Diabetes Research: Genes, GLP-1s, Exercise Timing & More

Dr Jedha, Host

Hello wonderful people, thanks for joining me for episode 123. Today, we’re exploring some fascinating new studies and headlines from the world of diabetes, metabolism, weight loss, and overall health.

As always, the goal here isn’t just to throw research papers at you. It’s to help translate what this information might actually mean in real life, and how you can use it to better understand your body, your metabolism, and your health.

Let’s start today’s discussion focused on a common medication – Metformin.

If you’ve been around the diabetes space for any length of time, you’ve almost certainly heard of metformin. It’s one of the most commonly prescribed medications for type 2 diabetes and prediabetes worldwide and has been around for decades.

So naturally, you’d assume researchers and doctors fully understand exactly how it works by now, right?

Well… not exactly.

A new paper by Sebo and colleagues highlights something really fascinating and surprising – researchers are still uncovering new mechanisms behind metformin’s effects.

And I think this is such an important reminder of how complex metabolism really is.

For years, metformin was thought to primarily work through the liver by reducing glucose production. That’s still considered part of the story, but this newer research suggests the intestine may play a much bigger role than previously thought.

What the researchers found is that metformin appears to inhibit something called mitochondrial complex I within intestinal cells.

Now don’t worry too much about the terminology there.

What’s important is that mitochondria are basically the energy-producing structures inside our cells. And according to this paper, metformin may alter how intestinal cells handle energy and glucose, essentially turning parts of the intestine into what researchers describe as a kind of “glucose sink.”

In other words, the intestine may start pulling more glucose out of circulation and using it up.

That’s really interesting because it helps explain some things we’ve observed clinically for years:

• why metformin can improve post-meal blood sugar
• why it increases glucose uptake in the intestine
• and potentially why gastrointestinal side effects are so common

Another fascinating detail from the paper is that metformin concentrations in the intestine are dramatically higher than what’s found in the bloodstream.

So the intestine isn’t just some passive organ sitting in the background here. It may actually be one of the major sites where metformin exerts its effects.

And I think there’s a broader lesson in all this.

Sometimes people talk about diabetes as though it’s very simple: “Blood sugar is high, just lower it.”

But the deeper science goes, the more we see that metabolism is interconnected with:

• mitochondrial function
• energy production
• circadian rhythms
• hormones
• the gut
• muscle
• the brain
• and so much more

This is also why there’s rarely one single magic solution.

And perhaps most importantly, it reminds us that science evolves.

Even with one of the oldest and most widely used diabetes drugs in the world, there are still unanswered questions and new discoveries being made.

So if you ever feel confused because nutrition advice or diabetes science seems to change over time, that’s partly because we are still learning.

And speaking of metabolism changing throughout the day… let’s move into the next study.

Recently in episode 120 we spoke about whether exercise helps to lower blood sugar, and overall, the answer is yes. Alongside nutrition, movement is another powerful tool we have for improving insulin sensitivity and blood sugar control. But what about the timing of your exercise, does that have any additional influence on blood sugar? As it turns out, this is an area of research that’s becoming increasingly interesting. 

A new paper focused heavily on circadian rhythms, which are essentially your body’s internal clocks that regulate things like:

• hormone release
• sleep and wake cycles
• insulin sensitivity,
• energy production
• and glucose metabolism

Now in healthy metabolism, many of these systems follow fairly predictable daily patterns. But in type 2 diabetes, those rhythms can become disrupted. And one of the really interesting things the researchers discuss is that insulin sensitivity changes throughout the day.

In people with type 2 diabetes, afternoon and evening exercise often appears to improve blood sugar control and insulin sensitivity more effectively than morning exercise. That doesn’t mean morning exercise is “bad.” But it may help explain something many people notice with their glucose readings.

For example, some people wake up with elevated fasting glucose, then go for a morning walk or workout, and their glucose actually rises instead of falls

And they think: “Wait… I thought exercise was supposed to lower blood sugar?”

But the body is more nuanced than that. In the morning, cortisol levels naturally rise — what’s often called the cortisol awakening response. Combined with the dawn phenomenon, the liver may release more glucose into circulation. 

So depending on:

• the timing
• the intensity
• the type of exercise
• stress levels
• sleep quality
• and the individual person…

you may see different glucose responses.

The paper also discusses how exercise acts as a time cue for the body clock. In simple terms, movement may help “reset” or reinforce healthier metabolic rhythms. Now of course, when it comes to exercise, consistency still matters more than perfection.

The best exercise is still the one you’ll actually do regularly, so if mornings are the only time you can exercise, that’s still fantastic. But if you’re someone struggling with stubborn fasting glucose or large post-meal spikes, this research suggests it may be worth experimenting with:

• post-dinner walks
• afternoon resistance training
• or even short movement sessions after meals

Certainly we know movement after meals is a highly effective strategy to lower post-meal glucose and A1c levels, something we talked about in episode 89. 

