Elevated Fasting FFA Drives Fasting Hyperinsulinemia in Obese Patients With Normal Glycemia

Close up of overweight female injecting insulin into fat stomach, diabetes
It is known that elevated free fatty acid levels in obesity cause insulin resistance and as a result increase blood glucose that drives hyperinsulinemia. But what are the mechanisms that drive hyperinsulinemia and insulin resistance in obese patients?

The combination of having elevated circulating levels of free fatty acids at fasting and normal blood glucose are believed to be the major driver behind hyperinsulinemia in obese patients, shows a new study.

“These results support the idea that hyperinsulinemia and insulin resistance may develop as part of a homeostatic adaptive response to increased adiposity and FFA,” write the Emanuel Fryka, et al. in the March 1 issue of EBioMedicine.

In this analysis, Swedish researchers describe two previously studies: MD-Lipolysis, which was a case-control study conducted by the Wallenberg Laboratory at Sahlgrenska University Hospital in Gothenburg, Sweden; and, POEM, a cohort study that assessed the validity of the circulating metabolites and its relation to adiposity and insulin resistance found in MD-Lipolysis study, which investigated the mechanisms of obesity-driven insulin resistance by a systemic metabolic analysis, measurements of adipose tissue lipolysis by microdialysis, and adipose tissue genomics.

The MD-Lipolysis study reports that in obese insulin resistant patients with normal glycemia, hyperinsulinemia was associated with elevated free fatty acids. Lipolysis (the breakdown of fats and other lipids by hydrolysis to release fatty acids) was similar between both the obese and lean patient control groups. But for obese patients, their fat tissue expressed fewer genes involved in lipid storage, but also those genes known to mediate the physiological process that involved the control of neurotransmitters such as epinephrine and dopamine. Fat tissue from the obese group also showed evidence of increased expression of genes that cell proliferation that could lead to the gross enlargement of an organ, for example.

The MD-Lipolysis case control study and the population-based POEM study show that elevated fatty free acids are likely to be the metabolic derangement driving hyperinsulinemia in subjects with increased adiposity but normal glycemic control.

“Using the microdialysis technique we have found that, in hyperinsulinemic obese with normal plasma glucose, elevated FFA levels can mostly be explained by their increased fat mass rather than by an overt and uncompensated adipose tissue insulin resistance. Adipose tissue analysis of gene expression showed that obese individuals display a reduced expression of key genes mediating catecholamine-driven lipolysis, de-novo lipogenesis and lipid storage, but increased expression of genes implicated in adipose tissue hyperplasia,” the authors wrote.

Disclosures:  This study was funded in part by the Novo-Nordisk-Foundation. Other contributors included the Swedish Research Council, The Diabetes Foundation in Sweden, The Cancer Foundation in Sweden and the Swedish-ALF-agreement.


Emanuel Fryka, Josefin Olaussona, Karin Mossberga, Lena Strindberga, et al. “Hyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids: A mechanistic case-control and a population-based cohort study,” EBioMedicine. March 1, 2021. https://doi.org/10.1016/j.ebiom.2021.103264