Abstract
Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans. Narrative review. Increased endogenous or administered FFAs induce insulin resistance. FFAs effects on insulin secretion are debatable; inhibition and stimulation have been reported, depending on the type and duration of lipids exposition and the study subjects. Chronically elevated FFAs seem to decrease insulin biosynthesis, glucose-stimulated insulin secretion and β-cell glucose sensitivity. Lipids infusion decreases the response to incretins with unchanged incretin levels in volunteers with normal glucose tolerance. In contrast, FFAs reduction by acipimox did not restore the incretin effect in type-2 diabetes, probably due to the dysfunctional β-cell. Possible mechanisms of FFAs excess on incretin effect include reduction of the expression and levels of GLP-1 (glucagon like peptide-1) receptor, reduction of connexin-36 expression thus the coordinated secretory activity in response to GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) receptors downregulation in islets cells. Increased circulating FFAs impair insulin sensitivity. Effects on insulin secretion are complex and controversial. Deleterious effects on the incretin-induced potentiation of insulin secretion were reported. More investigation is needed to better understand the extent and mechanisms of β-cell impairment and insulin resistance induced by increased FFAs and how to prevent them.
Highlights
The high incidence of type 2 diabetes, T2D, in western countries has been attributed to the obesity epidemic and physical inactivity
As discussed below one of the mechanisms implicated in the impaired incretin effect in diabetes might be the FFAs excess
As long as one of the incretins effects is the potentiation of insulin secretion, we investigated in volunteers with normal glucose tolerance, whether incretin-induced insulin secretion is reduced by an acute elevation of plasma lipids, and if an acute reduction of them is able to improve the incretin effect in patients with T2D [76]
Summary
The high incidence of type 2 diabetes, T2D, in western countries has been attributed to the obesity epidemic and physical inactivity. Insulin resistance is an important factor and has been reported in the liver, muscle and adipose tissue It is found even in T2D first-degree relatives before obesity and hyperglycemia [2] suggesting a causal role. FFAs effect on β-cell and on incretin actions contribute to muscle insulin resistance [4]. The increased circulating bacterial endotoxin contributes to inflammation in both obesity and diabetes This is suggested as an additional factor for insulin resistance and impaired insulin secretion [4,5]. Adipose tissue resistance to the antilipolytic insulin effect is frequent in T2D, impaired glucose tolerance, and centripetal obesity This condition contributes to adipose tissue high lipid turnover, thereby increases plasma FFAs availability and concentration at fasting and after glucose or mixed meal ingestion [6]. A few animal studies were included to explain some hypotheses and mechanisms
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