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Belligoli, Anna (2016) Adipose tissue and insulin secretion in the pathophysiology of obesity and its complications. [Ph.D. thesis]

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Abstract (english)

Type 2 diabetis mellitus (T2DM) and obesity are global health care problems that are closely linked together. The precise mechanisms linking the two conditions remain unclear. Indeed, while the close relationship between T2DM and weight gain is well established, not all obese subjects are diabetic and this paradox is still unexplained. Impaired tissue perfusion has been proposed as one of the common metabolic defects, but little is known about adipose tissue (AT) microangiopathy and its possible role in T2DM. In animal models of obesity and diabetes, expanding AT microvasculature appears structurally altered and the angiogenetic potential of adipose derived stem cells impaired.
Several studies, in humans, suggest that obesity leads to an impaired angiogenesis and AT hypoxia, inducing an inflammatory and a profibrotic response that plays a pivotal role in the pathogenesis of metabolic complications related to weight gain, first of all insulin resistance and diabetes. Moreover, from a pathophysiological point of view it is well established that dysfunctional visceral adipose tissue (VAT) is one of the major determinants of metabolic complications of obesity, while subcutaneous depots has been considered metabolically healthy. Nevertheless it could be hypothesized that in the progress of obesity through the metabolic impairment, SAT could become dysfunctional as VAT.
On the basis of these data, we planned to study both subcutaneous and visceral adipose tissue in terms of adipocytes size, capillary density, adipose tissue stem cells (ASCs), endotelial precursor of AT and adipogenic potential, in obese subjects compared to lean subjects and in obese patients with a different glyceamic profile.
We collected subcutaneous (SAT) and/or visceral (VAT) adipose tissue (AT) from 249 patients divided in 5 different groups: 18 lean normal weight and normoglycemic subjects (18.5 < BMI < 24,9 kg/m2) as control group, 68 normoglycemic obese subjects (ob N), 65 pre-diabetic obese subjects (ob pre-T2DM), 57 diabetic obese subjects (ob T2DM) and 41obese patients after underwent to a relevant weight loss (ob WL), corresponding to at least 10% of body weight. In different representative subgroups of these samples we performed: 1) immunohistochemical analysis to evaluate the morphometry of adipocyte and capillary density; 2) flow cytofluorimetric analysis of stromal vascular fraction (SVF) in order to quantify adipose tissue stem cells (ASCs), defined as CD45-CD34+CD31-, and endothelial precursors cells (EPs) defined as CD45-CD34+CD31+; 3) in vitro culture of ASCs obtained from SVF, in order to estimate the adipogenic potential in the different groups and different depot of AT; 4) gene expression profile by RT-Real Time PCR of PPRγ, Leptin, VEGFA, VEGF2, HIF1α to correlate their expression with previous findings.
Our study confirm that obese AT is less vascularized than lean AT but T2DM does not represent an aggravating factor to the vascular reduction already present in obesity. On the contrary, T2DM and also prediabetic condition are able to further modify AT architecture, remodeling mature adipocyte size and adipogenic potential mediated by ASCs, importantly reducing AT hyperplastic growth capacity. Moreover our results allow us to assume that primum movens in development of T2DM must be searched in AT architecture and that both depots, SAT and VAT, play a pivotal role in the development of this disease.
Furthermore, considering the continuous increase in bariatric procedures to treat both weigh gain and associated co-morbidities, we plan to evaluate the effects of laparoscopic sleeve gastrectomy (LSG) after one year. Indeed, whereas the beneficial effects of this bariatric procedure are well known, side effects are lesser known. In particular, postprandial hypoglycaemia is a well described side effect after RYGB, but few data are available for LSG..
We enrolled a total of 197 consecutive non-diabetic morbidly obese who underwent to LSG in our Center for the Study and the Integrated Treatment of Obesity (Ce.S.I.T.O.). All patients were studied 12 months before and after LSG and, anthropometrics parameters, medical history, clinical examination, complete blood count and complete metabolic panel including a 3- hour OGTT, were collected.
One year after LSG, all patients had a significant reduction in weight and BMI, a significant improvement in glucose and insulin profile, and a significant decrease in inflammatory markers. We found an high incidence of severe hypoglycaemia (32,8%) after a provocative test (OGTT). Patients with hypoglycaemic events had a lower weight and BMI and a greater %EBML after LSG. compared to patients without hypoglycemic events. Hypoglycaemia was more frequent in patients having lower age, lower fasting blood glucose levels and higher triglycerides levels before LSG.

