, VERY GOOD QUESTION. THERE’S SOMEONE IN THE AUDIENCE, DR. MURPHY, WHO KNOW AS LOT ABOUT GENDER AND SEX AND HEART FAILURE THAN I DO. NOT MANY STUDIES IN ANIMAL MODELS HAVE BEEN DONE. THERE HAVE BEEN SOME REALLY NICE HUMAN STUDIES BY LINDA PETERSON’S GROUP AT WASH U IN HUMANS, MALE AND FEMALE, WITH AND WITHOUT DIABETES. CLEARLY WHAT SHE HAS SHOWN THAT THE PATTERNS OF SUBSTRATE METABOLISM, WHAT SHE STUDIES, ARE DIFFERENT BETWEEN MALES AND FEMALES. SO THAT’S AT LEAST GIVING US A HINT. I THINK THERE’S A LOT MORE WE NEED TO DO, PARTICULARLY WITH REGARD TO MECHANISMS I SHOWED YOU.>>GREAT. I KNOW OUR SPEAKER HAS TO CATCH A PLANE BUT WE CAN TAKE TWO MORE QUICK QUESTIONS. PHIL?>>QUICKLY, BEAUTIFUL TALK.>>THANK YOU.>>SO AFTER THE DCCT IT WAS CLEAR THAT BETTER OUTCOMES FROM DISEASE.>>THAT’S CORRECT.>>YOU’RE RAISING THE QUESTION WHETHER THAT MIGHT BE A CONTRADICTION FOR MACROVASCULAR DISEASE. HOW SHOULD WE TRANSLATE TO A COMMUNITY AND SECOND YES HOW MUCH GLUCOSE DOES THE HEART USE ANYWAY?>>RIGHT. LET ME ANSWER THE SECOND QUESTION FIRST. SO THE HEART USES SOME GLUCOSE. I’LL GIVE YOU IN TERMS OF GRAMS AND KILL KILOGRAMS. IF YOU LOOK AT FAT AND GLUCOSE, NORMAL HEALTHY CIRCUMSTANCES, PROBABLY GETTING 50 TO 60% OF ATP FROM FAT, 20% LACTATE, THE REST FROM GLUCOSE. IF YOU COMPLETELY CONSTRICT GLUCOSE USE, AT LEASE IN ANIMAL MODELS, THE HEARTS AREN’T VERY HAPPY. SO YOU DO NEED SOME FLEW GLUCOSE. HOW MUCH IS TOO MUCH? THE COMPLICATION IN THE HEART IN DIABETES IS TWO-FOLD. NUMBER ONE, IT ENDS UP USING MORE FAT. AND THEN SECONDLY BECAUSE OF THE DEFECT YOU GET ACCUMULATION I BELIEVE OF THESE KIND OF INTERMEDIATE WHICH CAN HAVE AN IMPACT. YOUR EARLY QUESTION, HOW DO WE TRANSLATE THIS INTO PRACTICE. AT THIS STAGE WE REALLY HAVE TO SORT OF PERSONALIZE OUR MANAGEMENT OF OUR PATIENTS SO ONE OF THE THINGS AS A BROAD THEME IN DIABETES IN GENERAL IS THAT, YOU KNOW, NOT EVERYBODY SHOULD HAVE THEIR A1c DRIVEN TO FIX, PARTICULARLY IF YOU’RE ELDERLY AT RISK. IN THE CONTEXT OF HEART FAILURE HAVE TO BALANCE OPTIONS CAREFULLY, CERTAINLY THE HEART FAILURE HAS TO BE OPTIMALLY MANAGED, I THINK TRY TO MANAGE METABOLIC ABNORMALITIES IN A WAY THAT I WOULD ARGUE SHOULD PROMOTE LESS HYPERINULINSEMIA IF POSSIBLE, SHOULD NOT INCREASE VOLUME IF POSSIBLE, THAT DOES LIMIT. THE CARDIOVASCULAR COMMUNITY, EVERYBODY’S JUMPING ON TOP OF SGL2 INHIBITORS IN HIGH RISK PATIENTS. I WOULD CAUTION IT’S PROBABLY EARLY. THOSE ARE NARROW STUDIES. VERY, VERY PRE-DEFINED POPULATION, NOT SURE IF IT’S GENERALIZABLE. THERE ARE CLINICAL TRIALS UNDERWAY TO SEE IF SGL 2 INHIBITORS WILL HAVE AN OUTCOME. WE NEED TO WAIT ON THESE DATA.