Duration and degree of diet-induced metabolic acidosis prepartum alter tissue responses to insulin in dairy cows.

The objective of this experiment was to determine the effects of altering the dietary cation-anion difference (DCAD) fed for the last 21 or 42 d of gestation on glucose metabolism and tissue insulin responsiveness. Ninety parous Holstein cows at 232 d of gestation were assigned randomly to dietary treatments with 2 levels of DCAD (-70 or -180 mEq/kg) fed for 2 durations (short: the last 21 d of gestation; long: the last 42 d of gestation). For the short treatments, a diet with +110 mEq/kg was fed from 232 to 254 d of gestation. Intravenous glucose tolerance tests (IVGTT) were performed at either 250 or 270 d of gestation by infusing 0.25 g of dextrose/kg of body weight within 1 min. The following day, cows underwent an insulin challenge (IC) and received 0.1 IU of insulin/kg of body weight intravenously. Blood was sampled at min -15, -5, and 0 to establish a baseline and from 5 to 180 min relative to infusions; plasma concentrations of glucose, insulin, and fatty acids were determined, and the respective areas under the curves (AUC) were calculated. Liver was sampled after the IVGTT, and adipose tissue was sampled after the IVGTT and IC for quantification of mRNA expression and protein abundance. Reducing the DCAD altered acid-base balance compatible with a compensated metabolic acidosis. At 250 d, reducing the DCAD increased the AUC for glucose and reduced that of insulin following the IVGTT, whereas during the IC, clearance rate decreased and time to half-life of insulin increased with reducing DCAD, resulting in a tendency to a larger AUC for fatty acids. At 270 d, quantitative insulin sensitivity check index and the revised quantitative insulin sensitivity check index were smaller in cows fed the acidogenic diets for the last 42 d of gestation compared with the last 21 d of gestation, thereby suggesting reduced insulin sensitivity. In addition, cows fed for the long duration tended to have greater AUC for glucose but smaller AUC for insulin following an IVGTT than those fed for the short duration, thereby suggesting reduced insulin release and glucose disposal. Treatments did not affect hepatic mRNA expression of G6PC, PCK1, PCK2, and PC or adipose tissue mRNA expression of ATGL, ACC, B2AR, HSL, and PLIN1. On the other hand, for proteins, reducing the DCAD linearly reduced abundance of rabbit anti-mouse protein kinase B (AKT) and tended to reduce rabbit anti-human phosphorylated (Ser-9) glycogen synthase kinase-3 β (pGSK) and the pGSK:rabbit anti-human glycogen synthase kinase-3 β (GSK) ratio in hepatic tissue, whereas a linear increase in rabbit anti-human hormone-sensitive lipase (HSL) and rabbit anti-mouse phosphorylated (Ser-660) hormone-sensitive lipase (pHSL) in adipose tissue was observed after the IVGTT at 250 d. Moreover, reducing the DCAD resulted in a linear reduction of AKT and tended to reduce rabbit anti-human acetyl-CoA carboxylase (ACC) but increased pHSL linearly in adipose tissue after an IC at 250 d. Cows fed acidogenic diets for a short duration tended to have less pHSL in adipose tissue than those fed for a long duration after an IVGTT at 270 d. Associations were observed between blood pH and mRNA and protein abundance in hepatic and adipose tissues. Diet-induced metabolic acidosis altered insulin release and insulin signaling, resulting in a shift in adipose tissue metabolism that would favor lipolysis over lipogenesis.