Effects of selenized casein and carbohydrate components of milk on insulin sensitivity in rats

Abstract

Several epidemiological studies have demonstrated improvements in glucose tolerance and incidence of type II diabetes with increased dairy product consumption. Elucidating which components of milk have beneficial effects on insulin sensitivity could lead to the development of novel dairy products for the treatment and/or prevention of type II diabetes. This thesis involved supplementing rat diets with various milk components fed for up to 9 weeks prior to the use of the hyperinsulinemic-euglycemic clamp procedure enhanced by glucose tracer infusion to measure insulin sensitivity in vivo. Insulin signalling components in hepatic and peripheral tissues were analyzed in fasted vehicle- and insulin-stimulated rats. Dietary inclusion of selenium (Se)- enriched casein (a milk protein) to provide 1, 2 and 8 times the Se requirement, impaired hepatic insulin sensitivity when included in low-fat diets but had no impact on insulin sensitivity when included in high-fat diets. The ability for insulin to stimulate Akt phosphorylation at Thr308 was decreased in all insulin-responsive tissues. Hepatic oxidation state and expression of the selenoproteins SeP and GPx1 was unaffected while expression of IRS1, IRS2 and PGC-1 alpha was decreased with supra-nutritional Se and HF intake. Expression of PI3k-regulatory and catalytic subunits was decreased with supra-nutritional intake. A second study was designed to assess insulin sensitivity in response to 15% dietary inclusion of galactose, a monomer of the milk disaccharide lactose, compared to the monosaccharides glucose and fructose. In addition, the lactose-derived prebiotic galacto-oligosaccharides was assessed in comparison to methylcellulose. Galactose improved hepatic insulin sensitivity relative to glucose and fructose and increased fed-state hepatic glycogen content with increased ability for insulin to maintain active glycogen synthase abundance. Galacto-oligosaccharides elicited bifidogenic responses with no impact on insulin sensitivity. Of the milk components assessed in these studies, galactose demonstrated the greatest insulin sensitizing effects, while consumption of galacto-oligosaccharides improved gut microbial profile it did not alter insulin sensitivity. Intakes of Se-enriched casein to provide up to 8x the requirement impaired hepatic insulin sensitivity in a mechanism similar to high-fat feeding, via attenuated IRS/PI3K/AKT signalling and decreased PGC-1 alpha.