Attenuated GLP-1 secretion in obesity: cause or consequence?

Abstract

Background-Hypersecretion of insulinotropic factors such as glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-36)amide (GLP-1) have been postulated to account for the hyperinsulinaemia of obesity. Aims-To examine the role of GLP-1 and GIP in obese women and matched controls. Subjects-Six lean and six obese women subjects matched for age. Methods-The gut hormone, plasma glucose, and serum triglyceride responses were studied over 180 minutes after oral carbohydrate and fat meals. Heparin (10 000 units) was given intravenously at 120 minutes.Results-There was pronounced attenuation of plasma GLP-1 secretion to oral carbohydrate in the obese compared with lean subjects but no such difference in response to oral fat load. There were no differences in the plasma GIP responses to carbohydrate or fat feeding. There was an apparent fall in plasma GLP-1 values in all subjects after administration of heparin. Conclusion-Postprandial GLP-1 secretion in response to oral carbohydrate is considerably attenuated in obese subjects.The cause of this attenuation of GLP-1 secretion is not known although we suggest that both this fall and the overall reduction in GLP-1 values in obese subjects may be related to an increase in plasma non-esterified fatty acids. (Gut 1996; 38: 916-919) Keywords: GLP-1, obesity, carbohydrate meal, fat meal. strongly stimulates insulin secretion after carbohydrate, fat, and mixed meals. Molecular biology techniques have shown that posttranslational processing of proglucagon in the pancreas and ileum yields several novel glucagon-like peptides.67 Among these, the truncated fragment of GLP-1 (hitherto called GLP-1 in this paper), has been shown to be strongly insulinotropic and its secretion has been shown to increase after oral glucose and mixed meals.8 9 In addition to its insulinotropic effect, GLP-1 inhibits pancreatic glucagon secretion, decreases hepatic gluconeogenesis, and decreases insulin resistance.10 11 It has been postulated that an exaggerated 'incretin' factor may have a pathophysiological role in obesity. A role for GIP has been examined in this regard but has not been conclusively shown.5 In this context, it has been suggested that hypersecretion of GLP-1 may be the long sought 'incretin' factor in obesity. 12 Indeed, Fukase and colleagues have examined this hypothesis in a study where they showed increased secretion of glucagon-like peptide-1 in obese diabetic subjects but the responses in non-diabetic obese and matched controls were very similar.However, the methodology adopted by Fukase and workers for GLP-1 assay was indirect and less specific than that used in this study and included GLP-1(7-37), which is normally present at very low concentrations in plasma, and the two biologically inactive major proglucagon derived fragments. GLP-1 (7-36)amide, measured in this study, is the predominant circulating molecular species of glucagon-like peptides in humans. We undertook this study to clarify the conclusions of Fukase and colleagues that hypers...

Obesity may attenuate the HbA1c‐lowering effect of sitagliptin in Japanese type 2 diabetic patients

“…In some studies 19–22 , GLP‐1 levels in response to oral carbohydrate or a meal have been reduced in obese patients; this may have contributed to the decline in HbA1c reduction with this drug with increasing BMI, although which feature of the obese state is causally related to the inhibition of GLP‐1 release remains unknown. Circulating free fatty acids have been suggested to inhibit GLP‐1 release and stimulate GIP secretion 20 . However, Verdich et al.…”

Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men.

“…13,15,37 Thus, it can be speculated that the lower GLP-1 response in obese subjects after a meal, may result in a shorter period of inter-meal satiety and more frequent food intake to maintain an appropriate individual satiety level. Therefore, GLP-1 administered to obese subjects, may have an anorectic Figure 5 Mean AE s.e.m.…”

“…11,12 Obese subjects may have an attenuated release of GLP-1 in response to meals. 13,14 In a previous study, we demonstrated that intravenous infusion of GLP-1, for four hours, to six obese subjects, resulted in lower hunger ratings over four hours after the start of infusion. Concomitantly with the start of GLP-1 infusion, a meal was eaten on a universal eating monitor.…”

Reducing dietary fat from a meal increases the bioavailability of exogenous carbohydrate without altering plasma glucose concentration

“…However, whereas previous studies have found that dietary fat is a potent stimulus for gastrointestinal peptides secretion, we found a potent reduction in only GIP, with just a modest reduction in GLP-1 and PYY , when most of the fat was removed from the diet. This may be explained in part by the overweight status of our subjects, because secretion of GLP-1 and PYY in response to fat ingestion has been found to be attenuated in obesity (24,33). Unlike GLP-1 and PYY , GIP does not appear to be affected by an individual's body weight (33), which may explain why we found a more profound attenuation in GIP concentration when fat was removed from the meal.…”

“…This may be explained in part by the overweight status of our subjects, because secretion of GLP-1 and PYY in response to fat ingestion has been found to be attenuated in obesity (24,33). Unlike GLP-1 and PYY , GIP does not appear to be affected by an individual's body weight (33), which may explain why we found a more profound attenuation in GIP concentration when fat was removed from the meal. It is important to acknowledge that the effect of removing fat from the meal on the secretion of these peptides cannot clearly be differentiated from the effect of the reduction in total energy that was delivered through the gastrointestinal tract.…”