When we look at this research, I think that’s one of the biggest practical lessons here and something to remember: your blood sugar is not static.

It changes throughout the day in response to:

• food
• hormones
• Stress
• sleep
• movement
• and circadian rhythms – your sleep/wake cycle

Which is why understanding your own patterns is often far more useful than chasing one perfect number.

Now let’s move into one of the biggest stories in medicine right now — GLP-1 medications and obesity treatment.

You’ve probably seen the headlines everywhere lately:
“Record-breaking weight loss.”
“Game-changing drugs.”
“Obesity treatment revolution.”

These days it seems that GLP-1s are everywhere and we spoke about Ozempic and Wegovy back in episode 55, sharing many facts surrounding  these medications. 

Recently, Novo Nordisk released new analyses from their STEP UP trial looking at higher-dose Wegovy, or semaglutide, we’re talking massive dosage jumps from 2.4mg a day up to 7.2mg day.

The results are certainly impressive on the surface. In what they called “early responders,” people taking the higher 7.2 mg dose lost an average of nearly 28% of their body weight over 72 weeks. That’s enormous. And there’s no question these medications can produce substantial weight loss and improvements in blood sugar in many people. But I think it’s important we look beyond the headline numbers and ask a deeper question: What exactly is being lost?

Because when people lose weight rapidly, they’re not just losing fat.

They can also lose:

• muscle
• bone density
• water
• and other metabolically important tissue

This is something we covered in episode 55 and there is research to confirm these effects. Now in the press release, Novo Nordisk states that 84% of the weight loss came from fat mass, while muscle function was preserved. And that sounds reassuring. But there are a few important caveats here.

First, the body composition analysis was only done in a very small subgroup — just 55 participants. Second — and this is important — the press release appears to combine results from both the 2.4 mg and 7.2 mg semaglutide groups together when discussing body composition. So technically speaking, we don’t actually know from this new analysis whether the higher dose caused greater lean mass loss. And that matters. Because even the company reports around a 10% reduction in muscle mass relative to baseline.

Now some people might hear “only 10%” and think that sounds small. But muscle is incredibly important. Muscle is metabolically protective, critical for insulin sensitivity, important for glucose disposal, essential for healthy aging, balance, mobility, and long-term independence. And one of the major concerns with rapid weight loss — especially in older adults — is that regaining lost muscle is much harder than regaining fat.

That’s why I think we need to be careful not to reduce health down to a single number on the scales. Because yes, losing excess body fat can absolutely improve metabolic health.

But ideally, we want fat loss while preserving muscle, preserving strength, preserving bone health, and maintaining metabolic resilience. And this is where I think the conversation around these medications sometimes becomes overly simplistic online.

People get pushed into extremes: either “these drugs are amazing” or “these drugs are terrible.” But reality is usually more nuanced than that. These medications may absolutely help some people.

But they are not a replacement for adequate protein intake, resistance training, movement, sleep, stress management, and building long-term sustainable habits. Because ultimately, health is not just about becoming smaller. It’s about maintaining a body that is metabolically healthy, physically capable, and resilient long term.

So if someone is using a GLP-1 medication, I think the conversation should shift beyond simply: “How much weight did you lose?”

And instead include:

• How much muscle was preserved?
• Are you maintaining strength?
• Are you eating enough protein?
• Are you physically active?
• How is your energy?
• How sustainable is this long term?

Because those questions matter too.

So let’s move into the next paper, because this one is incredibly fascinating, because it highlights something we don’t talk about enough in diabetes and metabolic health. And that’s the connection between metabolism, mood, and the brain.

The study by Raffaelli and colleagues looked at insulin resistance, metabolic dysfunction, brain structure, and cognition in people with mood disorders like depression and bipolar disorder. Now, we often think about insulin resistance purely in terms of blood sugar, diabetes, weight, or cardiovascular risk. But insulin is doing much more than just regulating glucose.

The brain itself is highly metabolically active and contains insulin and leptin receptors in areas involved in memory, learning, emotional regulation, and cognition.

And what the researchers found was that markers of insulin resistance and leptin dysregulation were associated with poorer cognition and structural brain changes, particularly in people with bipolar disorder. Now, this doesn’t mean insulin resistance is the sole cause of mood disorders. Mental health is complex and multifactorial. But I think it reinforces the idea that metabolism and brain health are deeply interconnected. And this is something we see clinically all the time.

People with insulin resistance or poorly controlled blood sugar often report brain fog, fatigue, low motivation, poor concentration, disrupted sleep, mood changes, depression, and emotional burnout. And unfortunately, many people blame themselves for these experiences.

They think: “I’m just lazy.” “I have no willpower.” “I can’t stay motivated.” But biology matters. Hormones matter. Sleep matters. Inflammation matters. Metabolic health matters. And interestingly, the paper also discusses leptin.

