Beneficial Effects of Carbohydrate Restriction in Patients With Type 2 Diabetes Can Be Traced to Changes in Hepatic Metabolism

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Objectives: Carbohydrate restriction has profoundly beneficial effects on metabolic health in patients with type 2 diabetes (T2D), but the mechanism is not clear.The objective of this study was to test the hypothesis that markers of hepatic fuel metabolism would be associated with changes in metabolic health in patients with T2D over the course of a diet intervention.Methods: Participants were 56 adults with T2D not using insulin.Medications were discontinued 1-2 weeks (depending upon the medication) prior to baseline testing.A hyperglycemic clamp was used to assess the acute (first-phase) C-peptide response to glucose (ACP), and magnetic resonance imaging and spectroscopy were used to assess hepatic fat fraction, at baseline and after 12 weeks of controlled diet therapy (all food provided).Patients were randomized to either a eucaloric low carbohydrate (LC) diet (~9% energy from carbohydrate, 65% energy from fat) or a eucaloric low fat (LF) diet (~55% energy from carbohydrate, 20%energy from fat).Serum pyruvate (a marker of glycolytic flux) and palmitoleic acid (a marker of de novo lipogenesis) were measured with mass spectrometry, and beta-hydroxybutyrate (BHB) was measured on a clinical analyzer.Results: The LC diet led to decreases in pyruvate (-22%, P¼0.01) and palmitoleic acid (-55%, P< 0.01), and an increase in BHB (31%, P< 0.05), whereas changes from baseline in the LF group were minimal.The change in liver fat was positively associated with the change in pyruvate (r ¼ 0.34, P¼0.01), and inversely associated with the change in ACP (r ¼ -0.40, P< 0.01).Conversely, the change in ACP was inversely associated with the change in pyruvate (r ¼ -0.38, P< 0.05), and positively associated with BHB (r ¼ 0.73, P< 0.01).Conclusions: Pyruvate declines with carbohydrate restriction, and the decline is associated with improvements in liver fat and beta-cell function.A shift in hepatic metabolism from glycolysis to fat oxidation, with a concurrent increase in BHB and a decline in de novo lipogenesis, may underlie the beneficial effects of carbohydrate restriction on hepatic steatosis and glucose-induced insulin secretion.

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