Insulin resistance is usually talked about as a “type 2 diabetes problem.”
It’s time to start talking about Insulin Resistance as a T1D Problem!
Why?
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. This critically important finding motivates me to keep insulin resistance in check.
We know that people with type 1 diabetes (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 make 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.
Introducting,
The Ominous Octet of Insulin Resistance
This post is not my original work!
It’s an application key insights from my all-time top three episodes, all from The Drive hosted by Peter Attia (one of my mentors), to people living with T1D. The Three Podcasts are:
#87 – Rick Johnson, M.D.: Metabolic Effects of Fructose
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—though I encourage you to do so!
To make things easier, I’ve created two versions of my notes:
- Summary Version: Designed for Dani or anyone who might look after Grace or Jude if they develop type 1 diabetes. For 95% of people, this will be more than enough!
- Deep Dive: A detailed breakdown for those who love getting nerdy. Think of it as the guide I wish I had in 2008 when I was first diagnosed, hungry to understand exactly why things work the way they do. This is totally unnecessary, but at the same time fun, for those like me!
The Summary
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?
- Changes in lifestyle 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.
Where is Metformin?
Metformin does not enter muscle tissue because muscles lack the necessary organic cation transporter. This means it works exclusively in the liver, which was a surprise to me. Thank you Ralph (he did the mechanistic studies)!
For years, I’ve taught people with diabetes that Metformin works like oil on a rusty lock, helping muscle cells respond better to insulin. But thanks to Peter Attia’s podcasts, I’ve learned something new, and it’s making me a better educator!
How Metformin Works in the Liver:
It reduces fat oxidation by inhibiting energy production through the electron transport chain (Complex 1). As a result, the liver is forced to use glucose instead of fat for energy. This increases glucose consumption and decreases glucose output into the bloodstream, helping to prevent glucose toxicity from high blood sugar levels. So, Metformin has no direct improvement in muscle insulin sensitivity. Any insulin-sensitizing effects are secondary, often due to weight loss from those who have reduced appetite and belly-ache side effects. However, it’s cheap and research suggests modest benefits in T1D, reducing daily insulin needs by about 5%. Not to be sniffed at, but certainly not first, second or third line!
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
Defining Insulin Resistance in Type 1 Diabetes
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 as 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;
- 0.4–0.5 U/kg → Insulin sensitive. About 10% 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 50% of people with T1D
- More than 1.0 U/kg → High insulin resistance. About 10% of people living with T1D
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:
- 0.4–0.6 U/kg → Insulin sensitive. About 10% of people with T1D
- 0.6–0.8 U/kg → Insulin resistance begins. About 30% of people with T1D
- 0.8–1.2 U/kg → Significant insulin resistance. About 50% of people with T1D
- 1.2 U/kg → High insulin resistance. About 10% of people living with T1D
If you have just read that and thought OMFG!
“I have insulin resistance!”
Relax! You are no different to 90% of people living with T1D.
Why?
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. This is how nature intended it
The GNL Fundementals Podcast might help here.
But in T1D, insulin is injected or pumped into the fat under the skin (subcutaneously), not the portal vein. This creates major issues:
- The liver doesn’t get enough insulin, so it keeps pumping out extra glucose when you don’t need it, leading to glucotoxicity.
- Peripheral tissues, such as muscle and fat, receive excess insulin in people with T1D, leading to increased fat storage and metabolic dysfunction.
- This imbalance between the liver and muscle is a key driver of insulin resistance in T1D, making weight management extremely challenging.
- 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.
- 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.
Let’s break down the Ominous Octet step by step, discussing each component in detail. After that, we’ll explore strategies to reduce insulin resistance.
The Ominous Octet
- Beta-Cell Dysfunction
Even in people with long-standing type 1 diabetes, studies have shown that some beta-cell function may persist for years, particularly in those diagnosed later in life. This means:
- Some insulin may still be produced, even if only in tiny amounts.
- Insulin from Beta cells helps regulate glucagon by direct negative feedback to the alpha cell, which is often overactive in T1D.
- Glucose toxicity (high blood sugar) damages beta cells further, leading to even more dysfunction.
If insulin resistance is present, any remaining beta-cell function is even more impaired, making it harder to regulate glucose. Since beta cells suppress glucagon, their dysfunction means glucagon levels stay too high, driving excess liver glucose production, especially at night. This means that hyperglycemia worsens unchecked, and insulin requirements increase as the body struggles to suppress glucagon.
Management options for T1D:
- Keeping post-meal glucose in check (walking after meals, avoiding glucose spikes)
- Avoiding excessive fat intake (which worsens beta-cell dysfunction by increasing free fatty acids)
2. Muscle Insulin Resistance
Muscle tissue is the largest site for glucose disposal for people living with T1D, taking up about 75% of glucose after meals. If muscle insulin resistance develops, glucose stays in the bloodstream instead of being stored.
The main driver of muscle insulin resistance is fat accumulation inside muscle cells. When too much fat (in the form of diacylglycerols and ceramides) builds up, it blocks insulin signaling, making it harder for glucose to enter muscle cells.
