Effect of dietary protein on in vivo insulin action and liver glycogen repletion

To investigate the influence of dietary manipulation on in vivo glucose metabolism, we pair fed normal rats for 10 days with one of three diets: 1) high protein-low carbohydrate (Hi-PN) (n = 20); 2) intermediate protein (I-PN) (n = 11); and 3) low protein-high carbohydrate (Lo-PN) (n = 18). Fasting glucose, postmeal plasma glucose, and insulin concentrations were as follows: 118 ± 2 mg/dl, 138 ± 2 mg/dl, and 4.0 ± 0.2 ng/ml in Hi-PN; 111 ± 3 mg/dl, 147 ± 3 mg/dl, and 5.1 ± 0.3 ng/ml in I-PN; 102 ± 2 mg/dl, 162 ± 2 mg/dl, and 6.0 ± 0.2 ng/ml in Lo-PN, respectively. Basal hepatic glucose production (HGP) was 6.6 ± 0.2 in Hi-PN, 6.1 ± 0.2 in I-PN, and 5.6 ± 0.1 mg·kg^-1·min^-1 in Lo-PN. Insulin sensitivity was assessed with the euglycemic clamp using two insulin infusion rates: 2 and 4 mU·kg^-1·min^-1. The rate of glucose disappearance was 14.8 ± 0.4 and 25.3 ± 0.7 in Hi-PN, 15.3 ± 0.4 and 26.9 ± 0.5 in I-PN, and 16.1 ± 0.6 and 31.5 ± 0.5 mg·kg^-1·min^-1 in Lo-PN respectively. HGP was suppressed by 86 in the 2- and by 90% in the 4-mU insulin clamp in the Lo-PN, whereas HGP was suppressed by 45 and by 79% in the two steps in the Hi-PN group. To quantitate the pathways by which liver glycogen is repleted we administered [1-¹³C]glucose by constant intraduodenal infusion into awake 24-h fasted rats and determined the distribution of ¹³C label in glycogen by nuclear magnetic resonance spectroscopy (NMR). The amount of glycogen synthesized from the direct pathway was calculated to be 20 ± 6 in Hi-PN, 26 ± 2 in I-PN, and 52 ± 11% in Lo-PN. In conclusion Hi-PN feeding leads to 1) fasting hyperglycemia, 2) excessive basal HGP, 3) peripheral and hepatic insulin resistance, and 4) shift in liver glycogen repletion from the direct to indirect pathway.