Discovery of naturally occurring fats that may alleviate diabetes and inflammation
Working with a mouse model system, investigators have identified a group of fatty acids (a subgroup of lipids, or fat molecules) that appears to improve blood glucose control and reduce inflammation. Previously, they noticed that mice from a particular genetically engineered strain were obese, with high levels of fatty acids, but—unlike many other obese mice—these had very good blood glucose (sugar) control. The investigators wondered whether one or more of the elevated fatty acids might be helping to keep glucose under control, so they compared the lipids from the adipose (fat) tissue from this mouse strain with lipids of normal control mice. This analysis led to the discovery of a family of fat molecules called PAHSAs (palmitic acid-hydroxy stearic acids), which were present in both groups of animals but at much lower levels in the control mice. In a test of normal mice with diet-induced obesity and type 2 diabetes, they found several of the PAHSAs were significantly reduced in some tissues compared to levels seen in normal mice on a healthier diet. The researchers also found similar relationships between PAHSA levels and insulin resistance in a small group of human volunteers, suggesting that low PAHSA levels may be associated with increased risk for type 2 diabetes.
To test whether PAHSAs may have therapeutic potential, the researchers orally administered two forms of these fatty acids (designated 5-PAHSA and 9-PAHSA) to mice with diet-induced type 2 diabetes. They found that each of the compounds lowered fasting glucose levels in the mice, and greatly improved their ability to manage glucose levels after feeding. The results suggest these PAHSAs improve blood glucose control in at least two ways: by increasing the animals’ insulin sensitivity, and—when they are fed—by increasing their insulin-production response. When investigators examined insulin-producing β (beta) cells from non-diabetic human donors (one man and one woman) in the presence and absence of 5-PAHSA, they found a modest increase in glucose-stimulated insulin production. They observed a more pronounced effect in mouse intestinal cells: both 5- and 9-PAHSA stimulated these cells to produce the hormone GLP-1, which itself can stimulate β cells to produce more insulin in response to glucose. Because obesity-induced inflammation in adipose tissue has been linked to type 2 diabetes, the researchers also studied whether these compounds might have an effect on inflammation. They found that oral administration of 9-PAHSA to mice for 3 days significantly moderated the subsequent response to a potent inflammatory trigger by immune cells in their adipose tissue compared to cell from control mice that did not receive 9-PAHSA treatment. Because some of these results were from experiments in male mice, and others from experiments with females, further research could help determine whether they apply equally to both males and females, and whether PAHSAs are safe and effective for treating people with or at-risk for type 2 diabetes.