November 17, 2019
2018 Demystifying Medicine: Diabetes and Artificial Sweeteners

2018 Demystifying Medicine: Diabetes and Artificial Sweeteners


EVERYBODY KNOWS WHAT THIS IS? RIGHT? IT’S THE GOLDEN GATE BRIDGE OVER SAN FRANCISCO BAY, RIGHT? THIS IS THE MOST FAMOUS BRIDGE IN THE WORLD, THIS IS THE BROOKLYN BRIDGE AND I WOULD REMIND YOU AS I’VE DONE FOR THE PAST 17 YEARS THAT WE ARE LIKE THE 2 PEOPLE ON THE CAT WALK AND ON 1 SIDE IS BROOKLYN AND BASIC BIOLOGICAL SCIENCE AND ON THIS SIDE, THE NEW YORK SIDE IS CLINICAL MEDICINE AND THE WHOLE PURPOSE OF THE COURSE IS TO GET PEOPLE TO TALK TOGETHER ACROSS THESE DISCIPLINES AND TO HELP BUILD SOME BRIDGES. SO WE’RE ALL IN THE BRIDGE BUILDING BUSINESS AND TODAY IS A MARVELOUS EXAMPLE, ANOTHER 1. EACH WEEK AS ILLUSTRATES THE POINT BUT TODAY THE TOPIC IS DIABETES. FOR THOSE WHO ARE INTERESTED, THE WORD IS ANCIENT AND IT MEANS PASSING THROUGH. THE RECOGNITION THAT DIABETIC PATIENTS WERE URINATING A GREAT DEAL AND IN THE BEGINNING IT WAS A FATAL DISEASE, UNIFORMLY FATAL. IN 1921, INSULIN WAS DISCOVERED BY BANDING AT BEST, THAT INTRODUCED A WHOLE NEW CHAPTER, THERE IS NOW SOME THERAPY AND THAT LED TO THE CLASSIFICATION OF TYPE 1, TYPE 2, SOME PEOPLE ARE INSULIN RESISTANT, SOME AREN’T, AND THERE IS HAVE BEEN MAJOR DEVELOPMENTS THROUGHOUT THE YEARS IN INSULIN SIGNALING, HOW MANY MEASURE GLUCOSE IN AN EFFECTIVE WAY IN A PATIENT, INSULIN TYPES, DOSING AND DELIVERY AND A WHOLE BUNCH OF BIOLOGY, HOWEVER DESPITE ALL OF THIS, DIABETES IS STILL THE SEVENTH MAJOR CAUSE OF DEATH. SO WHY IS IT? AND WHERE DO WE STAND? AND SO TODAY’S SPEAKERS ARE GOING TO ADDRESS THAT AND OTHER ASPECTS. SO I WANT TO–BEFORE ASK A QUIZ. WHAT DID THESE THINGS HAVE IN COMMON? WHAT? YOU HAVE TO SPEAK UP. WELL I CAN’T HEAR YOU BUT IF YOU SWEETENERS YOU’RE ABSOLUTELY RIGHT. [LAUGHTER] AND THAT’S GOING TO BE THE TOPIC WHICH OUR SECOND SPEAKER WILL ADDRESS. SO OUR FIRST SPEAKER IS PHIL GORDEN WHO GOT HIS MEDICAL DEGREE FROM VANDERBILT UNIVERSITY, TRAINED IN MEDICINE AND ENDOCRINOLOGY AT YALE, CAME TO THE NIH IN 1966 AS A CLINICAL FELLOW HIS WORK AT THAT TIME WAS EXTREMELY SIGNIFICANT BECAUSE THAT WAS 1 OF THE HAY DAYS OF DEVELOPMENT OF UNDERSTANDING OF ENSURVEYS LYNN, MECHANISTICALLY HOW IT WORKS, THE INSULIN RECEPTOR AND PHIL WAS VERY, VERY MUCH A PART OF ALL THAT. HE SPENT A YEAR IN SWITZERLAND WITH ILLUMINATEIO ARCHI, DOING ELECTRON MICROSCOPY OF SOME OF THE ASPECTS OF THE RECEPTOR MEDIATED ENDOSIGNIFYITOSEIS PATHWAY HE WAS INTERESTED IN AND THEN CAME BACK TO NIH AS A MAJOR BRANCH CHIEF AND THEN A CLINICAL DIRECTOR OF THE NIDDK FROM 1986 FOR 13 YEARS UNTIL 1999 HE SERVED AS DIRECTOR OF THE NIDDK AND DURING HIS TENURE A SERIES OF REMARKABLE SIGNIFICANT CLINICAL STUDIES WERE PERFORMED WHICH EXAMINED ATTEMPTS TO PREVENT DIABETES, TO CONTROL DIABETES AND SO FORTH. IN 1999, HE RETURNED FULL-TIME TO THE INTRAMURAL PROGRAM WHERE HE HAS CONTINUED TO FOCUS ON MECHANISMS, AND ON THERAPIES. NOW OUR SECOND SPEAKER CHRISTINA ROTHER, RECEIVED HER MEDICAL DEGREE IN GERMANY AND ALSO GOT A DEGREE AT DUKE UNIVERSITY, A MEDICAL MASTERS IN HEALTH SCIENCES, A SPECIAL COURSE AND THEN SHE SPENT A RESIDENCY IN PEDIATRICS AND IN ENDOCRINEOLOGY ESSENTIALLY BY BOUNCING BETWEEN THE MAYO CLINIC, THE CHILDRENS HOSPITAL IN ZURICH, THE MASSACHUSETTS GENERAL HOSPITAL AND BACK TO ZURICH WHERE SHE WAS A VISITING SCIENTIST IN MOLECULAR BIOLOGY AND CAME HERE IN 1998 AND SHE IS A CLINICAL INVESTIGATOR, A SECTION CHIEF, IN CHARGE OF THIS SECTION ON PEDIATRIC DIABETES AND METABOLISM. SHE IS–HER WORK IS INCREASINGLY WELL KNOWN PARTICULARLY BECAUSE OF HER FOCUS ON SOME OF THE ISSUES THAT ARE REPRESENTED BY THE ARTIFICIAL SWEETENERS. SO, PHIL, WOULD YOU BEGENERATED, PLEASE? –BEGIN, PLEASE?>>THANK YOU VERY MUCH WYN, IS THIS VOLUME AND SO FORTH OKAY? I CAN–I KNOW IT’S NOT ON. OKAY, IS THAT BETTER? IS THAT OKAY. WELL I CAN ACTUALLY TALK LOUDER, BUT I CAN’T TALK ANY FASTER SO I CAN’T GIVE YOU A NEW YORK ACCENT LIKE DR. ARIAS’S SLIDE HERE, THERE’S FOE WAY THAT CAN HAPPEN. WHEN I WANTED TO DO BECAUSE OF THE NATURE OF THIS GATHERING AND I’M HAPPY TO ADMIT, I AM A BIT NERVOUS BECAUSE 1 OF MY FORMER MENTORS DR. YAN WOLF IS HERE AND HE MAKINGS ME A BIT NERVOUS WHEN HE’S IN THE AUDIENCE. HE ASKED SOMETIMES DIFFICULT QUESTIONS. SO WHAT I WANTED TO DO WAS GO THROUGH A FEW PRINCIPLES. GENERALLY, IN CLINICAL MEDICINE, WE START OUT WITH EYE KIND OF A–A KIND OF A BROAD GNLT GNLT–GENERALITY AND TRY TO NARROW IT DOWN TO SOMETHING SPECIFIC. SO THE TITLE OF THIS IS NOT WHAT WE’RE AIMING TOWARD, NOT WHERE WE ARE. SO WE’RE TRYING TO GET ESSENTIALLY FROM HERE TO THERE BY GOING FROM THE GENERAL TO THE MORE SPECIFIC. SO, LET’S LOOK. FREQUENTLY WHEN A PATIENT COMES IN TO TALK TO YOU, THEY WANT TO KNOW IF MY DISEASE OR MY CONDITION CAN BE CURED AND SO, LET’S JUST LOOK FOR A MINUTE AT THE CONCEPT OF THE CURE BECAUSE THIS IS REALLY A VERY IMPORTANT ISSUE AND 1 EXAMPLE WILL BE PNEUMOCOCKAL PNEUMONIA AND PENICILLIN TURNED OUT TO BE A DRAMATIC AND COMPLETE CURE FOR PNEUMOCOCKAL PNEUMONIA AND THEN WE COME TO THINGS LIKE VACCINES WHERE WE’VE ERADICATED A LOT OF DISEASES WITH VACCINES AND SO THIS IS ANOTHER FORM OF A CURE. AND THEN WE COME TO SOMETHING LIKE DUODENAL ULCER AND THIS IS A SPECIAL TEAM, GHASTROLOGY AS DR. ARIAS’ AREA, BUT LET ME JUST COMMENT FOR A MINUTE. WHEN THE H2 BLOCKERS, PROTON PUMP INHIBITORS, MANY OF YOU TAKE SOME OF THESE PEP SIDS OR VARIOUS ANT ACIDS AND THESE WERE USED TO TREAT PEPTIDE OIC ULCER DISEASE WHICH IS A COMMON AND DEVASTATING PROBLEM FOR A LONG TIME. AND IT COULD BE ASSUMED THAT THIS–BUT ASSUMED THIS WAS RELATED TO HYPER ACIDITY OF EXCESSIVE GASTRIC ACID PRODUCTION AND THESE THINGS WOULD SORT OF NEUTRALIZE GASTRIC ACID BUT WHEN YOU STOPPED THEM, IT ALL CAME BACK. AND THE PROBLEM WAS IS THAT WE DIDN’T KNOW IT AT THE TIME BUT THE REALITY OF IT WAS THAT WE DIDN’T UNDERSTAND THE ETICSIO LOGIC BASIS FOR THAT AND THEN COMES ALONG A DISCOVERY OF A BACTERIA HPYLORY WHICH TURNS OUT, NOW TO BE THE ETICSIO LOGIC BASIS FOR PEPTIDE OIC ULCER DISEASE AND NOW WE CAN GO THROUGH A SERIES OF ANTIBIOTIC THERAPIES AND VARIOUS TYPES AND COMPLETELY CURE THIS PROCESS. WE CAN DPO IT BECAUSE WE–DO IT BECAUSE WE UNDERSTAND THE ETIARAS O LOGIC BASIS OF THE PROCESS, THAT’S WHAT WE’RE AIMING FOR. NOW, SO HERE’S WHERE WE ARE TRYING TO GO. NOW LET’S LOOK AT 3 OF THE MAJOR CONDITIONS THAT LEAD TO THE GREATEST AMOUNT OF MORBIDITY AND MORTALITY IN THIS COUNTRY AND INDEED ALL OVER THE WORLD. HYPER TENSION, DISLIP DEEMIA AND DIABETES. THESE ARE VERY, VERY PREVALENT BUT UNFORTUNATELY THE ETICSIO LOGIC BASIS FOR THESE DISEASES, ALL OF THEM ARE ONLY KNOWN IN MAYBE 10-15% OF THE CASES. WE DO HAVE FORTUNATELY CAREFULLY CONTROLLED CLINICAL TRIALS USING VERY NONSPECIFIC TYPES OF THERAPY THAT CAN CONTROL THESE CONDITIONS. THE FIRST THAT SORT OF YIELDED WAS HYPER TENSION. THIS GOES BACK INTO THE 50S WHEN CONTROL CLINICAL TRIALS WERE DONE TO SHOW THAT YOU COULD ACTUALLY REDUCE THE MORBIDITY AND MORTALITY OF CARDIOVASCULAR DISEASE BY TREATING IEPER TENSION AND LATER IN THE 80S CAME THE DISLIP DEEMIA, CHOLESTEROL, ET CETERA. DIABETES LAGGED BEHIND BUT IN THE 90S, WE ACTUALLY WERE ABLE TO SHOW THAT THE MAJOR MORBID FEATURES OF DIABETES WHICH ARE GENERALLY REFERRED TO AS MICRO VASCULAR COMPLICATIONS. THAT IS COMPLICATIONS OF THE EYE, IF THE LEADING CAUSE OF BLINDNESS, COMPLICATIONS WAS KIDNEY, IT’S THE LEADING CAUSE OF AGED KIDNEY DISEASE AND COMPLICATIONS OF THE NERVES, NEUROPATHY CAN ACTUALLY NOT BE CURED BUT THEY CAN BE AMELIORATED AND MARKEDLY THE PREVALENCE CAN MARKEDLY BE REDUCED BY APPROPRIATE TREATMENT. HOWEVER, WE’RE STILL SORT OF SEARCHING FOR ETICSIO–ETIOLOGIC CLASSIFICATION, BECAUSE WITH DIABETES, THIS IS WHAT THE DOCTOR WAS REFERRING TO AND TYPE 1 DIABETES