Now most people think of leptin simply as a “satiety hormone,” – a hormone related to our feeling of fullness and appetite control, but leptin also plays important roles in brain signaling and cognition. When metabolic health becomes disrupted, those signaling systems may become dysregulated too. And I think this opens up a really important broader conversation: that our overall metabolism and metabolic health is about far more than weight or glucose numbers.

It influences how we think, how we feel, our energy levels, our resilience, and potentially even long-term brain health. It’s so interesting, and it’s why it’s so important to take a holistic view and have patience with yourself and your body when you’re working on treating your diabetes. You can make positive changes that turn your whole system around, the body is very intelligent like that, but it takes time. 

Now this next one is a little more science-heavy, but it’s also incredibly interesting. It’s another reminder that even in 2026, researchers are still uncovering completely new aspects of human metabolism. A potentially new discovery involving mechanisms iof glycogen regulation. Glycogen is basically the storage form of glucose.

Think of it as stored carbohydrate, mainly in the liver and muscle tissue. The liver uses glycogen to help maintain blood glucose levels between meals and overnight, while muscles use glycogen locally during movement and exercise.

So glycogen sits right at the center of blood sugar regulation, insulin sensitivity, exercise performance, fasting glucose, and overall metabolic flexibility.

And what researchers found here is that there may be a previously unrecognized mechanism involving ubiquitin — a molecule traditionally known for helping label proteins for recycling or breakdown. But now researchers are discovering it may also play a direct role in glycogen regulation itself. And some scientists involved described this as potentially “rewriting biology textbooks.”

Now whenever you hear phrases like that, it’s important not to get carried away because science headlines can sometimes overstate findings. But I still think the bigger message here is fascinating: our understanding of metabolism is still evolving. Even something as fundamental as glycogen — which we’ve known about for a very long time — may still contain hidden layers of regulation we didn’t fully appreciate. And this actually connects back to many things we talk about regularly in diabetes management.

It may help explain why fasting glucose can fluctuate, why stress impacts blood sugar, why exercise changes glucose handling, why some people tolerate carbohydrates differently, and why liver glucose output can become dysregulated in insulin resistance. Because underneath all of that is this incredibly complex network involving glycogen storage, glycogen release, hormones, mitochondria, circadian rhythms, muscle activity, and energy sensing systems. This is very early research, so practically speaking, it doesn’t suddenly change what people should do tomorrow morning. 

It’s just so fascinating. Metabolism is dynamic, adaptive, responsive, and deeply interconnected.

Let’s finish with a very hopeful study, especially for those with diabetes running in the family. Because in these cases, people often think, well, I’m just destined to get diabetes, it’s in my genes after all. 

And yes, genetics absolutely play a role in type 2 diabetes risk. But this large study by Zhao and colleagues reinforces something really important: genes are not destiny. The researchers looked at more than 332,000 people from the UK Biobank and examined both genetic risk and lifestyle factors together. And unsurprisingly, people with a higher genetic risk were more likely to develop type 2 diabetes. But what’s really important is what happened when lifestyle factors entered the picture.

The study found that unhealthy lifestyle behaviors dramatically increased diabetes risk across all levels of genetic risk. In other words, even if someone had a strong genetic predisposition, lifestyle still mattered enormously. And perhaps even more encouraging, people at high genetic risk could substantially lower their risk through healthier lifestyle habits. Now I think this is such an important message because genetics can sometimes make people feel powerless, like the outcome is already decided. But genes are really more like a predisposition, not a guarantee.

You may inherit a greater susceptibility toward insulin resistance or type 2 diabetes, but environmental and lifestyle factors still strongly influence whether those genes are expressed and to what degree. And this aligns with what we see clinically all the time. Two people can have very similar family histories but very different outcomes depending on their nutrition, movement patterns, sleep, stress levels, body composition, muscle mass, and overall health.

Now that doesn’t mean lifestyle guarantees perfect protection, and it certainly doesn’t mean people should blame themselves if they develop diabetes. But I think this study provides a really empowering middle ground. Your genes matter, but your daily habits matter too.

And importantly, meaningful improvements in your overall health often come from relatively simple but consistent actions repeated over time. Not perfection. Not extremes. Not trying to biohack every aspect of life. Just steadily improving the factors we can influence.

So wonderful people, I think that’s a really fitting way to end today’s episode.

Every study we discussed today points toward the same bigger picture: metabolism is complex, interconnected, and constantly adapting.

We’re still learning how medications work. We’re still uncovering new biological mechanisms. We’re learning that timing matters, muscle matters, sleep matters, mental health matters, and nutrition and lifestyle still matters even in the face of genetic risk.

And hopefully what this episode shows is that understanding your body is far more valuable than chasing simplistic answers or quick fixes. Because the goal isn’t perfection. It’s learning the patterns, making informed adjustments, and building a healthier metabolism over time.

All you have to do is take small positive steps forward each and every day. 

Dr Jedha, over and out.