Övervikt och fetma har utvecklats till ett hälsoproblem av epidemiska pro- portioner; WHO räknar med att 1,9 miljarder av jordens befolkning är över- viktiga och 600 miljoner obesa. Tyvärr saknas riktigt effektiva dieter eller medicinska behandlingar, och den enda vetenskapligt bevisat effektiva be- handlingen är överviktskirurgi. Den vanligaste operationen såväl över hela världen som i Sverige är Gastric Bypass (GBP). GBP innebär att en ny mag- säcksficka skapas av den övre delen av magsäcken (ca 15-30 ml stor), samt att resterande magsäck och början av tunntarmen kopplas bort. Detta leder till stora förändringar av hur maten passerar mag-tarmsystemet, hur maten bryts ned, det hormonella svaret på matintag, gall- och bukspottkörtel- saf- ternas passage, samt på den mikrobiella floran. Extremt feta, BMI>50 kg/m2
kan opereras med biliopankreatisk divergering med duodenal switch (DS), då magsäcken omformas till en tub, och hela tunntarmen utom sista 100 cm kopplas bort. Detta leder till liknande förändringar som efter GBP, men med tillägget att en betydande del av födan inte kan absorberas. I typfallet mins- kar en GBP patient med ca 10-15 BMI-enheter, och en DS patient med ca 20-25 BMI enheter.
Artikel I I denna studie undersöktes hur GBP operationen påverkar nivåerna av hjärtsviktshormonet NT-ProBNP på 20 patienter under ett år. Nivåerna förändras dramatiskt direkt efter operation, och kvarstår förhöjda under ett år från operation. Dessa förändringar är inte relaterade till föränd- ring i vikt, utan påverkas troligen av de hormonella faktorer som ändras omedelbart efter operation. Detta faktum är viktigt att beakta när patienter som genomgått GBP bedöms för hjärtsvikt eller annan hjärtåkomma.
Artikel II Baserat på GLP-1-analogers kända glukosstabiliserande effekt provades denna behandling på fem patienter med uttalade besvär av postprandiella hypoglykemier (anfall av lågt blodsocker efter måltid) där övrig behandling ej hjälpt. I studier finns beskrivet att svaret av det glukos- höjande mothormonet glukagon stigit mer hos patienter som behandlats med GLP-1-analog jämfört med placebo under hypoglykemi. Behandling med GLP-1-analoger fungerade väldigt väl hos dessa patienter, och effekten be- skrivs med hjälp av kontinuerliga glukos mätningar.
Artikel III För att utröna hur vanligt det är med hypoglykemier efter överviktskirurgi studerades 15 patienter efter GBP, 15 efter DS, och 15 obesa kontroller med kontinuerlig glukosmätning under 3 dygn, samtidigt som födointag och symptom registrerades. Resultatet visade att hypoglyke- mier är väldigt vanligt förekommande, GBP-patienter spenderar ca 40 minu- ter per dag med glukos under 3,3mmol/L, och DS-patienter c:a 80 minuter. Totalt sett drabbades 50 % av GBP-patienterna och 75 % av DS-patienterna av hypoglykemier. 80% av dessa var dock asymptomatiska, vilket indikerar en väldigt hög grad av nedreglering av symptom på hypoglykemi. Vidare kunde ses en väldigt hög variabilitet, dvs svängande glukos, i GBP-gruppen, medan DS-gruppen uppvisade en väldigt stabil glukos-kurva.
Artikel IV På basen av hur vanligt det i Artikel III visat sig vara med hypoglykemier undersöktes här motsvaret på hypoglykemi genom att under- söka 12 patienter före och efter GBP med en hypoglykem clamp (en under- sökning där blodsockret sänks under kontrollerade former med hjälp av in- sulindropp). Resultatet visade att motsvaret är generellt sänkt, såväl symp- tom, mothormoner (glukagon, cortisol, adrenalin, noradrenalin, och GH), inkretinhormoner (GLP-1 och GIP), och lipolys (glycerol och fria fettsyror), som svaret i det sympatiska nervsystemet. Detta pekar på att patienter efter GBP troligen har en nedreglering i centrala nervsystemet av svaret på hypo- glykemi, möjligen beroende av ett ökat intag av glukos till glukos- avkännande nervceller i hypotalamus.
Acknowledgements
This thesis would never have been possible without the help of many people, to whom I extend my greatest gratitude.
Obviously, this work has been made possible thanks to the Faculty of Medi- cine of the University of Uppsala. You are standing as strong as ever, de- fending science and education for the last 539 years, making it a privilege and honor to work within your walls.
Great thanks to all bariatric patients and control-subjects, giving of your time and effort to help advance the knowledge of the human body. It is of course invaluable to Medicine, and certainly to clinical science like this the- sis. Many thanks and may you keep your open spirit to research in the future.
