Hyperinsulinemia compensates for infection-induced impairment in net hepatic glucose uptake during TPN

Donmoyer, Christine M.; Chen, Sheng-Song; Hande, Scott A.; Lacy, D. Brooks; Ejiofor, Joseph; McGuinness, Owen P.

doi:10.1152/ajpendo.2000.279.2.e235

Cited by 10 publications

(5 citation statements)

References 23 publications

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“…Net glycogen accumulation attributed to fructose was calculated as the increment in [ 14 C]glycogen synthetic rate (difference between fructoseinfused group and corresponding saline-infused group) multiplied by the fraction of time of fructose infusion (total min/180 min). Analogous to glycogen accumulation, hepatic 14 C-labeled lipid deposition was calculated as total radioactivity divided by inflowing [ 14 and sham ϩ saline (ShamϩS) groups have been presented previously (10).…”

Section: Methodsmentioning

confidence: 99%

Fructose augments infection-impaired net hepatic glucose uptake during TPN administration

Donmoyer

Ejiofor

Lacy

et al. 2001

American Journal of Physiology-Endocrinology and Metabolism

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During chronic total parenteral nutrition (TPN), net hepatic glucose uptake (NHGU) and net hepatic lactate release (NHLR) are markedly reduced (downward arrow approximately 45 and approximately 65%, respectively) with infection. Because small quantities of fructose are known to augment hepatic glucose uptake and lactate release in normal fasted animals, the aim of this work was to determine whether acute fructose infusion with TPN could correct the impairments in NHGU and NHLR during infection. Chronically catheterized conscious dogs received TPN for 5 days via the inferior vena cava at a rate designed to match daily basal energy requirements. On the third day of TPN administration, a sterile (SHAM, n = 12) or Escherichia coli-containing (INF, n = 11) fibrin clot was implanted in the peritoneal cavity. Forty-two hours later, somatostatin was infused with intraportal replacement of insulin (12 +/- 2 vs. 24 +/- 2 microU/ml, SHAM vs. INF, respectively) and glucagon (24 +/- 4 vs. 92 +/- 5 pg/ml) to match concentrations previously observed in sham and infected animals. After a 120-min basal period, animals received either saline (Sham+S, n = 6; Inf+S, n = 6) or intraportal fructose (0.7 mg x kg(-1) x min(-1); Sham+F, n = 6; Inf+F, n = 5) infusion for 180 min. Isoglycemia of 120 mg/dl was maintained with a variable glucose infusion. Combined tracer and arteriovenous difference techniques were used to assess hepatic glucose metabolism. Acute fructose infusion with TPN augmented NHGU by 2.9 +/- 0.4 and 2.5 +/- 0.3 mg x kg(-1) x min(-1) in Sham+F and Inf+F, respectively. The majority of liver glucose uptake was stored as glycogen, and NHLR did not increase substantially. Therefore, despite an infection-induced impairment in NHGU and different hormonal environments, small amounts of fructose enhanced NHGU similarly in sham and infected animals. Glycogen storage, not lactate release, was the preferential fate of the fructose-induced increase in hepatic glucose disposal in animals adapted to TPN.

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Section: Methodsmentioning

confidence: 99%

Fructose augments infection-impaired net hepatic glucose uptake during TPN administration

Donmoyer

Ejiofor

Lacy

et al. 2001

American Journal of Physiology-Endocrinology and Metabolism

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“…A laparotomy was performed on healthy dogs under general anesthesia, as described previously (8). During the laparotomy, Silastic (Dow Corning, Midland, MI) catheters (0.04 in.…”

Section: Experimental Preparationmentioning

confidence: 99%

Impact of chronic fructose infusion on hepatic metabolism during TPN administration

Donmoyer

Lacy

Zhang

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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. Impact of chronic fructose infusion on hepatic metabolism during TPN administration. Am J Physiol Endocrinol Metab 283: E1151-E1158, 2002; 10.1152/ajpendo.00223.2001.-During chronic total parenteral nutrition (TPN), net hepatic glucose uptake (NHGU) is markedly elevated. However, NHGU is reduced by the presence of an infection. We recently demonstrated that a small, acute (3-h) intraportal fructose infusion can correct the infection-induced impairment in NHGU. The aim of this study was to determine whether the addition of fructose to the TPN persistently enhances NHGU in the presence of an infection. TPN was infused continuously into the inferior vena cava of chronically catheterized dogs for 5 days. On day 3, a bacterial clot was implanted in the peritoneal cavity, and either saline (CON, n ϭ 5) or fructose (ϩFRUC, 1.0 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , n ϭ 6) infusion was included with the TPN. Forty-two hours after the infection was induced, hepatic glucose metabolism was assessed in conscious dogs with arteriovenous and tracer methods. Arterial plasma glucose concentration was lower with chronic fructose infusion (120 Ϯ 4 vs. 131 Ϯ 3 mg/dl, ϩFRUC vs. CON, P Ͻ 0.05); however, NHGU was not enhanced (2.2 Ϯ 0.5 vs. 2.8 Ϯ 0.4 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Acute removal of the fructose infusion dramatically decreased NHGU (2.2 Ϯ 0.5 to Ϫ0.2 Ϯ 0.5 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ), and net hepatic lactate release also fell (1.6 Ϯ 0.3 to 0.5 Ϯ 0.3 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ). This led to an increase in the arterial plasma glucose (⌬13 Ϯ 3 mg/dl, P Ͻ 0.05) and insulin (⌬5 Ϯ 2 U/ml) concentrations and to a decrease in glucagon (⌬Ϫ11 Ϯ 3 pg/ml) concentration. In conclusion, the addition of chronic fructose infusion to TPN during infection does not lead to a persistent augmentation of NHGU.liver; lactate; dog TOTAL PARENTERAL NUTRITION (TPN) is administered chronically to patients unable to consume food by the enteral route. The liver is an important site of glucose disposal in normal animals receiving chronic nutritional support, taking up 45% of the TPN-derived glucose (19). Remarkably, upon adaptation to TPN, the concentrations of insulin and glucose are only slightly elevated. In the course of an infection, however, net hepatic glucose uptake (NHGU) in dogs receiving TPN is impaired (19) despite the presence of hyperglycemia and hyperinsulinemia, which typically stimulate glucose uptake. This is consistent with impaired glucose uptake by the splanchnic bed (gut and liver) observed in stressed malnourished patients administered TPN during recovery from surgery (15).Fructose is known to enhance hepatic glucose disposal acutely, even in insulin-resistant states. In normal fasted dogs, a small, acute (3-h) fructose infusion stimulated NHGU (24). We recently demonstrated that acute fructose infusion enhanced NHGU in infected dogs receiving chronic TPN and, more importantly, corrected the infection-induced impairment in NHGU (9). The addition of a small amount of fructose to an oral glucose load decreased the glucose and insulin responses to that load in bo...

