AAT protein restores blood glucose in type 1 diabetes model

October 13, 2008

BOSTON - A protein made by the liver in response to inflammation and used to treat patients suffering from a genetic form of emphysema has been shown to restore blood glucose levels in a mouse model of Type 1 diabetes mellitus, according to a new study led by researchers at Beth Israel Deaconess Medical Center (BIDMC).

The findings, which appear in the Online Early Edition of the Proceedings of the National Academy of Sciences (PNAS) this week, provide further proof that inflammation plays a key role in the development of Type 1 diabetes and suggest that the protein - known as AAT --might be an option for clinical testing in humans.

Formerly known as juvenile-onset or insulin-dependent diabetes, Type 1 diabetes is an autoimmune disease that develops when the body's immune cells (known as T-cells) overreact and attack and destroy its own pancreatic beta cells. Without beta cells, the body is unable to produce insulin, a hormone needed to convert glucose into energy. To prevent the development of serious - and even fatal -- complications, more than 21 million individuals with Type 1 diabetes, primarily children and young adults, must receive as many as three insulin injections each day.

"To cure Type 1 diabetes, it will not be enough to halt the destructive T-cell-dependent autoimmune attack on beta cells," explains the study's lead author Maria Koulmanda, PhD, Director of Non-Human Primate Research in the Transplant Center at Beth Israel Deaconess Medical Center (BIDMC) and Associate Professor of Surgery at Harvard Medical School (HMS). "We think that it will also be necessary to restore proper insulin signaling, and the way to do that is by eliminating the curious inflammatory state that exists in muscle, fat and other insulin-sensitive tissues."

Last year, Koulmanda, together with the paper's senior author Terry Strom, MD, Director of Transplant Research at BIDMC and Professor of Medicine at HMS, established a role for insulin resistance and inflammation in the onset of Type 1 diabetes, a finding that challenged many theories regarding the autoimmune disease. Their findings demonstrated for the first time that a form of inflammation in fat and muscle was preventing insulin from "allowing" blood glucose into tissues requiring glucose. They further demonstrated that normal blood glucose levels could be successfully restored in a non-obese diabetic (NOD) mouse model by administering a triple combination therapy consisting of both tolerance-inducing and anti-inflammatory properties.

In this new paper, Koulmanda borrowed the AAT protein to achieve the same results.

"The AAT protein is made by the liver and functions to halt unchecked inflammation," she explains. "In cases of Type 1 diabetes, inflammation is the factor that determines whether T-cells exert destructive or protective forms of immunity. We, therefore, hypothesized that [in cases of Type 1 diabetes] immune tolerance could be reestablished by using the AAT protein to modify a pro-inflammatory state and turn it into an anti-inflammatory state."

Using the NOD mouse model, the authors tested the hypothesis that inflammatory mechanisms directly trigger insulitis, insulin resistance, faulty insulin signaling and the loss of immune tolerance to islets.

"We were able to demonstrate that treatment with AAT - an agent that dampens inflammation but does not directly inhibit T-cell activation - ablates invasive insulitis and restores euglycemia [normal blood glucose concentration], immune tolerance to beta cells, normal insulin signaling and insulin responsiveness in NOD mice with recent onset Type 1 diabetes," she says.

Most dramatic, adds Koulmanda, their experiments found that the functional mass of beta cells actually expanded in the NOD mice treated with AAT.

The AAT protein is already in widespread use as a replacement therapy in treating Alpha-1 antitrypsin deficiency, an inherited disorder that can cause emphysema-like lung disease in adults and liver disease in children.

"In humans, AAT has been used for more than two decades, and has maintained an impressive safety record," says Koulmanda. "We believe that treatment with AAT will prevent and delay further loss of functioning residual beta cells in patients with recent onset Type 1 diabetes.

"With this study, we've shown that modifications in inflammation indirectly - but powerfully - modify ongoing destructive-type immunity," she adds. "And most exciting, by administering AAT to the diabetic mice, we actually achieved beta cell expansion, which has never been shown with any other treatment."
This study was funded by grants from the National Institutes of Health and the Juvenile Diabetes Research Foundation.

In addition to Koulmanda and Strom, coauthors include BIDMC investigators Manoj Bhasin, Lauren Hoffman, Zhigang Fan, Andi Qipo, Hang Shi, Prabhakar Putheti, Nicolas Degauque, Towia Libermann and Jeffrey Flier; Susan Bonner-Weir of the Joslin Diabetes Center; and Hugh Auchincloss, Jr., of Harvard Medical School.

Beth Israel Deaconess Medical Center is a patient care, education and research affiliate of Harvard Medical School and consistently ranks in the top four in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.

Beth Israel Deaconess 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.