Knocking out key protein in mice boosts insulin sensitivity

November 10, 2011

By knocking out a key regulatory protein, scientists at the University of California, San Diego School of Medicine and the Ecole Polytechnique Federale de Lausanne (EPFL) in Switzerland dramatically boosted insulin sensitivity in lab mice, an achievement that opens a new door for drug development and the treatment of diabetes.

The research, published in the November 11 issue of the journal Cell, reveals a new and previously unsuspected role for nuclear receptor corepressor (NCoR), a transcriptional coregulatory protein found in a wide variety of cells.

"Different transcription factors stimulate genes, turning them on and off, by bringing in co-activators or co-repressors," said Jerrold M. Olefsky, MD, associate dean for Scientific Affairs and Distinguished Professor of Medicine at UC San Diego and senior author of the paper. "All transcriptional biology is a balance of these co-activators and co-repressors."

Olefsky and colleagues focused their attention on NCoR, which was known to be a major co-repressor of Peroxisome Proliferator-Activated Receptor gamma or PPAR-gamma, a ubiquitous protein that regulates fatty acid storage and glucose metabolism, but which also appeared to act on other receptors as well.

"It seemed to be a general purpose co-repressor," said Olefsky. "It's unusual for one protein to do so many things. It's not very efficient and you don't see it too much in biology."

The scientists created a knock-out mouse model whose adipocytes or fat cells lacked NCoR. Though bred to be obese and prone to diabetes, Olefsky said the glucose tolerance improved in the NCoR knock-out mice. Moreover, they displayed enhanced insulin sensitivity in liver, muscle and fat, and decreased systemic inflammation. Resistance to insulin, a hormone central to regulating carbohydrate and fat metabolism, is a hallmark of diabetes, as is chronic inflammation.

"When NCoR was deleted, insulin sensitivity in the whole animal increased dramatically compared to normal obese mice, which remained insulin resistant. The sensitivity occurred not just in adipocytes, but in all cells," said Olefsky. "With NCoR knocked out of adipocytes, PPAR-gamma becomes active. This produces a robust increase in systemic insulin sensitivity."

Phosphorylation is a biochemical process in which a phosphate group is added to a protein or other organic molecule, activating or deactivating many protein enzymes. It turns out that NCoR facilitates phosphorylation of PPAR-gamma, so that without NCoR, the receptor remains unphosphorylated and active.

In related work also published in the same issue of Cell, EPFL scientists found that knocking out NCoR in muscle cells produced a surprising effect. It did not repress PPAR-gamma, but rather generated a different phenotype or set of results.

"In adipocytes, NCoR repressed PPAR-gamma, but in other cells, it appears to repress other transcription factors," Olefsky said. "That's a new principle: A repressor that's found in many cells, but performs a specific, different function depending on the cell type."

Though NCoR's role as a major co-repressor was known, it was considered a poor drug target because inhibiting it could cause unwanted de-repression in some cell types, producing adverse side effects. Olefsky said the newly discovered specificity of NCoR revitalizes the idea that NCoR may be an excellent drug target for type 2 diabetes and other insulin resistant diseases.

"If researchers can make a drug that's tissue-specific, repressing NCoR could be a powerful way to boost insulin sensitivity. It's doable. Already, we can create drugs that specifically target fat and liver cells. That might be good enough to produce a system-wide benefit."
-end-
Co-authors of the study are Pingping Li, WuQiang Fan, Jianfeng Xu, Min Lu, Dorothy D. Sears, Saswata Talukdar, DaYoung Oh, Ai Chen, Gautam Bandyopadhyay, Jachelle M. Ofrecio and Sarah Nalbandian of the Division of Endocrinology and Metabolism, Department of Medicine, UC San Diego; Hiroyasu Yamamoto and Johan Auwerx of the Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Federale de Lausanne and Miriam Scadeng, Department of Radiology, UC San Diego.

Funding for this study came, in part, from the National Institutes of Health, the EU Ideas Program, the Swiss National Science Foundation and the Eunice Kennedy Shriver National Institute of Child Health & Human Development as part of the specialized Cooperative Centers Program in Reproduction and Infertility Research.

University of California - San Diego

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.