Glucagon‐like peptide‐1 reduces hepatic glucose production indirectly through insulin and glucagon in humans

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Abstract
The effect of glucagon‐like peptide‐1 (GLP‐1) on hepatic glucose production and peripheral glucose utilization was investigated with or without infusion of somatostatin to inhibit insulin and glucagon secretion in 13 healthy, non‐diabetic women aged 59 years. After 120 min 3‐3H‐glucose infusion, GLP‐1 was added (4.5 pmol kg−1 bolus + 1.5 pmol kg−1 min−1). Without somatostatin (n = 6), GLP‐1 decreased plasma glucose (from 4.8 ± 0.2 to 4.2 ± 0.3 mmol L−1, P = 0.007). Insulin levels were increased (48 ± 3 vs. 243 ± 67 pmol L−1, P = 0.032), as was the insulin to glucagon ratio (P = 0.044). The rate of glucose appearance (Ra) was decreased (P = 0.003) and the metabolic clearance rate of glucose (MCR) was increased during the GLP‐1 infusion (P = 0.024 vs. saline). Also, the rate of glucose disappearance (Rd) was reduced during the GLP‐1 infusion (P = 0.004). Since Ra was reduced more than Rd, the net glucose flow was negative, which reduced plasma glucose. Somatostatin infusion (500 μg h−1, n = 7) abolished the effects of GLP‐1 on plasma glucose, serum insulin, insulin to glucagon ratio, Ra, Rd, MCR and net glucose flow. The results suggest that GLP‐1 reduces plasma glucose levels mainly by reducing hepatic glucose production and increasing the metabolic clearance rate of glucose through indirectly increasing the insulin to glucagon ratio in healthy subjects.

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