III. Metabolic signals

A. Metabolomics used as a tool to detect signals controlling insulin secretion
Metabolomics is the comprehensive profiling of metabolites at different scales (ie, cells, tissues, or whole organisms).42 This approach has undergone a rapid evolution during the last 20 years. When applied to beta cells, it allows for the detection of signals controlling insulin secretion.43 The current model is that glucose induces insulin secretion via its own glycolytic and oxidative metabolism, leading to an increase in the ATP:ADP ratio, inhibition of KATP channels, activation of voltage-gated Ca2+ channels, and influx of extracellular Ca2+ to stimulate insulin granule exocytosis. However, Christopher Newgard showed that a modified version of the central model has emerged in which the KATP channel–dependent pathway is the primary mediator of the triggering (or first phase) of insulin secretion and other signals are key drivers of the more prolonged amplifying (or second phase) of insulin secretion.44,45 In particular, the new glucose/isocitrate and S-AMP pathways of GSIS are viewed as complementary to the classic KATP channel–dependent initiating pathway.44 Whether these newly described pathways are additive or synergistic with each other and with the canonical KATP channel–dependent mechanism in terms of physiological response remains to be determined.43

B. Metabolic signals from lipid metabolism dysregulation control insulin secretion
As explained above, a number of lipid species are signalling molecules that can bind GPCRs at the beta cell plasma membrane. Marc Prentki stressed the point that intracellular lipid species are also important signalling modulators that can control the biological function of beta cells. Alterations in lipid homeostasis could lead to chronic pathologies, such as obesity and diabetes.46,47 Glucose and nonesterified fatty acid (NEFA) metabolism interface into the glycerolipid/NEFA cycle using its lipogenic and lipolytic arms (Figure 6). Lipolysis is mediated by the consecutive actions of (i) adipose triglyceride lipase (ATGL),9 which catalyzes the conversion of triglycerides to diacylglycerols (DAGs), (ii) hormone-sensitive lipase, which hydrolyzes DAGs to monoacylglycerols (MAGs), and (iii) monoacylglycerol lipase and α/β-hydrolase domain-containing protein 6 (ABHD6), which hydrolyze MAGs to NEFA and glycerol.48

Several MAGs are only recently being recognized as signalling lipid molecules in different tissues. In particular, recent studies indicate the importance of the ubiquitously expressed serine hydrolase ABHD6, which can hydrolyze MAGs, in both central and peripheral tissues, including in β-cells.49 Zhao et al showed that deletion of the ABHD6 gene (either whole body or β-cell specific) leads to an increase in GSIS that is due to the binding of MAGs to the exocytic effector Munc13-1, resulting in insulin secretion (Figure 6).49

Targeting ATGL in the islets is also of interest because β-cell–specific ATGL knockout mice showed decreased insulinemia and GSIS under chow diet or a high-fat diet, which was associated with enhanced insulin sensitivity. These findings led to the conclusion that the islet beta cell ATGL–lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion.48