Abstract (italian)

L’obesità e il diabete mellito tipo 2 (T2DM) sono due patologie strettamente correlate tra loro e, insieme, rappresentano una delle maggiori emergenze sanitarie a livello mondiale. I meccanismi fisiopatologici che legano le due patologie, non sono ancora stati completamente spiegati. Infatti, mentre sono abbastanza note le alterazioni che portano dall’aumento del peso corporeo alla comparsa di T2DM, meno noti sono i motivi per cui non tutti i pazienti obesi sviluppano la patologia diabetica. Per spiegare tale paradosso, alcuni studi si sono concentrati sulla possibile diversa capacità di espansione del tessuto adiposo (TA). Come tutti i tessuti, anche il TA, per poter espandersi, necessita di un’adeguata consensuale vascolarizzazione. E’ stato ipotizzato che un’alterata angiogenesi durante l’espansione del TA in alcuni soggetti, e la presenza di un danno a livello del microcircolo dello stesso TA, possano influire negativamente sul peggioramento del profilo glicemico. In alcuni modelli di animali, affetti da diabete e obesità, si sono evidenziate alterazioni a carico del microcircolo del TA e a carico del potenziale adipogenico. Consensualmente, alcuni studi sul TA dell’uomo, hanno suggerito che l’obesità porta ad una alterazione dell’angiogenesi a livello del TA con contemporanea comparsa di uno stato ipossico a sua volta responsabile della risposta infiammatoria e profibrotica. Infiammazione e fibrosi, hanno un ruolo fondamentale nello sviluppo dell’insulino-resistenza e quindi del T2DM. Inoltre, è noto che il tessuto adiposo viscerale (VAT) rappresenta il deposito di TA con maggior grado di infiammazione, mentre il tessuto adiposo sottocutaneo (SAT) è considerato un tessuto meno infiammato e in grado di avere un ruolo protettivo nei confronti dello sviluppo delle patologie metaboliche. Nonostante ciò, è possibile ipotizzare che con l’aumento progressivo del peso corporeo anche il SAT acquisisca caratteristiche disfunzionali come il VAT.
Sulla base di questi presupposti, abbiamo deciso di analizzare le possibili variazioni in termini di morfologia, di densità capillare, di quantità di precursori adipogenici, di potenziale adipogenetico sia nel SAT che nel VAT di pazienti obesi e di pazienti normopeso normoglicemici. Inoltre, tra i pazienti obesi, sulla base delle caratteristiche cliniche e biochimiche, abbiamo selezionato coloro che erano normoglicemici (ob N), pre-diabetici (ob pre-T2DM) e diabetici (ob T2DM).
Sono, quindi, stati raccolti campioni di SAT e/o il VAT da 249 pazienti divisi nei 4 gruppi sopra descritti: 18 pazienti normopeso e normoglicemici (18.5 < BMI < 24,9 kg/m2), 68 ob N, 65 ob pre-T2DM e 57 ob T2DM. Abbiamo, inoltre, avuto l’opportunità di analizzare il SAT di 41 pazienti obesi dopo significativo calo ponderale (ob WL). I campioni di TA sono stati studiati (1) mediante analisi immunocitochimica, al fine di valutare la morfologia degli adipociti e la densità capillare, (2) mediante analisi citofluorimetrica della frazione vasculo stromale (FVS) per quantificare la presenza di precursori adipocitari (CD45-CD34+CD31-) e di precursori endoteliali (CD45-CD34+CD31+), (3) attraverso la coltura dei preadipociti estratti dalla FVS, per valutare il potenziale adipogenetico; (4) mediante espressione genica di leptina, PPRγ, VEGFA, VEGF2 e HIF1-α.
