Reduced pancreatic responsiveness to glucose plus amino acids and incretins in early versus late lactation dairy cows

The action of insulin that influences partitioning of nutrients to milk in early lactation and to the body in later lactation is controlled by the effect of insulin on an array of insulin-dependent tissues and by pancreatic responsiveness to insulin secretagogues. To examine differences in pancreatic responsiveness between stages of lactation, pairs of cows in early (39 ± 24.3 DIM; n = 11) and late lactation (316.5 ± 77.3 DIM; n = 11) were feed restricted for 24 h and then subjected to a 2-h hyperglycemic, hyperaminoacidemic clamp (HGHAC) where glucose + 9 essential amino acids were infused intravenously to reach plasma concentration targets of 5 mM for glucose and 800 μM for branched-chain amino acids. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) were then added to the HGHAC for 2 more hours to isolate the pancreatic responsiveness to these incretins. Baseline, feed-restricted glucose and insulin concentrations before infusion were lower in the early-lactation group compared with late lactation, while baseline branched-chain amino acid and lysine concentrations were higher. Early-lactation cows needed 147 mmol/h more glucose to maintain hyperglycemia than those in late lactation, indicating a higher glucose disposition. The physiological basis for this response and for the low baseline glucose concentration is likely the high glucose uptake of the mammary glands of early lactation. In contrast, 224 mmol/h less amino acid was infused in early lactation to maintain hyperaminoacidemia, suggesting a faster endogenous entry of amino acid from body stores. Insulin concentrations during both sets of clamps showed that cows in early lactation exhibited reduced pancreatic responsiveness to glucose + amino acids and to incretins, compared with cows in late lactation. The opposing effects of stage of lactation on glucose and amino acid infusion rates reveal the existence of differences between glucose and amino acids in how the insulin sensitivities of their production and utilization are affected. Blunted pancreatic responsiveness may be more important than a decrease in insulin sensitivity for directing glucose and amino acids toward milk.