This is why eating a high-fat meal can cause delayed glucose spikes hours later. The excess fat prevents muscles from absorbing glucose efficiently. It’s worth showing the diagram again.
Since muscles aren’t absorbing glucose properly, more insulin is needed to compensate. This raises overall insulin levels, leading to:
- More fat storage in muscle worsens insulin resistance further.
- Increased reliance on glucose from the liver, worsening glucose swings.
- Difficulty achieving stable blood glucose despite adjusting insulin doses.
Management options for T1D:
- Strength training (forces the muscles to use glucose)
- Aerobic activity (clears out metabolic “clutter”)
- Pioglitazone (a drug that redistributes fat out of muscle, improving insulin sensitivity, a misunderstood drug)
- Just being active works in three ways: 1. Getting insulin to the muscles fast, 2. Non-insulin mediated glucose uptake to lower glucose toxicity, 3. Burns DAG’s to improve insulin signalling. The GNL Activity Snacking Podcast may help.
3. Liver Insulin Resistance
The liver is supposed to release glucose when fasting and stop releasing it when eating. The liver normally gets first access to insulin via the portal vein. But in type 1 diabetes, insulin is injected under the skin, meaning the liver never gets a strong insulin signal.
Because of this:
- The liver continues to release glucose even after meals.
- Insulin resistance further impairs the liver’s ability to shut off glucose production.
- Glucagon levels stay too high, keeping the liver in “on mode.”
Management options for T1D:
- GLP-1 receptor agonists (like Semaglutide & Tirzepatide) – reduce glucagon and liver glucose output
- Keeping post-meal glucose levels stable
4. Fat Cell Dysfunction
Fat cells play a crucial role in glucose and lipid metabolism. Their main job is to store fatty acids and release them only when the body needs energy—typically 3 to 5 hours after eating.
However, in insulin resistance, fat cells start releasing excessive free fatty acids (FFAs) continuously, instead of only when needed. This excess FFA release makes it harder for insulin to work effectively, contributing to metabolic dysfunction.
Whe this happens:
- Fat cells become resistant to insulin’s anti-lipolytic effects, meaning they release too many free fatty acids.
- High levels of FFAs block insulin signaling in muscle and liver cells, reducing glucose uptake.
- Excess FFAs increase glucose production in the liver, worsening hyperglycemia.
This means that people with higher insulin resistance often experience:
- More difficulty losing weight, since excess FFAs continue circulating.
- More glucose variability, as FFAs drive liver glucose production.
- Higher insulin requirements, due to constant FFA interference.
Management options for T1D:
- Lowering insulin doses to reduce excessive fat storage
- SGLT2 inhibitors (like Empagliflozin) to lower glucose toxicity
- Pioglitazone (redistributes fat properly and improves insulin signaling)
5. Kidney Dysfunction
The kidneys filter around 180 grams of glucose per day, deciding whether to reabsorb it or excrete it in urine. If the glucose level goes above 10.0 mmol/L (180 mg/dL) the kidneys dump glucose in the urine. But when insulin resistance develops, the kidneys start reabsorbing even more glucose than they should, increasing overall glucose levels. The SGLT2 transporter is responsible for reabsorbing 90% of the glucose filtered by the kidneys.
When insulin resistance is present, the kidneys overcompensate by upregulating SGLT2, meaning even more glucose is retained, making hyperglycemia worse. This creates a vicious cycle:
- Higher glucose levels increase SGLT2 activity, causing more glucose reabsorption.
- More glucose stays in circulation, leading to higher insulin needs.
- Higher insulin levels further increase insulin resistance, worsening the problem.
Management options for T1D:
- SGLT2 inhibitors – block glucose reabsorption in the kidneys
6. Brain Insulin Resistance
The hypothalamus in the brain is responsible for regulating hunger, metabolism, and energy balance. Insulin plays a key role in this process by signaling satiety; in other words, it tells your brain when you’ve had enough to eat. In insulin resistance, the brain stops responding properly to insulin, leading to:
- Increased hunger and food cravings.
- Greater difficulty with weight management.
- Higher insulin needs due to increased caloric intake.
Management options for T1D:
- GLP-1 receptor agonists – restore normal hunger signaling
- Regular activity to improve brain insulin sensitivity
7. Gut Hormone Dysfunction
After eating, K and L cells in the gut release GLP-1 and GIP, which play several important roles:
- Stimulate insulin release from whatever Beta cells still function
- Suppress glucagon production
- Signal the brain that we are full
- Slow down the stomach’s emptying process
However, in insulin resistance, the body becomes resistant to the effects of GLP-1 and GIP. This leads to a cascade of negative effects, as you can imagine from this wonderful graphic.
8. Hyperglucagonemia
Glucagon is the opposite of insulin, it tells the liver to release more glucose when needed. In type 1 diabetes, glucagon levels are often too high, leading to excess glucose output from the liver, especially overnight. As you know by now, insulin resistance and hyperglucagonemia go hand in hand!
Time to shift gears into how to overcome insulin resistance with T1D.
A reminder of the pyramid
We start at the bottom and work out way up.
