Type 2 Diabetes—Impaired Hepatic Insulin Clearance a New Consideration

A fresh look at factors affecting progression of type 2 diabetes led Cedars Sinai researchers to consider the possibility that insulin clearance in the liver may play a key role.

with Richard Bergman, PhD, Marilyn Ader, PhD, Fernando Bril, MD

Hepatic insulin clearance may be a contributing factor in the onset of type 2 diabetes (T2D), according to findings published in the journal, Diabetes, by a team of  researchers at Cedars-Sinai Medical Center in Los Angeles, California.

Many mechanisms have been proposed to account for the onset of T2D, including hyperinsulinemia, unhealthy lifestyle behaviors,1,2 β-cell failure,3,4 and hypersecretion of insulin.5 This newest analysis by Bergman et al identified a novel mechanism behind the development of diabetes which accounts for existing hypotheses and suggests how these factors may work collectively to initiate and foster progression of this chronic disease.6

Insulin clearance in the liver suggests a novel explanation for rate of diabetes progression.

“What our paper is about is a new concept of what may cause the onset of diabetes, or at least prediabetes. We propose a new way of thinking by focusing on the process of insulin degradation and clearance,” said Richard Bergman, PhD, the Alfred Jay Firestein Chair in Diabetes Research, professor of Medicine and director of the Sports Spectacular Diabetes and Obesity Wellness and Research Center at Cedars-Sinai.

Potential Role For and Beyond Lifestyle Modifications

“We have known that type 1 diabetes occurs with destruction of pancreatic β-cells as an immune response but in type 2 diabetes, the process is more complicated, and it seems that the β-cells must secrete more insulin to compensate for insulin resistance,”7 Dr. Bergman told EndocrineWeb. The question we entertained is: “what comes first—the insulin resistance, the β-cell failure, or some combination of these factors?”

In pursuing an answer, Dr. Bergman described the sequence of events that the team considered, beginning with the secretion of insulin from the pancreatic β-cells.

“After secretion, insulin drains into a vein that goes into the liver, but what is strange is that, of the insulin that enters the liver, only half reaches the rest of the body—meaning that half of the available insulin is degraded by the liver before it ever enters the body,” he said.

“So then why is such a large fraction of secreted insulin cleared during the passage of the hormone through the liver?” he said. "This loss of insulin seems so wasteful."

Dr Bergman and his team conducted a series of experiments and found that “in certain individuals or specific types of conditions, the amount of insulin cleared or the fraction used appears to change.” 6 For example, a high-fat diet leads to reduction in the amount of insulin cleared by the liver, resulting in a larger amount released into the general circulation, he said.

On the other hand, an increase in the level of physical activity has been shown to result in a greater amount of insulin cleared by the liver and therefore less released into systemic circulation.8

“We became interested in these differences because they show that the degradation of insulin might be controlled through modifiable factors, such as diet and exercise,” said Dr. Bergman.

Co-author and co-investigator Marilyn Ader, PhD, associate director of the Sports Spectacular Diabetes and Obesity Wellness and Research Center and Associate Professor of Biomedical Sciences at Cedars-Sinai, elaborated.

“It is known that in a person with obesity, a blood sample will show that the level of insulin is elevated as compared to someone at a healthy weight but what we discovered in these individuals is that the β-cells are producing more insulin and the liver is clearing less,” Dr. Ader told EndocrineWeb.

Assessing Genetic Influences in Insulin Metabolism

Data from study cohorts in both animals and humans have shown temendous individual variation in how much insulin is degraded by the liver, with some people clearing 20% while some may utilize as much as 70% of the hormone, and although “we don’t have a clear understanding of the mechanisms, we do know that other research has indicated that not only diet but also race and ethnicity may play a role in this variability of insulin uptake,” Dr Bergman said.

Case in point—data gathered by the Cedars-Sinai team from 203 nonobese children, ages 7-13 years, reflected a 74% lower hepatic insulin clearance in African-American (AA) children, compared with children of European ancestry (EA), while extrahepatic insulin clearance did not significantly differ by ethnicity.9

In another study, using a different dataset generated by Barbara A. Gower, PhD, professor of medicine in the Nutrition Obesity Research Center at the University of Alabama at Birmingham, the researchers compared the insulin uptake in African American adults to European American adults (n=69), all of whom were deemed overweight or had obesity, and were randomized to one of 2 diets (lower fat vs lower carb).10 The researchers reported arriving at similar conclusions such that the Black patients had significantly lower hepatic insulin clearance in comparison to those of Causian background.10   

“It is unclear whether the differences in [insulin] clearance are due to socioeconomic, lifestyle, environmental factors or whether the difference is due to genetics,” Dr Ader said, or a combination of these factors.

However, it is worth noting that the research was conducted in different physiologic states and among different age groups, and that “children have been exposed to these other [external and modifiable] influences for a shorter period of time, so any changes in hepatic clearance are more likely genetic,” she posited, adding “again, we have not yet conducted a study that confirms a causative factor in driving insulin clearance at this time.”

Provocative Finding of Individual Variability in Insulin Resistance  

This is a “provocative review article,” said Fernando Bril, MD, Assistant Professor of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, who reviewed the paper for EndocrineWeb but was not involved in the research.

“In a very elegant way, the authors provided significant data from important prior studies to support their theory and should be congratulated for a well written, and well- focused examination of this topic,” said Dr Bril

However, given the “myriad of metabolic derangements that take place in people with insulin resistance, it is oftentimes impossible to isolate one abnormality from another such that insulin resistance, insulin secretion, insulin levels, and insulin clearance are all intertwined,” he said.

For this reason, “establishing the true role of insulin clearance may be harder than expected and in a way, we are facing a chicken-and-egg situation whereby insulin clearance and insulin resistance are so tightly linked to each other that it will be hard to unveil which triggers the other effect,” Dr. Bril said.

He cautioned that until there is a clearer understanding of the mechanisms driving insulin action in the liver, he does not “envision any important diabetes management changes for clinicians and healthcare providers in their everyday patient care.”

Nevertheless, “we are at exciting times as our knowledge of type 2 diabetes grows exponentially every year” and if insulin clearance is proven to play a key role in the development of T2D, it may open the door to new pathways of research into new medications in the future,” said Dr. Bril.

Although these types of “paradigm shifts usually take quite some time, this review article certainly has set the ball rolling,” he said.

Dr Ader agreed that at present, these findings remain hypothetical and come from a “series of experiments and many avenues of research.” She sees the research needed to confirm the contributory factors as “clear and testable, with the potential to contribute enormously to the cause we already know about of T2D, and potentially develop new avenues for treatment of those who already have the disease or are at risk.”

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