Liver-Pancreas Crosstalk: The Silent Breakdown Driving Insulin Resistance

What You’ll Discover Inside:

• What most practitioners miss by focusing only on glucose, A1C, or symptoms
• How to spot early-stage metabolic collapse while there’s still time to reverse it
• Why blood sugar may be the last thing to change and what starts breaking down long before
• The overlooked conversation between two metabolic powerhouses and what happens when it goes quiet
• How hidden hormone signals spark a chain reaction of dysfunction no one’s talking about
• The surprising reason some clients wake up with high glucose even on a “perfect” diet
• Clues your clients are missing the mark, not because of willpower, but because of broken feedback loops

Resources and Links:

• See the Full Transcript here
• Download our FREE Glucagon, Insulin, and Blood Sugar chart.  
• Download our FREE Proinsulin, Insulin, and C-Peptide Chart
• Join the Next-Level Health Practitioner Facebook group here for free resources and community support
• Reserve your spot for The REINVENT HEALTHCARE Intensive Learn Proven,​​ Leading-Edge Frameworks to Enhance Clinical Skills, Improve 
• Visit INEMethod.com for advanced health practitioner training and tools to elevate your clinical skills and grow your practice by getting life-changing results. 
• Check out other podcast episodes here

What’s Inside This Episode?

• A conversation your client’s blood sugar is already having—between liver, pancreas, insulin, and glucose
  
• Why fatty liver disrupts insulin clearance and leads to silent hyperinsulinemia
  
• The glucagon paradox: how this “forgotten hormone” can drive glucose production even in the fed state
  
• Beta-cell stress decoded: how proinsulin and C-peptide ratios uncover hidden dysfunction
  
• The truth about “normal” A1C—and why it may just mean the pancreas is compensating
  
• What poor insulin clearance looks like—and how to spot liver stress using routine labs
  
• How and when to use labs like proinsulin, fasting glucagon, and FIB-4
  
• Natural strategies to restore liver-pancreas harmony with fasting, circadian alignment, and targeted nutrients
  

Transcript

Dr Ritamarie 

Behind every blood sugar reading is a hidden conversation. It's a conversation between the liver and the pancreas, between insulin and glucose, and between production and clearance. When that communication is strong, the system stays balanced. But when it breaks down silently, often years before glucose becomes abnormal, it sets the stage for metabolic collapse. And here's the catch.

Most practitioners are only listening to one side of the story. If we want to truly reverse insulin resistance, we need to understand the liver pancreas dialogue, not just the symptoms it creates. 

And on today's episode, we're talking about the metabolic crosstalk between two of the most powerful regulators of the body, the liver and the pancreas. We'll explore how fatty liver impairs insulin clearance, how the pancreas ramps up production in response, and how the feedback loops begin to spiral out of control. 

We'll learn how glucagon misfires, how beta cell stress starts years before blood sugar rises, and how lab markers like C-peptide and pro-insulin can reveal what glucose tests miss entirely. 

So most importantly, I'm going to show you how to identify these patterns early on, before they land you on a blood sugar roller coaster. So let's dive in.

The liver and the pancreas are metabolic partners, and they need to operate in balance. In a healthy system, the liver and pancreas operate as a metabolic team. The pancreas releases insulin after meals to help store glucose and signal the liver to stop producing glucose. During fasting, the liver listens to glucagon, also produced by the pancreas, which tells it to release glucose and maintain energy balance.

Dr Ritamarie (03:14.562)

The liver also helps clear insulin after its job is done. About 50% of insulin is removed during its first pass through the liver. This balance between insulin production and clearance keeps the system finely tuned. 

So what happens when the communication breaks down? In insulin resistance, especially in the presence of fatty liver, the feedback loop begins to fail. The liver can't clear insulin effectively when there's fat accumulation.

This leads to chronic hyperinsulinemia, high insulin, even when the pancreas isn't overproducing insulin, yet. Over time, the pancreas senses that the insulin isn't working and begins ramping up production to compensate. The result is high insulin from both impaired clearance and increased production. This overstimulation downregulates insulin receptors and drives insulin resistance system-wide.

So what's the story with glucagon? Insulin's often forgotten sibling and partner in the task of glucose regulation. Normally, glucagon, considered the counter hormone to insulin, is elevated during fasting to help release glucose. But in insulin resistant people, glucagon levels often stay high even in the fed state. This means that the liver's getting conflicting messages. Insulin says store, but glucagon says release.

The insulin resistance that happens causes the liver to be more sensitive to glucagon than to insulin, which amplifies hepatic glucose output and contributes to persistent high glucose, hyperglycemia. As liver dysfunction worsens, the pancreas continues to compensate. This leads to markers like C-peptide being elevated, which is a marker of total insulin secretion and also elevated pro-insulin, which is an early marker of beta cell stress.

Eventually the beta cells become overworked, the beta cells which produce insulin. And that can lead to the failure to produce adequate insulin. This starts happening often years before the blood sugar becomes abnormal. As I say all the time, blood sugar is the last thing to change. And as we're using that as the marker for metabolic distress, we're missing people who have earlier signs and can be helped a lot sooner to prevent the downfall. 

A normal A1C doesn't mean the metabolic system is working. It just means that the pancreas is still able to compensate. 

So here's how to detect early dysfunction. The lab marker that gives us a behind the scenes look at the pancreas is C-peptide.

