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Groundbreaking Research May Lead to New Method for Treating Type 2 Diabetes and Insulin Resistance

Released: Friday, December 13, 2019

Baton Rouge, Louisiana

New research suggests that preventing fat from entering muscle cells’ mitochondria may be a viable approach for treating type 2 diabetes and insulin resistance.

The study by LSU’s Pennington Biomedical Research Center shows that severely limiting muscle mitochondria’s ability to convert fat to energy forces the body to alter the normal way it burns fat, and those changes appear to improve health.

“The findings contradict the accepted wisdom, which is that when muscle can’t burn fat, fat accumulates in muscle, which is typically associated with a host of health problems, including type 2 diabetes, stroke and heart disease,” said Robert Noland, PhD, Director of Pennington Biomedical’s Skeletal Muscle Metabolism Laboratory, and corresponding author of the study. “Excess fat did accumulate in muscle in this study; however, the mice appear to be protected against metabolic disease.”

The new study suggests that under certain conditions, fat in muscle is not harmful and appears to be beneficial. The study, published in the Journal of Biological Chemistry, was an Editor’s Pick. In an accompanying commentary, P. Darrell Neufer, PhD, and Director of the East Carolina Diabetes and Obesity Institute, says the findings point to a potential new therapeutic approach for treating insulin resistance and type 2 diabetes.

Pennington Biomedical scientists tested genetically modified mice whose muscle cells' lacked the enzyme (carnitine palmitoyltransferase 1 or Cpt1) that allows fatty acids to enter the mitochondria, the power plants of the cell. As a result, another organelle in the muscle, the peroxisome, oxidized the fatty acids. Diverting fatty acids toward peroxisomes is likely to protect mitochondria from being burdened with excess lipid, which helps improve health.

"Biomarkers for heart disease, diabetes, cancer, fatty liver disease, kidney injury and kidney disease, vasculitis (inflammation of blood vessels), autoimmune disease, and inflammation all decreased in the mice. It's the opposite of what you would expect," said Randall Mynatt, PhD, and Professor in Pennington Biomedical’s Transgenics Core.

The study adds to a growing body of evidence that explains how insulin resistance – a leading cause of type 2 diabetes ­– develops at the molecular level. Insulin resistance is the body’s inability to use insulin, a hormone that helps the body regulate blood glucose (sugar) levels.

Previous research has shown that insulin resistance develops when the fuel supply, especially fatty acids, to mitochondria is persistently higher than the energy needed. Mitochondria convert nutrients into energy. When overloaded with fatty acids, particularly when cholesterol is also high, mitochondria have a hard time burning all of the fat.

“This excess mitochondrial lipid burden appears to be a key contributor toward insulin resistance,” Dr. Noland said.

The study’s findings cap years of effort and involved technological advances barely imaginable when the researchers began working on the mice in 2006. 

The scientists used an “omics” approach in the study. Omics refers to the technologies used to analyze the structure and functions of the entire makeup of a biological function. Instead of examining one or two variables, scientists can monitor the behavior of tens of thousands of variables at the same time.

Pennington Biomedical’s examined the mice’s levels of lipids, proteins and RNA. The study involved:

  • Metabolomics, the study of metabolites, or substances formed in or necessary for the chemical processes that occur to maintain life;
  • Proteomics, the study of proteins expressed by cells, tissues or organisms; and
  • Transcriptomics, the study of messenger RNA molecules expressed from genes.

“With these omics data sets, there’s so much information. It’s a huge task to go in and look at all the disease candidates, but it is precisely the integrative nature of the analysis that makes new insights possible” said Sujoy Ghosh, PhD, Adjunct Associate Professor in Pennington Biomedical’s Nutrient Sensing and Adipocyte Signaling Laboratory, and lead author of the study. 

Distilling the information to produce the study’s findings took close to six years and involved three research centers. Pennington Biomedical performed the genomics work, the University of Tennessee took care of the metabolomics, and Duke University in Durham, N.C. and Duke-National University of Medical School in Singapore handled the proteomics.

Dr. Noland said the data sets contain more information than Pennington Biomedical scientists could ever pursue independently. He hopes that other scientists will be able to use the data to investigate the mechanisms that led to the apparent health improvements.

This work utilized Pennington Biomedical core facilities (Genomics and Transgenic and Animal Phenotyping) that are supported in part by Center of Biomedical Research Excellence Grant 3P30GM118430 and Nutrition and Obesity Research Grant 2P30DK072476 from the National Institutes of Health. This work was also supported in part by the National Institutes of Health under award numbers 1R01DK103860, 1R01DK089641 and T32AT004094; by the American Diabetes Association under award number 1-10-BS-129; by the National Institute of General Medical Sciences of the National Institutes of Health under award number 2U54GM104940; and by the Botanicals and Dietary Supplements Research Center from National Institutes of Health under award number P50AT002776.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

 

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About LSU's Pennington Biomedical Research Center

LSU's Pennington Biomedical Research Center is at the forefront of medical discovery as it relates to understanding the triggers of obesity, diabetes, cardiovascular disease, cancer and dementia. The center conducts basic, clinical and population research, and is affiliated with Louisiana State University. The research enterprise at Pennington Biomedical includes over 450 employees within a network of 40 clinics and research laboratories, and 13 highly specialized core service facilities. Its scientists and physician/scientists are supported by research trainees, lab technicians, nurses, dietitians and other support personnel. Pennington Biomedical is located in state-of-the-art research facilities on a 222-acre campus in Baton Rouge, Louisiana.