DR. ROTHER CAN TELL YOU ABOUT MORE IF YOU HAVE MORE QUESTIONS, COUNTS FOR MAYBE 5-10% OF ALL DIABETES THAT WE SEE. TYPE 2 DIABETES WHICH IS THE WAY IT’S CLASSIFIED IS REALLY THE ADULT FORM OF DIABETES, ACTUALLY IS NOW SEEN UNFORTUNATELY VERY PREVALENTLY IN CHILDREN WHICH IS REALLY UNFORTUNATE. BUT IT IS THE COMMON FORM OF DIABETES THAT’S ASSOCIATED WITH OBESITY AND OTHER METABOLIC DISTURBANCES. THIS COUNTS FOR PROBABLY 90%. NOW WHAT WE’RE GOING TO BASICALLY FOCUS ON HERE, ARE WHAT’S REFERRED TO AS OTHER SPECIFIC TYPES OF DIABETES. MEANING THAT THERE’S A COLLECTION OF CONDITIONS, SOME ARE GENETIC, SOME ARE ACQUIRED, SOME ARE OTHER, THEY’RE RELATIVELY UNCOMMON, MAYBE ONLY ACCOUNTING OF 5% OF ALL CASES OF DIABETES BUT BECAUSE OF THE SEVERITY OF THESE CONDITIONS, IT OFFERS US AN OPPORTUNITY TO ACTUALLY UNDERSTAND THE ETIOLOGIC BASIS AND DEVELOP WHAT WAS SHOWNOT FIRST SLIDE, SOME SORT OF PROCISION TYPE OF THERAPY. GUESTATIONAL DIABETES IS VERY SPECIFIC, OCCURS DURING PREGNANCY AND WE WON’T REAL LE COVER THAT. NOW WHAT I’VE ESSENTIALLY SAID IS THAT WE’RE REACHING FROM RELATIVELY COMMON DISORDERS TO SO CALLED METABOLIC SYNDROME WHICH IS WHEN WE COMBINE HYPER TENSION AND DISLIP DEEMIA AND OBESITY AND TYPE 2 DIABETES ALTOGETHER, WE REFER TO IT AS A METABOLIC SYNDROME. ACTUALLY IT WAS DESCRIBED A NUMBER OF YEARS AGO BY JERRY REEDMAN WHO PASSED AWAY IN THE LAST FEW WEEKS WHO WAS JUST A REFERRED TO THIS AS SYNDROME X AND LATER SOME COMMITTEES, SEVERAL COMMITTEES DECIDED TO CALL IT METABOLIC SYNDROME AND THIS IS BASICALLY WHAT WE’RE TALKING ABOUT, EPIDEMIOLOGIC WHEN YOU SEE THESE OCCUR ESSENTIALLY IN THE SAME INDIVIDUAL. POLYCYSTIC OVARIANCE DISEASE IS THE LEADING CAUSE OF INFERTILITY IS ANOTHER VARIATION WHICH WE NOW KNOW IS ACTUALLY INFLUENCED IN AN IMPORTANT WAY BY INSULIN RESISTANCE. AND PERHAPS HAS SEVERAL DIFFERENT CAUSES BUT INFLUENCED IN A MAJOR WAY BY INSULIN RESISTANCE AND THEN TYPE 2 DIABETES. NOW WAWE’RE GOING TO FOCUS ON–WHAT WE’RE GOING TO FOCUS ON THEN IS A MORE SEVERE AND RARE TYPES OF CONDITIONS THAT ALLOW US OR LEND UTION THE POSSIBILITY OF–US THE POSSIBILITY OF ETIOLOGIC BASES FOR DEVELOPING SPECIFIC THERAPIES. ONE IS CALLED LIPO DYSTROPHY WHICH WE’LL TALK ABOUT MORE AND THE INSULIN RECEPTOR MUTATIONS AND AUTOBITS TO THE INSULIN RECEPTORS. NOW THIS IS A GROUP, LIP O DYSTROPHY SYNDROME IS REFERRED TO A COLLECTION OF DIFFERENT DISEASES THAT ARE CHARACTERIZED BY SELECTIVE LOSS OF ADIPOST TISSUE. IT CAN BE GENERALIZED AS YOU’RE SEEING HERE AND IT CAN BE PARTIAL, AS IT OCCURS IN WHERE DIFFERENT PARTS OF THE BODY ARE SPARED. THAT IS FREQUENTLY FAT IS LOST LARGELY FROM THE EXTREMITIES, MAINTAINED IN THE CENTRAL CORE OF THE BODY. THERE ARE A NUMBER OF GENETIC DEFECTS THAT ARE NOW KNOWN TO BE RELATED TO THIS, SEVERAL WERE ACQUIRED DISORDERS AND SO FORTH, WE DON’T HAVE TIME TO GET INTO ALL THE DETAILS OF THAT AND ALSO THIS OTHER CLASS OF DISEASES CALLED THE INSULIN RECEPTOR OP A THIES, AND THE INSULIN RECEPTOR IS A CELL FUR FASPROTEIN THAT WAS ACTUALLY CONCEPTUALIZED HERE AT THE NIH BY JESSE ROTH AND BOB LASKOWITZ A NUMBER OF YEARS AGO AS A CELL FUR FASRECEPTOR WHICH WAS THE FITTER STEP IN THE POLYPEPTIDE HORMONE AND GENERALIZED ALL POLYPEPTIDE HORMONES WHETHER IT’S INSULIN OR ANY OTHER PITUE TARY OR OTHER POLYPEPTIDE HORMONES THIS IS WHERE THEY FIRST ACT. WE THEN BEGENERATED TO SEE DISEASES THAT ARE ASSOCIATED WITH AUTOANTIBODIES TO THIS RECEPTOR. AND WE THEN BEGIN TO SEE DISEASES THAT WE SUSPECTED WERE GENETIC IN ORIGIN BUT WE DIDN’T HAVE THE TOOLS TO PROVE THAT IN THE BEGINNING, LATER ON IT TURNS OUT THAT WE WERE ABLE TO SHOW, THAT ANOTHER CLASS OF THESE INSULIN RESISTANT SYNDROME WERE TRULY DUE TO MUTATIONS IN THE INSULIN RECEPTOR. SO HERE’S AN EXAMPLE OF WHAT WAS ACTUALLY DISCOVERED. THE INSULIN RECEPTOR IS A CELL SURFACE PROTEIN. IT HAS–IT’S A HETEROGENEOUS ROW DIMER. IT HAS 2 ALPHA SUBUNITS AND 2 BETA SUBUNITS. AND THE ALPHA SUBUNIT IS THE BINDING DOMAIN OF THE RECEPTOR AND THE BETA SUBUNIT TURNS OUT TO BE A TYROSEEN KINASE. AND WHEN INSULIN BINDS TO THE ALPHA SUBUNIT THROUGH THE EXTRA CELLULAR DOMAIN IT SETS UP A SERIOUS OF ALOESTERRIC CHANGES THAT ALLOWS THE CONTRA LATERAL BETA SUBUNIT TO PHOSPHORALATE THE OTHER BETA SUBUNIT EMPLOY SO NOW WE A SYSTEM OF AUTOPHOSPHORYALATION THAT NOW ENERGIZES THIS ENTIRE SYSTEM. SO THESE DISEASES THAT I’M TALKING ABOUT RELATE TO EITHER AUTOANTIBODIES PREDOMINANTLY ASSOCIATED WITH THE EXTRA CELLULAR DOMAIN BUT COULD BE WITH THE INTRA CELLULAR DOMAIN, ALSO AND TO MUTATIONS THAT OCCUR IN ANY PART OF THIS RECEPTOR. AND WE COULD GO THROUGH AND CHARACTERIZE THESE THAT WE HAD MORE TIME, BUT THIS IS THE FUNDAMENTAL. NOW AFTER THE RECEIPTOR TYROSEEN KINASE HAS BEEN ACTIVATED THERE ARE A WHOLE SERIES OF STEPS THAT OCCUR DOWN STREAM OF THE RECEPTOR AND INTERESTINGLY ENOUGH, VERY FEW MUTATIONS OR OTHER ABNORMALITIES HAVE BEEN ASSOCIATED WITH DISEASES. THE MAJORITY OF WHAT WE SEE IN TERMS OF DISEASE ARE ASSOCIATED WITH THIS INSULIN RECEPTOR CELL SURFACE PROTEIN.>>ONE QUESTION WHY DO THE [INDISCERNIBLE] ANTIBODIES IDENTIFY [INDISCERNIBLE]–>>THERE ARE MANY DIFFERENT EPITAUPES. THERE’S A WHOLE SERIES OF EPITAUPES ARE BUT THERE ARE MANY DIFFERENT 1S. IT WOULD BE HARD TO DESCRIBE IT BRIEFLY. SO WHAT WE’RE GOING TO DO NOW IS LOOK AT SORT OF 3 STORIES. IN TERMS OF HOW WE MIGHT APPROACH THESE DISEASES BY UNDERSTANDING ETICSIO LOGIC BASIS AND DEVELOPING SOME SPECIFIC THERAPEUTIC
STRATEGIES.–YOU CAN
SEE THIS WOMAN HERE, SHE HAS THE HORMONE LEPTIN WE WILL TALK MORE ABOUT. SHE HAS INSULIN RESISTANCE, HYPER TRI GLYCERIDEEMIA THAT CAN YOU SEE IN HER SKIN. WHAT YOU SEE HERE WITH ALL OF THESE RED SPOTS ARE WHAT’S CALLED XANTHOMA, WHICH ARE DEPOSITS OF TRI GLYCERIDES OCCURRING EVERYWHERE AND IN THE SENSE SHE HAD THEM TO THE SOLES OF HER FEET TO THE POINT WHERE SHE COULDN’T EVEN WALK THEY WERE SO PAINFUL AND THEY GET MASSIVE FATTY INFILTRATION OF THE LIVER, WHICH LEADS TO A RARE FORM OF LIVER DISEASE WHICH IS NASH OR NONALCOHOLIC SERIES POINTS AT O HEPATITIS OR CIRRHOSIS, MAY TURN OUT TO BE ONCE THE–HEP A TIDDITY, OR I DON’T KNOW THE PLURAL OF IT, BUT ONCE THE VIRAL DISEASES OF THE LIVER ARE CONTROLLED, THIS FORM OF LIVER DISEASE MAY TURN OUT TO BE THE LEADING CAUSE OF END STAGE LIVER DISEASE. ANYWAY, YOU CAN SEE THAT THIS IS A PRETTY BAD SITUATION. SO, THE STORY OF HOW WE WANT TO BEGIN THE APPROACH OF THE TREATMENT OF THIS BEGINS WITH THIS MOUSE CALLED THE OBOB MOUSE, MARK BREITMAN KNOW THIS IS MOUSE, STUDIED IT IN GREAT DETAIL AND MADE BEAUTIFUL OBSERVATIONS ABOUT IT BUT THIS IS AN OBESE MOUSE THAT WAS CHARACTERIZED BY DOUG COLE MAN WHO DID SOME COST CIRCULATIONS TO NORMAL NONOBESE MOUSE–MICE AND FOUND THAT THE–IF HE DID CROSS CIRCULATION HE COULD MAKE THIS MOUSE STAND AND BASICALLY, HE BASICALLY FORMULATED THE THESIS THAT THERE IS ALMOST CERTAINLY A CIRCULATING MOLECULE OF SOME KIND THAT IS CONTROLLING SATIETY, IT’S THE THERMOMETER OF ENERGY BALANCE. HOWEVER, HE WAS NOT ABLE TO ACTUALLY CHARACTERIZE THIS IN FURTHER DETAIL OTHER THAN TO SAY THAT IT MUST BE THERE. ALONG COMES JEFF FREED MAN AT THE ROCKEFELLER ABOUT 22 YEARS AGO AND HE ACTUALLY DISCOVERS THE GENETIC MUTATION IN THIS MOUSE AND GIVES THE PROTEIN THE NAME LEPTIN AND IT TURNS OUT THAT THIS FULFILLS ALL THE CRITERIA THAT COLEMAN HAD POSTULATED. IT IS THE MAJOR HORMONE REGULATING ENERGY BOUNDS. THE PLACENTAS MA LEPTIN CONCENTRATION IS A FUNCTION OF ATAPOSSITY. THIS IS VERY SURPRISING BECAUSE WE DON’T THINK OF HORMONES BEING MADE BY FAT CELLS BUT IT TURNS OUT THAT MANY HORMONES ARE MADE IN FAT CELLS AND THIS IS 1 OF THE FIRST TO BE DISCOVERED. SO YOU AND IMAGINE NOW WHAT HAPPENED. IF YOU HAVE SOMETHING THAT CONTROLS SATTITYS, IT FOLLOWS, A FORTUNE WAS PAID TO THE ROCKEFELLER BY AMGEN TO PRODUCE THIS PRODUCT WHICH