Weaning Triggers Metabolic Shift That is Reversed in Diabetes

Two-Way Switch Governing Maturity of Insulin-Producing Cells in Mice Could Be a Target for New Diabetes Therapies

By Nicholas Weiler

The transition from mother’s milk to more complex foods is one of the most dramatic dietary changes in a mammal’s life. Now scientists at UC San Francisco have discovered that the weaning process triggers a major metabolic shift in mice. Intriguingly, examination of human tissue samples suggested that type 2 diabetes (T2D), a metabolic disease affecting more than 20 million people in the United States, may represent a reversion to a more infant-like metabolic state.

Type 2 diabetes affects more than 20 million people in the United States.

“We believe we have identified a central metabolic switch that gets flipped one way by changes in diet during early life, but gets put in reverse during T2D,” said Anil Bhushan, PhD, a professor with the UCSF Diabetes Center who oversaw the new research along with Diabetes Center colleague Suneil Koliwad, MD, PhD. “Defining this switch uncovers a host of new targets to curb T2D, an extremely widespread disease.” 

In T2D, the body’s tissues stop responding to insulin, a hormone produced by beta cells of the pancreas that normally tells cells when to take up glucose from the blood. At first the pancreas responds to this so-called insulin resistance by producing more insulin, but eventually the body loses the ability to keep blood sugar at normal levels, which can damage the eyes, kidneys, nerves, and heart. Scientists know that genetics and lifestyle factors contribute to T2D, but still don’t fully understand how the disease arises from changes in pancreatic beta cells at a molecular level.

In early life, the beta cells shift from an immature, growth-focused phase to a more mature state focused on efficient regulation of blood glucose. The new study — published July 2, 2019 in The Journal of Clinical Investigation — shows that this shift is triggered by a molecular transition within these cells — from a nutrient-sensing growth protein called mTORC1 to a protein called AMPK that prioritizes energy balance within cells over rapid growth.

Since this change typically occurs at about three weeks of age in mice, just as mouse pups are being weaned from fat-rich mothers’ milk to a more carbohydrate-heavy adult diet, the authors, led by Bhushan lab postdoctoral researcher Rami Jaafar, PhD, wondered whether weaning itself could be a trigger for beta-cell maturation. 

“As we transition from infancy, we go from nearly continuous consumption of milk to an adult diet that involves much longer periods of fasting followed by discrete meals with a highly varied nutrient composition,” said Koliwad, who is an associate professor and Gerold Grodsky, PhD/JAB Chair in Diabetes Research at the UCSF Diabetes Center. “Somehow the pancreas needs to be flexible enough to respond appropriately to whatever and whenever we eat. Our goal was to find out how early-life nutritional factors shape the identity of mature beta cells so they can successfully guide metabolic function throughout later life.” 

To test this, the researchers showed that enriching animals’ diets with milk fat past the normal weaning period and into adulthood prevented beta cell maturation. These animals’ adult beta cells not only had the enhanced mTORC1 activity and lower AMPK levels of a juvenile mouse, but also produced far too much insulin, much like immature beta cells. 

During the early stages of T2D, insulin resistance is known to cause adult beta cells to begin proliferating and over-producing insulin, much like immature beta cells. The authors wondered whether the development of T2D could reflect regression on a molecular level as well. They showed that in a mouse model of obesity-driven T2D, beta cells revert to expressing growth-oriented mTORC1 and reduce the mature, energy-balancing influence of AMPK.

Remarkably experiments in human beta cells in laboratory dishes showed the same pattern: beta cells from people with T2D, when compared with those from healthy individuals, showed the immature molecular signature seen in mice with T2D, with elevated mTORC1 and reduced AMPK.

This is particularly intriguing, the authors say, because drugs that boost AMPK levels have recently been tested for their ability to restore insulin sensitivity in tissues that have become resistant in an effort to stave off T2D. The new results suggest that AMPK-stimulating drugs may also have the complementary effect of preventing beta cells from reverting to an unhealthy, immature state in response to insulin resistance, thus maintaining their ability to effectively control blood sugar.

Authors: Additional authors on the study were Stella Tran, Ajit Shah, Martin Valdearcos, Simone Giacometti, and Matthias Hebrok of the UCSF Diabetes Center; Gao Sun and Guy A. Rutter of Imperial College London; Piero Marchetti, and Matilde Masini of the University of Pisa; Avital Swisa and Yuval Dor of Hebrew University-Hadassah Medical School in Jerusalem; Ernesto Bernal-Mizrachi of the University of Miami; and Aleksey Matveyenko of the Mayo Clinic. 

Funding: This project was supported by the National Institutes of Health (DK108666, DK103175, DK112304), including a Diabetes Research Center P30 grant (DK063720) and a Nutrition and Obesity Research Center P30 grant (DK098722).

Disclosures: The authors declare no competing interests.

The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes UCSF Health, which comprises three top-ranked hospitals, as well as affiliations throughout the Bay Area. 

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