L’analisi dei nostri dati ci ha permesso di confermare che il tessuto adiposo dei soggetti obesi è significativamente meno vascolarizzato, sia nel SAT che, dato ad oggi non noto, nel VAT, rispetto al tessuto adiposo dei soggetti magri. Diversamente da quanto ipotizzato, la presenza di un alterato profilo glicemico, come quello presente nel pre-diabete, o la presenza di un diabete franco, non peggiorano ulteriormente la vascolarizzazione del TA, né nel SAT, né nel VAT. Ciò che si modifica in maniera significativa e precoce è l’architettura del TA. Infatti, già nei pazienti ob pre-T2DM e, anche nei pz ob T2DM, abbiamo osservato un progressivo aumento del diametro degli adipociti. Inoltre, nel TA dei pazienti con alterato profilo glicemico abbiamo osservato una significativa riduzione sia nella percentuale dei preadipociti presenti nella FVS sia nella loro capacità di differenziare in vitro. Questi dati ci permettono di ipotizzare che il TA dei pazienti con alterato profilo glicemico cresce maggiormente per ipertrofia che per iperplasia e che il ”primum movens” nello sviluppo della patologia diabetica è da ricercare nelle modificazioni a carico della cellula adiposa più che nelle modificazioni del microcircolo del tessuto adiposo sia nel VAT ma, anche nel SAT.
Inoltre, considerando il progressivo incremento nell’utilizzo della chirurgia bariatrica per trattare sia l’aumento di peso ma anche le complicanze metaboliche a esso correlate, è stato eseguito uno studio sugli effetti della sleeve gastrectomy per via laparoscopica (LSG) a distanza di un anno dall’intervento. Mentre gli effetti positivi di questa procedura chirurgica sono ormai noti, meno noti sono gli effetti collaterali; in particolare, l’ipoglicemia post prandiale è stata ben descritta dopo intervento di by pass gastrico ma resta ancor poco indagata dopo intervento di LSG. Abbiamo, pertanto, reclutato 197 pazienti obesi non diabetici sottoposti a LSG e li abbiamo studiati prima e a distanza di un anno dall’intervento bariatrico. In tutti i pazienti è stata raccolta la storia clinica, è stato eseguito esame obiettivo e sono stati eseguiti gli esami bioumorali comprensivi di screening endocrino-metabolico completo, incluso OGTT prolungato a 180 minuti, e dosaggio delle citochine infiammatorie.
Un anno dopo l’intervento, tutti i pazienti hanno avuto una significativa riduzione del peso corporeo e del BMI, un significativo miglioramento dei parametri metabolici, compreso il profilo glicemico e insulinemico, e una significativa riduzione delle citochine infiammatorie. Il 32,8% dei pazienti ha sviluppato un’ipoglicemia severa dopo test provocativo (OGTT). I pazienti con ipoglicemie hanno mostrato un peso e un BMI significativamente minore rispetto ai pazienti che non hanno sviluppato ipoglicemia e una percentuale di perdita di BMI significativamente maggiore. L’ipoglicemia si è dimostrata essere più frequente in quei pazienti che, prima dell’intervento, erano più giovani, con un peso e un BMI inferiore e con livelli di trigliceridemia superiori ai pazienti che non avevano sviluppato ipoglicemie dopo LSG.

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EPrint type:Ph.D. thesis
Tutor:Vettor, Roberto
Supervisor:Milan, Gabriella
Ph.D. course:Ciclo 28 > Scuole 28 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > METODOLOGIA CLINICA, SCIENZE ENDOCRINOLOGICHE, DIABETOLOGICHE E NEFROLOGICHE
Data di deposito della tesi:01 November 2016
Anno di Pubblicazione:01 November 2016
Key Words:obesità, diabete, tessuto adiposo, chirurgia bariatrica, ipoglicemia obesity, diabetes, adipose tissue, bariatric surgery, hypogliceamia
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/09 Medicina interna
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:9776
Depositato il:09 Nov 2017 12:23
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