cAMP (cyclic AMP): An intracellular signaling molecule that regulates a variety of cellular functions such as insulin secretion. PKC (Protein Kinase C): An enzyme that adds phosphoric acid to proteins (phosphorylation), thereby regulating various intracellular signals such as insulin secretion. Adapted version of the Graphical Abstract in the JCI paper (DOI: 10.1172/JCI140046)

An international research group has clarified the action mechanism of incretin-based drugs (*1) in the treatment of diabetes. The research group headed by Professor SEINO Susumu included Researcher Okechi Oduori et al. (Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine), Professor SHIMOMURA Kenju (Fukushima Medical University), Professor Patrik Rorsman (University of Oxford, UK/University of Gothenburg, Sweden), and their teams.

Incretin-based drugs are used worldwide in the treatment of diabetes and in Japan they are currently prescribed to 70% of diabetic patients. However, the mechanism by which incretin-based drugs improve blood glucose levels has been poorly understood.

The findings of the study were published online in the American Scientific Journal Journal of Clinical Investigation on November 16, 2020. A commentary on this paper by Professor Colin G. Nichols and his colleagues at Washington University, St Louis, has also been published.

Main Point

• This study revealed for the first time that Gs, a major G-protein signal in normal pancreatic β-cells (*2), is switched to another G-protein signal Gq in the diabetic β-cells to promote insulin secretion, and that incretin-based drugs act on this Gq to promote insulin secretion, thereby improving blood glucose levels.

Research Findings

Incretins are the gut hormones that are secreted by enteroendocrine cells after meal ingestion. The most important function of incretins is to promote insulin secretion from pancreatic β cells. GLP-1 and GIP are known as incretins.

While both GLP-1 and GIP are required to maintain normal blood glucose levels in healthy subjects, incretins in patients with type-2 diabetes (T2D) don’t function properly. To improve incretin action, incretin-based drugs are used for the treatment of T2D. However, the reason why these drugs are effective has remained unknown.

This research investigated the mechanism of insulin secretion by G-protein signaling in normal β cells and diabetic β cells. Until now, it has been well accepted that the G protein Gs functions as a major signal that promotes insulin secretion in normal β cells. The research group revealed that in diabetes, there is a switch from Gs to Gq signaling in the pancreatic β cells due to continuous β cell excitation (*4). Furthermore, the group discovered that incretin-based drugs act on Gq to amplify insulin secretion, thus improving blood glucose levels.

The Significance of this Research

The results of this research are important not only for illuminating the mechanism behind diabetes, but for diabetes therapies. They might also provide a basis for the development of new treatments.

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Glossary

1. Incretin-based drugs: These are drugs developed to treat diabetes, which act by amplifying blood glucose-dependent insulin secretion. DPP-4 inhibitors and GLP-1 receptor agonists are incretin-based drugs that are currently used.
2. β (Beta) cells: These cells are found in the islets of Langerhans in the pancreas and secrete insulin, which regulates blood glucose levels.
3. G proteins: Intracellular signaling molecules. Gs, Gq and Gi are among the known types of G proteins.
4. Cell excitation: It is known that β cells, nerve cells and muscle cells are electrically excitable.