Insulin resistance is the primary characteristic underlying the development of type 2 diabetes mellitus. We have previously shown that high-fat diet-induced insulin resistance in rats can be ameliorated by a single glucose meal, but the mechanism has yet to be elucidated. To test whether this improvement in insulin sensitivity was dependent on delivery via the gastrointestinal tract, we administered glucose to high-fat fed rats either as a meal or as an infusion to either the jugular or portal vein.

Male wistar rats were fed a lard based high-fat diet (45% of energy as saturated fat) for three weeks. Two jugular vein cannula and a portal vein cannula were placed surgically at two weeks. Insulin sensitivity was assessed at three weeks using the hyperinsulinemic-euglycemic clamp technique. The evening prior to the clamp, rats were divided into four groups and received either isocaloric meals of high-fat (HF) or high-glucose (OG) diet, or a glucose infusion via the jugular vein (IVG) or portal vein (PG).

Body weight, clamped plasma glucose and insulin levels were not different between groups. HF rats and jugular infusion rats (IVG) had low GIRs (16.47 ± 0.68 and 16.48 ± 0.55 mg/kg/min respectively) indicative of insulin resistance. The OG rats fed a single glucose meal had a significantly higher GIR than both the HF and IVG rats (GIR 19.77 ± 0.64, p<0.05 for both) indicating improved insulin sensitivity, consistent with previous work. The rats which received portal infusions (PG) had a significantly higher GIR (23.22 ± 1.04) than the HF and IVG rats (p<0.0001) and also the OG rats (p<0.05).

These results demonstrate that the glucose-mediated reversal of insulin resistance in high-fat fed rats is mediated by factors relating to the hepatoportal system, and less likely to be the result of changes in gut hormones or microbiota.