Acute Effect of Metformin on Postprandial Hypertriglyceridemia through Delayed Gastric Emptying

Abstract

Postprandial hypertriglyceridemia is a potential target for cardiovascular disease prevention in patients with diabetic dyslipidemia. Metformin has been reported to reduce plasma triglyceride concentrations in the postprandial states. However, little is known about the mechanisms underlying the triglyceride-lowering effect of metformin. Here, we examined the effects of metformin on lipid metabolism after olive oil-loading in 129S mice fed a high fat diet for three weeks. Metformin administration (250 mg/kg) for one week decreased postprandial plasma triglycerides. Pre-administration (250 mg/kg) of metformin resulted in a stronger triglyceride-lowering effect (approximately 45% lower area under the curve) than post-administration. A single administration (250 mg/kg) of metformin lowered plasma postprandial triglycerides comparably to administration for one week, suggesting an acute effect of metformin on postprandial hypertriglyceridemia. To explore whole body lipid metabolism after fat-loading, stomach size, fat absorption in the intestine, and fat oxidation (¹³C/¹²C ratio in expired CO₂ after administration of glyceryl-1-¹³C tripalmitate) were measured with and without metformin (250 mg/kg) pre-treatment. In metformin-treated mice, larger stomach size, lower fat oxidation, and no change in lipid absorption were observed. In conclusion, metformin administration before fat loading reduced postprandial hypertriglyceridemia, most likely by delaying gastric emptying.

Keywords: Metformin; gastric emptying; postprandial hypertriglyceridemia.

Figure 1

Effects of oral metformin treatment for one week in 129S mice. (A): Body weight change one week after metformin treatment (50 and 250 mg/kg); (B) average daily food intake; (C) plasma glucose concentration profiles 0–2 h after oral glucose (1.0 g/kg) administration. Metformin (250 mg/kg) was administered 1 h before glucose-loading; (D) area under the curve (AUC) for plasma glucose concentrations during the oral glucose tolerance test. Filled circle: control group (n = 5); open triangle: metformin (50 mg/kg) treatment group (n = 3); open circle: metformin (250 mg/kg) treatment group (n = 6) (A–D); (E) plasma triglyceride concentration profiles 0–3 h after oral olive oil (0.4 mL) administration. Filled circle: control group (n = 12); open circle: metformin (250 mg/kg) treatment 6 h before oral lipid tolerance test (OLTT) group (n = 6); open square: metformin (250 mg/kg) treatment 1 h before oral lipid tolerance test (OLTT) group (n = 7); (F): AUC for plasma triglyceride concentrations during the OLTT. Data represent means ± SE. * p < 0.05, ** p < 0.01, and *** p < 0.001 versus the control group. ^$ p < 0.05 and ^$$ p < 0.01 versus the metformin (50 mg/kg) treatment group. ^# p < 0.05 versus the metformin (250 mg/kg) treatment 6 h before OLTT group. N.S. indicates not statistically significant.

Figure 1

Effects of oral metformin treatment for one week in 129S mice. (A): Body weight change one week after metformin treatment (50 and 250 mg/kg); (B) average daily food intake; (C) plasma glucose concentration profiles 0–2 h after oral glucose (1.0 g/kg) administration. Metformin (250 mg/kg) was administered 1 h before glucose-loading; (D) area under the curve (AUC) for plasma glucose concentrations during the oral glucose tolerance test. Filled circle: control group (n = 5); open triangle: metformin (50 mg/kg) treatment group (n = 3); open circle: metformin (250 mg/kg) treatment group (n = 6) (A–D); (E) plasma triglyceride concentration profiles 0–3 h after oral olive oil (0.4 mL) administration. Filled circle: control group (n = 12); open circle: metformin (250 mg/kg) treatment 6 h before oral lipid tolerance test (OLTT) group (n = 6); open square: metformin (250 mg/kg) treatment 1 h before oral lipid tolerance test (OLTT) group (n = 7); (F): AUC for plasma triglyceride concentrations during the OLTT. Data represent means ± SE. * p < 0.05, ** p < 0.01, and *** p < 0.001 versus the control group. ^$ p < 0.05 and ^$$ p < 0.01 versus the metformin (50 mg/kg) treatment group. ^# p < 0.05 versus the metformin (250 mg/kg) treatment 6 h before OLTT group. N.S. indicates not statistically significant.

