This is Part 2 of the Insulin Resistance in Type 1 Diabetes guide.
Here we use the Ominous Octet to explain eight biological reasons insulin becomes less effective over time — and how each mechanism behaves differently in the context of T1D.
This is not a checklist for blame. It’s a map. Most people with T1D have more than one mechanism active at the same time, and different mechanisms dominate in different seasons (puberty, illness, stress, weight gain, ageing, sleep disruption, and more).
Prefer a podcast? Listen to Episode 14.
How to use this page: you don’t need to “fix all eight”. You need to identify which mechanisms are driving your insulin requirement and glucose volatility — then target the most changeable levers.
1) Beta-cell dysfunction (residual insulin + C-peptide effects)
What it is: in type 1 diabetes, beta-cell insulin production is severely reduced. However, some people retain measurable C-peptide (and therefore some endogenous insulin) for years, especially when diagnosed later in life.
In my case, I was diagnosed at 27 and nearly 20 years later still have a C-peptide level around 100–150 pmol/L. I fully recognise this gives me a more forgiving experience compared to those with no measurable C-peptide.
Why it matters in T1D: even tiny amounts of endogenous insulin can have outsized benefits because it is delivered into the portal circulation and pancreatic microenvironment — which injected insulin cannot replicate.
- Some insulin may still be produced, even if only in tiny amounts.
- Endogenous insulin helps suppress glucagon output from alpha cells (a local paracrine effect).
- Glucotoxicity (high glucose) can impair remaining beta-cell function further.
How it shows up: people with residual function often need less insulin and experience less volatility. As insulin resistance rises, the buffering effect of residual beta-cell function weakens, and glucagon regulation tends to worsen.
2) Muscle insulin resistance (reduced glucose uptake)
What it is: skeletal muscle is the largest site of insulin-stimulated glucose disposal. If muscle becomes insulin resistant, glucose stays in the bloodstream and more insulin is required to push glucose into muscle after meals and during corrections.
Mechanism: one major driver is lipid accumulation inside muscle cells. When diacylglycerols (DAG) and ceramides build up, they disrupt insulin signalling and reduce GLUT4 translocation — meaning glucose uptake slows even when insulin is present.
This is one reason high-fat meals can produce delayed glucose rises hours later. It’s worth revisiting the DAG diagram.
Why it matters in T1D: injected insulin creates relatively high peripheral insulin exposure (muscle + fat), which can promote fat storage and gradually worsen muscle insulin signalling — especially when activity is low.
How it shows up:
- Higher meal insulin requirements over time.
- Corrections that work poorly unless activity increases.
- Delayed post-meal hyperglycaemia after high-fat meals.
3) Liver insulin resistance (glucose output that won’t shut off)
What it is: the liver produces glucose during fasting (glycogenolysis + gluconeogenesis). Insulin normally suppresses this output rapidly. When the liver becomes insulin resistant, glucose output continues even when insulin should be sufficient.
Why it matters in T1D: the liver normally receives insulin first via the portal vein. In T1D, insulin is delivered subcutaneously, and portal insulin levels are often lower than physiological. This creates a mismatch: the liver can be under-insulinised even when peripheral tissues are over-insulinised.
How it shows up:
- Dawn phenomenon and overnight glucose drift upwards.
- High fasting glucose despite “reasonable” basal dosing.
- Glucose rising even without food.
Amplifier: glucagon excess (common in T1D) further drives hepatic glucose output — and liver insulin resistance makes glucagon’s effect stronger.
4) Fat-cell dysfunction (excess free fatty acid flux)
What it is: fat tissue stores fatty acids and releases them when needed. Insulin normally suppresses fat release (anti-lipolysis). In insulin resistance, fat tissue becomes less responsive to insulin, and free fatty acids (FFAs) leak into circulation more continuously.
Why it matters in T1D: elevated FFAs directly worsen insulin resistance in liver and muscle (via lipid signalling and mitochondrial overload), increasing insulin requirements and amplifying glucose variability.
When this happens:
- FFAs interfere with insulin signalling in muscle and liver.
- FFAs increase hepatic glucose output.
- Glucose becomes harder to stabilise without increasing insulin doses.
