Introduction: Overcoming Insulin Resistance with T1D

Welcome to this three-part series on insulin resistance in type 1 diabetes.

In Part 1(this part), we introduce what insulin resistance is, define what it looks like in T1D, and why it matters.

Part 2 explores the eight main causes of insulin resistance.

In part 3, we dive into seven practical solutions to improve insulin sensitivity.

If you prefer a Podcast, listen to Episode 14.

This has been one of my favourite projects to put together, I hope you enjoy it!

Insulin resistance is often framed as a ‘type 2 diabetes issue,’ but it’s time to rethink that narrative because it plays a critical role in type 1 diabetes (T1D) too.

How?

Strong evidence indicates that as insulin resistance increases, the risk of cardiovascular events (heart attacks and strokes) and all-cause mortality (death) rises in a dose-response manner for people with T1D.

Why are people with T1D at high risk of insulin resistance?

We know that people with T1D don’t produce insulin, but that doesn’t mean they’re immune to insulin resistance. Delivering insulin into the subcutaneous (fat) tissue and not directly into the portal vein creates unique challenges that makes insulin resistance more of a problem for people living with T1D!

The classic “eat carbs, take insulin” model assumes that insulin is always effective. But when insulin resistance kicks in, the same dose stops working as well. Blood glucose control becomes erratic, insulin requirements creep up, and glucose swings become harder to manage.

This diagram gives you some idea of what people with T1D have to deal with when it comes to insulin resistance.

However, the DAG effect only explains one of the eight causes of insulin resistance.

So, it’s time to find out about the other seven.

Introducing,

The Ominous Octet of Insulin Resistance

This post is not my original work!

It’s an application of key insights garnered from three of my favourite Podcasts episodes and associated reading!

337 – Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.

140 – Gerald Shulman, M.D., Ph.D.: A masterclass on insulin resistance—molecular mechanisms and clinical implications

#87 – Rick Johnson, M.D.: Metabolic Effects of Fructose

All episodes are from The Drive hosted by Peter Attia (one of my mentors, though he does not know me!). I have a fantasy (not in a weird way of course!) that he will be on The GNL Podcast one day!

I doubt you’ll want to spend 25 hours listening (yes, I’ve listened to each episode three times) and another 25 hours creating notes and diagrams to develop a deep understanding.

To make things easier, I’ve created;

The Glucose Never Lies® Insulin Resistance Guide

Let’s begin.

The Ominous Octet framework was originally developed by Dr. Ralph DeFronzo, one of the world’s leading experts on insulin resistance. The eight causes are explained beautifully in the incredible ” Master Class in Insulin Resistance“.

The Octetet describes the eight key dysfunctions driving insulin resistance.

While the Ominous Octet is widely discussed in the context of type 2 diabetes, most of its principles also apply to type 1 diabetes. Therefore, I will focus on what it means for people living with T1D.

You’ll be glad to know that there are multiple ways to address each part of the Ominous Octet, and this pyramid is just a sneak peek!

The pyramid format helps illustrate how different solutions work together, considering three key factors: effectiveness, accessibility, and side effect profiles.

• Clear boxes represent lifestyle interventions.
• Dark boxes represent pharmacological options.

This is not medical advice. It’s for informational purposes only.

Why?

• Lifestyle changes often require adjustments to insulin doses. Without pre-planned adjustments, hypoglycemia is very likely.
• GLP-1 receptor agonists (GLP1-RA’s: Semaglutide and Tirzepatide) are not officially indicated for T1D in most guidelines. Research shows that insulin requirements are immediately reduced by around 30%. This can lead to serious hypo issues if insulin reductions are not pre-planned!
• SGLT-2 inhibitors may increase the risk of diabetic ketoacidosis (DKA) if not used carefully.
• Pioglitazone is often misunderstood and rarely prescribed. While it does cause weight gain, this is due to shifting fat from problematic areas (such as the liver, kidneys, and heart muscle) into subcutaneous fat tissue, where it is safer.

Now that’s clear, we’ll explore:

• How insulin resistance works mechanistically in eight different ways!
• Why it happens in T1D
• What can be done to fix it, through both lifestyle and pharmacology

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Defining Insulin Resistance in Type 1 Diabetes

The gold standard for measuring insulin resistance is the Hyperinsulinemic-Euglycemic Clamp, a research method that assesses how much glucose needs to be infused to maintain normal blood glucose levels while a high but steady dose of insulin is administered intravenously. Since the insulin level remains constant, greater glucose uptake indicates better insulin sensitivity. However, while this method is highly accurate, it is primarily used in research settings and is not practical for everyday clinical use.

In people with type 2 diabetes, insulin resistance is often assessed through fasting insulin levels or the HOMA-IR (Homeostatic Model Assessment of Insulin Resistance). However, measuring insulin resistance in type 1 diabetes is more complex because the body does not produce its own insulin. Instead, insulin resistance in T1D is typically evaluated using total daily insulin use. A higher total daily insulin dose relative to body weight (expressed in units per kilogram) can indicate increased insulin resistance, as more insulin is required to maintain glucose control.

How much insulin does an insulin-sensitive person without diabetes need?

In a healthy adult without diabetes, the body naturally produces around 35 units of insulin per day. This is considered insulin-sensitive and the lowest risk for health.

The average insulin dose for adults with T1D ranges from 0.4 to 1.0 units per kilogram (U/kg), but in some cases, it can be as high as 2.0 U/kg.

