Loss of enzyme produces diabetes-like symptoms

May 31, 2001

June 1, 2001 -- Researchers have identified a protein that appears to play an important role in signaling muscle cells to take up glucose from the bloodstream.

In genetic studies in mice, researchers knocked out the gene that produces the enzyme Akt2 and noted that the mice developed insulin resistance and symptoms that resembled type 2 diabetes. Insulin resistance is caused by environmental factors and genetic mutations that result in cells becoming resistant to insulin. Normally, cells respond to insulin by taking up glucose from the bloodstream. Type 2 diabetes mellitus ensues when the insulin-producing cells of the pancreas fail to compensate for abnormalities in insulin action. Diabetes causes high blood sugar levels, which can lead to cardiovascular disease, blindness and kidney malfunction.

In an article published in the June 1, 2001, issue of the journal Science, researchers led by Howard Hughes Medical Institute investigator Morris J. Birnbaum at the University of Pennsylvania School of Medicine reported that they have pinned down a function for the somewhat enigmatic protein, Akt2.

"Dozens of papers have been published arguing both for and against Akt2 as having a role in insulin-stimulated signaling of glucose transport," he said. "Most people agree that insulin's action on the insulin receptor activates the enzyme PI 3-kinase -- which initiates a signaling cascade that somehow leads to the movement of glucose transporters to the cell membrane.

"But PI 3-kinase was the most downstream member of the signaling pathway for which there was a consensus," he said. "The Holy Grail in this field is to link the signal transduction cascade to the movement of glucose transporters."

Akt2 was not necessarily a favorite candidate for being that downstream enzyme, said Birnbaum. In fact, some researchers had begun to discount Akt2, arguing that other similar protein kinases might play a more important role in insulin signaling. But in earlier experiments, Birnbaum and his colleagues had shown that overactivation of Akt2 mimicked insulin action in mice.

"While the data in those experiments were very clear, it was an artificial system that only showed that Akt could be sufficient under certain conditions. But the experiments did not address whether Akt2 was necessary for insulin-stimulated glucose transport," he said. Other scientists had reduced Akt2 activity in tissue culture cells, but their experiments proved inconclusive because they had not managed to eliminate Akt activity completely in their experimental systems.

Birnbaum's colleague and lead author on the Science paper, Han Cho, with the help of HHMI investigator Marisa S. Bartolomei, successfully created a strain of mice in which all Akt2 activity was eliminated. With Akt2 function abolished, the scientists found that the mice grew normally, but had mildly elevated blood sugar -- a telling symptom of diabetes. The researchers found that the elevated blood sugar was not caused by inadequate insulin production in the pancreas. Studies of the pancreas revealed that its insulin-producing cells had greatly increased, most likely to compensate for an insulin resistance characteristic of type 2 diabetes, said Birnbaum.

When Birnbaum and his colleagues studied the animals' muscle tissue, they discovered a partial defect in insulin-stimulated glucose uptake. Co-authors Jason Kim and HHMI investigator Gerald I. Shulman and at Yale University School of Medicine performed glucose clamp studies to measure the liver production of glucose in response to insulin. The researchers infused precise amounts of glucose and insulin through a small catheter inserted into a mouse's vein and measured the blood glucose levels. These experiments -- as well as studies using a radioactive glucose tracer -- revealed that the livers of the Akt2 knockout mice did not respond to insulin by lowering glucose production. Furthermore, the animals' tissues were consuming less glucose in response to insulin.

"These findings are important because they represent the first evidence in an intact animal of a signaling pathway by which insulin shuts off hepatic glucose production," said Birnbaum. "And taken together, finding effects in both liver and muscle are especially significant because dual abnormalities are exactly what occurs in type 2 diabetes," he said.

"No one believes that diabetes is caused by a defect in a single gene, but nonetheless it is striking that the phenotype we observed in these animals is so much like the multi-system effects of human diabetes," said Birnbaum.

Birnbaum and his colleagues plan to knock out Akt2 in specific tissues such as muscle, liver and fat, and study the effects on insulin signaling in those tissues. They also plan to explore the signaling pathway downstream of Akt2, in an effort to determine whether genetic defects in the Akt2 pathway could contribute to diabetes.

 

-end-


Howard Hughes Medical Institute

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.