Researchers have known for some time that alterations in secretion of the hormone glucagon from the pancreas play a major role in diabetes. At the same time, defective glucagon secretion can lead to hypoglycemia in people with diabetes, but how it happens has remained largely a mystery.
That is, until now. Ernesto Bernal-Mizrachi, M.D., and colleagues at the University of Miami Miller School of Medicine have discovered that loss of signaling by the protein complex mTORC1 (mammalian target of rapamycin complex 1) can alter glucagon secreting cells (alpha cells) in the pancreas and impair glucagon secretion.
“The important role of the mTORC1 pathway in secretion of glucagon was not known before,” said Bernal-Mizrachi, professor of medicine and chief of the Division of Endocrinology.
The findings, published in the Journal of Clinical Investigation, carry important implications for future diabetes treatments.
“This paper uncovers some of the pathways that could be important for regulating glucagon levels in unaffected people and those with diabetes,” Bernal-Mizrachi said. Understanding how glucagon secretion is regulated — and in particular the signaling pathways — could lead to a better understanding of how hyperglycemia occurs in diabetes, he added.
“We can then uncover potential targets for medications to control high glucagon levels in diabetes.”
Reversing Abnormal Responses
Bernal-Mizrachi and his team studied mice with tissue-specific deletion of the mTORC1 regulator Raptor in their alpha cells to learn more. They wanted to better understand why alpha cells in the pancreas sometimes fail to secrete glucagon during episodes of hypoglycemia.
The findings hold a lot of potential, Bernal-Mizrachi said. “These findings can be used to design novel medications or therapies to increase glucagon secretion in people with T1D who have recurrent episodes of low blood sugar. That is another important point.”
The research implicates loss of mTORC1 signaling in lower glucagon secretion and that severe loss of alpha cell mass in the absence of mTORC1 signaling likely contributes as well. The study also demonstrates that nutrients and nutrition could also affect alpha cell function given that mTORC1 is a nutrient-dependent signaling pathway. This finding further expands the possibilities for therapeutic targets in the future.
“It is possible that mTORC1 mediates the effects of over-nutrition in the increase in glucagon secretion in obesity and diabetes,” Bernal-Mizrachi said.
The Role of Rapamycin
Rapamycin is a specific inhibitor of mTOR. It is an immunosuppressant used following organ transplantation, particularly for kidney recipients. It is also used as a coating on coronary stents and to treat the rare lung disorder lymphangioleiomyomatosis.
People with diabetes and others taking rapamycin or related analogs called rapalogs could experience altered responses to hypoglycemia, Bernal-Mizrachi said. When people develop low blood sugar, the glucagon levels normally increase to produce glucose from the liver to compensate. The study suggests that rapamycin and rapalogs, by inhibiting mTORC1 signaling, could also worsen the response to hypoglycemia.
The investigators plan to continue studying the mechanisms downstream of mTORC1 signaling to learn more about alterations in glucagon secretion. “We are going to look at how mTORC1, acting on other components of the pathway, can control glucagon secretion.”
Miller School of Medicine