GLP-1 does not acutely affect insulin sensitivity in healthy man

Abstract

Previous studies have suggested that glucagon-like peptide-1 (GLP-1) (7-36 amide) may have the direct effect of increasing insulin sensitivity in healthy man. To evaluate this hypothesis we infused GLP-1 in seven lean healthy men during a hyper insulinaemic (0.8 mU.kg-1.min-1), euglycaemic (5 mmol/l) clamp. Somatostatin (450 micrograms/h was infused to suppress endogenous insulin secretion, and growth hormone (3 ng.kg-1.min-1) and glucagon (0.8 ng.kg-1.min-1) were infused to maintain basal levels. GLP-1 (50 pmol.kg-1.h-1) or 154 mmol/l NaCl (placebo) was infused after 3 h of equilibration, i.e. from 180-360 min. GLP-1 infusion resulted in GLP-1 levels of approximately 40 pmol/l. Plasma glucose, insulin, growth hormone, and glucagon levels were similar throughout the clamps. The rate of glucose infusion required to maintain euglycaemia was similar with or without GLP-1 infusion (7.69 +/- 1.17 vs 7.76 +/- 0.95 mg kg-1.min-1 at 150-180 min and 8.56 +/- 1.13 vs 8.55 +/- 0.68 mg.kg-1.min-1 at 330-360 min) and there was no difference in isotopically determined hepatic glucose production rates (-0.30 +/- 0.23 vs -0.16 +/- 0.22 mg.kg-1.min-1 at 330-360 min). Furthermore, arteriovenous glucose differences across the forearm were similar with or without GLP-1 infusion (1.43 +/- 0.23 vs 1.8 +/- 0.29 mmol/l), (ANOVA; p > 0.60, in all instances). In conclusion, GLP-1 (7-36 amide) administered for 3 h, leading to circulating levels within the physiological range, does not affect insulin sensitivity in healthy man.

Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones

“…Several studies have indicated that GLP-1 might have an insulin-independent effect on glucose homeostasis [26][27][28][29][30][31][32], while other researchers suggested that GLP-1 did not acutely affect glucose metabolism independently of insulin [33][34][35][36][37]. These conflicting results may be a consequence of the large variability in the model and methods used: healthy vs diabetic, diabetic hyperglycaemic vs diabetic maintained euglycaemic, clamp vs IVGTT etc.…”

Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans

“…In vitro studies have suggested that GLP-1 (7-36) alone or in combination with insulin can enhance liver, muscle and fat glucose uptake in isolated prepa- rations of these tissues [9,12,14,15,16,17]. We [23] and other investigators [21,22,24,33,34] have been unable to detect an effect of GLP-1 (7-36) on insulin action or glucose effectiveness in either non-diabetic or Type II diabetic subjects. Other studies [21,24,33] have reported that GLP-1 (7-36) does not alter insulin induced stimulation of glucose disposal in non-diabetic humans when GLP-1 (7-36) was infused for 3 h or less.…”

“…GLP-1 (7-36) has been reported to increase glucose uptake during hyperglycaemia and hyperinsulinaemia in diabetic rats [17], pancreatectomized dogs [18] and in Type I (insulin-dependent) diabetic patients [19,20]. In contrast, GLP-1 (7-36) has been reported to have no effect on the insulin action in non-diabetic human subjects [21] GLP-1 (7-36) is actively being evaluated as a therapy for diabetes mellitus. GLP-1 (7-36) increases insulin secretion, decreases glucagon secretion and delays gastric emptying [1,2,3,4,5,6,7].…”

“…GLP-1 (7-36) has been reported to increase glucose uptake during hyperglycaemia and hyperinsulinaemia in diabetic rats [17], pancreatectomized dogs [18] and in Type I (insulin-dependent) diabetic patients [19,20]. In contrast, GLP-1 (7-36) has been reported to have no effect on the insulin action in non-diabetic human subjects [21], in dogs [22] or Type II diabetic patients [23]. Interestingly, conflicting results have been obtained by several investigators [24] including ourselves [20].…”

“…A positive but small effect on insulin action has most consistently been observed in severely insulin deficient animals or Type I diabetic patients [18,20]. The methods used to assess insulin action also have differed ranging from clamps, to frequently sampled intravenous glucose tolerance tests to prandial infusions of glucose [17,18,19,20,21,22,23]. We were intrigued by the possibility that the pattern of degradation of GLP-1 (7-36) also might have influenced the results of these studies.…”