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Review
. 2020 Mar 6;432(5):1514-1534.
doi: 10.1016/j.jmb.2019.09.016. Epub 2019 Oct 16.

Recent Insights Into Mechanisms of β-Cell Lipo- and Glucolipotoxicity in Type 2 Diabetes

Maria Lytrivi  1 , Anne-Laure Castell  2 , Vincent Poitout  3 , Miriam Cnop  4
Affiliations
Review

Recent Insights Into Mechanisms of β-Cell Lipo- and Glucolipotoxicity in Type 2 Diabetes

Maria Lytrivi et al. J Mol Biol. .

Abstract

The deleterious effects of chronically elevated free fatty acid (FFA) levels on glucose homeostasis are referred to as lipotoxicity, and the concurrent exposure to high glucose may cause synergistic glucolipotoxicity. Lipo- and glucolipotoxicity have been studied for over 25 years. Here, we review the current evidence supporting the role of pancreatic β-cell lipo- and glucolipotoxicity in type 2 diabetes (T2D), including lipid-based interventions in humans, prospective epidemiological studies, and human genetic findings. In addition to total FFA quantity, the quality of FFAs (saturation and chain length) is a key determinant of lipotoxicity. We discuss in vitro and in vivo experimental models to investigate lipo- and glucolipotoxicity in β-cells and describe experimental pitfalls. Lipo- and glucolipotoxicity adversely affect many steps of the insulin production and secretion process. The molecular mechanisms underpinning lipo- and glucolipotoxic β-cell dysfunction and death comprise endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, impaired autophagy, and inflammation. Crosstalk between these stress pathways exists at multiple levels and may aggravate β-cell lipo- and glucolipotoxicity. Lipo- and glucolipotoxicity are therapeutic targets as several drugs impact the underlying stress responses in β-cells, potentially contributing to their glucose-lowering effects in T2D.

Keywords: Insulin; Islet; Lipotoxicity; Palmitate; Pancreatic β-cell.

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Figures

Figure 1:
Figure 1:. Types of FFAs and nomenclature.
FFAs can be categorized according to the length of the carbon chain (box), the presence of double bonds and the position of the first double bond. Depending on the presence of one or more double bonds, FFAs are classified into saturated (SFA), monounsaturated (MUFA) and polyunsaturated FFAs (PUFA). Depending on the position of the first double bond counting from the methyl end of the chain, FFAs are classified into omega-3, omega-6 etc. This figure does not provide an exhaustive list of common FFA names and symbols, but illustrates the FFAs mentioned in the text. Additional systems of FFA nomenclature exist.
Figure 2:
Figure 2:. FFA metabolic pathways.
Examples of FFA metabolic pathways, highlighting the action of elongases and desaturases, adapted from [204]. Elongases extend the chain of FFAs with two carbons. Stearoyl-coA desaturases (SCD) insert a double bond in saturated FFAs at position 9, counting from the carboxylic acid end (Δ9). Δ5- and Δ6-desaturases, designated as fatty acid desaturase 1 (FADS1) and 2 (FADS2) insert double bonds at positions Δ5 and Δ6, respectively. ACC: acetyl-CoA carboxylase; FASN: fatty acid synthase; ETA: eicosatetraenoic acid; EPA: eicosapentaenoic acid.
Figure 3:
Figure 3:. Impact of glucolipotoxicity on insulin production and secretion.
Glucose stimulates transcription of the insulin gene, pre-mRNA splicing, mRNA stability, proinsulin translation, protein maturation, and exocytosis. In contrast, lipo- and glucolipotoxic conditions have been shown to impair several of these steps. TF: transcription factor; +: stimulation; −: inhibition; 0: no effect; ?: not studied.
Figure 4:
Figure 4:. Signaling leading to the glucolipotoxic impairment of insulin gene transcription.
High glucose and the FFA palmitate stimulate ceramide production and activate the stress kinases JNK, ERK1/2 and PASK. These suppress the binding of the transcriptional regulators MafA, PDX1 and BETA2/NeuroD (B2) to the insulin promoter, in part through the activity of the transcriptional factors PGC1α and C/EBPβ. This results in decreased insulin transcription.
Figure 5:
Figure 5:. Effects of glucose on intracellular lipid metabolism in the β-cell.
In the presence of simultaneously elevated levels of glucose and FFAs, the increase in cytosolic malonyl-CoA resulting from glucose metabolism inhibits carnitine-palmitoyl transferase 1 (CPT-1). Transport of long-chain acyl-CoA (LC-CoA) in the mitochondria is blocked, and FFA metabolism is diverted towards the synthesis of lipid-derived signaling molecules such as sphingolipids, diacylglycerols (DG), phosphatidic acid (PA), phospholipids (PL) and triacylglycerols (TG). Adapted from [51] with permission.
Figure 6:
Figure 6:. Molecular mechanisms of lipo- and glucolipotoxic β-cell demise and potential treatments.
A prolonged increased FFA supply and/or unbalanced FFA composition, alone or in combination with high glucose, elicits stress responses in pancreatic β-cells. These include ER stress, oxidative stress with excessive ROS production, mitochondrial dysfunction, inflammation and impaired autophagic flux. Crosstalk between these pathways may give rise to feed-forward mechanisms, aggravating glucolipotoxic stress. Collectively, these phenomena culminate in β-cell dysfunction, apoptosis and possibly dedifferentiation. In vitro data suggest that metformin, GLP-1 analogs, thiazolidinediones and ER chaperones mitigate lipo- and glucolipotoxicity. These therapies (shown in red) target distinct stress pathways. The graphic illustrations used in this figure are from Servier Medical art (https://smart.servier.com).
Figure 7:
Figure 7:. Activation of ER stress pathways by palmitate.
Exposure of β-cells to palmitate induces aberrant protein palmitoylation and Ca2+ depletion in the ER, affecting ER folding capacity. The depletion of Ca2+ stores is aggravated by the downregulation of the sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) pump in high glucose conditions. In parallel, palmitate disrupts the export of cargo from the ER and trafficking to the Golgi, contributing to the buildup of unfolded or misfolded proteins. The misfolded proteins recruit the ER chaperone BiP, causing its dissociation from the luminal domain of the ER stress transducers PERK, IRE1 and ATF6. This, together with increased ER membrane lipid saturation, results in the activation of the ER stress transducers, eliciting downstream ER stress signaling. This in turn leads to the induction of the proapoptotic proteins CHOP, PUMA and DP5, the latter inhibiting anti-apoptotic members of the Bcl-2 family. These events culminate in mitochondrial permeabilization, cytochrome C release and mitochondrial apoptosis. Graphic elements used in this illustration come from Servier Medical art (https://smart.servier.com).
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