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A new Novo Nordisk project paper has uncovered the role of ACC1 enzyme in the regulation of glucagon secretion for the first time. This raises the prospect of a potential new therapeutic target in the context of type 2 diabetes and metabolic disorders characterised by hyperglycaemia.

Side by side pancreatic islets demonstrating prevalence of glucagon in normal animals and heavily reduced glucagon when ACC1 is knocked out.
Pancreatic islets stained for insulin (red) and glucagon (green) - glucagon is more prevalent in left hand islet (control animals) vs the right hand islet (KO animals) where ACC1 is knocked out

Tight regulation of blood glucose is essential for metabolic homeostasis. This is closely regulated by the interplay between two counterbalancing hormones: beta cell secreted insulin and alpha cell secreted glucagon. Insulin is released to stop blood sugar levels rising too high (hyperglycaemia) whereas glucagon is released to stop blood sugar levels dropping too low (hypoglycaemia). Poorly regulated glucagon secretion from pancreatic alpha cells is a key feature of both type-1 and type-2 diabetes (T1D and T2D). We have a good understanding of beta cell biology, so the management of insulin in diabetes is well understood and long-established in treatment. However, while glucagon is equally essential to maintaining safe glucose levels in the body, alpha cells remain a mystery. Alpha cells are a minority population in a minority group of cells in the pancreas, the islets of Langerhans, which comprise only 1-2% compared to the larger exocrine region of the organ. Consequently, this poses a major technical challenge when studying alpha cells resulting in fewer research advances in the field.

A new study led by Dr Anna Veprik and Novo Nordisk project leaders Associate Professor Heidi de Wet and Dr James Cantley has uncovered the essential role of the enzyme Acetyl-CoA-Carboxylase 1 (ACC1) in the function of pancreatic alpha cells and glucagon secretion. After an influx of nutrients enters the body following feeding, ACC1 is the first step in pathway called ‘de-novo lipogenesis’, which converts the available glucose from the nutrients into lipids to be stored for future use. In contrast to the hepatocytes of the liver, alpha cells in the pancreas are not known for substantial lipid storage. The research shows that ACC1 is acting as a central ‘nutrient availability sensor’ for the alpha cells, which is used to calculate the right amount of glucagon that needs to be released.

Researchers have presented both in vivo and in vitro data demonstrating a critical role for ACC1-coupled metabolic signalling in glucagon and glucagon-like peptide-1 (GLP-1) secretion. They found that knocking out ACC1 reduces glucose induced glucagon inhibition and the prevalence of glucagon. As secretion of glucagon prevents blood glucose levels from dropping during periods of fasting, loss of ACC1 reduced glucagon secretion, resulting in impaired metabolic homeostasis in mice with ACC1 knocked out.

First author Dr Veprik said: “Our use of both primary islets and transformed αTC9 alpha-cells, with ACC1 disrupted using either chronic tissue-specific gene knockout approaches or acute small-molecule inhibition, provided clear and consistent evidence for the intrinsic role played by ACC1 in alpha-cell function: in all models, loss of ACC1 activity prevents the increase in glucagon secretion triggered by low glucose. We provided further mechanistic insights, by identifying that KATP channel conductance at low glucose is impaired in primary gluACC1KO or TOFA-treated alpha cells, explaining why these cells do not respond to hypoglycaemia.”

“Glucagon is so essential for our survival that while there is more than one mechanism regulating its secretion, this is a big addition to our knowledge. In the past, we were much more likely to be in a fasted state, so maintaining blood glucose level was crucial to survival. It’s only now in modern life that we have food excess and suddenly we lack insulin, making us more prone to hyperglycaemia. As hyperglycaemia is associated with T2D and other metabolic disorders, our study raises the prospect of targeting the ACC1-pathway in alpha-cells as a therapeutic strategy to better control glucagon secretion, and thus lower blood sugar levels in hyperglycaemic patients.”

The full paper “Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion” is available to read in Communications Biology. An ongoing conversation about the paper can be followed on Twitter.

The study was carried out between DPAG, the Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), and the University of Dundee, performed as part of the Oxford Novo Nordisk fellowship hosted in the de Wet (DPAG) and Cantley (Dundee) groups, with experimental work also performed at the Novo Nordisk Research Centre Oxford.

Prof de Wet said: "This is one of the aspects I enjoyed most about this specific study – the fact that we were able to use expertise established in laboratories which specialize in the use of specific technically demanding techniques not readily available to everyone. This allowed us to really dig down into the underlaying mechanism of ACC1 function in alpha cells."

Dr Veprik said: “The academic-industrial collaboration benefited us by granting access to highly specialised equipment and support of the industrial side of science and their unique point of view and ways of working.” Dr Veprik is now working as a Postdoctoral Researcher at the Novo Nordisk Centre Oxford and continues her work in diabetes, developing novel approaches for genome wide CRISPR screens identifying genes involved in hepatic insulin resistance.

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