Why smokers have an increased risk of type 2.
Researchers at Lund University in Sweden have made two new discoveries with regard to the beta cells’ ability to release insulin. The study was conducted on mice and donated beta cells from humans, and is now published in the scientific journal Cell Reports.
The researchers have discovered that so-called nicotinic acetylcholine (nicotine-sensitive) receptors influence the normal release of insulin. They also show that a specific genetic alteration renders dysfunctional nicotine-receptors affecting the number of functional nicotine-sensitive receptors found in beta cells. A reduced number of functional receptors leads to a decrease in insulin secretion, thereby increasing the risk of developing type 2 diabetes.
“The receptors in the beta cells that stimulate the release of insulin are normally activated by the signal substance acetylcholine, but they can also be activated by nicotine. Never before has the importance of nicotine-sensitive receptors been shown in terms of the function of beta cells. Our research indicates that people who lack these receptors are at higher risk of developing type 2 diabetes,” says Isabella Artner, researcher at Lund University, which is responsible for the study.
Artner and her colleagues have also discovered that the gene MafA (muscoloaponeurotic fibrosacoma oncogene family A) found in insulin-producing beta cells control the number of nicotine-sensitive receptors and thereby their ability to receive signals from the central nervous system.
“The effect that this single gene, MafA, alone has on insulin secretion was previously unknown, and nicotine receptors have never before been connected to type 2 diabetes,” says Artner. She continues: “We know that smokers have an increased risk of developing type 2 diabetes, but the reason why has not been firmly established. Perhaps it has to do with the nicotine-sensitive receptors we describe. Our findings increase knowledge about the connection between smoking and type 2 diabetes.”
Monoamine and acetylcholine neurotransmitters from the autonomic nervous system (ANS) regulate insulin secretion in pancreatic islets. The molecular mechanisms controlling neurotransmitter signaling in islet β cells and their impact on diabetes development are only partially understood. Using a glucose-intolerant, MafA-deficient mouse model, we demonstrate that MafA controls ANS-mediated insulin secretion by activating the transcription of nicotinic (ChrnB2 and ChrnB4) and adrenergic (Adra2A) receptor genes, which are integral parts of acetylcholine- and monoamine-signaling pathways. We show that acetylcholine-mediated insulin secretion requires nicotinic signaling and that nicotinic receptor expression is positively correlated with insulin secretion and glycemic control in human donor islets. Moreover, polymorphisms spanning MafA-binding regions within the human CHRNB4 gene are associated with type 2 diabetes. Our data show that MafA transcriptional activity is required for establishing β cell sensitivity to neurotransmitter signaling and identify nicotinic signaling as a modulator of insulin secretion impaired in type 2 diabetes.
- MafA controls autonomic-nervous-system-mediated insulin secretion.
- MafA activates nicotinic receptor expression in mouse and human β cells.
- Nicotinic receptor signaling is required for acetylcholine-mediated insulin secretion.
- Polymorphisms in human nicotinic receptor genes affect islet expression and diabetes.
Researched and prepared by Devon Brooks, Doctor of Pharmacy Candidate from LECOM College of Pharmacy, reviewed by Dave Joffe, BSPharm, CDE
Cell Reports DOI.10.1016/j.celrep.2016.02.002.
Elvira Ganic , Tania Singh, Published online February 18, 2016 MafA-Controlled Nicotinic Receptor Expression Is Essential for Insulin Secretion and Is Impaired in Patients with Type 2 Diabetes
Lund University press release, March 8, 2016.