Microtubules act as cellular 'rheostat' to control insulin secretion

December 04, 2015

Microtubules -- cellular "highways" that deliver cargo to the cell membrane for secretion -- have a surprising role in pancreatic beta cells. Instead of facilitating glucose-stimulated insulin secretion, they limit it, a team of Vanderbilt investigators reported recently in Developmental Cell.

The findings reveal that microtubules act as a cellular "rheostat" to precisely control insulin secretion and suggest that disturbance of this control may contribute to beta cell dysfunction and type 2 diabetes. Targeting the microtubule regulation of insulin secretion may offer new ways to treat diabetes.

Irina Kaverina, Ph.D., Xiadong Zhu, Ph.D., and colleagues began using pancreatic beta cells as a model to study microtubule function -- to explore how microtubules "traffic" cargo such as insulin granules from the cell interior to the periphery.

In their initial studies, the researchers used compounds to destroy the microtubules, then stimulated the pancreatic islets with glucose and measured how much insulin was secreted. With the delivery highways missing, they expected to see a reduction in insulin secretion. Instead, they observed a strong increase in secretion.

"It was so surprising, we didn't believe it ourselves," said Kaverina, associate professor of Cell and Developmental Biology.

Together with Guoqiang Gu, Ph.D., associate professor of Cell and Developmental Biology, and other Vanderbilt laboratories, the investigators demonstrated using multiple systems and technologies that microtubules negatively regulate insulin secretion in beta cells. Importantly, Gu's team destroyed microtubules in mice and showed that both glucose-stimulated insulin secretion and glucose clearance from the blood increased compared to mice with intact microtubules.

"In any model we tested, destroying microtubules increased insulin secretion," Kaverina said. "How could it be that the structures that are supposed to be internal highways delivering things to the membrane actually suppress secretion?"

Applying super-resolution microscopy techniques, the investigators discovered that in beta cells, microtubules do not form highway-like tracks. Instead, they form a complex mesh.

"The insulin granules 'walk' randomly on the microtubule mesh, and the microtubules regulate the number of granules at the cell periphery to prevent over-secretion," Kaverina said.

Glucose, she explained, destabilizes microtubules just inside the cell surface to release the microtubule hold on insulin granules and allow secretion.

Strategies that destabilize microtubules -- perhaps using targeted drug delivery to the pancreas -- could increase insulin secretion as a way to treat diabetes, the researchers suggested.

The researchers also found that the microtubule meshwork was more dense in beta cells from mice with diabetes, compared to control mice.

The findings suggest that in response to the increased demand for insulin in diabetes, microtubules become more dense and less dynamic as a feedback mechanism, ultimately shutting down beta cell function, Gu said.

The investigators are now exploring how glucose regulates microtubule dynamics. They are also interested in studying human islets from patients with diabetes. Gu noted that such islets have usually lost the ability to secrete insulin, and he suggested it might be possible to restore insulin secretion by manipulating microtubule dynamics.

He also pointed out an association between anti-cancer therapies that target microtubules and increased risk of diabetes in treated patients. The new findings suggest that cancer treatments that stabilize microtubules may reduce insulin secretion and promote diabetes.

Regulating microtubule dynamics in beta cells, perhaps in combination with other insulin stimulators, offers a new way forward for treating diabetes, the researchers said.
Other Vanderbilt collaborators included Ruiying Hu, Marcela Brissova, Ph.D., Roland Stein, Ph.D., and Alvin Powers, M.D. The research was supported by grants from the National Institutes of Health (DK020593, GM078373, DK065949), the American Heart Association, the Department of Veterans Affairs and the Juvenile Diabetes Research Foundation.

Vanderbilt University Medical Center

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.