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Clinical Trial
. 2022 Feb 7;186(3):367-377.
doi: 10.1530/EJE-21-0850.

Metformin maintains intrahepatic triglyceride content through increased hepatic de novo lipogenesis

Charlotte J Green  1 , Thomas Marjot  1   2 , John Walsby-Tickle  3 , Catriona Charlton  1 , Thomas Cornfield  1 , Felix Westcott  1 , Katherine E Pinnick  1 , Ahmad Moolla  1 , Jonathan M Hazlehurst  1   4 , James McCullagh  3 , Jeremy W Tomlinson  1   5 , Leanne Hodson  1   5
Affiliations
Clinical Trial

Metformin maintains intrahepatic triglyceride content through increased hepatic de novo lipogenesis

Charlotte J Green et al. Eur J Endocrinol. .

Abstract

Objective: Metformin is a first-line pharmacotherapy in the treatment of type 2 diabetes, a condition closely associated with non-alcoholic fatty liver disease (NAFLD). Although metformin promotes weight loss and improves insulin sensitivity, its effect on intrahepatic triglyceride (IHTG) remains unclear. We investigated the effect of metformin on IHTG, hepatic de novo lipogenesis (DNL), and fatty acid (FA) oxidation in vivo in humans.

Design and methods: Metabolic investigations, using stable-isotope tracers, were performed in ten insulin-resistant, overweight/obese human participants with NAFLD who were treatment naïve before and after 12 weeks of metformin treatment. The effect of metformin on markers of s.c. adipose tissue FA metabolism and function, along with the plasma metabolome, was investigated.

Results: Twelve weeks of treatment with metformin resulted in a significant reduction in body weight and improved insulin sensitivity, but IHTG content and FA oxidation remained unchanged. Metformin treatment was associated with a significant decrease in VLDL-triglyceride (TG) concentrations and a significant increase in the relative contribution of DNL-derived FAs to VLDL-TG. There were subtle and relatively few changes in s.c. adipose tissue FA metabolism and the plasma metabolome with metformin treatment.

Conclusions: We demonstrate the mechanisms of action of metformin whereby it improves insulin sensitivity and promotes weight loss, without improvement in IHTG; these observations are partly explained through increased hepatic DNL and a lack of change in FA oxidation.

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Figures

Figure 1
Figure 1
Overview of study design. MRI/S, MRI and spectroscopy; IHTG, intrahepatic triglyceride content; ‘clamp’, two-step hyperinsulinaemic–euglycaemic clamp.
Figure 2
Figure 2
The effect of metformin treatment on (A) body weight (kg); (B) intrahepatic triglyceride (IHTG) %; (C) plasma glucose; (D) plasma insulin; (E) rate of disappearance (Rd) of glucose; (F) rate of appearance (Ra) of glucose at the end of the respective clamp phases during the two-step hyperinsulinaemic–euglycaemic clamp pre (black circles and black bars) and post (open circles and open bars) 12 weeks metformin treatment. Data are reported as mean ± s.e.m.
Figure 3
Figure 3
The effect of metformin treatment on (A) plasma non-esterified fatty acids (NEFA); (B) the incorporation of [U13C]palmitate in plasma NEFA; (C) the rate of appearance (Ra) of plasma (NEFA), (D) plasma triglycerides (TG); (E) the incorporation of [13C]palmitate in VLDL-TG; (F) proportion of newly synthesised palmitate in VLDL-TG (hepatic de novo lipogenesis); (G) plasma 3-hydroxybutyrate (3OHB); and (H) 13CO2 production at the end of the respective clamp phases during the two-step hyperinsulinaemic–euglycaemic clamp pre ( black bars) and post (open bars) 12 weeks metformin treatment. Data are reported as mean ± s.e.m.
Figure 4
Figure 4
Change in the s.c. abdominal adipose tissue expression of (A) adipose triglyceride lipase (PNPLA2); (B) hormone-sensitive lipase (LIPE); (C) lipoprotein lipase (LPL); and (D) fatty acid translocase (CD36) pre (black circles) and post (open circles) 12 weeks metformin treatment.
Figure 5
Figure 5
The plasma metabolome and the abundance in plasma (A) lactate, (B) monosaccharide, (C) citrulline, (D) ornithine, (E) leucine, (F) isoleucine, (G) valine, and (H) phenylalanine pre (black circles) and post (open circles) 12 weeks metformin treatment. Data are reported as median ± range.
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