OBVIOUSLY YOU COULD–THEY KNEW THE STRUCTURE, THEY COULD MAKE IT, MAKE ALL THAT THEY NEEDED. DID A HUGE CLINICAL STUDY OF TREATING A THOUSAND PEOPLE OR SO AND BASICALLY WHAT DID THEY FIND? THEY FOUND THAT IT DIDN’T DO ANYTHING OR IT DID ALMOST NOTHING. WHY IS THAT? WELL, IF THEY JUST THOUGHT ABOUT IT A LITTLE BIT THEY WOULD HAVE UNDERSTOOD THAT THE HORMONE, IF THEY WERE GIVING THE BIOLOGIC THEY WERE GIVING WAS A HORMONE, THAT WAS PRODUCED BY FAT CELLS AND IF YOU GOT A LOT OF FAT CELLS, IT’S PRETTY LIKELY THAT YOU GOT A LOT OF HORMONE AND IT TURNS OUT THAT THAT WAS TRUE. SO LEPTIN IS KIND OF SECRETED CONSTITTATIVELY, YOU HAVE A LOT OF FAT CELLS, YOU HAVE A LOT OF LEPTIN AND THERE’S A GENERAL PRINCIPLE OF ENDOCRINOLOGY THAT IS PROBABLY RELATIVE TO A LOT OF OTHER FIELDS, TOO. BUT IT SAYS THAT IF YOU GOT A LOT OF SOMETHING, AND YOU GIVE MORE THAT IT DOESN’T DO VERY MUCH. AND ACTUALLY THAT’S PROBABLY TRUE IN POLITICS, TRUE. NEVER REALLY THOUGHT ABOUT THAT BUT THINK ABOUT THAT JUST A LITTLE BIT. AT ANY RATE. THIS WAS THE STATE OF THIS WHERE IT LOOKED LIKE THIS WAS GOING TO KIND OF BE THE END OF THE STORY. AN INCREDIBLE SCIENTIFIC DISCOVERY BUT THIS SORT OF END OF STORY OR THE FACT THAT THIS MIGHT ACTUALLY BE EFFICACIOUS IN SOME OTHER WAY. SO IT’S MADE BY FAT CELLS, AS WE SAID, AS A NUMBER OF LITTLER KINDS–OF OTHER KINDS THAT ARE MADE BY FAT CELLS. NOW THE QUESTION IS HOW DO WE TAKE LEPTIN FROM A HORMONE TO A MAJOR PHARMACEUTICAL. THIS HAPPENED IN 2 STAGES, THE FIRST STAGE WAS STUDIES THAT MARK REITMAN DID CHARACTERIZING LEPTIN IN THIS MOUSE MODEL AND IN A MODEL OF LIPO DYSTROPHY ACTUALLY AND IT WAS ALSO CHARACTERIZED IN THIS OB OB MOUSE AND BASICALLY IT WAS ALSO BRIAN GOLDSTEIN ALSO HAD A MOUSE MODEL THAT COULD DEMONSTRATE THAT IF YOU DON’T–IF YOU DON’T HAVE FAT CELLS, THAT IS THIS IS THE SITUATION OF LOW LEPTIN CONCENTRATION. THE GENERAL PRINCIPLE OF IMMUNOLOGY, OF ENDOCRINOLOGY THAT IF YOU DON’T HAVE SOMETHING AND YOU GIVE IT, IT MAY WORK. HYPOTHYROID IS A CLASSIC EXAMPLE. GIVE THE HORMONE TO SOMEONE WITH HYPOTHYROIDISM, IT CURES. WELL ANYWAY, THIS IS BASICALLY THE IDEA. SO THIS IS WHAT HAPPENED IN THE HUMAN–OT HUMAN SIDE,OT MOUSE SIDE, IT WAS SHOWN THAT IF YOU GIVE LEPTIN TO THIS OBOB MOUSE, THE OBOB MOUSE BECAME DEAF AND THIS WAS ESSENTIALLY REPRODUCING DOUG COLEMAN’S EXPERIMENT, EXACTLY HA HAPPENED AND O’RILEY AND ASSOCIATES AND VERUKI, AND ASSOCIATINGS IN CAMBRIDGE DID THE SAME THING TO CHILDREN WITH THIS OB MUTATION, THE SAME MUTATION IN THE MOUSE THAT WAS OCCURRING IN HUMAN. THESE ARE MASSIVELY OBESE CHILDREN AND IF YOU GAVE THEM LEPTIN EXACTLY THE SAME WAY AS THE MOUSE, THEY BECAME THIN. SO NOW, THE QUESTION WAS WHAT ABOUT LIPO DYSTROPHY? WE HAD PATIENTS WITH THIS CONDITION, WE HAD BEEN STUDYING FOR YEARS FOR OTHER REASONS. THESE WERE INDIVIDUAL WHO IS HAD LOW LEPTIN CONCENTRATIONS BECAUSE THEY DEPARTMENT HAVE FAT CELLS. SO THIS WAS REALLY WHAT THE QUESTION WAS SO HERE’S AN EXAMPLE HERE’S AN EXAMPLE, 21 YEAR-OLD YOUNG WOMAN WITH GENERALIZED LIPO DYSTROPHY, POORLY CONTROLLED DIABETES, DIABETIC KETOACIDOSEIS, SEVERE, HYPER TRI GLYCERIDEEMIA AND VERY SEVERE PROTEIN IN THE URINE SO CAN YOU SEE THAT WHEN THIS PATIENT WAS GIVEN LEPTIN THAT THERE WAS A MARKED IMPROVEMENT IN HEMOGLOBIN AC1 C WHICH IS ANOTHER MEASURE OF CHRONIC GLUCOSE, INSULIN DOSE WENT FROM VERY LARGE AMOUNT TO NOTHING, TRI GLYCERIDE LEVELS FELL FROM HUGE LEVELS, THE UPPER LIMIT OF TRI GLID RIDE BEING AROUND 150 OF NORMAL. THESE ARE 6000, DOWN TO 179. AND URINE PROTEIN SECRETION FELL FROM THE NEFF ROTTIC RANGE DOWN TO ALMOST NORMAL. SO LEPTIN, THEN WAS HAVING A DRAMATIC EFFECT IN THIS PARTICULAR CONDITION OF LIPO DYSTROPHY AND THIS IS THIS YOUNG WOMAN THAT I SHOWED YOU BEFORE WHEN SHE WAS–OOPS–WHEN SHE WAS –THE YOUNG WOMAN I SHOWED YOU BEFORE WHO HAD THE SEVERE ENLARGEMENT OF THE ABDOMEN AND YOU CAN SEE, AFTER LEPTIN THERAPY SHE ESSENTIALLY LOST THIS HUGE LIVER SIZE. IT WAS FILLED WITH FAT, HER SKIN HAS ESSENTIALLY CLEARED OF THESE LIPID DEPOSITS AND SHE NOW HAS GONE FROM A LIPID TRI GLYCERIDE CONCENTRATION OF 12-13,000 DOWN TO LEVELS THAT ARE CLOSE TO 2-300. SO IT’S AGAIN A VERY DRAMATIC EFFECT. NOW THEN, BASED ON THE STUDIES THAT WERE CARRIED OUT HERE IN THE CLINICAL CENTER, LEPTIN IS AN APPROVED FOR THE TREATMENT OF LIPO DYSTROPHY BY THE FDA FOR GENERALIZED FORMS OF LIPO DYSTROPHY. SO WE HAVE A WAYS TO GO TO INCLUDE ALL THE PATIENTS BUT AT LEAST WE’VE GOT A FOOT IN THE DOOR HERE WITH THIS BEGINNING FORM OF LIPO DYSTROPHY. NOW LET’S LOOK AT AN EXAMPLE OF A NEW USE OF AN EXISTING TECHNOLOGY. SO THIS IS THE PATIENT, 21 YEAR-OLD YOUNG WOMAN AVERAGE BLOOD SUGAR 371. THIS IS VERY HIGH, EXTREME WEIGHT LOSS, MASSIVE POLIURATE PUTTING OUT 15 LIT LITTERS OF URINE A DAY, SEVERE SKIN CONDITION AND EXTREME INSULIN RESISTANCE. IN OTHER WORDS IF YOU GIVE THIS PATIENT THOUSANDS UNITS OF INSULIN, IT HAS VERY LITTLE EFFECT. AND THIS IS WHAT SHE LOOKED LIKE. THIS IS THIS CONDITION ACONITOSEIS, CAN YOU SEE IT ON HER BACK, HER FACE, HER HANDS AND PARTICULARLY IN THE AXILLA. SO WHAT WAS DONE HERE AND THERE ARE SO MANY EXPERTS ON IMMUNOLOGY AROUND AND I WENT TO EVERY 1 OF THEM I COULD FIND TO TRY TO GET THEM TO HELP ME. ALL WE NEED TO DO WAS TO WIPE OUT AN ANTIBODY. THIS IS PRODUCED BY CIRCULATING ANTIBODY. THE ANTIBODY DOESN’T CAUSE ANY KIND OF INFLAMMATORY CONDITION, DOESN’T CAUSE T-C DESTRUCTION OF TISSUES, LIKE TYPE 1 DIABETES, DOESN’T DO ANY OF THOSE THINGS BUT IT BINDS TO THIS RECEPTOR AS I TOLD AND YOU INHIBITS THE ACTION OF INSULIN TO THIS RECEPTOR. AND I CAN ONLY GET SORT OF INCREMENTAL ADVICE, SO FINALLY, WE DECIDED THAT WELL, LET’S JUST THINK ABOUT WHAT EACH OF THESE COMPONENT THINGS CAN DO. SOME OF YOU MAY BE FAMILIAR WITH A DRUG THAT’S COMMONLY USED FOR A VARIETY OF IMMUNE O LOGIC CONDITIONS, PARTICULARLY FOR B-CELL LYMPHOMA BECAUSE IT BASICALLY WILL DESTROY IMMATURE B-CELLS. BUT THEN, IF WE JUST GAVE THAT, IT HAD VERY LITTLE EFFECT IN THIS YOUNG WOMAN. SO WHAT DO YOU IN SOMEBODY LIKE MULTIPLE MYELOMA WHERE YOU HAVE ALL SORTS OF IMMUNE O GLOBUE LYNNS WITH RESTING CELLS THAT ARE NOT IMMATURE, THEY’RE JUST THERE, SO RETUXA MAB WON’T TOUCH THOSE MATURE CELLS. BUT IF YOU GIVE HIGH DOSE STEROIDS TO THOSE INDIVIDUAL, IT WILL EFFECT THOSE CELLS. AND THEN IF YOU USE SORT OF A NONSPECIFIC INHIBITOR SUCH AS ANY ALKALOID AGENTS LIKE CYCLOSPORIN, ANY DRUGS THAT WILL KNOCK OUT HELPER CELLS AND YOU COMBINE THEM, THESE ARE PRINCIPLES THAT HAVE BEEN USED IN ANTIBIOTIC TREATMENT FOR YEARS AND CANCER CHEMO THERAPY, EVERYONE TRIES TO USE A FORMULATION THAT WILL GIVE YOU THE MAXIMUM BENEFIT AND THE LEAST SIDE EFFECTS. WELL SOMETIMES YOU DO THAT BY COMBINING DRUGS TOGETHER AND THAT’S BASICALLY WHAT THE PRINCIPLE WAS. AND SO WHEN WE DID THIS, WE PUT THEM ALL TOGETHER, WE COULD ACTUALLY CURE THIS YOUNG LADY. SHE HAS ABSOLUTELY NO INSULIN RESISTANCE WHILE SHE WAS TAKING 15,000 UNITS OF INSULIN WITH ALMOST NO EFFECT, SHE TAKES NO INSULIN AT ALL. WE ACTUALLY NOW HAVE 20 PATIENTS THAT FALL INTO IT CATEGORY. IT’S OBVIOUSLY VERY RARE, BUT IT’S AN IMPORTANT PRINCIPLE. NOW I’M GOING TO JUST SHOW YOU 1 MORE EXAMPLE, THE COMBINATION OF THE OLD AND THE NEW. SO, I TOLD THAT YOU THERE’S 1 ADDITIONAL GROUP OF PEOPLE WHO HAD MUTATIONS IN THE INSULIN RECEPTOR AND THE QUESTION WAS, WELL, WHAT MIGHT WE DO FOR THAT GROUP OF PATIENTS? AND SO, WE BEGIN TO SORT OF THINK, NOW THIS IS A YOUNG MAN AND HE HAS THIS AGAIN AKAN–KANAITOSEIS, HE HAS OTHER FEATURES THAT GO ALONG WITH THE INSULIN RECEPTOR MUTATION BUT HE HAS SEVERE INSULIN RESISTANCE. AND SO THE IDEA WAS, IF WE LOOK AT THE INSULIN RECEPTOR THAT I’M SHOWING HERE ON THIS SIDE, THE ALPHA SUBUNIT, BETA SUBUNIT, THESE ARE DOWN STREAM, DOWN STREAM SUBSTRATES OF THE INSULIN RECEPTOR AND THE 1 THING THAT YOU WILL NOTICE HERE IS THAT THE INSULIN RECEPTOR AND THE LEPTIN RECEPTOR LEPTIN BEING A CYTOKINE HAS BASICALLY A COMMON PATHWAY AT 1 OF ITS SUBCELLULAR COMPONENTS, THAT IS THAT A PI3 KINASE, SO IS IT POSSIBLE THAT WE COULD GET CROSS TALK BY SHOWING AND BINDING TO THE LEPTIN RECEPTOR AND THAT THAT WOULD AND THIS WAS THE IDEA, AND THE FACT IS THAT–THE BUT THIS IS METABOLIC SYNDROME, ALL OF THESE TO THESE RARE CONDITIONS WHERE WE CAN NOW SORT OF DEFINE THE ETIOLOGIC BASIS, DEVELOP NEW STRATEGIES AND BEGIN TO THINK AND HOW WE MIGHT INTRODUCE A MORE PERSONAL AND SO WITH THAT I WILL STOP. [ APPLAUSE ]>>[INAUDIBLE QUESTION] –INSULIN THAT MIGHT BE EFFECTING THE MICROVESSELS CAUSING THE COMPLICATIONS?