Early initiation of low-level parenteral dextrose induces an accelerated diabetic phenotype in septic C57BL/6J mice

Abstract

Development of hyperglycemia during sepsis is associated with increased morbidity and mortality. Nutritional support is common practice in the intensive care unit, but the metabolic effects are not well understood. The purpose of this study is to determine the effect of early low-level calorie provision on the development of hyperglycemia in a clinically relevant murine model of sepsis. C57BL/6J mice underwent femoral arterial and venous catheterization followed by cecal ligation and puncture (CLP) or sham surgery and low-dose intravenous dextrose or saline infusion. Blood glucose, plasma insulin, and cytokines were measured after 24 h. Additional septic mice underwent hyperinsulinemic-euglycemic clamps or received intravenous insulin concurrent with dextrose to determine whole-body insulin sensitivity and test the efficacy of insulin to reverse hyperglycemia. Neither dextrose infusion nor CLP alone induced hyperglycemia. Early initiation of low-level dextrose in septic mice produced a variable glycemic response: 49% maintained euglycemia (blood glucose <200) and 27% developed severe hyperglycemia (blood glucose≥600). Hyperglycemia was associated with increased inflammation and reduced insulin secretion and sensitivity compared with control mice or CLP mice maintaining euglycemia. Insulin prevented the progression to severe hyperglycemia but was ineffective in reestablishing glycemic control once hyperglycemia had developed. In conclusion, early initiation of clinically relevant low-level dextrose (~20% daily caloric requirements) precipitated hyperglycemia akin to an acute diabetic phenotype in septic mice characterized by decreased insulin sensitivity, decreased insulin secretion, and an increased inflammatory response.

Glucose homeostasis in two degrees of sepsis lethality induced by caecum ligation and puncture in mice

“…; Singamsetty et al . ). Although the absence of any therapeutic manipulation (i.e., antibiotics, parenteral nutrition) impedes a more reliable translation of our data into a clinical context, we aimed to evaluate glucose homeostasis during the disease progression without therapeutic manipulation to avoid any confounding factors to study the disease in a more reliable pathophysiological context.…”

“…However, it seems to be not the factor behind hypoglycaemia, as CLP groups also showed a significant lethality‐dependent reduction in insulin sensitivity that reduces glucose disposal, as demonstrated by clamp studies in a similar murine CLP model at 22 h after surgery (Singamsetty et al . ). Downregulation of the insulin signalling pathway is demonstrated in adipocytes (Igarashi et al .…”

“…; Singamsetty et al . ). Although our ITT data revealed a reduction in the peripheral insulin sensitivity, we did not evaluate which tissue is involved in the reduction in the insulin response.…”

“…The gold standard preclinical model for studying sepsisrelated mechanisms is the caecum ligation and puncture Hypermetabolic sepsis stage involves increased circulating levels of catecholamines (Hahn et al 1995), corticosterone (Tang et al 1998) and glucagon (Yelich 1990) leading to enhanced gluconeogenesis and hyperglycaemia. This initial stage is followed by a hypodynamic and hypometabolic stage, which is related to decreased tissue perfusion, increased total peripheral vascular resistance and hypoglycaemia (Yelich 1990;Hahn et al 1995;Tang et al 1998;Maitra et al 2000;Heuer et al 2004;Sordi et al 2011;Singamsetty et al 2016;Yamashita et al 2017). With the progression of sepsis installation in rodents (from hypermetabolic to hypometabolic stages), that varies between 16 and 24 h post-CLP procedure, blood glucose may be found slightly increased (Igarashi et al 1992), unchanged (Kelleher et al 1982) or reduced (Maitra et al 2000;Heuer et al 2004;Sordi et al 2011;Singamsetty et al 2016;Yamashita et al 2017).…”

Pancreatic Islet Responses to Metabolic Trauma

“…This appears to be due to the combination of a glucose challenge on top of severe systemic inflammation, because LPS or glucose alone do not create metabolic dysfunction. A key component of this model is that induction of hyperglycemia appears to require the presence of inflammation and reduced insulin secretion (94). These studies, using a clinically relevant sepsis model in C57BL/6 mice, are consistent with previous work by our group and others showing that pro-inflammatory cytokine exposure impairs glucose-stimulated insulin secretion (95, 96).…”