Glycomacropeptide for Management of Insulin Resistance and Liver Metabolic Perturbations

Abstract

Background and Aims: The increasing prevalence and absence of effective global treatment for metabolic syndrome (MetS) are alarming given the potential progression to severe non-communicable disorders such as type 2 diabetes and nonalcoholic fatty liver disease. The purpose of this study was to investigate the regulatory role of glycomacropeptide (GMP), a powerful milk peptide, in insulin resistance and liver dysmetabolism, two central MetS conditions. Materials and Methods: C57BL/6 male mice were fed a chow (Ctrl), high-fat, high-sucrose (HFHS) diet or HFHS diet along with GMP (200 mg/kg/day) administered by gavage for 12 weeks. Results: GMP lowered plasma insulin levels (in response to oral glucose tolerance test) and HOMA-IR index, indicating a more elevated systemic insulin sensitivity. GMP was also able to decrease oxidative stress and inflammation in the circulation as reflected by the decline of malondialdehyde, F2 isoprostanes and lipopolysaccharide. In the liver, GMP raised the protein expression of the endogenous anti-oxidative enzyme GPx involving the NRF2 signaling pathway. Moreover, the administration of GMP reduced the gene expression of hepatic pro-inflammatory COX-2, TNF-α and IL-6 via inactivation of the TLR4/NF-κB signaling pathway. Finally, GMP improved hepatic insulin sensitization given the modulation of AKT, p38 MAPK and SAPK/JNK activities, thereby restoring liver homeostasis as revealed by enhanced fatty acid β-oxidation, reduced lipogenesis and gluconeogenesis. Conclusions: Our study provides evidence that GMP represents a promising dietary nutraceutical in view of its beneficial regulation of systemic insulin resistance and hepatic insulin signaling pathway, likely via its powerful antioxidant and anti-inflammatory properties.

Protective Effect of Glycomacropeptide on the Inflammatory Response of U937 Macrophages

“…Inflammation, oxidative stress, and dysregulated autophagy are common features in noncommunicable diseases and may be key targets for the development of novel therapeutic strategies [ 43 ]. Previous studies have shown that GMP exerts immunomodulatory, anti-oxidative, and anti-inflammatory activities in rodent models of noncommunicable diseases in which macrophage activation is related with pathophysiology [ 28 , 29 , 30 , 31 ]. However, the direct effect of GMP on human macrophage activation had not been studied.…”

“…GMP was found to exert immunoregulatory, anti-inflammatory, and antioxidant activities in models of allergy and intestinal inflammatory diseases [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. In relation to metabolic diseases, GMP intake has shown promising effects on the prevention of insulin resistance and liver dysmetabolism in mice receiving a high-fat and high-sucrose diet [ 28 ]. In a streptozotocin-induced and high-fat diet-induced diabetic mouse model, a papain hydrolyzed GMP showed antidiabetic effects [ 29 ].…”

“…Moreover, in vitro and in vivo assays have demonstrated that GMP reduces lipid accumulation in adipocytes, body weight gain, and hyperlipidemia in obese rats [ 30 , 31 ]. The effect of GMP in obesity and metabolic diseases has been partly associated with the regulation of gut microbiota and oxidant and inflammatory processes [ 28 , 29 , 31 , 32 ]. Whether GMP is modulating macrophage inflammatory response still needs to be clarified.…”

Glycomacropeptide as an Efficient Agent to Fight Pathophysiological Mechanisms of Metabolic Syndrome

“…Recently, our laboratory highlighted the ability of glycomacropeptide (GMP) to counteract oxidative stress (OxS) and inflammation in intestinal Caco-2/15 cells [ 12 ], along with the amelioration of some aspects of MetS, such as insulin resistance (IR). In a subsequent study, we validated these findings using a murine model exposed to a high-fat, high-sucrose diet [ 13 ]. Interestingly, the administration of GMP to high-fat, high-sucrose diet-fed mice resulted in significant attenuation of IR, which is central to MetS pathogenesis.…”

Vascular Function in Chronic Non-Communicable Diseases

“…An animal study by Sauvé M. F. investigated the impact of glycomacropeptide on insulin resistance and hepatic dysmetabolism. The authors concluded that glycomacropeptide supplementation for 12 weeks exerted important antioxidant and anti-inflammatory actions and improved insulin sensitivity [ 15 ].…”