>>AS BEST WE KNOW IN THAT, IT IS THE COMMON PHENOMENON IS HYPER AND IF WE TRY TO RELATE TO AREAS LIKE THE EYE AND THE KIDNEY, WE HAVE TO INVOKE THINGS LIKE OXIDATIVE STRESS AND SO FORTH WITH CELLS TAKING UP GLUCOSE BECAUSE THE GLUCOSE CONCENTRATION IS HIGH AND GLUCOSE THEN METABOLISM IS LEADING TOOXIDATIVE STRESS AND THIS IS 1 HYPOTHESIS THAT RELATES PARTICULARLY TO THE KIDNEY DISEASE BUT IT ALSO RELATES TO THE EYE DISEASE. AND IT’S REALLY THE ONLY THING WE CAN REALLY INVOKE IN THE SENSE THAT WE KNOW THAT LOWERING THE GLUCOSE CONCENTRATION WILL MARKEDLY ARK MELIORATE THESE CONDITIONS AND IN FACT, ALL THESE CONDITIONS THAT I HAVE MENTIONED HERE ARE CONDITIONS IN WHICH WE DON’T LOOK UNDER A SLIDE AND SEE, WELL THAT’S HYPER TENSION, WE DEFINE IT BY A RANGE OF BLOOD PRESSURE. WELL DIABETES IS DEFINED BY A RANGE OF GLUCOSES AND WE KNOW THAT WHEN YOUR GLUCOSE CONCENTRATION GOES ABOVE 126-MILLIGRAMS PERDESOLATOR, THAT IS WHEN YOU BEGIN TO SEE RETINAL LOCATION NUMBER OF PATIENTSATHY. RETINOP A THY. THAT’S HOW WE DEFINE IT AND IF WE CAN KNOCK THOSE LEVELS DOWN AND WE’VE SHOWN THAT WITH A CLINICAL TRIAL, THAT IT MARKEDLY AMELIORATES THE CONDITION AND THEN WE COME INTO HYPOTHESIS ABOUT MECH ANISTICALLY HOW DID DOES THAT WORK AND THAT GETS TO BE A BLACK BOX VERY QUICKLY.>>[INDISCERNIBLE]>>YOU HAVE TO KEEP IT THERE.>>WHEN I WAS IN MEDICAL SCHOOL ABOUT A HUNDRED YEARS AGO, I HAD TO GIVE A DEBATE ON TYPE CONTROL OF GLUCOSE OR NOT SO TIGHT. TODAY IN THE WASHINGTON POST, THIS ARGUMENT HAS REAPPEARED. WHAT’S THE CURRENT MORE SCIENTIFIC THING FOR VERY TIGHT CONTROL?>>OKAY. THIS ARGUMENT WAS RAGING EXACTLY IN THE WAY THAT YOU SAY UNTIL 1994. IN 19 WE COMPLETED A MAJOR STUDY CALLED THE DIABETES CONTROL AND COMPLICATION STUDY AND IT THAT STUDY WE SHOWED THAT 20% REDUCTION IN HEMOGLOBIN AC1 C WHICH WAS THE MEASURE OF GLUCOSE OF TOTAL GLUCOSE, YOU COULD GET VERY SIGNIFICANT REDUCTION IN RETINOP A THY, THAT WAS THE END POINT. THAT ESSENTIALLY, THAT STUDY WAS A BIG CLINICAL CONTROL TRIAL OF ITS TYPE ENDED THAT ARGUMENT BECAUSE THE ARGUMENT WAS BASED ON THE IDEA THAT IF YOU TRIED TO CONTROL GLUCOSE LEVELS TOO MUCH, YOU GOT HYPOGLYCEMIA AND THAT’S WHAT LED US TO THIS ARGUMENT. SO MANY PEOPLE SAID, WELL, WE DON’T DO A LOT OF GOOD TO GET THE BLOOD SUGAR DOWN SO WHY SHOULD WE RISK HYPOGLYCEMIA? WELL IN THE DIABETES CONTROL AND COMPLICATION TRIAL WE DEFINITELY HAD MORE HYPODPLISEMIA IN THE EXPERIMENTAL GROUP THAT GOT TO LOWER LEVELS BUT THEY GOT THIS BENEFIT AND SO THAT ENDED THE ARGUMENT AND SO IT–BIT OF AN ARGUMENT WENT ON IN TYPE 2 DIABETES, BUT EVEN THAT ARGUMENT HAS BEEN SORT OF AMELIORATED AND THEN WE HAVE THIS SORT OF ELEPHANT IN THE ROOM OF CARDIOVASCULAR DISEASE. BECAUSE WE KNOW THAT DIABETICS HAVE 3-4 TIMES AS MUCH CARDIOVASCULAR DISEASE AS NONDIABETICS. WHAT WE’VE NEVER BEEN ABLE TO SHOW YET IS THAT THIS TYPE OF CONTROL ACTUALLY REDUCES THE RATE OF CARDIOVASCULAR DISEASE. THE ONLY WAY WE’VE BEEN ABLE TO SHOW IT IS IN THE DIABETES CONTROL COMPLICATION TRIAL FOLLOW UP OVER MANY YEARS WHERE THE CONTROL HAS BEEN LEFT, LOST. THE GROUP THAT WAS IN THE TIGHTLY CONTROLLED GROUP HAVE LESS CARDIOVASCULAR DISEASE THAN THE ORIGINAL CONTROL GROUP. BUT THAT’S NOT A CONTROL TRIAL. AND SO WE’VE NEVER BEEN ABLE TO ACTUALLY SHOW THAT WHEREAS IN HYPER TENSION, DISLIP DEEMIA, YOU COULD ACTUALLY SHOW EFFECT ON CARDIOVASCULAR DISEASE. SO THIS IS–THIS IS SORT OF SOMETHING THAT STILL HAS TO BE DONE. OKAY. I’M GOING TO TURN THINGS OVER TO DR. ROTHER AND SHE CAN ANSWER ANY OTHER QUESTIONS.>>SO WHAT IS THE MECHANISM OF INSULIN RESISTANCE IN TYPE 2 DIABETES?>>OKAY, WE COULD GO ON FOR NOT ONLY THE REST OF THE EVENING–>>WE NEED 1 MORE HOUR.>>WE COULD GO ON SO–THERE HAVE BEEN–THE ONLY ANSWER THAT I CAN GIVE YOU THAT’S CLEAR CUT IS WHAT I’VE SHOWN YOU. IF YOU HAVE AN INSULIN RECEPTOR MUTATION, THAT IS THE CAUSE OF THE INSULIN RESISTANCE. IF YOU HAVE AN AUTOANTIBODY TO THE INSULIN RECEPTOR, THAT IS THE CAUSE OF THE INSULIN RESISTANCE. BUT WITH WE GET AWAY FROM THAT, WHICH IS 99% OF THE SITUATIONS WE ACTUAL LOW DON’T KNOW WHAT THE ANSWER TO THAT IS? WE CAN TALK ABOUT IN THE PLASMIC RETIC LUMSTRESS. WE CAN TALK ABOUT A WHOLE VARIETY OF MOLECULES. WE CAN TALK ABOUT ATYPICAL PROTEIN KINASES, IT DEPENDS ON WHICH INVESTIGATORS PET THEORY YOU WANT TO INVOKE AND WE CAN ALMOST KIND OF TURN THEM INSIDE OR AROUND. THERE ARE ABOUT 5 OR 6 HYPOTHESIS THAT GO INTO THIS AND MAYBE NONE OF THEM ARE REALLY TOTALLY RELEVANT OR ALL OF THEM. IT’S THAT KIND OF SITUATION THAT IS A VERY IMPORTANT ISSUE. WHAT WE DO KNOW IS IF WE CAN AMELIORATE OBESITY WHICH IS A FUNDAMENTAL DRIVER OF THE INSULIN RESISTANCE, WE CAN MARKEDLY IMPROVE THE INSULIN RESISTANCE. AND SO WE KNOW THAT, EXACTLY WHY WE’RE DOING THAT, WE CAN ACTUALLY SHOW MODULATION OF THE INSULIN RECEPTOR WHEN WE DO THAT. BUT THERE MUST BE MANY OTHER THINGS THAT ARE GOING ON THAT DO THAT. BUT IT’S A REAL ISSUE AND WE DON’T HAVE AN ANSWER FOR IT.>>WELCOME TO THE ENTERTAINING PART OF THIS AFTERNOON, NAMELY, THE TOPIC OF ARTIFICIAL SWEETENERS ON WHICH MOST PEOPLE HAVE AN OPINION. IT’S ALMOST LIKE OBESITY, WHAT CAUSES OBESITY, ARE ARTIFICIAL SWEETENERS GOOD OR BAD. SO I WANT TO START MY TALK WITH A QUIZ. THIS QUIZ IS BASED ON THE NORFOLK STUDIES BASED ON CANCER IN NUTRITION, THIS A LARGE SCALE STUDY MORE THAN 30,000 PEOPLE IN THE STUDY AND HAS BEEN WIDE AND TO ALSO INCLUDE OTHER TOPICS, NOT ONLY CANCER BUT FOR EXAMPLE, DIABETES. AND THEY GATHER INFORMATION ON THE DIETARY HABITS INCLUDING THE TYPE OF BEVERAGE THAT THE PARTICIPANT PARTICIPANTS, DRINK, CONSUME. AND WHAT DO YOU THINK? DO SODAS AND SUGAR SWEETENED MILK AND THINGS LIKE THIS DO TO YOUR RISK OF DIABETES. SO ON THE Y-AXIS YOU HAVE THE HAZARD RATIO AND AS YOU ALL EXPECTED IT CLEARLY INCREASES THE RISK OF DIABETES. NOW, OF COURSE, THE QUESTION IS, WHAT DOES DIET SODA COMSUMPTION DO? ANYBODY WANT TO RISK AN ANSWER? SIMILAR, MORE OR LESS? SOME OF YOU HAVE SEEN THIS AND I FEEL IT’S QUITE ASTONISHING NAMELY THAT THE RISK IS EXACTLY THE SAME AS WITH REGULAR SODA, SO WE WILL DO THIS 1 MORE TIME. THIS TIME FRAMINGHAM STUDY AND YOU SEE THE 2600 AND SOMETHING AND YOU MAY WONDER WHY ARE THERE SO FEW PEOPLE, FRAMINGHAM HAS MANY MORE, BUT ON THESE INDIVIDUALS THERE WERE LIVER ULTRA SOUNDS AND LIVER FUNCTION TESTS AVAILABLE AND THAT’S WHY THEY WERE INCLUDED IN THIS ASSESSMENT AND AGAIN, JUST LIKE WITH DIABETES, THE RISK OF DEVELOPMENT OF FATTY LIVER GOES UP IN A DOSE DEPENDENT WAY WITH THE INCREASE OF SUGAR SWEETENED BEVERAGE COMSUMPTION. SO HOW DOES THIS LOOK CLIEK CLIEK–LIKE WHEN YOU LOOK AT DIET SODA? JUST LOOKS THE SAME. VERY, VERY SIMILAR. SO HOW COME? THIS IS THE TOPIC OF THIS AFTERNOON, HOW COME THAT IN THE FIELD I’M GOING TO QUOTE YOU NOW, WHEN I STARTED ALL OF THIS RESEARCH, I REMEMBER YOU ASKING, NOW CHRISTINA, YOU ARE AWARE OF THE LAW OF THERMODYNAMICS. HOW CAN SOMETHING THAT DOESN’T HAVE ANY CALORIES CAUSE ADIPOSITY? AND THIS IS WHAT I WANT TO TRY TO EXPLAIN BY NOT VIOLATING ANY LAWS OF THERMOGENESIS. SO THE–THESE 2 STUDIES EPIDEMIOLOGIC LARGE EPIDEMIOLOGIC STUDIES, THEY BOTH WHEN