How a cellular enzyme regulates glucose production and offers new hope for diabetes treatment
Imagine your body as a sophisticated energy management system that must maintain perfect blood sugar levels around the clock—whether you've just enjoyed a meal or are sleeping through the night. At the heart of this system lies your liver, performing a crucial balancing act between storing and producing glucose. When this delicate balance is disrupted, type 2 diabetes can develop, characterized by dangerously high blood sugar levels. For decades, scientists have sought to understand the precise mechanisms controlling the liver's glucose production. Now, emerging research has uncovered a surprising new player in this process—a cellular enzyme called Ubiquitin-Specific Protease 2 (USP2)—that offers exciting new possibilities for diabetes treatment 5 .
People worldwide with diabetes (2019)
In diabetes prevalence since 1980
Annual global health spending on diabetes
This discovery represents a significant advancement in our understanding of metabolic health, connecting dots between our circadian rhythms, nutritional status, and fundamental cellular processes. The story of USP2 reveals how our bodies coordinate complex biological signals to maintain energy balance, and what happens when this coordination falters. As we explore this fascinating regulatory pathway, we'll uncover how a single enzyme influences blood sugar, how researchers discovered its importance, and why this finding might eventually lead to innovative diabetes therapies.
Gluconeogenesis, literally meaning "the creation of new glucose," is the metabolic pathway through which the liver produces glucose from non-carbohydrate sources during fasting periods. When you haven't eaten for several hours—such as overnight—your body must manufacture glucose to maintain adequate blood sugar levels for brain function and other essential processes. The liver achieves this by converting compounds like lactate, glycerol, and amino acids into glucose, which is then released into the bloodstream 1 .
This process stands in direct contrast to glycolysis (the breakdown of glucose for energy) and is critically important for survival. However, in type 2 diabetes, gluconeogenesis becomes abnormally active, resulting in excessive glucose production that contributes to high blood sugar levels even when the person hasn't eaten. This diabetic hyperglycemia stems from a failure of the normal control mechanisms that should suppress glucose production when it isn't needed 5 .
Gluconeogenesis is tightly controlled by a complex interplay of hormonal and circadian signals:
Insulin suppresses gluconeogenesis after meals, while glucagon and glucocorticoids stimulate it during fasting 1 .
Our internal body clocks ensure that glucose production follows daily rhythms, peaking just before we wake to prepare us for the day ahead 1 .
Key enzymes in the pathway, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), are regulated at the genetic level 1 .
Key Insight: Until recently, the discovery of USP2 added a new dimension to this understanding by introducing protein stabilization as a previously overlooked regulatory mechanism.
To appreciate the significance of USP2, we first need to understand the ubiquitin system—a fundamental cellular process that was the subject of the 2004 Nobel Prize in Chemistry. Ubiquitin is a small protein that can be attached to other proteins, essentially marking them for destruction by the cellular recycling machinery (the proteasome). This "kiss of death," known as ubiquitination, ensures that proteins are broken down when they're no longer needed 5 .
Deubiquitinating enzymes, including USP2, perform the reverse operation—they remove ubiquitin tags from proteins, thereby rescuing them from destruction and extending their functional lifespan. This dynamic process of ubiquitination and deubiquitination allows cells to rapidly adjust protein levels without waiting for new protein synthesis 1 5 .
The discovery of the ubiquitin system earned Aaron Ciechanover, Avram Hershko, and Irwin Rose the Nobel Prize in Chemistry in 2004, highlighting the fundamental importance of this cellular process.
Researchers made a crucial breakthrough when they decided to screen for deubiquitinating enzymes that respond to nutritional status. They examined the livers of mice under different feeding conditions—freely fed, fasted, and refed—and made a striking discovery: among 47 ubiquitin-specific protease family members, USP2 stood out as being significantly induced by fasting 1 .
Further investigation revealed that this nutritional regulation was specific to one variant of the enzyme, USP2-45, whose mRNA levels increased approximately 3.2-fold during fasting. Interestingly, this response was liver-specific, with other tissues like white fat and muscle showing little change in USP2 expression. Additionally, USP2-45 displayed a clear circadian rhythm in the liver, with levels peaking as mice prepared for their active phase (the equivalent of our morning) 1 .
The hormonal signals controlling USP2 expression were equally telling. In cultured liver cells, glucocorticoids (stress hormones that stimulate glucose production) robustly induced USP2-45, an effect that was further enhanced by glucagon and strongly suppressed by insulin. This pattern perfectly matches what we would expect for a genuine regulator of gluconeogenesis 1 .
To definitively establish USP2's role in glucose metabolism, researchers designed a comprehensive set of experiments using multiple approaches 1 :
Introducing extra USP2 into mouse livers using engineered viruses
Using RNA interference to reduce USP2 levels
Identifying downstream targets and molecular pathways
This multi-pronged strategy allowed the team to examine both what happens when USP2 is overactive and when it's suppressed, providing a complete picture of its biological function.
The results were striking. When researchers introduced additional USP2 into the livers of normal mice, these animals developed significant glucose intolerance—their blood sugar levels remained elevated for longer periods after a glucose challenge. Conversely, when USP2 was knocked down in obese, diabetic mice, their systemic glycemic control improved markedly 1 .
| Experimental Condition | Effect on Gluconeogenic Genes | Effect on Blood Glucose | Impact on Glucose Tolerance |
|---|---|---|---|
| USP2 overexpression | Increased | Elevated | Worsened |
| USP2 knockdown | Decreased | Reduced | Improved |
| Control (normal) | Baseline | Normal | Normal |
These effects were traced back to changes in the liver's glucose production. Mice with elevated USP2 levels showed increased glucose output, while those with reduced USP2 produced less glucose. This demonstrated that USP2 wasn't merely correlated with glucose metabolism—it was actively controlling it 1 .
