Increased sensitivity to nerve signals keeps diabetes at bayNerve signals relayed directly to the pancreas after eating a meal play a critical role in normal blood sugar control, according to a report in the June 7, 2006, Cell Metabolism. Therefore, drugs that increase the sensitivity to such signals might offer a new approach to diabetes treatment, the researchers said.
Mice in which the pancreas cells that produce insulin, or beta cells, lack so-called M3 muscarinic acetylcholine receptors develop some symptoms of diabetes, including impaired glucose tolerance and reduced insulin release, the authors report. M3 receptors are normally on the receiving end of messages relayed by involuntary nerves that indicate the presence of food.
In contrast, mice genetically altered to harbor an excess number of beta cell M3 receptors show the opposite: a profound increase in glucose tolerance and insulin release, the researchers found. Moreover, such animals become resistant to developing symptoms of diabetes or prediabetes when fed a high-fat diet.
The findings suggest that drugs that boost the activity of the M3 receptors on pancreatic beta cells might have therapeutic potential, said Jurgen Wess of the National Institute of Diabetes and Digestive and Kidney Diseases.
"There may be ways to specifically drive up the number of M3 receptors expressed in pancreatic beta cells," Wess said. "It might also be possible to enhance M3 receptor signaling in beta cells by targeting proteins that modulate M3 receptor function in a specific fashion."
Receptors of the same type are also found in other parts of the body, he explained. Therefore, drugs that directly stimulate M3 receptors in general would likely come with problematic side effects--for example, causing smooth muscles to contract.
One of three branches of the involuntary nervous system, the parasympathetic, or "rest and digest" system fulfills many roles--slowing the heart rate, dilating blood vessels, and stimulating digestive secretions.
Food intake is known to trigger an increase in parasympathetic nerve impulses involving signals of different origins that are integrated in the brain, the researchers said. In the pancreas, parasympathetic nerve endings release the messenger acetylcholine before and most likely after food is absorbed.
"However, the importance of parasympathetic innervation of pancreatic beta cells in maintaining normal glucose balance had remained controversial," Wess said. "Much of this controversy has arisen because peripheral parasympathetic nerves release at least five different neurotransmitters, and increased parasympathetic outflow affects the function of many organs and tissues that have important metabolic functions."
The researchers overcame those difficulties in the current study by examining the glucose tolerance and insulin release of otherwise normal mice that were deficient for M3 receptors only in pancreatic beta cells, and in mice that contained an increased number of M3 receptors specifically in beta cells.
"We've established an important role for the native M3 receptor in beta cells in maintaining normal insulin release and blood glucose levels," Wess said. "It's also clear from our findings that the parasympathetic nervous system's modulation of blood sugar is not a transient event--its effects on the pancreas are sustained for a long time after a meal."
The researchers include Dinesh Gautam, Jongrye Jeon, Bo Li, Jian Hua Li, Yinghong Cui, Huiyan Lu, Chuxia Deng, Thomas Heard, and Jurgen Wess of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland; Sung-Jun Han of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland and Institut Pasteur Korea in Seoul, Korea (present address); Fadi F. Hamdan of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland and Universite de Montreal in Montreal, Canada (present address); David Mears of Uniformed Services University in Bethesda, Maryland and University of Chile in Santiago, Chile (present address).
This research was supported by the Intramural Research Program of the NIH, NIDDK.
Gautam et al.: "A critical role for â cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo." Publishing in Cell Metabolism 3, 449-461, June 2006 DOI 10.1016/j.cmet.2006.04.009 www.cellmetabolism.org
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