Endocrine aspects of obesity and weight reduction by bariatric surgery : With special emphasis on beta cell function

University dissertation from Stockholm : Karolinska Institutet, Department of Medicine

Abstract: Severe obesity is the most predictive acquired risk factor for the development of type 2 diabetes. Bariatric surgery induces marked weight loss and reverses the diabetic state significantly. This could be explained not only by improved insulin secretion and insulin action, but also by a number of regulatory mechanisms emerging from adipose tissue, the enteroinsular axis, the hypothalamic-pituitary- adrenal (HPA) axis and the autonomic nervous system (ANS). The present research programme was set up to look into various aspects of beta cell function in obesity and to investigate the importance of hyperinsulinemia for glycaemic control and weight development. Emphasis was given to the effects of weight-reducing surgery. In studies I, IV and V, obese women were investigated before and after 30% weight reduction OR) by vertical banded gastroplasty (VBG). Reduction of hyperinsulinemia was associated with a pronounced increase in insulin sensitivity. The fall in circulating leptin was closely related to insulin levels. Increase in hepatic insulin extraction and reduction &circulating leptin, were correlated to increased concentration of insulin-l ike growth factor-binding protein-1 (IGFBP-1) (study V). These findings confirm that a reduction of chronic hyperinsulinemia has an impact on improvements in the regulation of GH/IGF-I during WR in obese subjects. The main finding in study IV, was that of a reduction of glucose counterregulatory responses after WR, consistent with a reduced activation of the vagal and the symphatoadrenergic systems. Most notably, we documented a completely abolished glucagon response. This "defect" may in itself predispose to low plasma glucose concentrations in the weight-reduced state. Cognitive function tested by a perceptual maze test during hypoglycaemic stress, showed differences within the same subjects, consistent with a speed-preferring strategy before vs. a more accuracy preferred problemsolving after WR. In studies II and III, obese women were examined before and after 15% and 25% WR respectively, and 1 and 2 years (study III) after bariatric surgery.Two different procedures were utilized, one gastric restrictive (VBG) and the other one malabsorptive, jejunoileal bypass (JIB). The inverse relationship between insulin sensitivityand insulin secretion resulted in a quantitatively more pronounced improvement in insulin sensitivity than the reduction in insulin secretion after WIZ indicating an improved beta cell function, as verified by the increment of the disposition index and by reduction in proinsulin-to-insulin ratios. The results from the enteroinsular axis showed that a high glucagon-like peptide-1 (GLP-1)and a low gastric inhibitory polypeptide (GIP) response were associated with lower insulin levels, improved glucose tolerance and maintenance of a reduced body weight. In study VI short-term treatment with oral diazoxide improved important parameters of beta cell function in 4 male and 4 female obese subjects with type 2 diabetes, indicating beneficial effects on beta cell function through relief from overstimulation. Conclusions: The improvements in carbohydrate metabolism after surgical treatment for obesity is associated with a more pronounced reduction in insulin resistance than the reduction of the hyperinsulinemia, an increase in IGFBP-1, an abolished glucagon response to hypoglycaemia and a reduced activation of the HPA-axis as well as the ANS. Beta cell rest induced by diazoxide results in improvements of parameters of beta cell function in obese type 2 diabetics. A high GLP-1 and a low GIP response to oral glucose after WR are associated with improved glucose tolerance and maintenance of reduced body weight.

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