Conference Coverage

Does reduced degradation of insulin by the liver cause type 2 diabetes?



To follow up on this concept, he and his colleagues used data from 100 African immigrants without diabetes to develop a model to estimate hepatic versus extrahepatic insulin clearance in humans (Diabetes. 2016;65[6]:1556-64). “This population was chosen because previous studies have suggested that individuals of African descent have reduced hepatic insulin clearance compared with Western subjects,” the authors wrote in the article. “Similarly, FSIGT [frequently sampled intravenous glucose tolerance test] data from two groups showed that African American women had much higher plasma insulin concentrations than European American women during periods of elevated endogenous secretion but not after intravenous insulin infusion, also suggesting reduced hepatic, but not extrahepatic, insulin clearance in African American subjects. Thus, this population was of special interest for applying a model that could quantify both hepatic and extrahepatic insulin clearance.”

The model was able to reproduce accurately the full plasma insulin profiles observed during the FSIGT and identify clear differences in parameter values among individuals. “The ability of the liver to degrade insulin is very variable across a normal human population,” Dr. Bergman said. “That means this may be a controlled variable.”

In a separate analysis of 23 African American and 23 European American women, Dr. Bergman, Francesca Piccinini, PhD, Barbara A. Gower, PhD, and colleagues found that hepatic but not extrahepatic insulin clearance is lower in the African American women, compared with their European American counterparts (Diabetes. 2017;66[10]:2564-70). Data from a cohort of children found the same thing (Diabetes Obes & Metab. 2018 Jul 18. doi: 10.1111/dom.13471).

“What does this mean that different ethnic groups have different clearance of insulin?” he asked. “It means that African Americans deliver a higher fraction of secreted insulin into the systemic circulation. We know that African Americans tend to be hyperinsulinemic. That isn’t necessarily due to oversecretion of insulin; it’s likely due primarily to reduced degradation of insulin. The question then is, can the reduced insulin clearance play a causal role in the pathogenesis of type 2 diabetes?”

He hypothesized that, in normal individuals, half of insulin secreted by the pancreas is exported into the systemic circulation and half is degraded. “We propose that in people at risk for diabetes, insulin is secreted by the pancreas but much less of it is degraded,” Dr. Bergman continued. “Insulin gets into the systemic circulation, so then you can get hyperinsulinemia, and insulin resistance. The resistance stresses the beta cells of the pancreas. Thus, the idea is that differences in clearance of insulin by the liver in some individuals may be pathogenic in the cause of diabetes.”

Dr. Bergman reported that he has done consulting/collaboration with Janssen, January, Novo Nordisk, and Zafgen. He has also received research grants from Astra Zeneca, Janssen, and the National Institutes of Health.

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