Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass

Abstract

Aims/hypothesisPancreatic beta cells secrete insulin to maintain glucose homeostasis, and beta cell failure is a hallmark of type 2 diabetes. Glucose triggers insulin secretion in beta cells via oxidative mitochondrial pathways. However, it also feeds mitochondrial anaplerotic pathways, driving citrate export and cytosolic malonyl-CoA production by the acetyl-CoA carboxylase 1 (ACC1) enzyme. This pathway has been proposed as an alternative glucose-sensing mechanism, supported mainly by in vitro data. Here, we sought to address the role of the beta cell ACC1-coupled pathway in insulin secretion and glucose homeostasis in vivo.MethodsAcaca, encoding ACC1 (the principal ACC isoform in islets), was deleted in beta cells of mice using the Cre/loxP system. Acaca floxed mice were crossed with Ins2cre mice (βACC1KO; life-long beta cell gene deletion) or Pdx1creER mice (tmx-βACC1KO; inducible gene deletion in adult beta cells). Beta cell function was assessed using in vivo metabolic physiology and ex vivo islet experiments. Beta cell mass was analysed using histological techniques.ResultsβACC1KO and tmx-βACC1KO mice were glucose intolerant and had defective insulin secretion in vivo. Isolated islet studies identified impaired insulin secretion from beta cells, independent of changes in the abundance of neutral lipids previously implicated as amplification signals. Pancreatic morphometry unexpectedly revealed reduced beta cell size in βACC1KO mice but not in tmx-βACC1KO mice, with decreased levels of proteins involved in the mechanistic target of rapamycin kinase (mTOR)-dependent protein translation pathway underpinning this effect.Conclusions/interpretationOur study demonstrates that the beta cell ACC1-coupled pathway is critical for insulin secretion in vivo and ex vivo and that it is indispensable for glucose homeostasis. We further reveal a role for ACC1 in controlling beta cell growth prior to adulthood.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4743-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Lipid-associated metabolic signalling networks in pancreatic beta cell function

“…Unfortunately, they measured these variables at a concentration of glucose where secretion was unchanged (20 mmol/l) and they did not show under their experimental condition that high glucose itself was able to inhibit fat oxidation, as anticipated. Interestingly, this study reported a novel role of ACC1 related to the control of beta cell mass prior to adulthood [60].…”

“…Acc1-knockout and -knockin mice A recent study employing beta cell-specific Acc1 (also known as Acaca)-knockout mice demonstrated that ACC1 is critical for GSIS [60]. Interestingly, ex vivo islet studies showed that the reduced secretion occurs at low and intermediate glucose concentrations and that the inhibitory effect was overridden at high (20 mmol/l) glucose.…”

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

“…Moreover, there is also concern that RIP‐Cre may affect GSIS in mice. Some studies indeed showed that RIP‐Cre showed impaired glucose tolerance and GSIS because some transgenic lines using Ins2 and PDX1 promoter fragments triggered Cre expression not only in islet β cells, but also in the brain . However, other researches also showed that RIP‐Cre does not affect gene express in the hypothalamus and other tissues .…”

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

“…1). 26,38 It has been proposed that malonyl-CoA impacts GSIS in beta cells by its well-known function as a suppressor of carnitine palmitoyl transferase 1 (CPT1). 36,37 In beta cells, a function of malonyl-CoA appears to be integrated into the regulation of GSIS; beta cellspecific knockout of ACC1 impairs insulin secretion both in vivo and in vitro.…”

“…36,37 In beta cells, a function of malonyl-CoA appears to be integrated into the regulation of GSIS; beta cellspecific knockout of ACC1 impairs insulin secretion both in vivo and in vitro. 26,38 It has been proposed that malonyl-CoA impacts GSIS in beta cells by its well-known function as a suppressor of carnitine palmitoyl transferase 1 (CPT1). Metabolic labeling of beta cells has confirmed that fatty acid oxidation is reduced upon glucose loading in beta cells, and blockade of beta-oxidation by etomoxir (CPT1 inhibitor) does not impair GSIS, indicating that beta-oxidation does not provide energy source for GSIS.…”