Abstract
Fatty acid (FA)-stimulated insulin secretion (FASIS) is reviewed here in contrast to type 2 diabetes etiology, resulting from FA overload, oxidative stress, intermediate hyperinsulinemia, and inflammation, all converging into insulin resistance. Focusing on pancreatic islet β-cells, we compare the physiological FA roles with the pathological ones. Considering FAs not as mere amplifiers of glucose-stimulated insulin secretion (GSIS), but as parallel insulin granule exocytosis inductors, partly independent of the KATP channel closure, we describe the FA initiating roles in the prediabetic state that is induced by retardations in the glycerol-3-phosphate (glucose)-promoted glycerol/FA cycle and by the impaired GPR40/FFA1 (free FA1) receptor pathway, specifically in its amplification by the redox-activated mitochondrial phospholipase, iPLA2γ. Also, excessive dietary FAs stimulate intestine enterocyte incretin secretion, further elevating GSIS, even at low glucose levels, thus contributing to diabetic hyperinsulinemia. With overnutrition and obesity, the FA overload causes impaired GSIS by metabolic dysbalance, paralleled by oxidative and metabolic stress, endoplasmic reticulum stress and numerous pro-apoptotic signaling, all leading to decreased β-cell survival. Lipotoxicity is exerted by saturated FAs, whereas ω-3 polyunsaturated FAs frequently exert antilipotoxic effects. FA-facilitated inflammation upon the recruitment of excess M1 macrophages into islets (over resolving M2 type), amplified by cytokine and chemokine secretion by β-cells, leads to an inevitable failure of pancreatic β-cells.
Highlights
The Janus face role of fatty acids (FAs) in relation to insulin secretion and the development of pre-diabetic and diabetic states of type 2 diabetes are discussed in this review
We summarize the simple fact that, on the one hand, the long chain C16–C18 FAs (LCFAs) are the most efficient stimulants of the insulin release in pancreatic β-cells [1,2], whereas, on the other hand, elevated LCFA
The LCFAs cleaved off the dietary fat stimulate the enterocyte GPR120/FFA4 receptor, inducing the secretion of incretins glucagon-like peptide 1 (GLP-1) [13] and glucose-dependent insulinotropic peptide (GIP) [14], both of which amplify the glucose-stimulated insulin secretion (GSIS) in β-cells via their receptors
Summary
The Janus face role of fatty acids (FAs) in relation to insulin secretion and the development of pre-diabetic and diabetic states of type 2 diabetes are discussed in this review. We summarize the simple fact that, on the one hand, the long chain C16–C18 FAs (LCFAs) are the most efficient stimulants of the insulin release in pancreatic β-cells [1,2], whereas, on the other hand, elevated LCFA concentrations in obesity via elevated oxidative stress and low-grade inflammation result in impaired insulin secretion and may lead to the disease progression of fully developed type 2 diabetes [3]. The direct effect of various FAs on β-cell function is complex and pleiotropic It depends on the chemical nature, concentration, exposure time, and interaction with other nutrients [4]. The molecules in focus will be long chain fatty acids
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