ADJUSTING FOR DMI SHOWED THAT DIET SODA NONCOMSUMPTION BECAME SIGNIFICANT AND THEREFORE THE AUTHORS CONCLUDED THAT DIET SOCIETIA COMSUMPTION HAS NOTHING TO DO WITH DIABETES OR FATTY LIVER DISEASE. AND MY COLLEAGUE ALLISON [INDISCERNIBLE] AND I DID NOT AGREE WITH THIS INTERPRETATION BECAUSE OBVIOUSLY OBESITY IS THE CENTRAL FACTOR IN DEVELOPMENT OF TYPE 2 DIABETES AND FATTY LIVER DISEASE AND SO, WE FELT THAT THEY WERE POURING OUT THE BABY WITH THE BATH WATER. SO I STRUBLGHTURED THE TALK IN THAT I WILL GIVE MORE SPECIFICS, INFORMATION ABOUT THE ARTIFICIAL SWEETENERS AND THE SWEET TASTE RECEPTOR AND THEN I WILL TALK ABOUT A FEW MORE HELT OUTCOMES OTHER THAN JUST OBESITY AND ULTIMATELY, I WANT TO CONVINCE YOU THAT THERE ARE PLAUSIBLE MECHANISMS THAT LINK ARTIFICIAL SWEETENERS WITH THESE HEALTH OUTCOMES. SO THERE’S 6 FDA APPROVED ARTIFICIAL SWEETENERS AND WHAT DOES IT MEAN FDA APPROVED? IT MEANS THAT THE FDA DETERMINES BASED ON TOXICOLOGY STUDIES WHICH IS THE UPPER LIMIT OF DAILY INTAKE THAT IS ASSESSED OR ASSUMED TO BE WITHOUT NEGATIVE HEALTH EFFECTS. AND OF COURSE, THE FDA FOCUSES ON CANCER AND HETEROGENEOUS ROW GENERATEDISSITY AND YOU CAN SEE HERE THE ADI, THE ACCEPTED DAILY INTAKE FOR SACCHARIN WITH 5-MILLIGRAMS PER KILOGRAM IS ABOUT 3 SODAS A DAY. SO YOU CAN DRINK A LOT OF DIET COKE BECAUSE THAT HAS ASPARTAME, 18 SODAS A DAY, SIEWK RAULOSE, 5 SODAS A DAY. SO MANY OF YOU PROBABLY NEED ONCE IN A WHILE CAFFEINE, MOSTLY CAFFEINE CONTAINING SODA SO CAN YOU FIGURE OUT WHAT YOUR INTAKE IS? INTAKE OF ARTIFICIAL SWEETENERS PER BODY WEIGHT BECAUSE THIS’ HOW YOU REGULATE IT? NO YOU CANNOT. THIS IS A FOOD LABEL, INGREDIENT LABEL HERE ON THE SIDE OF A SODA. AND WHAT IT SAYS, IT SAYS IT CONTAINS SIEWK RAULOSE AND POTASSIUM. NOW MOST EVEN AVERAGE EDUCATED CONSUMERS DOESN’T KNOW WHAT ACESULFAME, POTASSIUM IS, SURVEYS KRAULOSE, TRI CHLORINATED SUGAR AND ARTIFICIAL SWEETENER SO THE PROBLEM IS THAT ARTIFICIAL SWEETENERS ARE LISTED ON INGREDIENT LABELS JUST AS BEING PRESENT BUT THERE’S NO AMOUNT. SO YOU CANNOT FIGURE OUT WHETHER YOU SUPERSEED THE INTAKE RECOMMENDATIONS. HOW ARE ALL SWEET TASTE SIGNALED VIA SWEET TASTE RECEPTORS? AND AT LEAST AGAIN KIND OF THE HISTORIC ASPECT. YOU MAY REMEMBER THESE CHARTS OF TONGUES THAT HAVE SPECIFIC COLORS IN SPECIFIC PLACES AND IT SAID THAT IS WELL SALT IS PERCEIVED AND SUGAR IS PERCEIVED. THAT’S NOT TRUE. WE HAVE THESE TASTE RECEPTOR CONTAINING CELLS SITTING IN TASTE SPOTS AND THEY SIT IN THE APPLIEDILLA OF THE TONGUE AND BASIC LYE ALL OVER THE TONGUE AND IN THE ALSO PHARYNGES AND THE MUCOSA NOW THIS BELONGS TO THE PROTEIN COUPLED RECEPTOR AND IN FACT, THESE ARE KIND OF THE SISTERS HERE, SWEET TASTE RECEPTOR, BITTER TASTE RECEPTOR AND UMAMI RECEPTOR BECAUSE THEY ARE ALL 3 MADE UP OF DIMERS IN THE CASE OF SWEET TASTE RECEPTORS IS HETEROGENEOUS ROW DIMERS IN THE CASE OF BITTER TASTE RECEPTORS OF WHICH WE HAVE BROADER ABOUT 30 SO ONLY 1 SWEET TASTE RECEPTOR BUT THE WARNING OF SOMETHING TOXIC IS MORE IMPORTANT THAN WHAT CONTAINS NUTRIENTS. SO THESE G-PROTEIN COUPLED RECEPTORS ARE BEING ACTIVATED BY A SWEET TASTE AND COMES ON THE TONGUE OR IN THE ORAL CAVITY AND IS THEN SIGNALED VIA CRANIAL NERVES, SPECIFICALLY HERE TO THE LATERAL ASPECT OF THE BRAIN, THE OPERC LUM, THE INSURVEYS LUM. WHAT I THOUGHT WAS TRULY FASCINATING IS THAT TASTE RECEPTORS OBVIOUSLY ARE IN THE OROPHARYNX BUT IF YOU LOOK AT THIS FLY, YOU SEE THE FLY HAS TASTE RECEPTORS ON THE WINGS,OT FEET, EVERYWHERE AND HOW IS THIS WITH HUMANS? WELL WE HAVE THEM ALL OVER THE PLACE, TOO. WE HAVE TASTE RECEPTORS IN THE BRAIN, ON BONE, IN THE LUNGS, IN THE LIVER, PANCREAS AND OF COURSE MOST INTERESTING HERE IS THE PANCREATIC BETA CELL. WE HAVE THEM IN THE INTERSTIEN, I’M GOING TO TALK ABOUT INTERENDOCRINE CELLS. WE HAVE SWEET TASTE RECEPTORS ON ADIPOE SITES AND SOME HAVE THEM IN THE TESTIS AND I REFER TO MALES. SO WHAT ABOUT ENDOCRINE CELLS, SO HERE WE HAVE AN L-CELL, ENDOCRINE CELL IN THE INTERSTIEN, THEY HAVE GLUCOSE TRANSPORTERS LIKE SGL, T-2 OR GLUE 2, THEY ALSO HAVE SWEET TASTE RECEPTORS AND WHEN YOU FOR EXAMPLE, VIA NG2, TO PUT SOMETHING SWEET INTO THE GUT, WOULD YOU PERCEIVE THAT AS SWEET? OF COURSE NOT, YOU DON’T PERCEIVE IT AS SWEET BUT THERE IS SIGNALING THAT TAKES PLACE THAT IS SIMILAR TO THE SIGNALING IN THE TASTE BUDS AND IN THE L-CELL IN THE GUT, YOU WILL THEN SECRETE GLP1. GLP1, OBVIOUSLY A HORMONE THAT WE’RE USING IN A PHARMACOLOGIC WAY AS A MEDICATION DECREASING GASTRIC EMPTYING, DECREASING APPETITE, DECREASING GLRKS LUCOGONZALEZ, AND INCREASING INSULIN LEVELS SO THE STIMULATION OF GLP1 IS CLEARLY SOMETHING THAT IS BEING USED AT THE TREATMENT OF DIABETES AND APPEARS TO BE SOMETHING POSITIVE. IN FACT, WE TRIED TO FIGURE OUT WHETHER ARTIFICIAL SWEETENERS DO CLINICALLY STIMULATE GLP 1 IN A SIMPLE EXPERIMENT, STARTING HERE ON THE RIGHT SIDE, WE GAVE EITHER A GLASS OF WATER OR DIET SODA CONTAINING ARTIFICIAL SWEETENERS TO HEALTHY STUDY PARTICIPANTS AND THEN WE STIMULATED INSULIN SECRETION WITH AN ALL DPLUICOSE TOLERANCE TEST. SO FIRST DIET SODA, WATER, AND THEN THE GLUCAGON, AND THEN THE TREATMENT, THESE ARE THE SAME INDIVIDUALS THEY DO THIS ON 2 OCCASIONS AND THE GLP1 IS HIGHER WHEN THE PRETREATMENT IS DIET SODA. IT SHOULD DO THIS IN INDIVIDUALS WITH TYPE 1 DIABETES. YOU SEE THE SAME RESULT, A LITTLE MORE MARKED, SO IN 1 CASE, THE AREA UNDER THE CURVE WAS 34% HIGHER AND THE OTHER 143% HIGHER SO THAT SOUNDS LIKE THAT’S GREAT. BUT WE ALSO TRIED TO LOOK AT THE CLINICAL RELEVANCE. I WAS JUST OUTLINING GLP 1 EFFECTS AND TO OUR DISAPPOINTMENT WHEN WE GAVE CO ADMINISTER THE TEST WITH ASIT O MINNOW FEN WE SAW NO SLOWING OF GASTRIC EMPTYING. WE ALSO DID NOT ELICIT ANY CHANGE IN APPETITE ON A SIMPLE VISUAL ANALOGUE SCALE AFTER ONLY 1 ADMINISTRATION OF THE SODA SO CAN YOU SAY WHAT IS THE CLINICAL RELEVANCE BECAUSE THIS IS AN ACUTE TEST, WE SHOULD TEST THIS AFTER CHRONIC ADMINISTRATION, WE DIDN’T DO GLUCAGON TESTING BUT OTHERS HAVE FOUND NO DIFFERENCE AND THEN INSULIN, YEAH, SAW A CONSIST EPT INCREASE WITH VARIOUS STIMULI OF ARTIFICIAL SWEETENERS BUT IT WAS NOT STATISTICALLY SIGNIFICANT AND SO, I REALLY WANT TO LEAVE THIS QUESTION MARK THERE. THE GLP1 INCREASE WE SAW IS THIS REALLY OF ANY CLINICAL RELEVANCE? WHAT I WANT TO SAY IS THOUGH THAT YOU NEED TO CHOOSE YOUR PARTICIPANTS SMARTLY. AND [INDISCERNIBLE] PEPIN WHO WORKED WITH SAM KLEIN SHE CHOSE HER PARTICIPANTS IN A STUDY THAT WAS DONE THE SAME WAY AS WE DID IT. FIRST EITHER WATER OR ARTIFICIAL SWEETENER, THEN ORAL GLUCOSE TOLERANCE TEST, SHE CHOSE WOMEN, MOSTLY AFRICAN AMERICAN WOMEN, CAN YOU SEE HERE, OBESE WITH A BMI OF 42 AND IN THESE WOMEN SHE ACTUALLY SHOWED A GREATER INCREASE IN GLUCOSE AND FOLLOWED BY A GREATER INCREASE IN INSULIN SO IT IS OUR INTERPRETATION THAT SINCE WE HAD WIDE RANGE OF INDIVIDUALS PARTICIPATING IN OUR STUDIES WE HAD A VERY LARGE STANDARD DEVIATION OF OUR INSULIN RESULTS AND THAT PROBABLY LEADS TO NONSTATTISTICALLY SIGNIFICANT OUTCOMES. SO, THE QUESTION REMAINS WHETHER SUSCEPTIBLE INDIVIDUALS, INDIVIDUALS WHO ALREADY ARE INSULIN RESISTANT AND NOW INGEST ARTIFICIAL SWEETENERS WHETHER THEY ACTUALLY MAY WORSEN THEIR INSULIN RESISTANCE. SO LET ME GET TO A FEW OTHER HEALTH OUTCOMES BEYOND OBESITY. SO FOR OBESITY, I KIND OF COUNT INTO THE REALM OF OBESITY LIVER, INTERSTIEN ADIPOS TISSUE BUT WHAT ABOUT FOR EXAMPLE, THE BRAIN. WHAT DO ARTIFICIAL SWEETENERS DO IN THE BRAIN. SO OUR SWIGHTERS, OUR COLLEAGUE IN INDIANAPOLIS IS VERY CONVINCED THAT ARTIFICIAL SWEETENERS LEAD TO A CONFUSION. BECAUSE IF YOU ADMINISTER THEM ALONG ENOUGH, THE BRAIN ASSUMES THAT SWEETNESS IN THE INSURVEYS LA IS NOT ASSOCIATED WITH CALORIES. SO THAT CONCEPT AS ONLY BEEN SHOWN IN MICE OR BETTER SHE DOES IT IN RATS. DECREASED REWARD IS ANOTHER POSSIBILITY AND THERE ARE