Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion

Abstract

Dysregulated glucagon secretion from pancreatic alpha-cells is a key feature of type-1 and type-2 diabetes (T1D and T2D), yet our mechanistic understanding of alpha-cell function is underdeveloped relative to insulin-secreting beta-cells. Here we show that the enzyme acetyl-CoA-carboxylase 1 (ACC1), which couples glucose metabolism to lipogenesis, plays a key role in the regulation of glucagon secretion. Pharmacological inhibition of ACC1 in mouse islets or αTC9 cells impaired glucagon secretion at low glucose (1 mmol/l). Likewise, deletion of ACC1 in alpha-cells in mice reduced glucagon secretion at low glucose in isolated islets, and in response to fasting or insulin-induced hypoglycaemia in vivo. Electrophysiological recordings identified impaired KATP channel activity and P/Q- and L-type calcium currents in alpha-cells lacking ACC1, explaining the loss of glucose-sensing. ACC-dependent alterations in S-acylation of the KATP channel subunit, Kir6.2, were identified by acyl-biotin exchange assays. Histological analysis identified that loss of ACC1 caused a reduction in alpha-cell area of the pancreas, glucagon content and individual alpha-cell size, further impairing secretory capacity. Loss of ACC1 also reduced the release of glucagon-like peptide 1 (GLP-1) in primary gastrointestinal crypts. Together, these data reveal a role for the ACC1-coupled pathway in proglucagon-expressing nutrient-responsive endocrine cell function and systemic glucose homeostasis.

Genomic insights into the comorbidity between type 2 diabetes and schizophrenia

“…In cases of impaired ACC-alpha function, biotin supplementation can help support proper enzyme activity as a cofactor, leading to better overall metabolic health 74 . An ACC inhibitor was tested in a phase II clinical trial for type 2 diabetes and there is evidence that the ACC-alpha pathway in pancreatic alpha cells could be a therapeutic strategy in type 2 diabetes by limiting glucagon secretion 75 .…”

Structurally Diverse Triterpene-26-oic Acids as Potential Dual ACL and ACC1 Inhibitors from the Vulnerable Conifer Keteleeria fortunei

“…ACL is an important enzyme linking carbohydrate to lipid metabolism by converting citrate to acetyl-CoA, ,, while ACC1 is also a potential biomarker and target for the regulation of fatty acid synthesis. , Nowadays, novel ACL/ACC1 inhibitors are in great demand for the discovery of new therapeutic agents, especially those with dual inhibitory effects. ,− Continuing with our previous work, ,− ACL/ACC1 inhibitory activities of all the isolates were investigated. Among them, compounds 2 , 7 , 9 , 12 , and 14 exhibited dual inhibitory effects against ACL (IC 50 : 5.7 to 11.4 μM) and ACC1 (IC 50 : 7.5 to 10.5 μM), as depicted in Table .…”

“…A series of key enzymes targeting the regulation of glycolipid metabolism have been evaluated and identified, including ATP-citrate lyase (ACL) and acetyl-CoA carboxylase 1 (ACC1). − In 2020, bempedoic acid (a synthetic ACL inhibitor) was approved by the FDA for lipid-lowering therapy as the first and the only oral non-statin cholesterol lowering drug in the past two decades. − As for ACC1, some synthetic inhibitors (e.g., firsocostat, formerly ND-630, GS-0976) are under clinical trials. , Indeed, more structurally diverse ACL/ACC1 inhibitors are needed. ,, Nowadays, a promising pharmacological strategy for metabolic diseases is finding dual-target compounds. − A good example is tirzepatide, a dual glucose-dependent insulin insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist approved recently by the FDA in 2022 for the treatment of type 2 diabetes. , …”

Genomic insights into the comorbidity between type 2 diabetes and schizophrenia

“…In cases of impaired ACC-alpha function, biotin supplementation can help support proper enzyme activity as a cofactor, leading to better overall metabolic health 92 . An ACC inhibitor was tested in a phase II clinical trial for type 2 diabetes and there is evidence that the ACC-alpha pathway in pancreatic alpha cells could be a therapeutic strategy in type 2 diabetes by limiting glucagon secretion 93 .…”