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 my insulin resistance in check.
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!
#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 my 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
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 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 and need to get to 0.4 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 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.
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:
- 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
1. 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.
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.
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.”
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.
When 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:
- Difficulty in losing weight, since excess FFAs continue circulating causing insulin resistance.
- More glucose variability, as FFAs drive liver glucose production.
- Higher insulin requirements, due to constant FFA interference.
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 reabsorb 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.
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 (as depicted in the fantastic graphic):
- Increased hunger and food cravings.
- Greater difficulty with weight management.
- Higher insulin needs due to increased caloric intake.
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!
It’s time to shift gears to how to overcome insulin resistance with T1D.
A reminder of the pyramid.
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.
If insulin resistance has eight different causes, can one strategy alone be enough? Unlikely.
You’ll likely need a combination of approaches, depending on where you’re starting from.
We begin with the foundation—lifestyle—and build up from there, step by step, like a pyramid.
1. Activity: Aerobic Exercise, Strength Training, Movement, Post-Meal Walking
Physical activity plays a critical role in improving insulin sensitivity, enhancing glucose disposal, and reducing metabolic dysfunction, all of which are key to addressing the Ominous Octet in T1D.
Strength training is one of the most effective ways to enhance muscle insulin sensitivity by increasing glucose uptake without needing insulin. Strength training also helps prevent muscle loss, which is particularly important for staying insulin sensitive, especially if you lose weight.
Aerobic exercise also plays a crucial role in clearing metabolic “clutter”, particularly by burning intramuscular fat deposits known as DAGs (diacylglycerols). Regular aerobic activity, such as brisk walking, cycling, or swimming, helps remove excess fat from muscle and liver cells, improving how the body processes glucose. It also enhances liver insulin sensitivity, helping regulate glucose production and preventing unnecessary spikes in blood sugar.
Beyond structured exercise, simply being active throughout the day is essential for glucose control. Movement improves insulin action in three key ways: it helps insulin reach muscles faster, enhances non-insulin-mediated glucose uptake, and burns stored fats that interfere with insulin function. Staying physically active also improves brain insulin sensitivity, which helps regulate hunger, metabolism, and overall energy balance. By incorporating small activity “snacks” throughout the day—such as standing up every 30–60 minutes, doing short bodyweight exercises, or walking between tasks—you can continuously support glucose regulation. Another powerful yet simple strategy is post-meal walking, to stop glucose rises and prevent the need for extra correction insulin.
To effectively counteract insulin resistance and optimise glucose metabolism, consider integrating the following strategies into your routine:
- Take a 10–15-minute walk after meals: This enhances glucose disposal through non-insulin-mediated uptake in muscles and supercharges to bolus insulin so you need less or don’t get after-meal spikes.
- Engage in strength training 3–4 times per week: Use compound movements (e.g., squats, deadlifts, presses) to increase muscle sizes and GLUT4 transporters and improve insulin sensitivity.
- Incorporate aerobic exercise (3–5 times per week): Cycling, swimming, or brisk walking to burn excess fats in muscle and liver cells, reducing insulin resistance.
- Stay active throughout the day: Stand up regularly, walk instead of driving short distances, and engage in active hobbies like gardening or dancing.
- Mix resistance and aerobic training: This provides synergistic improvements in glucose control and fat metabolism. Be mindful of HIIT (high-intensity interval training), as it may temporarily raise glucose before improving long-term sensitivity if done with no bolus insulin in the last four hours.
- Use activity “snacking“: Short bursts of movement like bodyweight exercises, stretching, or stair climbing to keep the metabolism active throughout the day.
For more insights, check out The GNL Activity Snacking Podcast, where we dive deeper into how movement supports metabolic health!
2. Weight Management (Weight Loss)
If you are overweight, losing body fat can significantly improve insulin sensitivity and overall metabolic health. However, even if you are not classified as overweight, you may still carry excess fat around the liver and central organs. This is often referred to as visceral fat. This type of fat is particularly harmful as it contributes to insulin resistance, inflammation, and metabolic dysfunction.
Losing 5–10% of body weight has been shown to provide meaningful improvements in insulin sensitivity. However, losing 15–20% can be extremely effective, particularly in reversing insulin resistance in the liver and muscle. The key to effective fat loss is ensuring that the weight lost comes from fat rather than muscle. To achieve this, it’s essential to follow specific strategies that prioritise muscle preservation and metabolic health while reducing body fat.
- Prioritise protein intake: Aim for 1.5–2g of protein per kg of body weight to maintain muscle mass while in a calorie deficit. Protein helps prevent muscle loss, supports satiety, and aids in metabolic function.
- Incorporate strength training: Engaging in resistance training at least 3–4 times per week helps preserve lean muscle mass and ensures that the weight lost comes from fat rather than muscle.
- Create a calorie deficit: Aim for a 500–1,000 kcal deficit per day, which supports a steady weight loss of 0.5–1.0 kg per week. This gradual approach prevents muscle loss and promotes sustainable fat reduction.