SOME DATA WHICH I FIND QUITE INTRIGUING. SO HERE’S A FUNCTIONAL MRI, WHERE PARTICIPANTS RECEIVE EITHER SUGAR SURVEYSCROSE OR ARTIFICIAL SWEETENER SUCRAULOSE, IF YOU GIVE SUGAR, THE INSULIN LIGHTS UP AND THAT’S WHERE THE SWEETNESS IS, AND THEN THE HYPOTHALAMUS, DOPAMINE SECRETION WHERE YOUR REWARD IS BEING SIGNALS. HOW DOES THIS LOOK LIKE WHEN YOU GIVE SUCR AULOSE? I THINK THIS IS NOT A REPRESENTATIVE fMRI BECAUSE IT BEING LOAMACYS SO CLEAN BECAUSE WHAT YOU SEE HERE IN THE MIDDLE IS NOTHING. SO THAT MEANS THAT THERE IS DECREASED DOPAMINE, THAT’S THE AREA IN WHICH YOU WOULD SEE DOPAMINE ACTIVITY, YOU SEE THE SWEETNESS IN THE LATERAL ASPECT OF THE BRAIN, BUT YOU SEE DIFFERENT ACTIVITY IN THE CENTER. SO THE THOUGHT IS THE HYPOTHESIS IS THAT YOU GET THE SWEETNESS BUT WITHOUT THE SAME REWARD. SO YOU WILL KEEP SEEKING SWEETNESS WHICH MEANS YOU WILL KEEP EATING. WHAT ABOUT THE THYROID? SO THERE’S A SMALL STUDY IN MICE THAT PROPOSES THAT SUCRAULOSE ADMINISTRATION FOR MICE FOR A PROLONGED PERIOD OF TIME CAN LEAD TO LOWER TSH, A SICK THYROID SYNDROME SO LOW OR NORMAL THYROID HORMONE LEVELS AND LOWISH TSH, NOW IF THIS WAS TRUE IN HUMANS THEN THAT MIGHT CONTRIBUTE TO OBESITY. THE ONLY HUMAN DATA WE HAVE ARE ON AUTOIMMUNE THYROIDITEIS AND THERE IS THE QUESTION WHETHER IT PROMOTES AUTOIMMUNE DISEASE. HOW ABOUT BONE? THIS IS THE LATEST. SO THIS IS 2018 STUDY JUST CAME OUT AND I’M GLAD THAT IT’S FINALLY BEAUTIFULLY PRESENTED NAMELY THAT OFTIO CLAOF THES HAVE SWEET TASTE RECEPTORS. [LAUGHTER] SO STIMULATION OF OFTIO CLAST WOULD THEN EXPLAIN EPITEEMIO LOGIC FINDINGS POSSIBLY OF LOWER BONE MASS AND HIGHER FRACTURE RISK. SO THE LOWER BONE MASS IS A STUDY THAT COMES FROM IRISH GIRLS THAT SHOWS LOWER BONE MASS IN THE KIDS IN THE GIRLS WHO CONSUME MORE ARTIFICIAL SWEETENED BEVERAGES, BUT OF COURSE, SO THERE’S REVERSE CAUSALITY IN LOTS OF OBESITY TRIALS BUT THERE IS–THERE ARE SO MANY OTHER FACTORS IN AN EPIDEMIOLOGIC STUDY THAT CAN EXPLAIN THIS QUALITY OF FOOD, LESS MILK DRINKING IF YOU DRINK MORE DIET SODA ALL OF THIS CONTRIBUTE TO LOWER BONE MASS. THE HIGHER FRACTURE RISK WAS SHOWN IN THE NURSE’S HEALTH STUDY SO THIS IS MORE THAN 300 WOMEN FROM BOSTON SO THAT’S–THESE ARE SOLID DATA BUT THEY DO NOT PROVE CAUSALITY AND THEN VERY INTERESTING HERE, REPRODUCTIVE SYSTEM. SO IN GIRLS WITH HIGHER ASPARTAME COMSUMPTION EARLY PUBERTY SEOBSERVED AND THAT’S SOMETHING YOU DON’T WANT BECAUSE IT’S ASSOCIATE WIDE HIGHER CARDIOVASCULAR RISK. DELIVERY, THAT’S INTERESTING, SOPHISTICATED A DANISH STUDY, THE DANES HAVE WONDERFUL REGISTRIES SO IN A DANISH STUDY THEY LOOKED IN THE REGISTRY AND THEY FOUND AN ASSOCIATION BETWEEN DIET SODA COMSUMPTION AND EARLY DELIVERY. SO THE SWEET SET OF REGISTRIES TOO, WE CHECK IT OUT IN OUR REGISTRY AND THEY ALSO FOUND THIS ASSOCIATION. AND THEN A STUDY THAT CAME FROM CANADA. SO INFANTS OF MOTHER WHO IS CONSUME ARTIFICIAL SWEETENERS& DURING PREGNANCY AND LACTATION HAVE A HIGHER BMI AT 1 YEAR OF AGE AND THAT IS CORRECTED FOR MATERNAL WEIGHT, MATERNAL WEIGHT GAIN AND SO ON. SO HOW–HOW IS THIS POSSIBLE? HERE ON THIS SLIDE I WANT TO REMIND MYSELF OF BARBARA CORKY WHO RECEIVED IN 2011 THE HIGHEST AWARD OF THE AMERICAN DIABETES ASSOCIATION WITH THE BANTING MEDAL FOR SCIENTIFIC ACHIEVEMENT. SHE GAVE A BEAUTIFUL TALK. SHE BASICALLY ASKED, IS IT CHICKEN OR EGG, IS IT HYPER INSULIN OBESITY OR OBESITY CALLING HYPER INSULIN-EMIA, AND THAT GOES TO YOUR QUESTION REQUEST INSULIN RESISTANCE. SO WHERE DOES IT START? AND SHE ARGUED THAT HIGHER INSULIN SECRETION COULD LEAD TO OBESITY AND SHE LOOKED AROUND IN THE ENVIRONMENT AND WHAT HAS CHANGED IN THE LAST 20-30 YEARS AND SHE INDID YOU BAITED HER CELLS WITH ALL KINDS OF STUFF EMULSIFIERS, IRON, ARTIFICIAL SWEATENERS, AND AND LOW AND BEHOLD WHEN YOU PUT ARTIFICIAL SWEETENERS ON TO YOUR PET RIDISH WITH PAN KRISTATTIC EYELETS THEY START SECRETING INSULIN. NOT SURPRISING THEY HAVE SWEET TASTE RECEPTORS, RIGHT? HOW ABOUT ADIPOSE SITES SO IT’S BEEN SHOWN THAT THESE CELLS, 3 SITES DIFFERENTIATE PREFERENTIALLY FASTER INTO MATURE ADIPOSE SITES ALSO SHOWN BY OUR COLLEAGUE [INDISCERNIBLE] AT GW THAT MESSENTERY EVERYONE AMILLIOAL STEM CELLS DIFFERENTIATE INTO ADIPOS SITES AND I WANT SHOW YOU WHAT THAT MIGHT MEAN AND IF THIS WERE TRUE, THAT THE STEM CELLS UPON ARTIFICIAL SWEETENER EXPOSURE OR PREFERENTIALLY DIFFERENTIATE INTO ADIPOE SITES AND LET’S SAY A BABY AND INTRODUCED TO ARTIFICIAL SWEETENERS AND THROUGH LACTATION AND TO MORE AND LESS BONE DEVELOPMENT. EARLY ON, ARTIFICIAL SWEETENERS WERE PRAISED FOR THEIR FANTASTIC EFFECT ON THE–ON BEING PROTECTIVE AGAINST CARRIES BECAUSE THEIR BACTERIA STATIC. SO THE DENTISTS WERE HAPPY ABOUT THE ADDITION OF ARTIFICIAL SWEETENERS IN ESPECIALLY CHEWING GUM, BUT THEN OUR COLLEAGUE SUSAN SCHIFFMAN, EARLY ON BEFORE SHE HAD THE TOOLS OF SHOTGUN SEQUENCING, SHE LOOKED AT THE MICROBIOME OF HER RATS AFTER 12 WEEKS OF SUCRAULOSE AND SHE TOOK THE REAL SPLENDA AND SWEET INGREDIENT IS SUCRAULOSE, AND SO SHE FOUND CHANGES IN THE INTESTINAL MICROFLORA. SHE DID THIS WITH CULTERS SO THIS WAS AN EARLY START BUT HERE IS THE PIVOTAL STUDY THAT WAS CONDUCTED BY [INDISCERNIBLE] SO THIS IS ERINLLENOFF ONLY 1, BUT HE’S DYNAMITE. WHEN YOU HEAR ABOUT HIM TALK ABOUT A BIG SUBJECT AND HE’S NOT A SPECIALIST ON ARTIFICIAL SWEETENERS HE TAKES ON BIG TOPICS IN MEDICINE, THIS 1 HERE HE SHOWED VERY BEAUTIFULLY THAT WHEN YOU EXPOSE MICE, SO THESE ARE JUST REGULAR C57 BLACK MICE, TO EITHER SACCHARIN, SUCRAULOSE, OR ASPARTAME HE CHOSE SACCHARIN FOR MOST OF THE STUDIES YOU CAN SEE THAT AFTER 5 WEEKS THEY DEVELOP GLUCOSE INTOLERANCE. THEY HAVE HIGHER GLUCOSE VALUES. AND THE IMPORTANT POINT HERE IS WHERE YOU GO FROM JUST AN OBSERVATION TO REALLY CAUSALITY IS, HE THEN TOOK THE INTESTINAL MICRO FLORA OF THESE EXPOSED MICE PLUS THE CONTROL MICE, PUT THIS, TRANSPLANTED THIS INTO GERM-FREE MICE, IN THE GERM-FREE MICE 6 DAYS LATER WHEN UNDERGOING ORAL GLUCOSE–NOT ORAL, PERO TON EEL GLUCOSE TOLERANCE TEST THEY HAD THE SAME ABNORMAL GLUCOSE TOLERANCE LEVELS. SO I THINK THERE IS CAUSE AND EFFECT AND THAT WAS ESTABLISHED BY THIS NATURE PAPER IN SEPTEMBER OF 2014. SO AT THE SAME TIME WE DID A LITTLE STUDY. WE FOUND ARTIFICIAL SWEETENERS AND IN BREAST MILK AND THAT HAD NOT BEEN KNOWN UNTIL THEN. WHAT WE DID IS WE RECRUITED 20 ANONYMOUS DONORS AND ASKED THEM TO FILL OUT A QUESTIONNAIRE ABOUT THE ARTIFICIAL SWEETENER COMSUMPTION AND THEN PETER WALTER CHECKED FOR ARTIFICIAL SWEETENER OR CONCENTRATIONS IN THE BREAST MILK SAMPLE. IT’S 84% POSITIVE. ALSO IN SOME OF THE WOMEN WHO DID NOT REPORT ANY INTAKE. SO BECAUSE WE FOUND THIS, WE ASKED WHAT DOES THIS MEAN. SO IF BABIES GET EXPOSED TO ARTIFICIAL SWEETENERS THROUGH BREAST MILK, THEY OBVIOUSLY ABSORB THE ARTIFICIAL SWEETENERS JUST LIKE WE DO BUT THEY HAVE A LOWER GLUE MERRIAL FILTRATION RATE. DOES THIS MEAN THEY’RE CIRCULATING CONCENTRATIONS ARE HIGHER? WELL WE DON’T DO INUTER O STUDIES. SWEET TASTE EFFORTS, IN RATS IT’S BEEN SHOWN IF YOU EXPOSE THEM TO ARTIFICIAL SWEETENERRINGS, BETTER, NO MATTER WHAT KIND OF SWEETENERS WHEN THEY’RE OLDER. MICROBIOME CHANGES, OBVIOUSLY THEY HAD SHOWN THEM BEAUTIFULLY, AND WHAT DOES THIS MEAN FOR KID? S WHILE WE’RE DISCUSS THANKSGIVING AND DISCUSSING THIS WITH THE YOUNG SCIENTISTS SITTING HERE ON THE LEFT, STEPHANIE [INDISCERNIBLE], SHE SAID WELL I CAN CHECK IT OUT, I WILL CHECK THIS OUT IN MY MICE. AND THAT’S WHAT SHE DID AND WITH THE–WITH HER RESULTS, I WANT TO FINISH THE TALK. AND SINCE THEY’RE NOT MY RESULTS I CAN SAY THEY ARE PRETTY STUNNING. SO STEPHANIE TOOK MICE AND EXPOSED THEM DURING GUESTATION TO ARTIFICIAL SWEETENERS AT CONCENTRATIONS THAT ARE EITHER AT THE ACCEPTED DAILY INTAKE LEVEL DETERMINED BY THE FDA SO CONCENTRATIONS THAT ARE RELEVANT FOR HUMAN COMSUMPTION OR TWICE THE CONCENTRATION. BECAUSE