How it shows up: rising total daily insulin alongside fat gain (especially visceral fat), more variability, and a more “resistant” pattern to meals and corrections.
5) Kidney dysfunction (glucose reabsorption as a “set point”)
What it is: the kidneys filter glucose continuously and reabsorb most of it via SGLT2 transporters. If blood glucose rises high enough, glucose spills into urine.
Important: the renal threshold is not a fixed value (it varies between individuals and can change over time), so avoid treating 10.0 mmol/L as a universal cutoff.
Why it matters: in insulin resistant states, evidence suggests the kidney can reabsorb more glucose (a higher threshold), meaning hyperglycaemia persists longer and insulin has to do more work to bring glucose down.
How it shows up: sustained highs that are harder to break once glucose is elevated, and more “momentum” towards prolonged hyperglycaemia.
Clinical note: this is where SGLT2 inhibitors act — but in T1D the DKA risk means they require exceptional care, education, and ketone awareness.
6) Brain insulin resistance (appetite + defensive physiology)
What it is: insulin acts in the brain (especially the hypothalamus) as a signal of energy abundance. It contributes to satiety and helps regulate appetite, reward, and autonomic output.
In insulin resistance, the brain becomes less responsive to insulin signalling, which promotes hunger and undermines weight regulation. In T1D there is an additional layer: recurrent hypoglycaemia (or fear of it) can bias behaviour and physiology towards defensive eating and higher glucose targets.
How it shows up:
- Increased hunger and cravings.
- Difficulty losing weight without destabilising glucose.
- More frequent eating to prevent or treat lows.
7) Gut hormone dysfunction (GLP-1, GIP, gastric emptying)
What it is: after eating, K and L cells release incretin hormones (notably GLP-1 and GIP). These influence glucose control through multiple pathways:
- Stimulate insulin secretion from any remaining beta cells.
- Suppress glucagon secretion.
- Signal satiety in the brain.
- Slow gastric emptying (delaying glucose absorption).
Why it matters in T1D: even without beta-cell insulin secretion, GLP-1 effects still matter via appetite regulation, gastric emptying, and glucagon suppression — which is why GLP-1 receptor agonists can meaningfully reduce insulin requirements in some people with T1D.
How it shows up: reduced satiety signalling, sharper post-meal excursions (faster gastric emptying), and higher insulin needs via increased intake and altered meal kinetics.
8) Alpha-cell dysfunction + hyperglucagonaemia (the insulin opponent that won’t switch off)
What it is: glucagon is insulin’s functional opposite. It tells the liver to release glucose. In people without diabetes, glucagon falls after meals and rises during hypoglycaemia.
In T1D, alpha cells often become dysregulated: glucagon may be too high when glucose is high, and too low when glucose is low. This increases glucose volatility and drives higher insulin requirements.
Why it matters in T1D: injected insulin does not provide the same pancreatic micro-signal that endogenous insulin provides to suppress glucagon. Residual beta-cell function helps here — but many people have none.
How it shows up:
- Overnight hepatic glucose output and fasting highs.
- Exaggerated post-meal spikes (especially protein-driven excursions).
- Higher basal requirements and more stubborn correction resistance.
Essential point: insulin resistance and hyperglucagonaemia amplify each other. The more resistant the liver becomes, the more glucose output glucagon produces — and the harder insulin has to work to oppose it.
What happens next
You now have the map. The next step is using it.
- Part 3: Seven Solutions to Improve Insulin Sensitivity — lifestyle and pharmacology as tools, matched to mechanisms, with realistic trade-offs.
Navigation
- Part 1: What is Insulin Resistance with T1D
- Part 2: Eight causes for insulin resistance
- Part 3: Seven solutions to improve insulin sensitivity
GNL References
- Episode 14: Overcoming Insulin Resistance.
- Epiddose 17: GLP-1 Podcast
- Episode 8: Activity Snacking podcast
- Activity Guide
- Exercise Guide
- GLP-1 FAQ
Peter Attia “The Drive” Must Listens
- Attia #87 — Rick Johnson on fructose
- Attia #140 — Gerald Shulman masterclass
- Attia #337 — Ralph DeFronzo masterclass
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