Effect of Glucagon-Like Peptide 1 (7-36 Amide) on Insulin-Mediated Glucose Uptake in Patients With Type 1 Diabetes

Abstract

OBJECTIVE -To examine the insulinomimetic insulin-independent effects of glucagon-like peptide (GLP)-1 on glucose uptake in type 1 diabetic patients. RESEARCH DESIGN AND METHODS -We used the hyperinsulinemic-euglycemic clamp (480 pmol ⅐ mϪ2 ⅐ min Ϫ1 ) in paired randomized studies of six women and five men with type 1 diabetes. In the course of one of the paired studies, the subjects also received GLP-1 at a dose of 1.5 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 . The patients were 41 Ϯ 3 years old with a BMI of 25 Ϯ 1 kg/m 2 . The mean duration of diabetes was 23 Ϯ 3 years.RESULTS -Plasma glucose was allowed to fall from a fasting level of ϳ11 mmol/l to 5.3 mmol/l in each study and thereafter was held stable at that level. Plasma insulin levels during both studies were ϳ900 pmol/l. Plasma C-peptide levels did not change during the studies. In the GLP-1 study, plasma total GLP-1 levels were elevated from the fasting level of 31 Ϯ 3 to 150 Ϯ 17 pmol/l. Plasma glucagon levels fell from the fasting levels of ϳ14 pmol/l to 9 pmol/l during both paired studies. Hepatic glucose production was suppressed during the glucose clamps in all studies. Glucose uptake was not different between the two studies (ϳ40 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ).CONCLUSIONS -GLP-1 does not augment insulin-mediated glucose uptake in lean type 1 diabetic patients. Diabetes Care 26:837-842, 2003G lucagon-like peptide (GLP)-1 is a hormone released from the enteroendocrine cells of the gut. Plasma levels of GLP-1 increase after eating, and it has already been shown that GLP-1 augments insulin secretion in response to meals. In vitro studies have found that GLP-1 augments insulin-mediated glucose uptake (1-7), but the results of in vivo studies are conflicting (8 -15). The exogenous administration of GLP-1 lowers blood glucose levels in both type 1 and type 2 diabetic subjects (9,(11)(12)(13)(14)16). It has been proposed that a component of the glucose-lowering effects of GLP-1 occurs via insulin-independent mechanisms-so-called insulinomimetic actions (8,17). When taking this possible component of the action of GLP-1 into account, experimental designs are always confounded by the fact that GLP-1 induces endogenous insulin release. Recently, we have shown in elderly type 2 diabetic subjects that GLP-1 increases both insulin-mediated and non-insulinmediated glucose uptake when somatostatin is used to suppress endogenous insulin release in response to 18). This led us to postulate that in insulin-resistant states (e.g., aging), we see insulinomimetic properties of GLP-1 that we did not appreciate in an earlier study of young lean subjects where glucose uptake was normal (11). In another model of insulin resistance, obese subjects with a BMI of Ͼ30 kg/m 2 , we found that GLP-1 infusions increased glucose uptake by 25% above that due to insulin alone (19).In this study, we again looked for insulinomimetic effects of GLP-1 during a hyperinsulinemic-euglycemic clamp. Because the subjects had type 1 diabetes, endogenous insulin release by GLP-1 was not an issue. Euglycemia was maintained...

β-Cell Secretory Products Activate α-Cell ATP-Dependent Potassium Channels to Inhibit Glucagon Release

“…Moreover GLP-1 had no effect on pyruvate-induced glucagon secretion in isolated ␣-cells, in agreement with the earlier study where cAMP levels in ␣-cells were unaffected by GLP-1 (20). These findings correlate with studies in type 1 diabetic subjects where GLP-1 had no effect on plasma glucagon levels during a hyperinsulinemic-euglycemic clamp (21). Assertions that GLP-1 acts as a direct inhibitor of glucagon secretion are founded upon studies where paracrine factors may have mediated an apparent suppression.…”

“…We have also addressed the issue of a direct action of the gluco-incretin glucagon-like peptide 1 (GLP-1) on ␣-cell glucagon secretion. Despite assertions that GLP-1 directly modulates glucagon secretion (18,19), evidence to the contrary exists (20,21). To this end, we have studied ␣-cell activity at the level of the perfused pancreas, intact and dispersed islets, and fluorescence-activated cell sorter (FACS)-isolated adherent ␣-cells.…”

Effects of 3 Months of Continuous Subcutaneous Administration of Glucagon-Like Peptide 1 in Elderly Patients With Type 2 Diabetes

“…To our knowledge, we are the first group of investigators who have shown a reduction in insulin clearance rate with prolonged administration of GLP-1. We have also observed this effect in an acute GLP-1 infusion protocol (240 min) in type 1 diabetic volunteers (11) We could not demonstrate change in the molar ratio of C-peptide to insulin during the hyperglycemic clamp in the GLP-1 treatment group. This is most likely due to the small changes in insulin secretion compared with changes in insulin levels during its exogenous administration and a possible type 2 error because of the small number of subjects.…”

“…Recombinant GLP-1 (7-36 amide) was produced by prokaryotic fermentation, and a COOH-terminal amide was added to the peptide as previously described (11). This preparation is Ͼ99% pure and displays a single peak on highperformance liquid chromatography.…”

Impact of Chromosome 2 Obesity Loci on Cardiovascular Complications of Insulin Resistance in LDL Receptor–Deficient C57BL/6 Mice

“…These data indicated a detachment between the dyslipidemia and hyperglycemia typically associated with insulin resistance. However, differences in non-insulin-mediated glucose uptake (17,18) may contribute to the discrepancy between insulin metabolic studies and plasma insulin and glucose assays.…”