Anders Karlsson, Professor Emeritus by formal title but as active as ever
when it comes to science. Your efforts are of course completely invaluable to this thesis from beginning to end. Your energy, free thinking, analytical skills, and thoroughness are impressive and a standard to strive to. As is your skepticism towards formalist and muddy science, a true defender of the faith. Scientia gratia scientias!
Britt Edén Engström, main supervisor and a constant force in this work.
You’re always positive and ready to pull up your sleeve and do some hard science work. Your meticulousness with the manuscripts is amazing, and of course a perfect complement to my own non-formal attitude towards punctu- ation. Also possesses an amazing capability to always answer an e-mail im- mediately, regardless of time of day or night. Many thanks for this time!
Jan Eriksson, co-supervisor. Arrived a couple of years ago to our department
with an impressive mixture of experience and entrepreneur-ship. Your ener- gy, high pace and wide knowledge of the field are impressive and you man- age to have more “irons in the fire” than anyone can count. Great thanks for everything!
Magnus Sundbom, co-supervisor and a true modern surgeon. A remarkable
mix of a classic surgical attitude - that naturally is truly needed in a medical science group, with the modern thinking that it’s not always best to perform
surgery. Has the ability to stop needless overworking of aspects and move the work forward which is needed in this group of otherwise “medical think- ers”. Many thanks for all help!
Östen Ljunggren, co-supervisor in the beginning of it all. Helped solve all
formal administrative issues in the beginning and always positive and will- ing to share a good advice. May you continue to help new PhD-students along the way for many years to come.
All the members of the Diabetes research team; Jan Hall for all the invalua- ble work with the hypoglycemic clamps, Joey Lau Börjesson for the terrific cooperation on paper IV, Prasad, Cherno, Caroline, Lovisa and Maria for invaluable assistance on paper 4. All you other guys in the group Ana, Moni-
ka, Desireé, Per, Tanya, Maria, Dariush, Carola, Gretha and Greg. Every-
body’s always positive to help and push the science-work forward in a pragmatic way which makes it very fun and satisfying to work in our group.
Maria and Elisabeth for all your great work on paper III, it would not have
been possible without you! Margareta for all the excellent lunches!
All my wonderful colleagues at the Endocrinology department; Magnus,
Karin, Jarl, Andreas, Selwan, Petros, Steinunn, Katarina, Eleni, Arvo, Per- Ola, Daniel, Jose, Thomas- not the least for making it possible for me to
leave the clinic in your competent hands, and do some science!
Everybody at the Endocrinology & Diabetes Unit, not just for being great
colleagues during everyday work but also for your invaluable work with the patients in paper II, which would not have been possible without your will- ingness to work and think outside the box. Makes me proud to work with you!
Everybody at the Obesity Unit; Joanna, Helene, Helena, Lisa, Sven, Jenny,
Agneta, Britt, Agneta, Erika, Marina and Arvo for all your inspiring hard work with these patients, leading the way of care for all of Sweden.
The fantastic inspiring friends at the Swedish Medical Association in Uppsa-
la, for all your exceptional hard work for making Ackis a better place for
everybody! Anna, Birgitta, Thomas, Bengt, Torbjörn, Stefanie. You’re all irreplaceable!
The crew at the AT-Avdelningen; Christina, Sune, Erik, Pernilla, Stina,
Marcus, Mattias, Johan, Ioannis, Karin, Helene, Greta, Helena, Daniel, Sandra for all your fantastic efforts in making Ackis the very best AT-
hospital in Sweden, your never-ending energy and enthusiasm for AT is inspiring.
Friends in Scrubs!: Jens, Martin W, Martin S, Kirti, Axel, Emil, Gabriel,
Katarina, Karin & Fredrik, Ashkan, many thanks for enlightening my days! Martin, Magnus, Per, Crille, o Mats. The original members of the feared
super-5, ensuring that one doesn’t take science, or anything for that matter, too seriously.
Dennis ”skrik högst” Lyxzén, Zeb ”Dont make me get off my horse” Maca- han, Roger “Im too old for this shit” Murtaugh, for all your inspiration.
All the sweaty hard-hitting thugs in the basement of Kyokushin Karate for making it easy to clear my mind from work, and painful if I don’t.
Mom and Dad Siw and Jan-Olof for all the support during the years, like- wise to aunt Ann. Late grandmother Inez for sharing the virtues of hard work and education. Brother Daniel for everything during the years!
Finally, all love and thanks to my beloved family; my dear sons - the broth- ers of mayhem and meaning of life Elliot and Caspian. Cissa – my amazing wife, for all support and love, love you and thank you for everything!
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