Protein-Restricted Diet Is Effective in Decreasing Glycemia, HbA1c, and Cholesterol in Type 2 Diabetic Subjects by the Activation of the GCN2 Pathway

Abstract

Dietary restriction increases lifespan across the evolutionary spectrum and decreases metabolic disease risk in mammals. It has been shown that amino acid restriction is sufficient to promote some of the beneficial effects of dietary restriction in rodents. This phenomenon is dependent on GCN2 (general control nonderepressible 2), a kinase activated by amino acid restriction that controls protein synthesis and stress response. Our results show that treatment of type 2 diabetic subjects on a protein restriction diet for 4 weeks exhibited a 61% reduction in fasting glucose levels and a 14% decrease in Hb1Ac. These patients had a 32% reduction in Total Cholesterol with a 33% decrease in LDL. We noticed a reduction of 4.5% of body weight, with a decrease of 11% of fat mass and maintenance of lean mass. In addition, all subjects had systemic blood pressure normalization, with a decrease of 23% in systolic pressure and 44% in diastolic pressure. In order to understand in detail the action of protein restriction we evaluated the gene expression in the subcutaneous adipose tissue of these individuals. We observed the activation of GCN2 expression (p=0.0394) and consequently the activation of ATF4 (Activating transcription factor 4) and CHOP (C/EBP homologous protein) (p=0.0360 and p=0.0011 respectively). This findings suggesting that in fact, protein restricted diet affects the GCN2 pathway in humans, modulating the energy metabolism and enabling glycemic and lipidemic control.