Sheng-Song Chen

Glucagon-mediated impairments in hepatic and peripheral tissue nutrient disposal are not aggravated by increased lipid availability

Glucose, fat, and glucagon availability are increased in diabetes. The normal response of the liver to chronic increases in glucose availability is to adapt to become a marked consumer of glucose. Yet this fails to occur in diabetes. The aim was to determine whether increased glucagon and lipid interact to impair the adaptation to increased glucose availability. Chronically catheterized well controlled depancreatized conscious dogs (n = 21) received 3 days of continuous parenteral nutrition (TPN) that was either high in glucose [C; 75% nonprotein calories (NPC)] or in lipid (HL; 75% NPC) in the presence or absence of a low dose (one-third basal) chronic intraportal infusion of glucagon (GN; 0.25 ng.kg(-1).min(-1)). During the 3 days of TPN, all groups received the same insulin algorithm; the total amount of glucose infused (GIR) was varied to maintain isoglycemia ( approximately 120 mg/dl). On day 3 of TPN, hepatic metabolism was assessed. Glucose and insulin levels were similar in all groups. GIR was decreased in HL and C + GN ( approximately 30%) and was further decreased in HL + GN (55%). Net hepatic glucose uptake was decreased approximately 15% in C + GN, and HL and was decreased approximately 50% in HL + GN. Lipid alone or combined with glucagon decreased glucose uptake by peripheral tissues. Despite impairing whole body glucose utilization, HL did not limit whole body energy disposal. In contrast, glucagon suppressed whole body energy disposal irrespective of the diet composition. In summary, failure to appropriately suppress glucagon secretion adds to the dietary fat-induced impairment in both hepatic and peripheral glucose disposal. In addition, unlike increasing the percentage of calories as fat, inappropriate glucagon secretion in the absence of compensatory hyperinsulinemia limits whole body nutrient disposition.

Continuous low-dose fructose infusion does not reverse glucagon-mediated decrease in hepatic glucose utilization

An adaptation to continuous total parenteral nutrition (TPN; 75% of nonprotein calories as glucose) is the liver becomes a major consumer of glucose with lactate release as a by-product. The liver is able to further increase liver glucose uptake when a small dose of fructose is acutely infused via the portal system. Glucagon, commonly elevated during inflammatory stress, is a potent inhibitor of glucose uptake by the liver during TPN. The aim was to determine if continuous fructose infusion could overcome the glucagon-mediated decrease in hepatic glucose uptake. Studies were performed in conscious, insulin-treated, chronically catheterized, pancreatectomized dogs that adapted to TPN for 33 hours. They were then assigned to 1 of 4 groups: TPN (C), TPN + fructose (4.4 μmol kg(-1) min(-1); F), TPN + glucagon (0.2 pmol kg(-1) min(-1); GGN), or TPN + fructose and glucagon (F + GGN) for an additional 63 hours (33-96 hours). Insulin, fructose, and glucagon were infused into the portal vein. During that period, all animals received a fixed insulin infusion of 0.4 mU·kg(-1)·min(-1) (33-96 hours); and the glucose infusion rates were adjusted to maintain euglycemia (6.6 mmol/L). Continuous fructose infusion was unable to further enhance net hepatic glucose uptake (in micromoles per kilogram per minute) (31.1 ± 2.8 vs 36.1 ± 5.0; C vs F), nor was it able to overcome glucagon-mediated decrease in net hepatic glucose uptake (10.0 ± 4.4 vs 12.2 ± 3.9; GGN vs F + GGN). In summary, continuous fructose infusion cannot augment liver glucose uptake during TPN; nor can it overcome the inhibitory effects of glucagon.

Liver, but not muscle, has an entrainable metabolic memory.

Hyperglycemia in the hospitalized setting is common, especially in patients that receive nutritional support either continuously or intermittently. As the liver and muscle are the major sites of glucose disposal, we hypothesized their metabolic adaptations are sensitive to the pattern of nutrient delivery. Chronically catheterized, well-controlled depancreatized dogs were placed on one of three isocaloric diets: regular chow diet once daily (Chow) or a simple nutrient diet (ND) that was given either once daily (ND-4) or infused continuously (ND-C). Intraportal insulin was infused to maintain euglycemia. After 5 days net hepatic (NHGU) and muscle (MGU) glucose uptake and oxidation were assessed at euglycemia (120 mg/dl) and hyperglycemia (200 mg/dl) in the presence of basal insulin. While hyperglycemia increased both NHGU and MGU in Chow, NHGU was amplified in both groups receiving ND. The increase was associated with enhanced activation of glycogen synthase, glucose oxidation and suppression of pyruvate dehydrogenase kinase-4 (PDK-4). Accelerated glucose-dependent muscle glucose uptake was only evident with ND-C. This was associated with a decrease in PDK-4 expression and an increase in AMP-activated protein kinase (AMPK) phosphorylation. Interestingly, ND-C markedly increased hepatic FGF-21 expression. Thus, augmentation of carbohydrate disposal in the liver, as opposed to the muscle, is not dependent on the pattern of nutrient delivery.