Adipose tissue and insulin secretion in the pathophysiology of obesity and its complications

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.