Sorting and secreting insulin by expiration date

July 06, 2020

A study in the Journal of Biological Chemistry describes a new way to determine the age of insulin-storage parcels, known as granules, and sheds light on how their age affects their release into the bloodstream. The findings could help experts better understand diabetes and fine-tune therapies for it.

Insulin is a hormone that manages the level of sugar, or glucose, in the bloodstream. It is secreted by the pancreas into the bloodstream when blood sugar levels rise. When insulin circulates in the bloodstream, muscle and other cells absorb glucose to use it as fuel, and so blood sugar levels decline. In Type 2 diabetes, formerly known as adult-onset diabetes, this process fails. Glucose builds up in the blood, either because the pancreas cannot produce enough insulin to keep up with dietary sugar intake or because the gland simply isn't working as it should.

About one in 10 Americans and more than 415 million people worldwide have diabetes, according to the Centers for Disease Control and Prevention. Up to 95% of them have Type 2. Treatment often requires painful and frequent insulin injections or the use of mechanical insulin pumps. There is no cure.

The researchers noted in
Insulin is produced by β-cells of the pancreas and stored in insulin granules, which are then organized into pools and finally secreted into the bloodstream. Pools of young insulin granules are preferred for secretion over pools of old ones, for reasons that remain unclear.

The scientists whose work was published in JBC wanted to learn more about how pancreatic cells can distinguish between pools with young or old insulin granules.

"Current therapeutics do not take the existence of pools into consideration," said Melkam Kebede, an assistant professor at the University of Sydney who oversaw the study. "By evolution, the (pancreatic) cells have determined what to secrete and what not. Understanding the mechanism and molecular differences between the pools definitely is going to lead us into something meaningful."

In their paper, the researchers describe a technique they developed to distinguish younger insulin granules from older ones. The scientists placed a fluorescent protein, called Syncollin-dsRedE5TIMER, into newly created insulin granules and used a laser and detector to visualize that marker. In younger granules, the marker emits a green fluorescent light; as granules get older, the marker begins to emit a red fluorescence.

The authors monitored the movements of and other changes in insulin granule pools and saw that, as predicted, both mouse and human cells preferentially release younger insulin granule pools into the bloodstream in response to glucose.

The researchers then set out to learn more about how pancreatic cells sort insulin granules into pools and release them when they are experiencing metabolic stress. The concern is that, when under stress, "β-cells could potentially lose their ability to distinguish young (granules) from old," they wrote in their paper.

The team isolated β-cells from mice and simulated chronic low, high and normal blood sugar levels and found different glucose levels determine which pools of insulin granules, young or old, are secreted. They saw similar results when they used a common mouse model for Type 2 diabetes known as the db/db mouse.

These findings are important, Kebede said, because "all the drugs that affect insulin secretion...just push any granule within the cell and eventually fail."

Older insulin granules are naturally degraded in normally functioning beta cells, noted lead author Belinda Yau of the University of Sydney, but, in diabetes, a greater percentage of insulin granule pools are secreted, and there's a mismatch in how they're released.

Being able to visualize insulin granules as they age and understanding better how their age affects their secretion may lead to the discovery of new biomarkers capable of indicating the development of diabetes and could help in the creation of therapies for Type 2 diabetes.

"If we can understand what makes up the granules and makes them do what they do, we can figure out a way to target the things that slow down or speed up their secretion," Yau said.
This research was conducted by scientists at the University of Sidney, the University of Chicago the Garvan Institute of Medical Research in Australia, St. Vincent's Institute in Australia, and the Centre for Transplant and Renal Research at Westmead Hospital in Australia. The work was supported by the National Health and Medical Research Council (NHMRC) of Australia grant ID GNT1139828.

DOI: 10.1074/jbc.RA120.012432

About the Journal of Biological Chemistry

JBC is a weekly peer-reviewed scientific journal that publishes research "motivated by biology, enabled by chemistry" across all areas of biochemistry and molecular biology. To read the latest research in JBC, visit

American Society for Biochemistry and Molecular Biology

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 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