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Evidence against Pathway-Selective Hepatic Insulin Resistance in Mice

Insulin suppresses hepatic glucose production and increases hepatic de novo lipogenesis (DNL). Paradoxically, hepatic DNL remains elevated in insulin-resistant subjects, leading to the hypothesis that hepatic insulin resistance is pathway-selective. Prior studies of DNL in hepatic insulin resistance are complicated by confounders, such as use of markedly unphysiologic animal models or comparison of animals on different diets and thus different availability of DNL precursors. We measured DNL in InsrT1150A knockin (KI) mice, a strain protected from diacylglycerol-mediated hepatic insulin resistance, and in littermate controls. Diets were matched: 60% high fat diet (HFD) with 1% dextrose in drinking water. After two days of fat-feeding, before the development of significant insulin resistance, KI and WT mice displayed similar rates of DNL (KI 24.3% ± 3.6; WT 22.2% ± 3.5). After 9 days of HFD, when WT but not KI mice have developed hepatic insulin resistance, rates of DNL were reduced in WT mice but preserved in KI mice (KI 16.4% ± 2.4; WT 7.4% ± 1.3; P Conclusion: Regulation of DNL is subject to lipid-induced hepatic insulin resistance, challenging the selective hepatic insulin resistance hypothesis. Increased DNL seen in insulin resistant subjects may be due to hyperinsulinemia and diversion of substrate from the insulin resistant periphery. Disclosure D.F. Vatner: None. M.C. Petersen: None. X. Li: None. J.C. Rogers: None. G. Cline: None. V. Samuel: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..