A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

Abstract

Aims/hypothesis The enzyme hormone-sensitive lipase (HSL) is produced and is active in pancreatic beta cells. Because lipids are known to play a crucial role in normal control of insulin release and in the deterioration of beta cell function, as observed in type 2 diabetes, actions of HSL in beta cells may be critical. This notion has been addressed in different lines of HSL knockout mice with contradictory results. Methods To resolve this, we created a transgenic mouse lacking HSL specifically in beta cells, and characterised this model with regard to glucose metabolism and insulin secretion, using both in vivo and in vitro methods. Results We found that fasting basal plasma glucose levels were significantly elevated in mice lacking HSL in beta cells. An IVGTT at 12 weeks revealed a blunting of the initial insulin response to glucose with delayed elimination of the sugar. Additionally, arginine-stimulated insulin secretion was markedly diminished in vivo. Investigation of the exocytotic response in single HSL-deficient beta cells showed an impaired response to depolarisation of the plasma membrane. Beta cell mass and islet insulin content were increased, suggesting a compensatory mechanism, by which beta cells lacking HSL strive to maintain normoglycaemia. Conclusions/interpretation Based on these results, we suggest that HSL, which is located in close proximity of the secretory granules, may serve as provider of a lipidderived signal essential for normal insulin secretion.

Lysosomal acid lipase and lipophagy are constitutive negative regulators of glucose-stimulated insulin secretion from pancreatic beta cells

“…There is, however, residual lipase activity in mouse models of HSL and ATGL depletion, so additional enzymes may contribute to lipid hydrolysis in pancreatic beta cells [11,13]. To investigate lipase expression in the mouse pancreatic beta cell line, MIN6, we carried out RT-PCR (Fig.…”

“…One possibility focuses on the turnover of intracellular lipid stores [10,39]. Evidence for this comes from studies in which lipase activity is inhibited either pharmacologically [14] or in HSL [11,40] and ATGL [13] knockout mice, which show aberrant insulin secretion. Thus, while there is a key role for neutral lipases in GSIS, our study provides the first evidence that lysosomal lipid metabolism contributes as well, but in a very different manner.…”

“…The mechanisms underlying amplification are much less well understood than those of initiation [5][6][7][8] but the turnover of endogenous lipid stores, and consequent generation of a lipid signalling molecule, is one possibility [5,6,9,10]. Evidence for this includes the inhibition of GSIS by deletion of neutral lipases, such as hormone-sensitive lipase (HSL) [11,12] and adipose triglyceride lipase (ATGL) [13], or their pharmacological blockade using the pan lipase inhibitor orlistat [14]. In addition, at least one substrate of the neutral lipases, triacylglycerol (TG), is hydrolysed during GSIS, as witnessed by an acute glucose-stimulated, and orlistat-inhibited, release of glycerol from beta cells [9,15,16].…”

Monoacylglycerol as a Metabolic Coupling Factor in Glucose-Stimulated Insulin Secretion

“…However, the precise lipid molecule(s) or the enzyme involved has not been identified. Even though the role of HSL, which conducts DAG hydrolysis in the GL/FFA cycle, in insulin secretion has been debated (Mulder et al, 2003), Prentki group provided convincing evidence for the importance of HSL (Peyot et al, 2004;Roduit et al, 2001) in the regulation of GSIS both in vivo and in vitro and this has been confirmed recently by others (Fex et al, 2009) using -cell specific HSL-knockout mice. Specific inhibition of another DAG hydrolyzing enzyme, sn1-DAG lipase, by RHC80267 in -cells was also found to reduce GSIS (Guenifi et al, 2001;Konrad et al, 1994).…”

“…While some reports showed no influence on insulin secretion in HSL-KO mice other reports showed clear reduction in insulin secretion especially in fasted male mice (Mulder et al, 2003;Peyot et al, 2004). This discrepancy was resolved in the beta cell-specific HSL-knockout mice, which showed significantly reduced insulin secretion (Fex et al, 2009) During fasting (a), the ¦Â -cell triggering pathway of glucose signaling is inactive, ensuring that insulin secretion remains low even though FFA are elevated under this nutritional condition. Furthermore, FFA are preferentially oxidized rather than cycled, as the level of glucose-derived malonyl-CoA (MalCoA) is low.…”