Emptying of the gastric substitute, glucagon-like peptide-1 (GLP-1), and reactive hypoglycemia after total gastrectomy

Abstract

Postprandial glucagon-like peptide-1 (GLP-1), pancreatic glucagon, and insulin were measured in 27 tumor-free patients 43 months (median) after total gastrectomy and in four controls using a 99technetium-labeled 100-g carbohydrate solid test meal. Emptying of the gastric substitute was measured by scintigraphy. Fourteen patients suffered from early dumping symptoms, and five of them also reported symptoms suggestive of reactive hypoglycemia (late dumping). The median emptying half-time (T1/2) of the gastric substitute was 480 sec. Sigstad's dumping score was 8.5 +/- 1.6 (mean +/- SE) in patients with rapid emptying (T1/2 less than 480 sec), and 3.0 +/- 1.5 in patients with slow emptying of the gastric substitute (P = 0.02). The peak postprandial concentration of GLP-1 was 44 +/- 20 pmol/liter in controls, 172 +/- 50 in patients without reactive hypoglycemia, and 502 +/- 116 in patients whose glucose fell below 3.8 mmol/liter during the second postprandial hour. Plasma GLP-1 concentrations peaked at 15 min, and insulin concentrations at 30 min after the end of the meal. A close correlation between integrated GLP-1 responses and integrated insulin responses (r = 0.68) was observed. Multiple regression revealed that three factors were significantly associated with the integrated glucose concentrations during the second hour (60-120 min): Early (first 30 min) integrated GLP-1 (inverse correlation; P = 0.006), age (P = 0.006), and early integrated pancreatic glucagon (P = 0.005). There was a close (inverse) relationship of T1/2 with early integrated GLP-1 and pancreatic glucagon, but not with insulin. Gel filtration of pooled postprandial plasma of gastrectomized individuals revealed that all glucagon-like immunoreactivity eluted at Kd 0.30 (Kd, coefficient of distribution), the elution position of glicentin. Almost all of the GLP-1 like immunoreactivity eluted at Kd 0.60, the elution position of gut GLP-1. The authors contend that GLP-1-induced insulin release and inhibition of pancreatic glucagon both contribute to the reactive hypoglycemia encountered in some patients following gastric surgery. Rapid emptying seems to be one causative factor for the exaggerated GLP-1 release in these subjects.

Glucose-Sensing in Glucagon-Like Peptide-1-Secreting Cells

“…Retarding sugar absorption in humans using the ␣-glucosidase inhibitor acarbose results in earlier and larger increments in plasma GLP-1 levels, which has been attributed to the greater supply of sugar reaching distal populations of L-cells (42,43). The reactive hypoglycemia observed in dumping syndrome, which is associated with the arrival of high concentrations of sugar in the distal small intestine and colon, has also been attributed to increased GLP-1 release (44,45). Augmentation of GLP-1 secretion by forskolin and IBMX.…”

Prolonged successful therapy for hyperinsulinaemic hypoglycaemia after gastric bypass: the pathophysiological role of GLP1 and its response to a somatostatin analogue

“…'Late dumping' typically occurs 1-3 h after a meal; it is postulated that this is due to hypoglycaemia from rapid absorption of glucose and overactivation of the incretin axis, leading to inappropriate hyperinsulinaemia. Elevated GLP1 levels have been implicated as a cause of this inappropriate insulin response in patients who have undergone partial or total gastrectomy (10,11).…”

“…2). An exaggerated GLP1 response (up to 12 times higher than the controls) is also found in non-obese patients who undergo total gastrectomy for indications other than morbid obesity (11), contributing to the late dumping syndrome. Therefore, it appears that the presence of glucose distal to the stomach is necessary to stimulate GLP1 release.…”

Roles of the Gut in Glucose Homeostasis

“…Because GIP-producing K cells are located in the duodenum, their exposure to nutrients and, therefore, secretion rate highly depend on the rate of gastric emptying (5). The more distal location of L cells adds complexity to the postprandial profile of GLP-1 concentrations (61). An early initial peak in GLP-1 secretion triggered by the appearance of nutrients in the jejunum is associated with slowing of gastric emptying, and at lower nutrient flow rates, the duodenal absorption capacity can keep up with supply, so the overspill of nutrients into the distal gut is reduced (62).…”