"Glucose and insulin stimulate DNL in insulin-sensitive subjects while failing to stimulate incremental DNL in insulin-resistant subjects; fructose stimulated DNL equally in insulin-sensitive and insulin-resistant subjects"
Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease

https://doi.org/10.2337/dc20-1644

#MetabolicSyndrome #InsulinResistance #NAFLD #Obesity
Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease

OBJECTIVE Both glucose and triglyceride production are increased in type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical...

https://doi.org/10.2337/dc20-1644
- "Taken together, our data provide experimental evidence against the pathwayselective hepatic insulin resistance hypothesis. In humans, hepatic DNL and insulin resistance travel together...
"...Hepatic DNL is increased in patients with NAFLD...

Refs:
https://doi.org/10.1053/j.gastro.2013.11.049
https://doi.org/10.1172/jci23621
Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals With Nonalcoholic Fatty...

There have been few studies of the role of de novo lipogenesis in the development of nonalcoholic fatty liver disease (NAFLD). We used isotope analyse…

https://doi.org/10.1053/j.gastro.2013.11.049
"... and increased in subjects with peripheral insulin resistance...

Refs:
https://doi.org/10.2337/db12-0206 https://doi.org/10.1073/pnas.1110105108
Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogene...

Skeletal muscle insulin resistance has been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and atherogenic dyslipidemia associated with the metabolic syndrome by altering...

https://doi.org/10.2337/db12-0206
"... More recently, the relationship between hepatic DNL and insulin resistance was shown to hold across a continuum of subjects with varying degrees of insulin sensitivity

Ref:
https://doi.org/10.1172/jci134165
"...In that wellconducted study, hepatic DNL was not only inversely related to hepatic and whole-body insulin sensitivity but also directly related to 24-h plasma glucose and insulin concentrations...
"...suggesting that increased glucose and/or insulin concentrations (in the context of insulin resistance) may stimulate hepatic DNL in subjects with NAFLD"
- "Our study extends those findings... The data indicate that obese individuals with resistance to insulin’s ability to suppress hepatic glucose production also have resistance to insulin’s ability to stimulate hepatic DNL...
"...Moreover, supporting an alternative explanation for increased DNL, we found that hepatic ChREBP was constitutively more active in individuals with NAFLD...
"...Because ChREBP activity is a readout for intrahepatic carbohydrate availability, hepatic exposure to lipogenic substrate may largely explain the increased overnight DNL observed in NAFLD, and simple substrate push could explain acute changes in lipogenic flux"
- "In conclusion, this series of translational experiments demonstrates that humans with NAFLD have 1) hepatic and extrahepatic insulin resistance, 2) attenuated hepatic insulin signaling at the level of the insulin receptor...
"...3) reduced glucose-stimulated/insulin-mediated DNL, 4) intact fructose-stimulated DNL under low-insulin conditions, and 5) constitutively elevated hepatic ChREBP expression with increased overnight DNL...
"...Taken together, increased hepatic DNL in obese humans with NAFLD may be better explained by increased substrate availability rather than by an increase in incremental hepatocellular insulin action...
"...In the end, increased DNL in the insulin-resistant patient is no paradox at all."
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