In vivo evidence for hepatic autoregulation during FFA-stimulated gluconeogenesis in normal humans

Abstract

To examine the effect of increased gluconeogenesis [by increasing free fatty acids (FFA)] on hepatic glucose output (HGO) and on the first substrate (glucose) cycle, a primed continuous infusion of [2-3H]- and [6-14C]glucose was infused to isotopic steady state in 12 normal male volunteers after an overnight fast. Blood samples for the determination of glucose specific activity were obtained before and after an infusion of saline (n = 6) or 10% Intralipid and heparin (90 mU.kg-1.min-1, n = 6). Plasma FFA (593.3 +/- 74.5 to 971.1 +/- 127.1 mumol/l, P = 0.007) and glycerol (68.0 +/- 5.9 vs. 222.4 +/- 32.0 mumol/l, P = 0.002) increased during the lipid infusion, and beta-hydroxybutyrate levels rose from 0.24 +/- 0.12 to 0.50 +/- 0.17 mmol/l (P = 0.01). No change in plasma glucose, insulin, or glucagon levels was observed during the study, and levels of the gluconeogenic substrates alanine and lactate were also unchanged. Baseline rates of glucose cycling (rate of appearance of [2-3H]glucose minus rate of appearance of [6-14C]glucose) were similar in the two groups [1.44 +/- 0.33 vs. 1.33 +/- 0.44 mumol.kg-1.min-1, not significant (NS)] and did not change during either saline or lipid infusion, respectively. However, Cori cycle activity (the conversion of [6-14C]- to [1-14C]glucose) increased significantly from 0.59 +/- 0.19 to 1.28 +/- 0.19 mumol.kg-1.min-1 (P = 0.002) after FFA and glycerol levels had been increased, in marked contrast to the saline control (0.51 +/- 0.18 to 0.39 +/- 0.18 mumol.kg-1.min-1, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

The biochemical basis of increased hepatic glucose production in a mouse model of type 2 (non-insulin-dependent) diabetes mellitus

“…It has been suggested that increased gluconeogenesis would not result in increased HGP since infusion of intralipid [47] or lactate [48] in healthy subjects has been shown to increase the rate of gluconeogenesis without increasing HGR This has been interpreted as showing autoregulation of HGP by the liver. In the NZO mouse however, increased gluconeogenesis is associated with increased HGR This does not necessarily indicate the failure of an autoregulatory mechanism.…”

Effects of Free Fatty Acids and Glycerol on Splanchnic Glucose Metabolism and Insulin Extraction in Nondiabetic Humans

“…The ability of FFAs to stimulate gluconeogenesis is well established (37)(38)(39). However, the effects of FFAs on hepatic glucose release are less certain.…”

“…However, the effects of FFAs on hepatic glucose release are less certain. Most (10,15,16,22,40), but not all (39), studies indicate that elevated FFAs impair insulin-induced suppression of endogenous glucose production. Although the liver is generally assumed to be the source of the increased glucose release, this has yet to be established in humans because only the effects of FFAs on total-body (commonly referred to as endogenous) glucose production has been measured.…”

Role of substrate competition in the pathogenesis of insulin resistance in man

“…These effects of lipid substrates have also been observed in vivo in humans. Infusion of a triglyceride emulsion stimulated gluconeogenesis from lactate in healthy volunteers (50). However, as observed during infusion of gluconeogenic substrates, such a stimulation of gluconeogenesis failed to stimulate endogenous glucose production.…”