Having established that USP2 influences glucose production, the critical question became: how? The answer emerged when researchers discovered that USP2 strongly induces the expression of 11β-hydroxysteroid dehydrogenase 1 (HSD1), an enzyme that activates glucocorticoid hormones within the liver 1 .
HSD1 performs a crucial conversion—it transforms inactive cortisone (in humans) or dehydrocorticosterone (in rodents) into active cortisol or corticosterone. These active glucocorticoids then bind to their receptors and directly stimulate the expression of gluconeogenic enzymes, thereby increasing glucose production 1 .
Experimental Confirmation: To confirm that HSD1 was essential for USP2's effects, the researchers conducted two key experiments. First, they used a pharmacological inhibitor of HSD1 called carbenoxolone (CBX). Second, they employed liver-specific RNA interference to knock down HSD1 directly. In both cases, blocking HSD1 activity significantly impaired USP2's ability to stimulate gluconeogenesis, demonstrating that HSD1 is a crucial downstream mediator of USP2's effects 1 .
| Protein | Function | Role in Gluconeogenesis |
|---|---|---|
| USP2 | Deubiquitinating enzyme | Removes ubiquitin from target proteins, stabilizing them |
| HSD1 | Enzyme that activates glucocorticoids | Converts inactive glucocorticoids to their active forms |
| Glucocorticoid receptor | Transcription factor | Binds active glucocorticoids and activates gluconeogenic genes |
| PEPCK | Gluconeogenic enzyme | Key regulatory step in glucose production |
| C/EBPα | Transcription factor | Regulates HSD1 expression; potential USP2 target |
Further experiments revealed that USP2 stabilizes the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) by removing its ubiquitin tags. Since C/EBPα is known to regulate HSD1 expression, this finding completed the molecular pathway: USP2 deubiquitinates and stabilizes C/EBPα, which then increases HSD1 expression, leading to enhanced local glucocorticoid activation and subsequent stimulation of gluconeogenesis 1 5 .
Fasting induces USP2 expression through hormonal and circadian signals
USP2 deubiquitinates and stabilizes the transcription factor C/EBPα
C/EBPα increases expression of HSD1, enhancing local glucocorticoid activation
Active glucocorticoids bind receptors and activate gluconeogenic genes
This mechanism also helps explain the circadian regulation of glucose metabolism. Our liver's sensitivity to glucocorticoids follows a daily rhythm, and USP2—itself regulated by the core clock component BMAL1—appears to be an important part of this timing mechanism 1 5 .
The discovery of USP2's role in gluconeogenesis opens up exciting possibilities for diabetes treatment. Current diabetes medications that target glucose production work through various mechanisms, but none directly address the deubiquitination pathway. Developing USP2-specific inhibitors could offer a novel therapeutic approach that might benefit patients who don't respond adequately to existing treatments 5 .
This approach might be particularly valuable because USP2 appears to function as a central node that integrates multiple signals—nutritional status, hormonal cues, and circadian rhythms. Targeting such a integrative regulator might provide more precise control over gluconeogenesis than addressing individual components alone.
The study of USP2 relies on sophisticated research tools that allow scientists to precisely manipulate and measure its activity:
| Research Tool | Application | Utility in USP2 Research |
|---|---|---|
| Adenoviral vectors | Gene delivery | Allows introduction of USP2 into liver cells |
| RNA interference | Gene knockdown | Enables reduction of USP2 levels in specific tissues |
| Primary hepatocytes | Cell culture model | Provides isolated liver cells for mechanistic studies |
| Quantitative PCR | Gene expression analysis | Measures mRNA levels of USP2 and related genes |
| Chromatin immunoprecipitation | Protein-DNA interaction study | Identifies direct transcriptional targets |
While the initial findings are promising, translating this discovery into clinical applications will require considerable additional research. Scientists need to develop specific USP2 inhibitors that don't affect related enzymes, test these compounds in animal models, and eventually conduct human trials. Additionally, since USP2 may have functions beyond glucose control, researchers must carefully evaluate potential side effects of inhibiting it 5 .
Compound Screening
Identify USP2 inhibitorsPreclinical Testing
Animal model validationClinical Trials
Human safety & efficacyTherapeutic Use
Patient treatmentNevertheless, the uncovering of USP2's role represents a significant step forward in our understanding of metabolic health. It illustrates how basic scientific research into fundamental cellular processes can reveal unexpected insights with important medical implications.
The discovery of USP2's role in controlling hepatic gluconeogenesis showcases how much we still have to learn about the intricate systems that maintain our health. What began as a survey of deubiquitinating enzymes has revealed a key regulatory pathway that connects our circadian rhythms, nutritional status, and cellular protein management to glucose metabolism.
This story also highlights the beauty of scientific discovery—how following curious observations (a fasting-induced enzyme) can lead to unexpected insights and potential new therapeutic approaches. As research continues to unravel the complexities of metabolism, USP2 stands as a promising example of how understanding fundamental biology can open doors to innovative treatments for common conditions like type 2 diabetes.
Final Thought: While much work remains before USP2-targeted therapies might become available, this discovery reinforces the importance of supporting basic scientific research. You never know when the study of an obscure cellular enzyme might shed light on one of humanity's most pressing health challenges—and offer new hope for millions living with diabetes.