Activty: Aerobic Exercise, Strenght Traning, Movement, Post-Meal Walking
High postprandial glucose levels damage insulin signaling pathways and promote resistance. Avoiding chronic high blood sugar exposure helps prevent the deterioration of glucose metabolism. How to do this:
- Use rapid-acting insulin effectively (pre-bolusing 10–15 minutes before meals when possible).
- Use post-meal activity (e.g., a short 10–15 minute walk) to help glucose disposal via non-insulin-mediated uptake in muscle.
- Consider a GLP-1 receptor agonist (like semaglutide or Trizepatide) to slow gastric emptying and blunt large glucose excursions. Remember, daily insulin doses need lowering by around 30% on initiation.
Preventing Lipotoxicity (Fat-Induced Insulin Resistance)
Excess free fatty acids (FFAs) released by fat cells in insulin-resistant states impair insulin receptor function and promote muscle and liver insulin resistance. In T1D, excessive peripheral insulin delivery over-suppresses fat breakdown (lipolysis), locking fat in storage and making weight loss difficult. How to fix this:
- Engage in regular resistance training and aerobic exercise to improve fat metabolism and insulin sensitivity.
- Use SGLT2 inhibitors cautiously to help burn off excess glucose without increasing insulin doses.
- Consider pioglitazone (PPAR-gamma activator) to redistribute fat away from liver/muscle back into subcutaneous stores.
Balancing Insulin Doses to Avoid Hyperinsulinemia
Chronic high peripheral insulin levels contribute to muscle insulin resistance and downregulate insulin signaling over time. How to manage this:
- Optimise basal insulin: Use CGM trends to assess whether basal is set correctly.
- Keep total daily insulin close to 35 units/day when possible, using lifestyle modifications and adjunct therapies (GLP-1s, SGLT2s).
- Avoid excessive insulin stacking by ensuring proper meal bolusing and correction strategies.
Optimising Muscle Insulin Sensitivity
Skeletal muscle is the largest site for glucose disposal, but muscle insulin resistance is a major driver of high glucose levels. How to enhance muscle insulin sensitivity:
- Strength training 3–4 times per week improves glucose uptake and increases GLUT4 transporters in muscle.
- Post-meal walking (even 10 minutes) significantly enhances glucose clearance.
- Low/moderate carb diets can reduce postprandial insulin spikes and minimise glucose variability.
Suppressing Excess Glucagon (The Liver Glucose Problem)
In T1D, because there is no pancreatic insulin release, glucagon secretion is dysregulated, leading to excess hepatic glucose production. How to address this:
- GLP-1 receptor agonists (like Ozempic or Mounjaro) can help suppress glucagon production and reduce post-meal glucose spikes.
- Basal insulin should be optimized to prevent overnight glucose rises (often due to excess glucagon activity).
The Role of Gut Hormones & Incretins
Gut hormones like GLP-1 and GIP play a crucial role in normal insulin signaling and glucose regulation, but in insulin resistance, receptor sensitivity is reduced. How to leverage this:
- GLP-1 receptor agonists help restore appetite regulation, suppress glucagon, and improve insulin efficiency.
- Focusing on fiber-rich, whole-food meals supports better gut hormone responses and slower digestion.
Improving Insulin Sensitivity with Weight Loss
If a person with T1D is overweight, weight loss improves insulin sensitivity at all levels. How to approach weight loss safely in T1D:
- Prioritise protein intake (1.5-2g/kg of body mass) to maintain muscle mass while reducing calories.
- Use a CGM to monitor glucose trends during calorie restriction and exercise.
- Consider adjunct therapies (GLP-1s, SGLT2s) to support metabolic improvements.
Targeting the Kidneys to Reduce Glucose Toxicity
The kidneys reabsorb glucose through SGLT2 transporters, which in insulin resistance states leads to excess glucose retention. How to improve this:
- SGLT2 inhibitors (like Jardiance or Farxiga) allow glucose to be excreted via urine, lowering blood sugar naturally. Be careful, there is an increased risk of diabetic ketoacidosis (DKA) that needs managing.
- Stay well-hydrated and monitor ketones to prevent diabetic ketoacidosis (DKA) when using SGLT2 inhibitors in T1D.
A Comprehensive Approach is Needed
Managing insulin resistance in T1D is not just about insulin doses; it requires a multi-targeted approach that includes lifestyle modifications, adjunct therapies, and a deep understanding of metabolic physiology.
Key Takeaways
- Post-meal activity (walking, resistance training) improves glucose uptake and insulin sensitivity.
- Avoiding excessive insulin dosing prevents muscle insulin resistance.
- Managing fat intake and using targeted therapies (SGLT2s, GLP-1s, pioglitazone) reduces lipotoxicity.
- Gut hormones like GLP-1 and GIP play a crucial role in insulin efficiency—leverage them through diet and medication.
- Weight management significantly improves insulin sensitivity; every % of weight lost reduces insulin resistance.
This is not about treating blood glucose, it’s about treating insulin resistance itself. By shifting focus to improving insulin sensitivity, people with T1D can optimise their insulin use, reduce complications, and improve long-term metabolic health.
A final reminder of the Octet and how to overcome them!
Hope this was helpful
John
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