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“…Previous studies by our laboratory and others have demonstrated using hyperinsulinemic-euglycemic clamps that lipopolysaccharide (LPS) induces insulin resistance (39). Skeletal muscle is a major site of insulin-stimulated glucose disposal and a major contributor to sepsis-induced insulin resistance (12,34,35). Alterations in muscle glucose disposal, the control of which is distributed between delivery of glucose to muscle, glucose transport in the myocyte, and subsequent metabolism within the myocyte, can contribute to insulin resistance in skeletal muscle.…”

Section: Introductionmentioning

confidence: 99%

Rapid changes in the microvascular circulation of skeletal muscle impair insulin delivery during sepsis

Mignemi

McClatchey

Kilchrist

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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Introduction Hyperglycemia is prevalent in hospitalized critically ill patients, even in those without a prior diagnosis of diabetes. In patients without pre‐existing diabetes, hyperglycemia is associated with increased morbidity and mortality. Hyperglycemia is one of the earliest clinical indications of sepsis, and clinical trials show that if the hyperglycemia is controlled, patient outcomes are improved. Previous investigations have focused on events in the myocyte (e.g. insulin signaling, glucose transport and subsequent metabolism) as the causes for this insulin resistant state. However, the delivery of insulin to the skeletal muscle (SkM) is an important determinant of insulin action. Hypothesis Reduced capillary blood flow to skeletal muscle belies the insulin resistance of sepsis by reducing insulin delivery to the myocyte and that protecting the endothelium from sepsis‐induced inflammation will prevent insulin resistance and reduced capillary blood flow. Method Intravital microscopy was used to track fluorescent beads in mouse gastrocnemius muscle capillaries. Briefly, C57BL/6J mice with jugular vein catheters were anesthetized with isoflurane, and the gastrocnemius was exposed. Mice were then injected florescent beads. Images were subjected to a positional tracking. This data was used to build capillary flow speed maps for enhanced spatial visualization of flow data using MATLAB. Insulin delivery and insulin efflux out of the vessels were also examined using intravital microscopy and insulin conjugated with Alexa Flour 647. Results This hypothesis was examined in mice treated with lipopolysaccharide (LPS) followed by intravital microscopy of the SkM microcirculation. We found that flowing capillary area was reduced by ~50% (Figure 1A) and velocity of blood flowing in the capillaries was slowed (Figure 1B) as well as more tortuous (Figure 1C) after LPS administration. We assessed capillary barrier permeability to insulin and surprisingly found no significant difference in insulin exchanges rates (iKT) for either control (0.25 Min−1) or LPS treated mice (0.21 Min−1). Next we determined insulin delivery to the SkM using two independent methods and found that sepsis rapidly reduces insulin delivery to the skeletal muscle by ~40%; this was driven by decreases in capillary flow velocity and number of perfused capillaries (Figure 2A&B). Further, the changes in SkM microcirculation occur prior to changes in both cardiac output and arterial blood pressure. Finally, we created mice with an endothelial specific knockdown of NFκB signaling through the deletion of P65 (P65eko) and found they were protected from both LPS‐induced reductions in blood flow speed and increases in blood flow tortuosity (Figure 2C). Conclusion These data suggest that a rapid reduction in skeletal muscle insulin delivery contributes to the induction of insulin resistance during sepsis. Additionally, we determined that protecting the endothelium from inflammation prevents altered microvascular flow during sepsis. Support or Funding Informati...

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Hyperinsulinemia compensates for infection-induced impairment in net hepatic glucose uptake during TPN

Cited by 10 publications

References 23 publications

Fructose augments infection-impaired net hepatic glucose uptake during TPN administration

Fructose augments infection-impaired net hepatic glucose uptake during TPN administration

Impact of chronic fructose infusion on hepatic metabolism during TPN administration

Rapid changes in the microvascular circulation of skeletal muscle impair insulin delivery during sepsis

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