SOME OF THE EARLIER STUDIES THAT WE HAVE ESPECIALLY INVITRO STUDIES THEY WERE DONE WITH CONCENTRATIONS THAT ARE REALLY IN THE PHARMACOLOGIC RANGE AND YOU ALWAYS HAVE TO ASK WHAT DOES THIS MEAN. WHAT’S THE RELEVANCE, BUT HERE, STEPHANIE WORKED WITH CONCENTRATIONS THAT ARE RELEVANT FOR HUMAN COMSUMPTION. AND THEN SHE STUDIED THE OFFSPRING. THIS HERE IS THE MICROBIME SEQUENCING RESULT OF A GROUP OF CONTROL MICE AND WHAT YOU CAN SEE IN RED ARE THE MICROBIA INCLUDING FOR EXAMPLE, ARCHEMENCIA AND IN THEN IN BLUE, YOU SEE THE BACTERIA AND GREEN AND THEN YOU DON’T NEED ANY MAJOR STATISTICAL ANALYSIS TO SEE THE DIFFERENCE. SO HERE YOU CAN SEE GROUPS OF PUPS THAT WERE EXPOSED TO ARTIFICIAL SWEETENERS DURING PREGNANCY AND DURING A PERIOD OF TIME DURING LACTATION, AND THEIR MICROBIOME LOOKS DIFFERENT. NOW HAVE YOU DONE EVEN MORE ANALYSIS IN THE MEAN TIME SO BASICALLY WHETHER THE MICE WERE EXPOSED TO 1 TIME OF THE ACCEPTED DAILY INTAKE OR TWICE, THERE’S NOT MUCH DIFFERENCE. THEY CLEARLY HAVE A LACK OF THE RED GROUP IN WHICH ARCH MENSIA IS AN IMPORTANT BACTERIA, IN ADDITION WHEN YOU LOOK AT THE RATIO OF BACTERIA WHICH IS A MEASURE OF HOW HEALTHY A MICROBIOME IS, THERE IS AN INCREASE OF THE RATIO WHICH TENDS TO GO ALONG WITH WHAT WE OBSERVE IN HUMAN OBISITY. HOW ABOUT THE MOTHERS. WELL, I SHOW YOU THE CONTROL AS WELL AS THE EXPOSED AT THE SAME TIME AND IT’S NOT IMPRESSIVE. ULTIMATELY WHEN YOU LOOK AT THE RATIO AGAIN OF FARM CUTES AND BACTERIA, YOU SEE SOMETHING SIMILAR BUT IT’S NOT VERY IMPRESSIVE AND I THINK THIS IS WHAT IS IMPORTANT. SO HERE AGAIN, YOU DON’T SEE IMPRESSIVE RESULTS IN ANIMALS THAT HAVE AN ESTABLISH TD MICROBIOME BUT YOU SEE A BIG RESULT IN THE PUPS. SO, THE NEXT QUESTION IS, IS THIS A DIRECT–IS THIS BASICALLY A TOXIC EFFECT, THIS IS BACTERIA STATIC AT LEAST ON THE ARCH MENSIA, AND WHEN THE ARCH MENSIA WAS INCUBATED AND YOU CAN SEE THIS IN THE ORANGE AND THE RED LINES WITH NONNUTRIATIVE SWEETENERS AT THE LOWER AND HIGHER CONCENTRATION, THEY GROUP. SO IT IS NOT A TOXIC EFFECT DIRECTLY ON THE BACTERIA. IT MUST BE AN EFFECT ON THE ENVIRONMENT IN WHICH THESE BACTERIA TYPICALLY GROW. WHEN STEPHANIE LOOKED AT THE LIVERS OF THESE PUPS, SHE ALSO SAW A DOSE DEPENDENT EFFECT AND BASICALLY WHAT YOU CAN SEE HERE IS A–WHEN YOU GO FROM LEFT TO RIGHT, SO CONTROL TO 1 TIME, TWICE THE ACCEPTED DAILY INTAKE OF SUCRAULOSE AND POTASSIUM TO SEE THAT THESE LIVERS BECOME GRADUALLY UNHEALTHY IN THE WHITE AND WHAT DOES THAT MEAN? IT COULD MEAN THAT IT’S A FATTY LIVER. THAT WAS THE FIRST THOUGHT, OF COURSE, FATTY LIVER. BUT IT’S NOT A FATTY LIVER. YOU STAINED THE LIVERS AND YOU DID NOT SEE THAT THIS SPEAKS FOR FATTY LIVER. SO, THAT 1 WAS OUT, INFECTION, THESE ANIMALS ARE NOT INFECTED SO IS IT ANEMIA FOR EXAMPLE, IS IT DECREASED CLEARANCE OF FOR EXAMPLE, THE NONNUTRIENT SWEETERS? AND YOU DID THE STUDIES AND IN FACT ALL POINTS TO A DETOXIFICATION PROBLEM. SO THERE IS AN INCREASE OF REACTIVE OXYGEN INTERMEDIATES AND THERE IS A DECREASE IN THE EXCRETION AND METABOLISM OF THE NONNUTRIENT SWEETENERS OR OTHER PRODUCTS OF COURSE. SO TO SUMMARIZE STEPHANIE’S RESULTS ARTIFICIAL SWEETENERS DRASTICALLY ALTERED THE MICROBIOME OF THE PUPS CIALTION ALSO OF THE MOTHERS, THERE WAS A CHANGE THAT IS A CHANGE THAT’S SIMILAR TO CHANGES THAT I OBSERVED IN HUMANS, THAT I ARE ASSOCIATE WIDE OBESITY BUT THE MOST INTERESTING 1 WAS REALLY THE ARCH MENSIA WAS SO REDUCED AND IT APPEARED TO BE A RESULT DUE TO A LACK OF THE ABILITY TO COLONIZE THE PUB MICROBIOME NORMALLY. THE VERTICAL TRANSMISSION APPEARED TO BE NORMAL SO FROM MOTHER TO BABY, THE ARCH MENSIA WAS TRANSMITTED BUT THEN DIDN’T GROW. AND THERE’S EVIDENCE AT THIS LOW CONCENTRATIONS AND IN FACT, AGAIN, PETER WALTER WITH HIS MASS SPEC MEASURED, I HAVE TO SAY, FIRST, YOU HAD TO MILK THE MICE TO GET BREAST MILK AND THEN PETER WALTER MEASURED IN THE BREAST MILK THE ARTIFICIAL SWEETENERS AND THEN THEY ARE AT VERY LOW CONCENTRATIONS AND STILL YOU SEE THIS EFFECT. SO THERE’S EVIDENCE OF LIVE TOXICITY IN PUPS WITH EVIDENCE FOR DOWN REGULATION OF DETOXIFICATION. ANDWITH THAT I FEEL IT IS FAIR TO SAY THAT THERE IS NO CONVINCING EVIDENCE THAT ARTIFICIAL SWEETENERS PREVENT OR ALLEVIATE OBESITY. IN FACT, I HAVE SHOWN YOU EXAMPLES OF THE EFFECTS OF ARTIFICIAL SWEETENERS ON THE MICROBIOME, ON INSULIN SECRETION, INVITRO AND INVIVO, ADIPO-GENESIS, THIS IS SOMETHING THATNYs TO BE FURTHER INVESTIGATES AND GOOD NEWS IS THAT [INDISCERNIBLE] IS DOING THIS. LESS REPARADIGM, AND THEN OF COURSE THERE ARE OTHER POTENTIAL EFFECTS THAT I THINK WE NEED TO START LOOKING INTO AND THAT’S JUST THE BEGINNING FOR EXAMPLE, BONE AND REPRODUCTIVE SYSTEM. SO WITH THAT, WHEN SOMEBODY ASKS YOU KNOW WHAT YOU DO YOU RECOMMEND? WE ARE ALWAYS BEING TOLD ESPECIALLY BITE THE OFFICE OF PUBLIC RELATIONS, DO NOT GIVE RECOMMENDATIONS. YOU ARE JUST A RESEARCHER. SO I’M NOT GIVING ANY RECOMMENDATIONS. BUT I’VE JUST SHOWN YOU THE DATA. SO WITH THAT I REALLY WANT TO THANK MY COLLABORATORS AND COWORKERS. THERE’S FOR EXAMPLE, ELEN CONWAY AND ILEAN HERE IN THE AUDIENCE AND STEPHANIE HAS DONE A LOT OF THE WORK WITHOUT THE WALTERS THIS COULD NOT BE DONE BECAUSE MARY WALTER DOES ALL THE HUMAN ASSAYS AND PETER WALTER, THE MASS SPEC ASSAYS. SO WITH THAT, I SHOULD ALSO THANK MY BOSS. MARK WRIGHT MAN IS SITTING RIGHT OVER THERE BECAUSE HE ALLOWS ME TO DO THESE STUDIES. AND WITH THIS, THANK YOU. [ APPLAUSE ]>>THAT WAS GREAT. SO WE HAVE QUESTIONS? WE HOPE? I SEE ON YOUR VISUAL THERE, HAVE YOU STEVIA AND TRUVIA AND THEY ALSO SAY THEY’RE DIFFERENT FROM ART FIRNL SWEETENERS BECAUSE THEY’RE MADE FROM PLANTS, ARE THEY REALLY DIFFERENT OR NOT?>>SO, THE STEVIA PLANT CONTAINS VARIOUS GLYCO SIGHTS BUT ULTIMATELY COCA-COLA BASICALLY FOCUSED ON [INDISCERNIBLE] AND THAT’S THE 1 THAT IS IN TRUVIA TOGETHER WITH ERYTH ROUGH ATOM TROL AND SUGAR ALCOHOL SO IT’S MORE ERYTH ROTAROL AND THEREFORE I THINK THIS IS MOSTLY AN ADVERTISEMENT TRICK SAYING THAT THIS IS NATURAL. WE ALL KNOW ALSO THAT MANY NATURAL THINGS ARE VERY TOXIC SO IT’S NEITHER NATURAL WHETHER IT’S TOXIC, I DON’T KNOW. IN ADDITION THERE ARE FEWER STUDIES. SO I REALLY HAVE FOCUSED ON SUCROULOSE AS POTASSIUM AND SACCHARIN BECAUSE THE DATA ARE THERE FOR STEVEIA THERE ARE FEWER STUDIES.>>ON THE SAME QUESTION, WHEN YOU SEE LIVER CHANGES WHEN YOU DESCRIBED TO DETOXIFICATION, THESE ARE CHEMICALLY VERY DIFFERENT MATERIALS AND THE DETOXIFICATION WOULD EXPECT IT TO BE DIFFERENT. WAS THIS SPECIFIC FOR ONLY 1 OF THE ITEMS.>>SO I WANT TO CORRECT MYSELF THERE IN THAT SUCRAULOSE IS BASICALLY NOT METABOLIZED AT ALL. IT’S BEING TAKEN UP ONLY ABOUT 20% OF WHAT IS INGESTED. THE REST IS EXCRETED IN THE FEE CEASE, FF FF FECES SO THE 10-20% ARE EXCRETED VIA THE KIDNEYS. THE OTHER 1 AS A POTASSIUM IS ALSO NOT METABOLIZE SAID AND BASICALLY 100% ABSORBED AND ALL EXCRETED VIA THE KIDNEYS. SO WHATEVER METABOLITES BECOME TOXIC METABOLITES AND FOR EXAMPLE, ULTIMATELY LEAD TO LIVER TOXICITY, THESE ARE OTHER METABOLITES SO IT IS THAT THE MACHINERY IS IS REALLY AFFAIRS TEAM LEADERRERRED AND THEREFORE LEADS TO TAXISITY ARTIFICIAL SWEETENERS IN GENERAL ONLY INCREASE WITH GLUCOSE TRANSPORT OR INSULIN SECRETION WHEN GIVEN TOGETHER WITH GLUCOSE. YOU NEED TO GIVE THEM TOGETHER.>>OH, I SEE.>>I WANT TO MENTION SOMETHING I THINK IS REALLY INTRIGUING IS THAT IS THE CALCIUM SENSING RECEPTOR IS VERY CLOSELY RELATED TO THE SWEET TASTE RECEPTOR AND IN THE CALCIUM SENSING RECEPTOR IT HAS BEEN SHOWN THAT SUCRAULOSE AND ITSELF IN POTASSIUM IS AN ALOESTERRIC MODIFIER SO THAT THE MESSAGE OF CALCIUM IS INCREASED. SO I THINK THAT A LOT OF THE EFFECTS MAY ACTUALLY BE THAT IT IS DUE TO MODIFICATION AND AUGMENTATION OF A RESPONSE THAT HAPPENS ANYWAY WITH GLUCOSE. THE POINT IS THAT MOST OFTEN WE INGEST, WE’RE NEVER REALLY IN THE FASTING STATE DURING THE DAY SO WE INGEST ARTIFICIAL SWEETENERS IN A NONFASTING BODY. THEREFORE IT’S ARTIFICIAL SWEETENERS WITH GLUCOSE.