- Reduce processed carbohydrates and refined sugars: While total calories matter most, reducing processed foods can help stabilise blood sugar levels and prevent excessive insulin spikes.
- Support fat metabolism with activity: Regular aerobic exercise and strength training improve the body’s ability to burn stored fat, particularly in the liver and muscles, where excess fat storage contributes to insulin resistance.
- Prioritise sleep and stress management: Poor sleep and chronic stress can increase cortisol levels, making it harder to lose fat and increasing insulin resistance. Aim for 7–9 hours of quality sleep per night.
3. Nutrition (Low Sugar Intake, High Vegetables, High Fibre)
Nutrition plays a crucial role in optimising glucose control, reducing insulin resistance, and supporting weight management. Making strategic food choices can enhance insulin action, prevent glucose spikes, and improve beta-cell function over time. While individual needs vary, certain dietary principles are universally beneficial for people with type 1 diabetes.
- Avoid excessive fat intake: High-fat diets can worsen beta-cell dysfunction by increasing free fatty acids (FFAs), which impair insulin secretion and action. Moderating fat intake, particularly saturated fats, helps support healthy insulin signaling.
- Consider a moderate carbohydrate approach: Reducing excessive carbohydrate intake can minimise post-meal insulin spikes, improve glucose stability, and reduce overall insulin requirements. However, balance is key—carbohydrate intake should be tailored to activity levels, insulin dosing, and metabolic needs.
- Limit sugar intake: The podcast by Dr. Rick Johnson highlights how excessive sugar, particularly fructose, contributes to insulin resistance and fat accumulation in the liver. Prioritising natural, whole-food sources of carbohydrates can help reduce metabolic stress.
- Focus on fibre-rich, whole-food meals: High-fibre foods slow down glucose absorption, improve gut hormone responses, and enhance satiety, leading to better post-meal glucose control. Aim for a diet rich in vegetables, legumes, whole grains, and nuts.
- Monitor glucose trends using a CGM: A CGM provides real-time feedback on how different foods affect blood sugar, helping refine meal timing, portion sizes, and insulin dosing. This is especially useful during caloric restriction and exercise to prevent hypoglycaemia or excessive glucose swings.
- Pre-bolus insulin 15–20 minutes before most meals: Taking insulin ahead of meals allows it to start working before glucose enters the bloodstream, leading to smoother postprandial glucose levels and less variability.
4. GLP1-RA’s (Semaglutide or Tirzepatide)
GLP-1 receptor agonists (such as semaglutide and tirzepatide) offer several metabolic benefits beyond glucose control, making them valuable tools for improving insulin sensitivity and reducing insulin needs in people with type 1 diabetes. These medications enhance the body’s natural hormone responses, addressing multiple aspects of glucose regulation, appetite control, and insulin efficiency.
- Reduce glucagon levels & liver glucose output: Excess glucagon drives unnecessary glucose release from the liver, contributing to hyperglycaemia. GLP-1 receptor agonists suppress glucagon, helping to stabilise fasting and post-meal glucose levels.
- Restore normal hunger signaling & appetite regulation: Many people with insulin resistance experience dysregulated appetite control, leading to overeating and weight gain. GLP-1 receptor agonists help restore proper hunger cues, reducing cravings and excessive food intake.
- Improve insulin efficiency: By reducing post-meal glucose spikes and slowing gastric emptying, these medications make insulin work more effectively, lowering the amount needed to control blood glucose
- Blunt large glucose excursions: Slowing gastric emptying means glucose enters the bloodstream more gradually, reducing rapid glucose spikes and minimising the need for large insulin doses.
However, GLP1-RA’s are not indicated for T1D in most current guidelines. So, prescriptions may be off-label by your Doctor and you both should consider reading this excellent opinion of GLP1-RA for T1D. It highlights the need for;
- Lower daily insulin doses by approximately 30% upon initiation to prevent hypoglycaemia, as the medication reduces glucose absorption and insulin requirements.
- Monitor for nausea or digestive side effects, as slowing gastric emptying can cause temporary gastrointestinal discomfort in some individuals.
- Easier to manage on an AID system due to delayed food absorption, making insulin dosing challenging.
- Pair with strength training and protein intake to preserve muscle mass while benefiting from reduced appetite and weight loss.
- Use a CGM to track glucose trends and adjust insulin dosing accordingly, particularly for post-meal boluses.
5. SGLT2 Inhibitors
SGLT2 inhibitors (such as empagliflozin, dapagliflozin, and canagliflozin) provide a unique approach to lowering blood glucose levels without increasing insulin doses. They work by blocking glucose reabsorption in the kidneys, allowing excess glucose to be excreted in urine, which helps reduce glucose toxicity and insulin resistance.
- Lower glucose toxicity by reducing overall glucose burden: By excreting glucose through urine, SGLT2 inhibitors help prevent excess glucose from accumulating in the bloodstream, reducing insulin resistance over time.
