Hepatic glucose uptake and disposition during short-term high-fat vs. high-fructose feeding

Abstract

In dogs consuming a high-fat and -fructose diet (52 and 17% of total energy, respectively) for 4 wk, hepatic glucose uptake (HGU) in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery is markedly blunted with reduction in glucokinase (GK) protein and glycogen synthase (GS) activity. The present study compared the impact of selective increases in dietary fat and fructose on liver glucose metabolism. Dogs consumed weight-maintaining chow (CTR) or hypercaloric high-fat (HFA) or high-fructose (HFR) diets diet for 4 wk before undergoing clamp studies with infusion of somatostatin and intraportal insulin (3-4 times basal) and glucagon (basal). The hepatic glucose load (HGL) was doubled during the clamp using peripheral vein (Pe) glucose infusion in the first 90 min (P1) and portal vein (4 mg·kg(-1)·min(-1)) plus Pe glucose infusion during the final 90 min (P2). During P2, HGU was 2.8 ± 0.2, 1.0 ± 0.2, and 0.8 ± 0.2 mg·kg(-1)·min(-1) in CTR, HFA, and HFR, respectively (P < 0.05 for HFA and HFR vs. CTR). Compared with CTR, hepatic GK protein and catalytic activity were reduced (P < 0.05) 35 and 56%, respectively, in HFA, and 53 and 74%, respectively, in HFR. Liver glycogen concentrations were 20 and 38% lower in HFA and HFR than CTR (P < 0.05). Hepatic Akt phosphorylation was decreased (P < 0.05) in HFA (21%) but not HFR. Thus, HFR impaired hepatic GK and glycogen more than HFA, whereas HFA reduced insulin signaling more than HFR. HFA and HFR effects were not additive, suggesting that they act via the same mechanism or their effects converge at a saturable step.

Keywords: Glucokinase; glycogen; glycogen phosphorylase; glycogen synthase; insulin signaling.

Fig. 1.

Mean daily energy intake. Daily energy intake was recorded in dogs fed a control (CTR), a high-fat (HFA), or a high-fructose (HFR) diet for 4 wk. Data are means ± SE; n = 5/group. Dogs fed the HFA or HFR diets were provided isoenergetic quantities of their respective diets over the course of 4 wk, but both groups were hypercalorically fed relative to CTR dogs.

Fig. 2.

Plasma hormone concentrations during hyperinsulinemic hyperglycemic (HIHG) clamps. Arterial plasma insulin (A) and glucagon (B) and hepatic sinusoidal insulin (C) and glucagon (D) during basal (−20 to 0 min) and experimental periods (0–180 min) of HIHG clamps in CTR (◻), HFA (▲), or HFR (○) diet groups. Po, portal. Data are means ± SE; n = 5/group. *P < 0.05, CTR vs. other groups.

Fig. 3.

Arterial blood glucose (A), hepatic glucose load (HGL; B), unidirectional hepatic glucose uptake (HGU; C and D), and net hepatic glucose balance (NHGB; E and F) in CTR (◻), HFA (▲), and HFR (○) during the basal (−20 to 0 min) and experimental periods (0–180 min) of HIHG clamps. Data are means ± SE; n = 5/group. *P < 0.05 vs. CTR.

Fig. 4.

Arterial blood lactate (A) and glycerol (C) and plasma nonesterified fatty acid (NEFA; E) concentrations and net hepatic balances of lactate (B), glycerol (D), and NEFA (F) during basal (−20 to 0 min) and experimental periods (0–180 min) of HIHG clamps in CTR (◻), HFA (▲), and HFR (○) diet groups. Data are means ± SE; n = 5/group. *P < 0.05, CTR vs. other groups; **P < 0.05, HFR vs. other groups; †P < 0.05, HFA vs. CTR; ‡P < 0.05, HFR vs. CTR.

Fig. 5.

Hepatic glucokinase (GK) and glucokinase regulatory protein (GKRP) and phosphorylated (p)-Akt, a marker of insulin signaling. Levels of GK mRNA (A), protein (B), and activity (C), GKRP protein (D), and p-Akt on Ser⁴⁷³ (E) in CTR (open bars), HFA (black bars), and HFR (hatched bars) groups. All proteins are expressed relative to tissue actin, and data for the HFA and HFR groups are normalized to those in CTR. Data are means ± SE; n = 5/group. Groups with the same letters are not significantly different from each other; where there are no letters, there are no significant differences among groups.

Fig. 6.

Markers of hepatic glycogen metabolism. Activity ratios of glycogen synthase (GS; A) and glycogen phosphorylase (GP; B), terminal liver glycogen concentrations (C), and glycogen synthesized via the direct pathway (D) for CTR (open bars), HFA (black bars), and HFR (hatched bars). Data are means ± SE; n = 5/group. Groups with the same letters are not significantly different from one another; where there are no letters, there are no significant differences among groups. L/H, ratio of low to high glucose 6-phosphate.