For example:

A 75 kg male typically requires 30–75 units of insulin, but this can go up to 150 units at the higher end. A 60 kg female typically requires 24–60 units, with a possible upper range of 120 units. Therefore;

• Less than 0.4 U/kg → Very insulin sensitive. About 14% of people with T1D
• 0.4–0.5 U/kg → Insulin sensitive. About 11% of people with T1D
• 0.5–0.7 U/kg → Insulin resistance. About 30% of people with T1D
• 0.7–1.0 U/kg → Significant insulin resistance. About 35% of people with T1D
• More than 1.0 U/kg → High insulin resistance. About 9% of people living with T1D
• Estimated from: DCCT data

For children aged 1–12, the same dose range as adults applies (0.4–1.0 U/kg).

However, from ages 12–18, due to hormonal changes, insulin needs increase slightly:

• Less than 0.4 U/kg → Very insulin sensitive. About 2% of people with T1D
• 0.4–0.6 U/kg → Insulin sensitive. About 11% of people with T1D
• 0.6–0.8 U/kg → Insulin resistance begins. About 29% of people with T1D
• 0.8–1.2 U/kg → Significant insulin resistance. About 53% of people with T1D
• 1.2 U/kg → High insulin resistance. About 5% of people living with T1D
• Imputed form: German DPV data

If you have just read that and thought OMFG!

“I have insulin resistance and need to get to 0.4-0.6 units per kg, like, erm, yesterday!”

Relax! You are no different to 90% of people living with T1D.

Using 0.4 units per kilogram of insulin is just like trying to achieve 90%+ time in range (3.9-10.0 mmol/L or 70-180 mg/dL). It’s an aspirational goal. However, it’s important to balance what it takes to get there with where you’re starting from.

• If you’re currently using >1.0 units/kg, that’s similar to having a 40% time in range. Improving from 40% to 50% is significant, just as reducing insulin from >1.0 units/kg to below 1.0 units/kg is meaningful.
• If you’re at 0.7 units/kg, that’s like a 60% time in range, and moving to 0.6 units/kg (~70% time in range) is a major improvement.

I could sit here feeling smug, saying I use just 35 units of insulin per day at 100 kg. This means my insulin requirement is 0.35 u/kg! That must mean I’m incredibly insulin-sensitive thanks to all the activity I do and my amazing diet, right?

Well… some of that is true. But there’s another factor at play. I still have measurable C-peptide levels between 100-150 pmol/L, meaning my beta cells aren’t completely out of the game yet. That residual insulin production is helping me a lot.

If you’re curious about C-peptide and whether it’s playing a role in your insulin needs, check out this article.

Many factors influence daily insulin needs, including ethnic background, gender, medications, sleep, and more. The information above is a general guide, but remember, I don’t know your circumstances. Again, I don’t have skin in your game. I’m simply reporting the average, and it’s your job to interpret the information based on your circumstances.

This reminds me of one of my favorite sayings about focusing on other people’s business before taking care of your own! Dr. Carmel Smart once gave me a polite but pointed reminder of this while I offered unsolicited feedback, and I have to say, she was right, what a gem!

Run your race, one that’s possible for you to win!

Essential point: Don’t sacrifice glucose control just to reduce insulin use. Lowering insulin at the expense of higher glucose levels is not a worthwhile tradeoff. The benefits of improved insulin sensitivity only matter if you maintain or enhance your current glucose control. Don’t rob Peter to pay Paul!

Why do people with T1D have higher insulin use than those without?

There are key physiological differences between people with and without T1D.

In people without diabetes, the pancreas releases insulin directly into the portal vein (which feeds into the liver). This ensures that the liver gets first access to insulin, shutting down excess glucose production before it floods the bloodstream. This also ensures that most of the glucose from a meal is efficiently stored in the liver. This means there is little exposure to high glucose levels (glucotoxicity) after eating, which causes insulin resistance. At the same time, insulin levels in the peripheral circulation remain relatively low, preventing excessive fat storage in the adipose (fat) tissues.

The GNL Fundamentals Podcast might help if this is all new to you.

But in T1D, insulin is injected or pumped into the fat under the skin (subcutaneously), not the portal vein. This creates major issues:

1. The liver doesn’t get enough insulin, so it keeps pumping out extra glucose when you don’t need it, leading to glucotoxicity.
2. Peripheral tissues, such as muscle and fat, receive excess insulin in people with T1D, leading to increased fat storage and metabolic dysfunction.
3. This imbalance between the liver and muscle is a key driver of insulin resistance in T1D, making weight management extremely challenging.
4. Once fatty acids are stored in the fat cell (adipocyte), getting them back out becomes nearly impossible. The “storage door” (lipoprotein lipase) stays wide open due to high peripheral insulin levels, while the “exit door” (hormone-sensitive lipase) is slammed shut, preventing fat release.
5. As a result, when you reduce food intake, your body struggles; it’s starving because you have reduced energy intake but cannot access fatty acids stored in the fat cells. Simply, starving from the outside and inside! Sound familiar? And yes, it’s very annoying!

Therefore, understanding and addressing insulin resistance is crucial for overall health.

If you’re using 100 units of insulin per day, it’s not realistic to suddenly drop to 35 units. However, reducing insulin by just 10-20% can have a meaningful impact, and that’s more than just management; it’s progress.

Now it’s time for part 2, where we break down the Ominous Octet step by step, discussing each component in detail.