Dietary proteins and amino acids are important modulators of glucose metabolism and insulin sensitivity. Although high intake of dietary proteins has positive effects on energy homeostasis by inducing satiety and possibly increasing energy expenditure, it has detrimental effects on glucose homeostasis by promoting insulin resistance and increasing gluconeogenesis. Varying the quality rather than the quantity of proteins has been shown to modulate insulin resistance induced by Western diets and has revealed that proteins derived from fish might have the most desirable effects on insulin sensitivity. In vitro and in vivo data also support an important role of amino acids in glucose homeostasis through modulation of insulin action on muscle glucose transport and hepatic glucose production, secretion of insulin and glucagon, as well as gene and protein expression in various tissues. Moreover, amino acid signaling is integrated by mammalian target of rapamycin, a nutrient sensor that operates a negative feedback loop toward insulin receptor substrate 1 signaling, promoting insulin resistance for glucose metabolism. This integration suggests that modulating dietary proteins and the flux of circulating amino acids generated by their consumption and digestion might underlie powerful new approaches to treat various metabolic diseases such as obesity and diabetes.

The aim of the present study was to determine the effects of feeding various dietary proteins on insulin sensitivity and glucose tolerance in rats. Male Wistar rats were fed for 28 days with isoenergetic diets containing either casein, soy protein, or cod protein. Cod protein-fed and soy protein-fed rats had lower fasting plasma glucose and insulin concentrations compared with casein-fed animals. After intravenous glucose bolus, cod protein- and soy protein-fed rats induced lower incremental areas under glucose curves compared with casein-fed animals. Improved peripheral insulin sensitivity was confirmed by higher glucose disposal rates in cod protein- and soy protein-fed rats (15.2 +/- 0.3 and 13.9 +/- 0.6 mg. kg(-1). min(-1), respectively) compared with casein-fed animals (6.5 +/- 0.7 mg. kg(-1). min(-1), P < 0.05). Moreover, test meal experiments revealed that, in the postprandial state, the lower plasma insulin concentrations in cod protein- and soy protein-fed animals could be also due to decreased pancreatic insulin release and increased hepatic insulin removal. In conclusion, the metabolic responses to three common dietary proteins indicate that cod and soy proteins, when compared with casein, improve fasting glucose tolerance and peripheral insulin sensitivity in rats.

The cellular mechanism by which high-fat feeding induces skeletal muscle insulin resistance was investigated in the present study. Insulin-stimulated glucose transport was impaired (ϳ40 -60%) in muscles of high fat-fed rats. Muscle GLUT4 expression was significantly lower in these animals (ϳ40%, P < 0.05) but only in type IIa-enriched muscle. Insulin stimulated the translocation of GLUT4 to both the plasma membrane and the transverse (T)-tubules in chow-fed rats. In marked contrast, GLUT4 translocation was completely abrogated in the muscle of insulin-stimulated high fat-fed rats. High-fat feeding markedly decreased insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity but not insulin-induced tyrosine phosphorylation of the insulin receptor and IRS proteins in muscle. Impairment of PI 3-kinase function was associated with defective Akt/protein kinase B kinase activity (؊40%, P < 0.01) in insulin-stimulated muscle of high fat-fed rats, despite unaltered phosphorylation (Ser473/Thr308) of the enzyme. Interestingly, basal activity of atypical protein kinase C (aPKC) was elevated in muscle of high fat-fed rats compared with chow-fed controls. Whereas insulin induced a twofold increase in aPKC kinase activity in the muscle of chowfed rats, the hormone failed to further increase the kinase activity in high fat-fed rat muscle. In conclusion, it was found that GLUT4 translocation to both the plasma membrane and the T-tubules is impaired in the muscle of high fat-fed rats. We identified PI 3-kinase as the first step of the insulin signaling pathway to be impaired by high-fat feeding, and this was associated with alterations in both Akt and aPKC kinase activities.

In the present study, we tested the hypothesis that fish protein may represent a key constituent of fish with glucoregulatory activity. Three groups of rats were fed a high-fat diet in which the protein source was casein, fish (cod) protein, or soy protein; these groups were compared with a group of chow-fed controls. High-fat feeding led to severe whole body and skeletal muscle insulin resistance in casein- or soy protein-fed rats, as assessed by the euglycemic clamp technique coupled with measurements of 2-deoxy-D-[(3)H]glucose uptake rates by individual tissues. However, feeding cod protein fully prevented the development of insulin resistance in high fat-fed rats. These animals exhibited higher rates of insulin-mediated muscle glucose disposal that were comparable to those of chow-fed rats. The beneficial effects of cod protein occurred without any reductions in body weight gain, adipose tissue accretion, or expression of tumor necrosis factor-alpha in fat and muscle. Moreover, L6 myocytes exposed to cod protein-derived amino acids showed greater rates of insulin-stimulated glucose uptake compared with cells incubated with casein- or soy protein-derived amino acids. These data demonstrate that feeding cod protein prevents obesity-induced muscle insulin resistance in high fat-fed obese rats at least in part through a direct action of amino acids on insulin-stimulated glucose uptake in skeletal muscle cells.