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J Endocrinol. 2019 Jun 1;241(3):189-199. doi: 10.1530/JOE-18-0566.

Glucose mediates insulin sensitivity via a hepatoportal mechanism in high-fat-fed rats.

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The University of Sydney, Charles Perkins Centre, School of Life and Environmental Sciences, Sydney, New South Wales, Australia.
The University of Sydney, Charles Perkins Centre, School of Medical Sciences, Sydney, New South Wales, Australia.


Poor nutrition plays a fundamental role in the development of insulin resistance, an underlying characteristic of type 2 diabetes. We have previously shown that high-fat diet-induced insulin resistance in rats can be ameliorated by a single glucose meal, but the mechanisms for this observation remain unresolved. To determine if this phenomenon is mediated by gut or hepatoportal factors, male Wistar rats were fed a high-fat diet for 3 weeks before receiving one of five interventions: high-fat meal, glucose gavage, high-glucose meal, systemic glucose infusion or portal glucose infusion. Insulin sensitivity was assessed the following day in conscious animals by a hyperinsulinaemic-euglycaemic clamp. An oral glucose load consistently improved insulin sensitivity in high-fat-fed rats, establishing the reproducibility of this model. A systemic infusion of a glucose load did not affect insulin sensitivity, indicating that the physiological response to oral glucose was not due solely to increased glucose turnover or withdrawal of dietary lipid. A portal infusion of glucose produced the largest improvement in insulin sensitivity, implicating a role for the hepatoportal region rather than the gastrointestinal tract in mediating the effect of glucose to improve lipid-induced insulin resistance. These results further deepen our understanding of the mechanism of glucose-mediated regulation of insulin sensitivity and provide new insight into the role of nutrition in whole body metabolism.


high-fat-fed rats; insulin resistance; metabolic adaptation; nutrition; portal vein


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