- Block glucose reabsorption in the kidneys: Normally, the kidneys reabsorb glucose back into the bloodstream. SGLT2 inhibitors interrupt this process, allowing glucose to be eliminated instead.
- Help reduce glucose burden without increasing insulin doses: Unlike other glucose-lowering therapies, SGLT2 inhibitors do not increase insulin production or require additional insulin administration, making them a useful option for reducing insulin dependence.
However, SLGT2s are not always offered to people who live with T1D due to increased DKA risk. So, your Doctor and you should consider reading this excellent opinion of SGLT2s for T1D. It highlights;
- Increased risk of diabetic ketoacidosis (DKA): SGLT2 inhibitors can lower insulin levels while still allowing glucose to be excreted, potentially increasing ketone production. This can raise the risk of euglycaemic DKA (normal blood glucose but high ketones), which requires careful monitoring.
- Stay well-hydrated: Increased urinary glucose loss can lead to dehydration, making proper fluid intake essential to prevent complications.
- Monitor ketones regularly: Since SGLT2 inhibitors can increase ketone production, it’s important to check ketone levels, especially during illness, fasting, or periods of low carbohydrate intake.
Pioglitazone (Actos)
Pioglitazone is a PPAR-gamma activator that plays a unique role in insulin sensitivity by redistributing fat from harmful locations (such as the liver and muscles) back into subcutaneous fat stores, where it is less metabolically damaging. Despite being misunderstood and often overlooked, pioglitazone offers significant benefits for improving insulin signalling and reducing insulin resistance.
- Improves insulin sensitivity by redistributing fat properly: Excess fat in the muscles, liver, and pancreas contributes to insulin resistance and metabolic dysfunction. Pioglitazone helps move fat away from these critical organs into safer subcutaneous fat stores, where it has a lower impact on glucose metabolism.
- Enhances insulin signaling: By reducing intramuscular and liver fat, pioglitazone helps restore proper insulin action, making insulin more effective at regulating blood sugar.
- Lowers liver insulin resistance: Pioglitazone reduces hepatic fat accumulation, preventing excess glucose production by the liver, which is a major contributor to high fasting glucose levels.
- Reduces systemic inflammation: By addressing metabolically harmful fat storage, pioglitazone helps lower chronic inflammation, which is a key driver of insulin resistance.
Some considerations:
- It does not cause “true” weight gain: While pioglitazone shifts fat storage, leading to an increase in total body weight, this is due to redistribution rather than fat accumulation. The metabolic benefits outweigh the change in scale weight.
- Monitor for fluid retention: In some cases, pioglitazone may cause mild fluid retention, which should be monitored, especially in individuals with heart conditions.
- Takes time to show effects: Unlike rapid-acting glucose-lowering therapies, pioglitazone works gradually by improving fat metabolism and insulin sensitivity over weeks to months.
- Best used alongside strength training: Since it redistributes fat rather than burning it, pairing pioglitazone with resistance training and a high-protein diet helps preserve muscle mass and optimise body composition.
Metformin
Metformin is often thought of as a general insulin sensitiser, but its effects are actually limited to the liver because muscle tissue lacks the necessary organic cation transporter required for metformin uptake. This means it does not directly improve muscle insulin sensitivity, which was a surprising revelation. Cheers to Dr. Ralph DeFronzo for his groundbreaking mechanistic studies!
For years, I taught that metformin works like oil on a rusty lock, helping muscle cells respond better to insulin. However, after listening to Peter Attia’s podcast, I’ve come to realise that metformin’s action is entirely liver-based—making me a better educator in the process!
How metformin works in the liver:
- Reduces fat oxidation by inhibiting energy production through the electron transport chain (Complex 1).
- Forces the liver to use glucose instead of fat for energy, which increases glucose consumption and reduces glucose output into the bloodstream.
- Lowers blood glucose levels by decreasing hepatic glucose production, preventing glucose toxicity.
Why metformin isn’t the best first-line option for T1D but will be beneficial in a multi-drug approach:
- No direct impact on muscle insulin sensitivity—any benefits in insulin resistance are secondary and largely due to modest weight loss (often from reduced appetite and GI side effects).
- Insulin-lowering effects are mild. Research suggests it may reduce daily insulin needs by about 5%, which is helpful but not transformative.
- It’s cheap and has a fantastic safety profile, making it a reasonable option for a multi-drug approach. but it’s not a first, second, or even third-line treatment for improving insulin sensitivity in T1D.
Insulin resistance is a multi-faceted problem that needs a combination approach
If there’s one key takeaway from this, it’s that insulin resistance in T1D isn’t just about insulin. It’s about the bigger picture. How you move, eat, sleep, and manage stress all play a role. Small, consistent changes in these areas can have a significant impact, improving insulin sensitivity and making diabetes management that bit easier.
So, whether it’s adjusting your nutrition, being more intentional with movement, or prioritising recovery, the goal isn’t perfection, it’s progress. And every small step counts. If lifestyle is not enough, you now know which drugs to discuss with your doctor!
A final reminder of the Octet and how to overcome them!
Hope this was helpful
John
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