Metabolic endotoxaemia in type 2 diabetes
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page264
2025-12-10
30
While the relationships between obesity, diet, and metabolic endotoxaemia have received particular attention, epidemiological data also implicate circulating endotoxin in risk for type 2 diabetes. Higher plasma LPS concentrations have been reported in both adults with impaired fasting glucose relative to healthy controls and those with overt type 2 diabetes. In addition, a larger analysis involving the FINRISK97 cohort of ~6600 Finnish adults found that circulating endotoxin concentrations at baseline were significantly higher in the individuals with type 2 diabetes and were predictive of those who developed overt type 2 diabetes over the 10- year follow- up period. Likewise, another prospective study, which quantified total 16s rDNA concentration present in the circulation, as a surrogate of intestinal permeability, at baseline and following nine years of follow- up, found that higher baseline concentrations were predictive of type 2 diabetes development over follow- up. Given these relationships, understanding the physiological responses to increased transit of microbial moieties across the gut mucosa may provide further insight into the pathogenesis of type 2 diabetes.
While the impact of sepsis on glucose metabolism has been established, ethical and logistical challenges mean that few studies have directly manipulated plasma LPS and/or the intestinal microbiota as a way to establish causality for type 2 diabetes. However, LPS infusion in a mouse model has been shown to induce changes in insulin sensitivity and glucose levels, supporting a causal role for metabolic endotoxaemia in type 2 diabetes development. Chronic low- dose subcutaneous LPS infusion (300 μg/ kg/d) over four weeks elicited increases in fasting glucose and insulin, impaired glucose clearance in response to an oral glucose load, and increased hepatic gluconeogenesis, all suggesting the loss of glycaemic control. In healthy humans, the acute effects of intravenous LPS infusion (20 U/kg ~2 ng/kg total dose) have been assessed during a 10- hour euglycaemic hyperinsulinaemic clamp protocol and significant reductions in glucose utilization were noted. Subsequent studies have also reported decreases in insulin sensitivity and increased insulin resistance in response to low- dose LPS infusion protocols, further implicating LPS as a causal factor in the development of insulin resistance.
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