>>SO THE MOST IMPORTANT THING IS TO STUDY THE BINDING OF THIS ARTIFICIAL SWEETENERS TO THE LIGAND OR RECEPTOR IN THE CELL. YOU MENTIONED THEY ARE INTERACKING WITH THE DPLUICOSE-OF-INTERACTING WITH THE GLUCOSE RECEPTOR IN THE CELL? IS THAT TRUE? IS IT STUDIED PROPERLY?>>ONE POINT IS VERY IMPORTANT NAMELY THAT ANIMALS THAT WERE KNOCK OUT ANIMALS FOR THE SWEET TASTE RECEPTOR HAD SUCRAULOSE INDUCED EFFECTS. SO SUCRAULOSE MUST MEDIATE IT’S EFFECTS AND ALSO SWEET TASTE RECEPTOR INDEPENDENT WAY. THAT’S 1 THING SO I THINK JUST TO FOCUS ON THE SWEET TASTE RECEPTOR WOULD BE OVERSIMPLIFICATION. AND ALSO, WHEN YOU THINK OF THE MICROBIOTA. I DON’T THINK THIS IS THE BACTERIA, THE RESPONSE TO SWEET TASTE RECEPTORS. THIS IS THE DIRECT EFFECT OF THESE BACTDERRIA TAKING UP–BACTERIA TAKING UP THE ARTIFICIAL SWEETENERS SO THESE ARE SWEET TASTE RECEPTOR INDEPENDENT EFFECTS.>>[INDISCERNIBLE]–SIGNAL TO [INDISCERNIBLE].>>YEAH, YEAH. SO WE TRY TO DO THESE STUDIES AND WE HAD LONG DISCUSSIONS FOR EXAMPLE IN THE BRANCH MEETINGS WITH MARK, WE HAVE LONG DISCUSSIONS, SHOULD WE MAX OUT THE DOSES AND GO TO THE ALLOWED DOSES, THE UPPER LIMIT OR DO SOMETHING, WHAT WE HAVE DONE, WE GIVE A DIET SODA SO THIS IS WAY BELOW THE ACCEPTED DAILY INTAKE. AND STILL, WE SEE EFFECTS, SO I FEEL IT’S IMPORTANT TO REALLY LOOK AT THE WHOLE RANGE AND AS YOU CAN SEE IN THE PUPS, THE PUPS I EXPOSED, MOST PUPS EXPOSED TO VERY LITTLE ARTIFICIAL SWEETENER AND THEY HAVE THIS MAJOR EFFECTS.>>THAT PROMPTS A QUESTION. DO THE ARTIFICIAL SWEETENERS CROSS THE PLACENTA?>>SO WE WANT TO WORK WITH OUR COLLEAGUES AT WALTER REED IN ORDER TO GET SPECIMENS AMNIOTIC FLUID SPECIMENS FROM WOMEN WHO UNDERGO ELECT RIFF C-SECTIONS AND IN THE PROCESS OF WORKING ON THE PROTOCOL. BUT IN THE MEAN TIME LOOKING AT DATA FROM ANIMALS, SO AS A SELF-I POTASSIUM AND AS WELL AS SACCHARIN HAD BEEN SHOWN TO DO THAT AND ACTUALLY STEPHANIE MADE WE AWARE OF DATA ON SIEWK RAULOSE TOO SO YES, THEY APPEARED TO CROSS THE PLACENTA.>>SO WHAT IS YOUR EXPLANATION FOR WHY THE BACTERIAL POPULATION IN THE GUT OF THE NEW BORN, THE NEW BORN, YOU SAY RECEIVES VERY, VERY LITTLE OF THESE THINGS THROUGH THE MILK AND YET AT THE TIME THEY ARE BORN IS WHEN YOU MEASURE THIS.>>SO I SHOULD CLARIFY THIS, WHAT WE HAVE DONE IS WE EXPOSED THE MOTHERS, WE LOOKED AT AND THE NEW PUPS BUT SPECIFICALLY THE MICROBIOME ANALYSIS AND SOPHISTICATED–THERE WERE PUPS THEY WERE 3 WEEKS OLD AND THAT’S THE TIME WHEN THEY STOPPED BREAST FEEDING. SO THEY HAD THE WHOLE EXPOSURE DURING PREGNANCY AND DURING THE LACTATION. AND WHAT STEPHANIE HAS DONE IS SHE LOOKED VERY EARLY, AND VERY EARLY THE NEW BORN PUP LOOKS JUST FINE, THERE’S NO DIFFERENCE BUT WHEN YOU LOOK AT THE CONTINUED EXPOSURE OF THESE PUPS, IT’S VERY INTERESTING, SO THE DEVELOPMENT OF THE NORMAL MICROBIOME IN PUPS AND HUMANS HAS BEEN STUDIED AND THERE IS A–TRULY EXPLOSIVE GROWTH OF A VARIETY OF BACTERIA WITH AGING INDIVIDUALS. SO THE NORMAL MICROBIOME IN A HUMAN IS ESTABLISHED BETWEEN 1 AND 2 YEARS OF AGE. SO WITHIN THE EARLY MONTHS THERE’S A SMALL VARIETY THEN IT GETS LARGER AND THE SAME THING OF COURSE IN FOR THE MICE. BUT THE QUESTION, I CAN’T ANSWER IT. NAMELY, WHAT EXACTLY IS IT IN THE INTERSTIEN WHICH DOES NOT ALLOW A NORMAL COLONIZATION. WHAT WE KNOW WHAT IT’S NONAPOPTOTIC IS IT’S NOT A DIRECT TOXIC EFFECT.>>I HAVE A QUESTION THAT MAY BE TO BOTH OF YOU THAT YOU MAY WANT TO TACKLE YOU SHOWED SOME OF THE VARIOUS PET STUDIES, RESPONSE TO SUGAR AND RESPONSE TO ARTIFICIAL SWEETENERS, WE KNOW FROM ALL THE STUDIES THAT ADDICTION, AND INCLUDING DIFFERENT OTHER TYPES OF ADDICTION INCLUDING FOOD ADDICTION DEPENDS VERY CLOSELY OR RELATES VERY CLOSELY TO ACTIVATION OF [INDISCERNIBLE] SARCOMAS AND OTHER PARTS OF THE BRAIN THAT YOU SHOWED AND I DON’T KNOW IF YOU-OF ANY OF YOU HAVE HAD A CHANCE TO TAKE A LOOK AT THE ARTIFICIAL SWEETENERS AND FOOD ADDICTION GO TOGETHER?>>BASICALLY NEED TO DECLARE IGNORANCE BASED ON MY OWN RESULTS. THE GOOD THING IS WE HAVE LORENZO IN THE AUDIENCE SO MAYBE–[LAUGHTER] –LORENZO WANTS TO SAY SOMETHING ABOUT ADDICTION, BUT I THINK AT THE PRESENT TIME IT’S PREMATURE TO TALK ABOUT ADDICTION WITH REGARD IT ARTIFICIAL SWEETENERS, BUT LORENZO YOU STUDIED–SO I DIDN’T PUT THIS INTO THE TALK BECAUSE 1 VERY INTERESTING FINDING IS THAT IN VARIOUS STUDIES WHEN YOU GIVE ARTIFICIAL SWEETENERS COMPARED TO SUGAR, GRELLEN IS NOT EQUALLY SUPPRESSED. SO THAT WAS 1 MECHANISM AND HERE’S THE SPECIALIST ON GRELLEN, AND ADDICTION, SO.>>I DON’T THINK THERE’S ANYTHING ON ADDICTION, SO PATIENTS WITH ADDICTION, BUT WE STUDY PRIMARILY ALCOHOL. YOU DOINT THINK THERE’S ANYTHING ON ARTIFICIAL SWEETENERS IN PATIENTS WITH ALCOHOL SUBSTANTIAL DISORDER. MAYBE THERE’S SOMETHING ON THE SWEET PREFERENCE AND ADDICTION, WHEN WE HAVE A PAPER AND A REVIEW BUT ALSO UNC [INDISCERNIBLE] WHO WORKS WITH MARTA–WITH CHRISTINA, THEY HAVE SHOWN THAT SWEET LIKERS SEEM ON TO HAVE A HIGHER RISK OF DEVELOPING ALCOHOL USE DISORDER. SO, MORE RECISELY, LIKE GETTING [INDISCERNIBLE] SHOWED THE SWEET LIKER VS A HIGHER HISTORY OF A FAMILY HISTORY OF ALCOHOLIC USE DISORDER AND 1 OF THE MEDICATIONS WHO WILL USE THE PRACTICE [INDISCERNIBLE] WHICH WORKS ON OCULAR RECEPTOR IS BY THE FDA, THERE ARE 2 STUDIES [INDISCERNIBLE] FROM UNC SHOWING THAT THE LIKERS BETTER RESPONDER TO NITRICKS AND COMPARE THE DISLIKERS. ONE MARKER WE CHECK WE ARE TRYING TO POSE IN OUR PAPER IS HOW WE DEFINE SWEET LIKERS VERSUS [INDISCERNIBLE] WE APPLIED A SORT OF HEAT MAP APPROACH AND BASED ON THE [INDISCERNIBLE] WE USE THE DEFINITION COULD VARY PROFILE OF THE PATIENTS. SO THAT’S AS MUCH AS WE KNOW I THINK.>>THANK YOU.>>I’M SORRY THIS IS PROBABLY A QUESTION FOR BOTH DR. GORDEN AND FOR YOU AND THAT’S ABOUT THE ROLE OF INSULIN AND THINGS IN THE BRAIN IN ALZHEIMER AND IF ARTIFICIAL SWEETENERS HAVE THE SAME EFFECT WHAT IS THE EFFECT WITH ALZHEIMERS.>>I THINK THIS IS A SUPERB QUESTION BUT I WOULD AT THE PRESCRIBING EPT TIME TAKE IT AS AN IDEA TO BE STUDIED WITH REGARD TO ARTIFICIAL SWEETENERS I DON’T THINK THERE’S ANY EVIDENCE BUT I FEEL IT’S A VERY IMPORTANT QUESTION.>>I WOULD HAVE TO SAY THE SAME THING. I THINK THAT THE ISSUE OF INSULIN EFFECT IN THE BRAIN IS SORT OF A WORK IN PROGRESS. IT’S AN INTERESTING IDEA. BUT I THINK THAT IT’S NOT QUITE MATURE ENOUGH TO REALLY SAY VERY MUCH ABOUT AT LEAST FROM MY PERSPECTIVE.>>OKAY, WELL, IF THERE ARE NO OTHER QUESTIONS, I WANT TO THANK YOU.>>ONE MORE.&>>IF YOU STOP THE ARTIFICIAL SWEETENER, DO WE GET OUR BACTERIA BACK MICROBIOME BACK?>>SO SUSAN SHIVE MAN I WOULD SAY THIS IS A STAGE QUESTION BECAUSE SHE’S DONE THIS. SHE LOOKED AT 12 WEEKS OF EXPOSURE OF HER RATS AND THEN SHE STOPPED THE EXPOSURE AND SHE LOOKED AGAIN, 12 WEEKS LATER AND THERE WERE STILL CHANGES IN THE MICROBIOME SO THEY HAD NOT REVERTED TO NORMAL. DO I KNOW THIS IS THE CASE IN HUMANS, NO?>>[INDISCERNIBLE]>>YEAH.>>[LAUGHTER]>>ALL RIGHT. WELL THANK YOU AGAIN AND THANK YOU ALL FOR COMING. [ APPLAUSE ]

5 thoughts on “2018 Demystifying Medicine: Diabetes and Artificial Sweeteners

  1. I wish there were more studies on xylitol ; apparently, it increases bone density:
    https://www.ncbi.nlm.nih.gov/pubmed/21271323

  2. Diet POP is bad for you. Diet pop is evil. Artificial sweeteners are poison. Diet Coke is WEIGHT GAIN Coke. Once you allow the trash into the food chain, embryos and fetuses are exposed to this trash. So sad. So sad. All for profit. Buyer beware. 1:08:01 Sadly it is in breast milk. You have been fooled. Artificial sweetener producers / sellers should be sent to jail for decades or to a nice island with nothing but artificial sweeteners to eat.

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