Overcoming Insulin Resistance in Type 1 Diabetes

Why insulin resistance matters in type 1 diabetes

Type 1 diabetes tends to increase insulin doses over time. Higher insulin doses are associated with increased risk of cardiovascular disease and mortality. Understanding and addressing insulin resistance is therefore one of the most consequential things a person with type 1 diabetes can do for long-term health.

The metabolic disadvantage in type 1 diabetes

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.

Measuring insulin resistance practically

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: insulin sensitive
• 0.5 to 0.7 units/kg: mild insulin resistance
• 0.7 to 1.0 units/kg: moderate insulin resistance
• Above 1.0 units/kg: 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 approaches

Physical activity

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.

Weight management

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. This needs to be built around glucose management, not despite it.

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. Dietary fibre and pre-bolusing strategies further support post-meal glucose management.

Pharmacological approaches

Several agents show evidence of benefit in type 1 diabetes, though not all are licensed for this indication. All pharmacological decisions require individual clinical input.

1. GLP-1 receptor agonists (e.g. semaglutide): an RCT in type 1 diabetes showed approximately 10% weight loss and 10 percentage-point improvement in time in range. Benefits include reduced insulin requirements and glucagon suppression.
2. Dual GLP-1/GIP agonists (e.g. tirzepatide): observational data in type 1 diabetes suggest a 30% reduction in insulin dose. Not yet licensed for type 1 diabetes.
3. SGLT-2 inhibitors: block glucose reabsorption in the kidney and increase urinary glucose excretion. Require careful management due to DKA risk in type 1 diabetes.
4. Pioglitazone: redistributes ectopic fat from liver and muscle to subcutaneous depots. Effective but often mischaracterised due to minor weight redistribution.
5. Metformin: acts primarily at the liver to reduce hepatic glucose output. Less potent than other agents — approximately 5% insulin dose reduction.