The International Diabetes Federation estimates that approximately one in nine adults worldwide have type 1 or 2 diabetes, and that number is projected to jump to one in eight—a 46 percent increase—by 2050. The rising incidence of diabetes in the global population has made research into its causes critical for understanding and treating this disease.
Vanderbilt has been a global leader in field of diabetes research for over 50 years. One of the key players, Jacquelyn A. Turner and Dr. Dorothy J. Turner Professor of Diabetes Research Alan Cherrington, has focused on understanding the metabolic processes that govern blood sugar regulation and was involved in the development of GLP-1 receptor agonists, which are a class of medications that have become a favorite tool to treat diabetes and obesity.
In a new paper spearheaded by recent Ph.D. graduate Hannah Waterman, Cherrington and a team of researchers from the Department of Molecular Physiology and Biophysics, including senior author Dale Edgerton, a research professor in the department, report their latest findings on the “second-meal effect,” the body’s metabolic response to the first meal of the day, which influences glucose regulation during subsequent meals. Understanding the body’s metabolic response to meals can help physicians and scientists better understand how they go wrong in conditions like diabetes.
We sat down with Waterman to learn more about their paper, which was published in Frontiers in Endocrinology in April.
What issue/problem does your research address?
Most people think of blood sugar regulation as something that resets after each meal. However, clinical and experimental evidence suggests that the body’s response to one meal can influence glucose handling at the next meal. This “second-meal effect” was first described over 100 years ago, but its mechanisms remain poorly understood.
Our research addresses a key unanswered question about this phenomenon: How do early-day hormonal signals, specifically insulin and glucagon (the major glucose-regulating hormones, which lower and raise blood sugar levels, respectively), shape the liver’s ability to regulate glucose later in the day? While insulin is known to “prime” the liver for improved glucose storage after a meal, glucagon is traditionally viewed as opposing insulin and raising blood glucose levels by increasing the liver’s glucose production. We asked whether glucagon also has longer-lasting effects that alter how the liver responds hours after a subsequent meal.
What were your top three findings?
- A hormone pattern in the morning changes how the liver handles sugar later in the day: When glucagon was elevated in the morning, the liver was less able to take up and store glucose during a later meal, even though insulin and blood sugar levels were the same at that time.
- Early insulin-glucagon balance determines whether the liver stores or releases glucose later: The normal “priming” effect of insulin, which prepares the liver to efficiently store glucose after a meal, was weakened when glucagon was present earlier in the day. This shifted the liver toward producing and releasing more glucose in the afternoon instead of storing it.
- This effect is linked to changes in how the liver processes glucose at a molecular level: Morning glucagon prevented the normal insulin-driven increase in glucokinase, an important enzyme that allows the liver to trap and store glucose. In turn, this reduced the liver’s ability to efficiently convert incoming glucose into stored energy later in the day.
These results indicate that glucagon, just like insulin, is a regulator of the liver’s metabolic memory and demonstrate that early-day hormone dynamics shape the liver’s response to subsequent challenges (meals).
![Two-part graphic showing what's going on in the liver at two points of the day. The top half shows a clock at 6:00 a.m. and subtext that says "AM HIEG CLAMP." Insulin is shown going into the portal vein, connected to the liver, while in the liver glucagon goes up. A diagram of what's going on in the liver says, "AM insulin --> [up arrow] GCK transcription/translation." A caption on the right says AM [up arrow] insulin establishes hepatic metabolic memory, which is altered by AM [up arrow] glucagon." The bottom half shows a clock at 12:00 p.m. and subtext that says "PM HIEG CLAMP." Insulin and glucose are shown going into the portal vein, connected to the liver, which has a big arrow over it that says "Glucose Uptake"; two smaller arrows feed that large arrow and are labeled "Insulin action (hyperinsulinemia)" and "glucose action (portal signal and glucose effectiveness." A diagram of what's going on in the liver shows a transmembrane channel with glucose going through it. An arrow from the glucose inside the implied cell is labeled "GCK" and points to "glucose-6-phosphate," which in turn points to "glycogen." A caption on the right says AM [up arrow] glucagon blunts enhancement in PM NHGU and glycogen synthesis induced by AM [up arrow] insulin."](https://cdn.vanderbilt.edu/t2-main/medschool-prd/wp-content/uploads/sites/101/2026/05/Waterman-Cherrington-abstract-2026.jpg)
We hope this work changes how clinicians and researchers interpret day-to-day glucose control in both healthy individuals and people with type 2 diabetes. Instead of viewing elevated post-meal glucose as an isolated response to a single meal, these findings highlight that prior hormonal conditions earlier in the day can influence how the liver responds later.
