Mechanisms of insulin resistance during acute endotoxemia.

Abstract

We characterized the mechanisms underlying acute endotoxin-induced alterations in glucose metabolism and determined the extent to which catecholamines mediate these changes. Acute endotoxemia was induced in chronically catheterized awake rats by a bolus injection of lipopolysaccharide (LPS; 1 mg/kg; LD10). Basal glucose turnover (Rt; infusion of [5-3H]glucose), in vivo insulin action on overall glucose utilization (euglycemic clamp), glycolysis, and glycogen synthesis were determined in four groups of rats. These groups received 1) LPS (LPS rats; n = 6), 2) saline (control rats; n = 6), 3) LPS and alpha beta-blockade (alpha beta-blockade and LPS rats; n = 9), or 4) saline and alpha beta-blockade (alpha beta-blockade control rats; n = 9). In the basal state, LPS induced hypotension and transient hyperglycemia. These changes were associated with glycogen depletion in both skeletal muscle and liver, and increased Rt. During hyperinsulinemia, whole body glucose disposal was 37% decreased (105 vs. 166 mumol/kg.min; P < 0.01). This whole body insulin resistance was characterized by decreased glycogen synthesis and glycogen synthase activity, but not by altered whole body glycolysis. alpha beta-Blockade abolished transient hyperglycemia, increased Rt, and accelerated basal liver glycogen depletion (45 vs. 105 mmol/kg dry, LPS and alpha beta-blockade rats vs. LPS rats; P < 0.05), but inhibited muscle glycogenolysis. alpha beta-Blockade did not reverse the insulin resistance induced by endotoxin. These data suggest that catecholamines counteract the LPS-induced increase in basal glucose turnover and stimulate muscle glycogenolysis during acute endotoxemia. These effects might explain the better preservation of hepatic glycogen in the absence than in the presence of alpha beta-blockade and serve as a defense mechanism against hypoglycemia. Catecholamines do not seem to be the immediate causes of insulin resistance during acute endotoxemia.

Augmented Lipopolysaccharide-Induced TNF-α Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK

“…These findings confirm previous findings that LPS lowers blood glucose in animals and humans (35). Several mechanisms have been reported as to how LPS lowers blood glucose including enhanced systemic consumption of glucose (35), depletion of glycogen from liver and muscle (36), and impaired hepatic gluconeogenesis (37). Likely due to the extended time course of LPS-induced sickness in db/db mice (6), significant LPS-induced glucose lowering was seen in db/db mice at 8 h. Fig.…”

Effects of endotoxin lipopolysaccharide administration on the somatotropic axis

“…In our study insulin secretion was decreased after acute, but not during chronic LPS administration. Several alterations in carbohydrate metabolism have been described during acute endotoxemia, such as insulin resistance (Virkamaki & Yki-Järvinen 1994), reduced or increased plasma insulin and increased secretion of glucagon (Yki-Järvinen et al 1989, Bundz et al 1995. However, insulin and glycemia alterations last only 2-3 h.…”

Identification of a novel class of dithiolethiones that prevent hepatic insulin resistance via the adenosine monophosphate-activated protein kinase-p70 ribosomal S6 kinase-1 pathway

“…7A), consistent with a previous obser- vation. 17 Mice treated with oltipraz in combination with LPS displayed hypoglycemic responses versus LPS-treated controls. Moreover, oltipraz did not change normal blood glucose levels in animals not administered LPS.…”