Relationship between muscle/adipose tissue morphology, insulin sensitivity and beta cell function in diabetic and nondiabetic obese patients: effects of bariatric surgery

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Abstract: \nBackground and aims: Obesity is associated with low-grade inflammation in adipose tissue (AT), high lipolytic activity, ectopic fat \ndeposition and insulin-resistance (IR). Bariatric surgery leads to major fat mass loss and improvements in IR and ß-cell function \n(ß-GS). Aim of this study was to relate the improved metabolic status after Roux-en-Y gastric bypass (RYGB) to the morphological \nchanges of subcutaneous (SAT) and visceral AT (VAT) and skeletal muscle. \nMaterials and methods: 14 non-diabetic (ND) and 14 type 2 diabetic (T2D) obese patients (BMI = 50 ± 2 and 52 ± 2 kg/m2) \nreceived a euglycaemic clamp study (to measure IR) with 2H5-glycerol infusion (to measure lipolysis) and a mixed meal test (to \nmeasure insulin secretion and ß-GS) before and one year after RYGB. During RYGB, VAT (omental), SAT and rectus abdominis \nsamples were excised for light (LM) and electron microscopy (EM) analysis. \nResults: Before surgery, both T2D and ND patients showed marked IR and enhanced lipolysis, T2D also had impaired ß-GS. On \nLM, perivascular and interfibrillar muscle fat content was similar in ND and T2D; intramyocellular fat was more abundant in T2D \nthan ND patients (1.0 [1.5] vs 0.1 [0.5] units, p=0.008). In SAT, adipocyte area and density of crown-like structures (CLS) were \nsimilarly increased in T2D and ND. In VAT, adipocyte area (5806 [1793] vs 5056 [1320], p=0.01) and CLS density (3.60 [7.31] vs \n0.00 [1.75], p=0.0002) were higher in T2D than ND. ß-GS was inversely related to VAT adipocyte area (r = -0.58, p=0.004) and \nCLS density (r = -0.50, p=0.02). On EM, SAT and VAT adipocytes showed necrotic material, fibrosis, thickened capillary basal \nmembrane, degenerating adipocytes with thin cytoplasm with extrusion of free lipids in interstitium and small mitochondria. In T2D \npatients, VAT and SAT blood capillaries contained neutrophils. After RYGB (33% weight loss), IR and lipolysis were markedly \nimproved, equally in ND and T2D (p<0.003 for all). In T2D, ß-GS was improved (p=0.04) but not normalized. By LM, in both ND \nand T2D fat deposits were reduced in all muscle locations (p<0.03) as were adipocyte area and CLS density in SAT (p<0.0001). \nBy EM, SAT adipocytes were generally smaller, in advanced state of delipidation, with thicker cytoplasm rim and more \nmitochondria. In T2D, capillaries were free of neutrophils. In the whole dataset, SAT adipocyte area and CLS density were strongly \nrelated to BMI, IR and lipolysis (r2’s between 0.40 and 0.81, all p<0.0001). ß-GS was related to SAT CLS density (r = 0.46, \np=0.006) and intramyocellular fat (r = 0.53, p=0.001); the post-surgery increase in ß-GS was related to the concomitant decrease \nin intramyocellular fat (r = -0.79, p=0.002). \nConclusion: In morbid obesity, fat accumulation results in adipocyte enlargement, lipid extrusion, macrophage infiltration and cell \nnecrosis. In both T2D and ND, these changes correlate with IR and lipolysis; in VAT, histology is worse in T2D than ND and \ncorrelates with ß-cell dysfunction. After surgically-induced major weight loss, AT/muscle histology and IR improve in parallel; in \nT2D, however, ß-cell glucose sensitivity remains abnormal despite the restoration of tissue morphology, suggesting a different \norigin for ß-cell incompetence.

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