Hepatic glucose production is more sensitive to insulin-mediated inhibition than hepatic VLDL-triglyceride production

Abstract

Insulin is an important inhibitor of both hepatic glucose output and hepatic VLDL-triglyceride (VLDL-TG) production. We investigated whether both processes are equally sensitive to insulin-mediated inhibition. To test this, we used euglycemic clamp studies with four increasing plasma concentrations of insulin in wild-type C57Bl/6 mice. By extrapolation, we estimated that half-maximal inhibition of hepatic glucose output and hepatic VLDL-TG production by insulin were obtained at plasma insulin levels of approximately 3.6 and approximately 6.8 ng/ml, respectively. In the same experiments, we measured that half-maximal decrease of plasma free fatty acid levels and half-maximal stimulation of peripheral glucose uptake were reached at plasma insulin levels of approximately 3.0 and approximately 6.0 ng/ml, respectively. We conclude that, compared with insulin sensitivity of hepatic glucose output, peripheral glucose uptake and hepatic VLDL-TG production are less sensitive to insulin.

Reduced insulin-mediated inhibition of VLDL secretion upon pharmacological activation of the liver X receptor in mice

“…Previous reports have shown effects of LXR activation on glucose metabolism in diabetic rodents (23)(24)(25). In the present study, we tested the effect of T0901317 on insulin-mediated changes in VLDL parameters.…”

“…In normal mice, acute insulin infusion reduces VLDL-TG production rate (24), albeit more insulin is needed to suppress VLDL secretion than hepatic glucose production (25). Studies performed in vitro have shown that insulin is able to inhibit VLDL release via acceleration of apoB degradation (26), and as a result, insulin reduces the number of VLDL particles secreted.…”

FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice

“…It is known that hepatic VLDL production depends on substrate availability, which is sensitive to insulin inhibition (7,(42)(43)(44). Such an inhibitory effect has been viewed as an acute mechanism to prime liver for rapid adaptation to metabolic shift from fasting to fed states.…”

“…While the pathophysiology of hypertriglyceridemia is poorly understood, its close association with visceral adiposity and type 2 diabetes implicates insulin resistance as a causative factor for hypertriglyceridemia (3)(4)(5). VLDL is assembled and produced in the liver, which depends on substrate availability and is sensitive to insulin inhibition (6,7). In visceral obesity and type 2 diabetes, aberrant insulin action in coalition with increased influx of FFAs into liver promotes excessive VLDL-TG production, contributing to the pathogenesis of hypertriglyceridemia (3,4,8).…”

High-fat diets rich in medium- versus long-chain fatty acids induce distinct patterns of tissue specific insulin resistance

“…Hyperinsulinemic euglycemic clamps were performed as described before [17][18][19][20][21], with minor modifications. Clamp experiments were performed after an overnight fast and under anesthesia by intraperitoneal injection with a combination of Acepromazin (0.5 mg/kg, Sanofi Santé Nutrition Animale, Libourne Cedex, France), Midazolam (0.25 mg/kg, Roche, Mijdrecht, The Netherlands) and Fentanyl (0.025 mg/kg, Janssen-Cilag, Tilburg, The Netherlands).…”