Figure 2

Effects of oral metformin treatment for one week (A,B) and a single metformin treatment (C–F) in 129S mice; (A) plasma triglyceride concentration profiles 0–2 h after oral olive oil (0.4 mL) administration. Metformin (250 mg/kg) was administered 1 h before olive oil-loading. Filled circle: control group; open circle: long-term metformin treatment for one week group; open square: single metformin treatment group; (B) area under the curve (AUC) for plasma triglyceride concentrations during the OLTT. Data represent means ± SE. n = 4 mice/group; ** p < 0.01, *** p < 0.001 versus the control group; (C) plasma triglyceride concentration profiles 0–2 h after oral olive oil (0.4 mL) administration. Open circle: metformin 1 h pre-treatment group; open square: metformin 0.5 h post-treatment group; open triangle: metformin simultaneous-treatment group; (D) AUC for plasma triglyceride concentrations during the OLTT. (E) Plasma glucose concentration profiles 0–2 h after oral glucose (1 g/kg) administration. Open circle: metformin 1 h pre-treatment group; open square: metformin 0.5 h post-treatment group; open triangle: metformin simultaneous-treatment group; (F) AUC for plasma glucose concentrations during oral glucose tolerance tests (OGTTs). Data represent means ± SE. n = 4 mice/group; * p < 0.05 versus the metformin (250 mg/kg) post-treatment group.

Figure 2

Effects of oral metformin treatment for one week (A,B) and a single metformin treatment (C–F) in 129S mice; (A) plasma triglyceride concentration profiles 0–2 h after oral olive oil (0.4 mL) administration. Metformin (250 mg/kg) was administered 1 h before olive oil-loading. Filled circle: control group; open circle: long-term metformin treatment for one week group; open square: single metformin treatment group; (B) area under the curve (AUC) for plasma triglyceride concentrations during the OLTT. Data represent means ± SE. n = 4 mice/group; ** p < 0.01, *** p < 0.001 versus the control group; (C) plasma triglyceride concentration profiles 0–2 h after oral olive oil (0.4 mL) administration. Open circle: metformin 1 h pre-treatment group; open square: metformin 0.5 h post-treatment group; open triangle: metformin simultaneous-treatment group; (D) AUC for plasma triglyceride concentrations during the OLTT. (E) Plasma glucose concentration profiles 0–2 h after oral glucose (1 g/kg) administration. Open circle: metformin 1 h pre-treatment group; open square: metformin 0.5 h post-treatment group; open triangle: metformin simultaneous-treatment group; (F) AUC for plasma glucose concentrations during oral glucose tolerance tests (OGTTs). Data represent means ± SE. n = 4 mice/group; * p < 0.05 versus the metformin (250 mg/kg) post-treatment group.

Figure 3

Stomach size and stomach content weights after olive oil administration in 129S mice following metformin (250 mg/kg) treatment (A,B). Data represent means ± SE. n = 4/group; *** p < 0.001.

Figure 4

ApoB-48 secretion from isolated enterocytes of metformin-treated 129S mice into culture medium. Data represent means ± SE. n = 6–7 mice/group; N.S. indicates not statistically significant.

Figure 5

Changes in the ¹³C/¹²C ratio in expired CO₂ after administration of glyceryl-1-¹³C tripalmitate in 129S mice following metformin (250 mg/kg) treatment. Data represent means ± SE. n = 5/group; * p < 0.05, and *** p < 0.001.