Figure 2.

Triacylglycerol (TG) synthesis and lipolysis in beta cells. Fatty acids (FA) enter cells with or without the aid of facilitators and form FA-CoA.²⁷ Glucose transporter 1 and 2 mediate uptake of glucose into beta cells.⁶ Glycerol-3-phosphate (glycerol 3-p) generated from glucose undergoes sequential reactions mediated by glycerol-3-phosphate acyltransferase (GPAT) and 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) to attach two fatty acid chains to form phosphatidic acids at the endoplasmic reticulum (ER).¹²⁵ Phosphate of phosphatidic acids is removed by lipin to form 1,2-diacylglycerol (1,2-DAG). The addition of a third fatty acid chain to 1,2-DAG within the bilayer of the ER membrane by diacylglycerol transferase (DGAT) 1 and 2, or at lipid droplets (LD) by DGAT2 forms triacylglycerol (TG).¹²⁵ TG created within the bilayer of the ER membrane will bud off as LD or will be transferred to LD, as LD often maintain a connection with the (ER).¹²⁵ Thus, TG primarily resides in LD that are covered by a single phospholipid layer and studded with lipid metabolism enzymes and a perilipin family of lipid droplet proteins. Human beta cells express PLIN2, 3, and 5.¹³¹ Adipose triglyceride lipase (ATGL) is a major TG lipase that initiates lipolysis by removing FA from Sn1 or Sn2 position.⁴⁷ Hormone-sensitive lipase (HSL) has high activity against DAG and preferentially releases FA from Sn3.⁴⁷ In beta cells, membrane-bound ABHD6 is reported to function as a monoacylglycerol lipase and releases the last FA from monoacylglycerol (MAG).⁴⁹ FA being released can be secreted from beta cells and activate cell surface fatty acid receptors, such as FFAR1, or are converted to FA-CoA and reused for TG synthesis.⁶ *, Metabolites that have known targets to increase insulin secretion; **, metabolites that potentially increase insulin secretion but are not confirmed to be directly released from the ER; and ***, metabolites implicated for insulin secretion but that do not have confirmed targets.