Clinically, this could help explain why some patients show worsening glucose control as the day progresses even when fasting glucose levels in the morning appear reasonable. It encourages a more time-integrated view of glucose regulation in which the pattern of hormonal exposure across the day is considered when interpreting high blood sugar levels after meals.
More immediately, it may help clinicians better understand variability in patient responses to meals, oral glucose tests, and insulin-based assessments, laying the groundwork for more individualized interpretation of glycemic patterns in type 2 diabetes.
What are your highest translational/clinical aspirations that might come from this research?
Our long-term aspiration is to improve how type 2 diabetes is treated by moving beyond a single, blood sugar–measurement approach and toward a more integrated view of how the liver regulates glucose across the entire day.
We aim to define how early-day hormone patterns shape later metabolic responses so that therapies can be designed to not only lower blood sugar in the moment but also restore normal day-long regulation of liver glucose storage and production.
A key translational goal is to inform the development and optimization of treatments that target insulin and glucagon together, including dual-hormone or dual-agonist strategies. Ultimately, the goal is to improve how the liver handles glucose after meals and between meals in a way that is more physiologic, more sustained, and better aligned with how our metabolism functions over time.
Who or what made the difference in your research? What small things contributed to your work?
This work was shaped by close collaborations and sustained scientific discussions within the Department of Molecular Physiology and Biophysics. Drs. Richard O’Brien, Karin Bosma, and Derek Claxton provided key expertise in specialized assays that helped validate and strengthen interpretation of the findings when unexpected patterns emerged in the data.
More broadly, feedback from the Metabolism Interest Group, departmental seminars, and my thesis committee played an important role in refining how the results were interpreted and integrated across datasets.
A major contributor was the extended collaboration with Dr. Cherrington, with whom this dataset was interpreted over the course of more than a year. The iterative, hands-on process of working through complex results together, often at a whiteboard, was essential for shaping the final conclusions and ensuring that the physiology was interpreted rigorously and cohesively.
Where is this research taking you next?
We aim to better define the molecular mechanisms that regulate the second-meal effect in the liver. While this study shows that prior hormonal conditions can influence how the liver responds to a later metabolic challenge, the underlying gene and protein networks that drive this response are still not fully understood.
To address this, we are preparing follow-up studies to identify coordinated changes in hepatic signaling pathways that control glucose uptake, storage, and production across sequential metabolic states. This approach will allow us to move beyond individual enzymes and capture the broader biological programs that determine how the liver integrates signals over time.
More broadly, this work will help connect whole-body physiological responses with the molecular pathways that govern them, providing a more complete understanding of how the liver adapts across meals and how this regulation may be altered in metabolic disease.
Go deeper
The paper “Morning glucagon disrupts insulin induced hepatic metabolic memory and subsequent afternoon glucose metabolism in canines” was published in Frontiers in Endocrinology in April 2026.
Funding
This research used funds from the National Institutes of Health.
Open access
The study was published open access through a transformative agreement negotiated by Vanderbilt University’s Jean and Alexander Heard Libraries. Transformative agreements eliminate traditional paywalls and remove the obstacle of article processing charges, ensuring immediate and unrestricted access to research worldwide. Vanderbilt authors can learn more about the Heard Libraries’ agreements supporting open access publishing in this research guide.