>>THANK YOU.>>NEXT QUESTION.>>DALE, THANK YOU FOR THE OUTSTANDING TALK. WE’VE SEEN FLEXIBILITY, HEALTHY SUBJECTS IN TERMS OF UTIZEATION, DO YOU THINK BASED ON THE MODEL IF YOU COULD SHIFT THE HEART TOWARDS INCREASED GLUCOSE UTILIZATION THERE WOULD SHALL LESS GENERATION OF ROS BE ON WOULD HYPERGLYSEMIA LEAD TO SAME KINDS OF PROBLEMS?>>LIKE EVERYTHING IN LIFE THERE’S A BALANCE. AND WE HAVE DONE THOSE EXPERIMENTS, SO WE HAVE MOUSE MODELS WHERE WE CAN INDUCABLY INCREASE THE EXPRESSION OF GLUCOSE TRANSPORTERS, WHAT WE SEE IN THE CONTEXT OF THE PRESSURE OVERLOADED MODEL, WE DO SEE LESS REMODELING. WITH THAT SAID, IF WE TURNED UP TOO MUCH WE THEN SEE GLUCOSE INJURY. SO I AGREE WITH YOU THAT HAVING THE METABOLICS FLEXIBILITY IS IMPORTANT, HOW ONE CAN ACHIEVE THAT, YOU KNOW, IN CLINICAL CONTEXT, THAT I THINK IS A CHALLENGE.>>WELL, YOU’VE GIVEN US A WONDERFUL EXAMPLE OF A LOT OF WONDERFUL BASIC SCIENCE THAT ALSO TRANSLATES INTO REALLY PRACTICAL CLINICAL IMPLICATIONS. IF WE COULD JUST FIGURE OUT HOW TO PUT THAT TOGETHER.>>RIGHT.>>YOU’VE GOTTEN US WELL ALONG THE WAY.>>KEEP FUNDING ME, KEEP FUNDING ME. [LAUGHTER]>>I SEE, YOU LEFT THE DOOR OPEN TO MORE WORK NEEDS TO BE DONE, AS THEY ALL DO. LET’S THANK OUR SPEAKER AGAIN FOR A WONDERFUL PRESENTATION. [APPLAUSE]>>THANK YOU.

3 thoughts on “Sugar and the beating heart: the conundrum of heart failure in diabetes

  1. Baxter Montgomery, MD, cardiac physician, proponent of Whole Foods plant based diet low in fat, high in carbohydrates, including fiber and starches, working down in Houston, Texas, is reversing heart failure…. with epigenetic modulation aka lifestyle aka diet

  2. Were the mice really fed a high fat diet? Or was it high carb (sugar) diet? Because i can’t understand how high fat alone could make the mice hyperinsulinaemic.

  3. WOMEN AT HIGHER RISK THAN MEN TO DIE OF HEART FAILURE DUE TO DIABETES

    Women living with Type-2 diabetes are at a higher risk of heart failure than men, says a study. In India, Type-2 diabetes becomes a cause of 9% higher risk of heart failure for women than men.

    According to the International Diabetes Federation (IDF), 415 million adults are living with diabetes and 199 million of them are women. The IDF expects this number to go up consistently and reach 313 million by the year 2040. And 8.8% of India's population is living with diabetes.

    READ MORE STORIES : 

    https://www.beyondpinkworld.com/news/health-wellness/women-higher-risk-heart-failur-5629

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