Abstract
Obesity is characterized by insulin-resistance (IR), enhanced lipolysis, and ectopic, inflamed fat. We related the histology of subcutaneous (SAT), visceral fat (VAT), and skeletal muscle to the metabolic abnormalities, and tested their mutual changes after bariatric surgery in type 2 diabetic (T2D) and weight-matched non-diabetic (ND) patients. We measured IR (insulin clamp), lipolysis (2H5-glycerol infusion), ß-cell glucose-sensitivity (ß-GS, mathematical modeling), and VAT, SAT, and rectus abdominis histology (light and electron microscopy). Presurgery, SAT and VAT showed signs of fibrosis/necrosis, small mitochondria, free interstitial lipids, thickened capillary basement membrane. Compared to ND, T2D had impaired ß-GS, intracapillary neutrophils and higher intramyocellular fat, adipocyte area in VAT, crown-like structures (CLS) in VAT and SAT with rare structures (cyst-like) ~10-fold larger than CLS. Fat expansion was associated with enhanced lipolysis and IR. VAT histology and intramyocellular fat were related to impaired ß-GS. Postsurgery, IR and lipolysis improved in all, ß-GS improved in T2D. Muscle fat infiltration was reduced, adipocytes were smaller and richer in mitochondria, and CLS density in SAT was reduced. In conclusion, IR improves proportionally to weight loss but remains subnormal, whilst SAT and muscle changes disappear. In T2D postsurgery, some VAT pathology persists and beta-cell dysfunction improves but is not normalized.
Highlights
Obesity is characterized by insulin-resistance (IR), enhanced lipolysis, and ectopic, inflamed fat
These observations made in animal models and humans have led to the concept that the insulin resistance of obesity is a disease of the adipose tissue, which propagates to muscle10 and liver11
The main findings of this study are: (a) the alterations of fat and skeletal muscle morphology of the obese correlate well with the insulin resistance and associated metabolic abnormalities that characterize this condition; (b) both visceral fat (VAT) and subcutaneous adipose tissue (SAT) adipocytes exhibit more marked histologic abnormalities in type 2 diabetic (T2D) than ND subjects; (c) VAT histology is associated with beta-cell dysfunction in T2D; and (d) following major weight loss, tissue histology and metabolic function improve consensually; in T2D incomplete recovery of beta-cell function suggests the presence of an inherent secretory defect
Summary
Obesity is characterized by insulin-resistance (IR), enhanced lipolysis, and ectopic, inflamed fat. In obese mice and humans, as hypertrophic adipocytes become insulin resistant, their lipolytic activity is accelerated; as a consequence, nonesterified fatty acids (NEFA) flux is partially shunted away from adipose tissue toward ectopic depots (in liver, muscle, and other organs) These changes in the metabolic phenotype are accompanied by an increased expression and release of inflammatory cytokines, which further stimulate lipolysis. For adipocytes of the same size CLS density is higher in visceral adipose tissue (VAT), suggesting that adipocytes at this location are more fragile and reach a critical size that triggers death, termed the ‘critical death size’, earlier than adipocytes in subcutaneous adipose tissue (SAT)9 These observations made in animal models and humans have led to the concept that the insulin resistance of obesity is a disease of the adipose tissue, which propagates to muscle (intramuscular lipid accumulation) and liver (steatosis). Whether T2D is associated with adipose tissue changes distinct from those of simple obesity is not clear given the frequent co-existence of the two conditions
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