Increased plasma branched short-chain fatty acids and improved glucose homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES)

Authors: ASLAMY, ARIANNE - Cedars-Sinai Medical Center; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); JENSEN, ELIZABETH - Wake Forest School Of Medicine; BERTONI, ALAIN - Wake Forest School Of Medicine; SHERIDAN, PATRICIA - Metabolon, Inc; WONG, KARI - Metabolon, Inc; RAMESH, GAUTAM - University Of California, San Diego; ROTTER, JEROME - Harbor-Ucla Medical Center; CHEN, YII-DER - Harbor-Ucla Medical Center; GOODARZI, MARK - Cedars-Sinai Medical Center

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/18/2023
Publication Date: 11/22/2023
Citation: Aslamy, A., Wood, A.C., Jensen, E.T., Bertoni, A.G., Sheridan, P.A., Wong, K.E., Ramesh, G., Rotter, J.I., Chen, Y.I., Goodarzi, M.O. 2023. Increased plasma branched short-chain fatty acids and improved glucose homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES). Diabetes. https://doi.org/10.2337/db23-0401.
DOI: https://doi.org/10.2337/db23-0401

Interpretive Summary: Short chain fatty acids (SCFA) have potential beneficial roles in helping people maintain healthy blood sugar levels, and therefore in the prevention of type 2 diabetes. However, most of this research has focused on butyrate, acetate, and propionate, and ignored a class of SCFAs called branched SCFAs( BSCFAs). Therefore, we sought examine whether three BSCFAs (isobutyrate, isovalerate, and methylbutyrate) were associated with blood sugar levels. In an ethnically-diverse analysis, we found that those with high levels of the BSCFAs were less likely to have high blood sugar levels when fasted, and also regulated their blood sugar levels better after consuming sugar (glucose), than those with low levels of these BSCFAs. As one of the first investigations into BCFAs and blood sugar levels in humans, this study sets the stage for further investigation of BSCFA as a novel target for prevention or treatment of diabetes.

Technical Abstract: Short chain fatty acids (SCFA) have been extensively studied for potential beneficial roles in glucose homeostasis and risk of diabetes; however, most of this research has focused on butyrate, acetate, and propionate. The effect on metabolism of branched short chain fatty acids (BSCFA), isobutyrate, isovalerate, and methylbutyrate, is largely unknown. In a cohort of 219 non-Hispanic Whites and 126 African Americans, we examined the association of BSCFA with dysglycemia (prediabetes and diabetes) and oral glucose tolerance test-based measures of glucose and insulin homeostasis, as well as with demographic, anthropometric, lifestyle, lipid traits, and other SCFA. We observed a bimodal distribution of BSCFA, with 25 individuals having high levels (HBSCFA group) and 320 individuals having lower levels (L-BSCFA group). The prevalence of dysglycemia was lower in the H-BSCFA group compared to the L-BSCFA group (16% versus 49%, P=0.0014). This association remained significant after adjustment for age, sex, race, BMI, and levels of other SCFA. Consistent with the lower rate of dysglycemia, fasting and postprandial glucose were lower and disposition index was higher in the H-BSCFA group. Additional findings in H-BSCFA versus L-BSCFA included lower fasting and postprandial Cpeptide levels and lower insulin clearance without differences in insulin levels, insulin sensitivity, insulin secretion, or other variables examined, including diet and physical activity. As one of the first human studies associating higher BSCFA levels with lower odds of dysglycemia and improved glucose homeostasis, this study sets the stage for further investigation of BSCFA as a novel target for prevention or treatment of diabetes.