Endocrine Abstracts

Background: Fasting hyperglycaemia and hypertriglyceridemia are characteristic of insulin resistance (IR), type 2 diabetes, and non-alcoholic fatty liver disease, but the underlying mechanisms remain unclear. Rodent work has suggested this is due to selective hepatic IR; defined by increased hepatic gluconeogenesis (GNG) and de novo lipogenesis (DNL). The aim of this study was to determine if signatures of selective hepatic IR were associated with hyperinsulinemia or liver fat content in humans.

Methods: 182 medication-free participants were classified as hyperinsulinemic or normoinsulinemic (HI or NI) and as having high or low liver fat (HF or LF). Magnetic resonance spectroscopy was used to measure liver fat content and stable isotope tracer methodology was used to measure fractional GNG and hepatic DNL following an overnight fast.

Results: HI and HF groups had higher fasting plasma glucose and triglyceride concentrations compared to the NI and LF groups, respectively. Despite this, there was no difference in fractional GNG between the HI and NI groups. HF compared to LF participants, tended (P=0.08) to have lower fractional GNG. HI participants had higher fasting hepatic DNL compared to NI participants (6.7 vs 5.0 %, P=0.013) but no difference was observed between the HF and LF groups. There was no association between fractional GNG and DNL across all participants (r=0.05, P=0.5).

Conclusions: Hepatic glucose production, from gluconeogenic and glycogenolytic pathways, contributes to hyperglycaemia in the fasting state and GNG is often suggested to be the major contributor. From our observations, both pathways appear to be equally upregulated in hyperinsulinemia but glycogenolysis may play a greater role in those with HF. DNL may contribute to hypertriglyceridemia in individuals with HI but not those with HF. Taken together, this suggests that selective hepatic IR may be driven more by hyperinsulinemia than liver fat content alone and glycogenolytic pathways should also be considered.