FFAInduced Insulin Resistance Early Studies

In 1963, Randle et al. (153) demonstrated that incubation of rat muscle with fatty acids diminished insulin-stimulated glucose uptake. They proposed a "glucose fatty-acid cycle" (better known later as the Randle cycle) that revolved around the notion that cardiac and skeletal (diaphragm) muscle could shift readily back and forth between carbohydrate and fat as sources of energy for oxidation, depending on substrate availability. In its original formulation of the Randle cycle, oxidation of fatty acids led to inhibition of the Krebs cycle and glucose oxidation, impairing glycolytic flux, and eventually leading to product inhibition of hexokinase function and glucose transport. More specifically, fat oxidation in muscle led to substrate accumulation of acetylCoA and citrate, which inhibited both pyruvate dehydrogenase (PDH) and phosphofructokinase (PFK), respectively. As a consequence of this inhibition, glucose-6-phosphate (G-6-P) would increase within the cell and inhibit hexokinase, which led to a reduction in glucose transport. A decrease in glucose transport would also impair gly-cogen synthesis.

As such, the theory was incredibly attractive to help explain defects in both pathways reported in T2DM. Early studies in healthy humans appeared to support this notion (143, 154-159), as they demonstrated that a lipid infusion that increased plasma FFA, or just kept FFA constant during an infusion of insulin, inhibited glucose oxidation and/or impaired insulin-stimulated glucose uptake. Additional support came from observations in which lipid infusion increased approximately four- to fivefold muscle acetyl-CoA content and the acetyl CoA/freeCoA ratio (160) and inhibited muscle pyruvate dehydrogenase activity (160, 161), as would be expected from elevated muscle acetyl-CoA levels.

However, in the early 1990s other mechanisms also appeared to play a role. For example, overnight hyperglycemia (plasma glucose clamped at ~180 mg/dL) prevented FFA-induced insulin resistance, an unexpected and rather puzzling finding if the glucose fatty-acid cycle was the basis for insulin resistance in T2DM (162, 163). Additional studies suggested a direct effect of FFA on early steps of glucose metabolism (i.e., at the level of glucose transport and/or phosphorylation), and reported a discordance between the rapid FFA-induced reduction in glucose oxidation and the delay in the inhibition of insulin-stimulated glucose uptake (164), as well as by inconsistencies in the temporal inhibition by FFAs of glucose uptake, glycogen synthesis, and glycolysis (160, 163) . Subsequent studies could not find the expected rise (based on the Randle hypothesis) in skeletal muscle G-6-P concentration at a time when lipid infusion had already decreased insulin-stimulated glucose uptake (165-168).

Another important contradiction to the glucose fatty-acid cycle was the "metabolic inflexibility" observed in obese and T2DM subjects, in which they are unable to switch from fat to glucose oxidation to increase glucose uptake during insulin-stimulated conditions (fed state). In leg muscle of hyperglycemic T2DM subjects (133, 162) there was a substrate utilization "paradox" using leg (local) balance techniques that suggested that glucose oxidation was slightly increased in the fasting state (rather than decreased) and that the rate of fat oxidation during insulin stimulation was rather "fixed" with a lack of suppression to insulin, which would be the opposite of what would be expected by the glucose fatty-acid cycle hypothesis.

Taken together the above observations called for a broader view and clearly suggested that the glucose fatty-acid (Randle) cycle was inadequate to fully account for diminished insulin action by FFA. Likely, additional mechanisms were at play involving other than impaired glycolytic flux or accumulation of G-6-P regarding FFA-induced muscle insulin resistance in humans.

Impact of Lipotoxicity on Skeletal Muscle Insulin Signaling Excess FFA Induces Insulin Resistance by Impairing Insulin Signaling in Healthy Subjects

A series of studies have now suggested that FFA and triglyceride-derived metabolites from intramyocellular lipid accumulation directly disrupt early steps of insulin signaling (Fig. 2). Inhibition of insulin-stimulated muscle glucose transport has been reported by many laboratories both in vitro and in animal studies as fatty acid concentrations increase in the incubation medium or in plasma, respectively (133,169). Moreover, fatty acid lipotoxicity may be associated with mitochondrial deoxyribonucleic acid (DNA) fragmentation, caspase-3 cleavage, cytochrome-c release, and production of reactive oxygen species with subsequent apoptosis in L6 rat skeletal muscle (170). In humans, FFA

glucose

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glucose

Insulin Q Q

T IMCL T ceramide T DAG

T other toxic lipid metabolites

Fig. 2. Free fatty acids induce skeletal muscle insulin resistance in humans by inhibition of insulin signaling.

T IMCL T ceramide T DAG

T other toxic lipid metabolites

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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