Dr Ritamarie (05;11)

When the pancreas makes insulin, it actually starts by producing something called pro-insulin, which gets split into two parts, insulin, which does the blood sugar work, and C-peptide, which is actually biologically inactive, but it's an incredibly useful diagnostic tool. C-peptide is released in equal amounts to insulin, but it sticks around longer. So it gives us a much clearer picture of how much insulin the pancreas is truly producing. Here's where it gets clinically powerful.

In both insulin and C-peptide, if they're both high, the pancreas is working over time, usually due to insulin resistance. If insulin is high, but C-peptide is low, the problem may be poor insulin clearance and can be a sign of liver dysfunction. And if C-peptide is low, it tells us the pancreas is struggling to keep up. It may be exhausted or damaged. 

So when we're trying to understand whether somebody is insulin resistant, insulin deficient, or just not clearing insulin well, C-peptide becomes a critical part of the puzzle. And unlike insulin, it's not affected by insulin injections. So people who are on insulin therapy, it helps to be able to measure this C-peptide.

Dr Ritamarie (06:25)

Another lab marker that's not routinely tested, and should be, is pro insulin. Pro insulin is the raw form of insulin, the molecule the pancreas produces, before it's split into insulin and C-peptide. And under normal conditions, pro insulin gets processed cleanly. But when the beta cells are under stress, like in early insulin resistance, they start releasing more unprocessed pro insulin into the bloodstream. So again, it's an early marker.

So when you see elevated pro insulin, it's a red flag that the pancreas is struggling. It's working over time, but not efficiently. This often shows up before the big shifts in insulin or blood sugar. 

One of the most insightful patterns is the pro insulin to C-peptide ratio. When that ratio is high, it tells us the beta cells are dysfunctioning, even if they're still producing enough insulin for now. In other words, pro insulin gives us an early warning sign that the metabolic machinery is starting to break down, before we hit full-blown diabetes. And wouldn't people like to know that this is all a wreck, before they become diabetic, so we can turn it around? 

If you're listening in, you can see a helpful chart in the show notes on the podcast page. Here's a chart that shows the relationship between pro-insulin, insulin, and C-peptide. 

We can also test glucagon, which is rarely done, but it can be useful in select cases to assess fasting versus post meal dynamics. Glucagon is made by the alpha cells in the pancreas, and its job is the exact opposite of insulin, as we've been saying. It tells the liver to release glucose by breaking down glycogen and making new sugar from proteins and fats. That process is called gluconeogenesis. 

Dr Ritamarie (08:08)

But here's the problem. In people with insulin resistance or fatty liver, glucagon levels are often too high and when they're not supposed to be. This leads the liver to overproduce glucose, especially while fasting. And it's one reason why people can have high blood sugar, even if they haven't eaten. I hear this all the time in my patients and my clients that go through our Sweet Spot Solution. 

So testing glucagon can give a deeper look as to why someone's glucose is elevated, especially if the insulin levels don't really explain it. But it's not a common test. You won't find it on most standard lab panels. It has to be drawn on very specific conditions. The blood has to be collected in special tubes, kept cold, and processed quickly. It's also not a marker you'd test frequently, because it's more of a snapshot, not something we use to track over time. 

So when should you test glucagon? I recommend considering it in cases of unexplained high fasting glucose, or when you suspect the liver is overproducing sugar despite recent insulin output. A fasting glucagon level tends to be the most informative. If it's high, it tells us that the liver is getting the wrong message, essentially being told to dump sugar into the bloodstream, even when the tank is already full. 

If you're listening, I suggest you take a look at the glucagon, insulin, and C-peptide comparison chart in the show notes. Here's a chart comparing glucagon, insulin, and C-peptide. 

All of the pancreas markers should be paired with these markers to get a fuller picture. ALT, AST, GGT, FIB-4, which is a combination formula, which I talked about in our previous episode, and triglyceride:HDL ratio.

These patterns help you catch metabolic disease and breakdown, before it becomes diabetes. And isn't that what we want? To prevent the damaging effects of diabetes? 

To restore balance between the liver and the pancreas, consider these lifestyle and nutrition actions. 

One, intermittent fasting or time-restricted eating helps to reduce insulin burden and allows the liver insulin clearance to improve. Include nutraceuticals like berberine and bitter melon and inositol and other liver supporting herbs, those can be helpful. 

Prioritize sleep, movement, and low fructose nutrition to help hepatic fat. Use phased insulin testing to track improvements over time. This is not just about blood sugar. It's about preserving pancreatic function and restoring liver detox and insulin sensitivity.

We are the future of healthcare, those of us committed to putting the care back in healthcare, not going into just symptom suppression, but really addressing the root causes of imbalance. If the pancreas and liver aren't communicating well, the whole system breaks down. But if we catch the early signs before glucose becomes a problem, we can reverse the process and prevent irreversible damage. 

I've dedicated my life to empowering people to take charge of their health and to mentoring practitioners who want to make a real difference by using food, lifestyle, and functional insights to transform lives. 

If you're ready to take your practice to the next level, visit INEmethod.com. And if you want to explore insulin resistance in more depth, check out our other podcast episodes and head over to the show notes where I'll put some links to powerful tools and charts for additional trainings. Thank you, and let's together continue the movement to reinvent healthcare. 

And until next time, shine on.