Episode 14, overcoming insulin resistance in type 1 diabetes

Why this episode exists

If you live with type 1 diabetes, you have probably noticed that insulin doses tend to drift upward over the years. It rarely announces itself; it just turns up as a slightly bigger basal, a slightly heavier ratio, a correction that does less than it used to. That drift is not a personal failing, and understanding why it happens is one of the most consequential things you can do for your long-term health.

It matters because higher insulin doses are associated with increased risk of cardiovascular disease and mortality. Type 1 diabetes tends to increase insulin doses over time, so addressing the resistance behind that creep is worth the attention.

In this episode

John works through why insulin resistance behaves differently in type 1 diabetes, how to put a practical number on it without a research laboratory, and the eight biological mechanisms that drive it. The thread running underneath is that resistance is rarely a single-cause problem; several mechanisms usually operate at once, and the approaches that help most are the ones that address several at the same time.

From there the conversation turns to what actually moves the needle: the lifestyle levers that consistently reduce resistance, and the expanding set of pharmacological options, with the evidence and the caveats laid out plainly. The aim is not a protocol to follow but a map of the mechanisms, so you can explore what makes a difference for you alongside your care team.

Key themes

The metabolic disadvantage built into injected insulin

In people without diabetes, insulin is released from the pancreas into the portal vein and reaches the liver first, where it directly suppresses glucose output. In type 1 diabetes, insulin is injected subcutaneously and absorbed into peripheral circulation instead. The result is that peripheral insulin levels are four to eight times higher than they would be in someone without diabetes. This chronic peripheral hyperinsulinaemia is itself a driver of insulin resistance.

Putting a practical number on resistance

The gold-standard method for measuring insulin resistance is the euglycaemic clamp, not used in clinical practice. A practical alternative is total daily insulin dose expressed per kilogram of body weight. Research by Maahs and colleagues provides reference ranges: below 0.4 units/kg is insulin sensitive; 0.5 to 0.7 units/kg is mild insulin resistance; 0.7 to 1.0 units/kg is moderate insulin resistance; above 1.0 units/kg is high insulin resistance. Residual C-peptide production substantially influences these figures. People with meaningful residual function tend to need less exogenous insulin and sit lower on this scale.

The eight mechanisms, Dr Ralph DeFronzo’s ominous octet

John draws on Dr Ralph DeFronzo’s framework for understanding the multiple biological sites where insulin resistance can operate. In type 1 diabetes, several of these mechanisms compound each other:

1. Beta-cell dysfunction, no suppression of glucagon after meals, leading to continued hepatic glucose output
2. Muscle insulin resistance, intramyocellular fat accumulation blocks insulin signalling in muscle tissue
3. Liver insulin resistance, continued glucose output from the liver after meals despite rising insulin levels
4. Fat cell dysfunction, high insulin levels lock fat inside adipose tissue, making fat mobilisation and weight management harder
5. Kidney insulin resistance, increased glucose reabsorption via SGLT2 transporters
6. Brain insulin resistance, altered hunger signalling increases appetite and energy intake
7. Gut hormone dysfunction, reduced GLP-1 and GIP response blunts post-meal insulin efficiency
8. Hyperglucagonaemia, excess glucagon drives ongoing glucose release from the liver

The practical significance is that insulin resistance in type 1 diabetes is rarely a single-cause problem. Multiple mechanisms typically operate at once, and the most effective approaches address several simultaneously.

Lifestyle, where the biggest levers sit

Activity is consistently the most powerful tool for reducing insulin resistance. It reduces total daily insulin dose, improves insulin sensitivity acutely and chronically, and targets muscle insulin resistance directly. Regular movement addresses more mechanisms than any single pharmacological agent. Even small amounts help: three minutes of movement every 30 minutes has demonstrated improvements in time in range. Alongside activity, a five to 20% body weight reduction improves insulin resistance significantly; a practical strategy involves higher protein intake (1.5 to 2 g per kilogram), strength training to preserve lean mass, and a modest energy deficit of 500 to 1,000 kcal per day, built around glucose management rather than despite it. On nutrition, limiting saturated fat and liquid sugars (particularly fructose) reduces hepatic and fat-cell insulin resistance; moderate carbohydrate intake (approximately 25 to 40% of daily energy) tends to reduce insulin doses; using glucose-only hypo treatments avoids unnecessary fat and fructose exposure; and dietary fibre and pre-bolusing strategies further support post-meal glucose management.

The pharmacological options, with the caveats kept attached

Several agents show evidence of benefit in type 1 diabetes, though not all are licensed for this indication, and all pharmacological decisions require individual clinical input. Open any option below for the evidence and the caveats.

Practical exploration

For people living with type 1 diabetes and their families

The most useful first step is to understand the mechanisms and then explore what makes a difference for you, with your care team. None of the below is a dose instruction; it is a set of things worth looking at.

• Total daily insulin per kilogram is a useful practical proxy for insulin resistance in everyday conversation. Working out roughly where you sit on the Maahs scale (below 0.4 units/kg sensitive, up to 1.0 and above) can frame a conversation with your team.
• Activity reduces total daily insulin dose and improves insulin sensitivity both acutely and chronically, and even small amounts count; three minutes of movement every 30 minutes has demonstrated improvements in time in range.
• Weight, nutrition, and the type of carbohydrate all feed into the same mechanisms; a moderate carbohydrate intake (approximately 25 to 40% of daily energy) tends to reduce insulin doses, and glucose-only hypo treatments avoid unnecessary fat and fructose.
• If you have meaningful residual C-peptide production, you may need less exogenous insulin and sit lower on the resistance scale; it is worth knowing your own picture.

For clinicians and educators

The episode is a reminder that insulin resistance in type 1 diabetes is multi-mechanism, and that the framing of any intervention matters as much as the intervention itself.

• Total daily insulin per kilogram, read against the Maahs reference ranges, gives a practical proxy for resistance in clinic without recourse to the euglycaemic clamp.
• The ominous octet is a useful structure for explaining why a single agent rarely solves the problem and why lifestyle, which reaches several sites at once, is the broadest lever.
• The pharmacological options are expanding (GLP-1 receptor agonists, dual GLP-1/GIP agonists, SGLT-2 inhibitors, pioglitazone, metformin), but several are unlicensed for type 1 diabetes and SGLT-2 inhibitors carry a DKA risk; all require careful individual clinical assessment.
• Peripheral hyperinsulinaemia from subcutaneous dosing is itself a driver of resistance, which is worth naming when discussing why doses creep over time.

About the host

John Pemberton hosts The Glucose Never Lies Podcast. In this episode he draws on Dr Ralph DeFronzo’s framework for the multiple biological sites of insulin resistance, and on the reference ranges published by Maahs and colleagues, to map how insulin resistance arises in type 1 diabetes and what the evidence says about reducing it.

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