Insulin resistance: symptoms, diagnosis and what is known to reverse it

Insulin resistance is the situation in which cells respond less well to insulin and the pancreas compensates by producing more. It is the central pathogenic mechanism behind disorders of glucose metabolism, but it is not a disease with a validated diagnostic cut-off for the consulting room: in Spain, the diagnosis is based on glucose and HbA1c, not on insulin. And what best reverses the picture has been measured in detail: sustained weight loss and physical activity.

What it is exactly and why it develops

When insulin stops doing its job properly in muscle, liver and adipose tissue, the pancreas responds by secreting more in order to keep blood glucose within range. That balance can hold for years without blood glucose shifting at all. The problem arrives when the pancreatic beta cell starts to run out of capacity: in prediabetes the two things already coexist, insulin resistance and beta-cell dysfunction, according to the review published in Medicina (Kaunas) in 2019.

The mechanism that best explains what lies beneath all this is the so-called twin cycle, described by the group led by Roy Taylor and Michael Lean: in susceptible people, ectopic fat accumulates, that is, fat where it should not be, in the liver and the pancreas. That accumulation is harmful, but reversible. In fact, losses of 10 to 15 kg frequently normalise blood glucose in type 2 diabetes of short duration. That is the key that makes sense of everything else: we are not talking about inevitable decline, but about a state that is largely modifiable.

Symptoms: the honest part of the answer

The internet is full of lists of insulin resistance symptoms: post-meal tiredness, sugar cravings, brain fog, dark patches on the neck. We are not going to reproduce them as though they were a clinical fact, because there is no list of insulin resistance symptoms validated against a primary source. What is documented is the opposite: prediabetes is an asymptomatic condition that has to be actively looked for through preventive checks, rather than waiting for it to announce itself.

That changes the useful question. It is not «do I have these symptoms?», but «do I have risk factors that justify checking my glucose?». The Spanish Diabetes Society consensus recommends opportunistic screening with fasting blood glucose every 4 years in people over 45. The absence of symptoms does not mean there is nothing to be done: it means the finding comes from a blood test.

How it is diagnosed in Spain: what your doctor actually measures

According to the SED consensus, the criteria for prediabetes in Spain are HbA1c between 6 and 6.4%, fasting blood glucose between 110 and 125 mg/dl, and 2-hour glucose on an oral glucose tolerance test between 140 and 199 mg/dl. It is worth knowing that Spain, following the WHO/SED criterion, uses 110 mg/dl as the threshold for impaired fasting glucose, while the American Diabetes Association uses 100 mg/dl. That difference creates real diagnostic discrepancies: the same blood test can be labelled differently depending on which guideline the person reading it applies.

The scale of the problem in Spain was set out by the [email protected] study, with fieldwork carried out between 2009 and 2010: prediabetes in 14.8% of the population, impaired fasting glucose in 3.4%, impaired glucose tolerance in 9.2%, both abnormalities in 2.2% and type 2 diabetes in 13.8%. In total, 28.6% of the adult population had some abnormality of carbohydrate metabolism. There is, by contrast, no prevalence figure for insulin resistance in Spain, for the simple reason that there is no operational definition with which to count it.

HOMA-IR and raised fasting insulin

If you have arrived here with a HOMA-IR result in your hand, this is the part that concerns you. HOMA-IR is a calculation based on fasting glucose and insulin that allows insulin resistance to be assessed, and it is widely used in research. But there is no universally agreed threshold: in the United States values between 2.0 and 3.0 are used and the NHANES survey applies 2.5 or above. No major guideline, neither ADA nor EASD, endorses it for routine clinical use or for making treatment decisions.

There are further nuances that explain that caution. HOMA-IR is not reliable in established diabetes, in lean people, in those over 60, or during an acute illness. Insulin assays are not standardised across laboratories, so the same serum sample can give different numbers at two different centres. The real gold standard is the hyperinsulinaemic-euglycaemic clamp, a research technique that is not performed in clinical practice. Nor is it part of standard NHS testing or of NICE diagnostic pathways; it is fundamentally a research tool. Even in polycystic ovary syndrome, NICE recommends assessing metabolic risk with HbA1c or fasting glucose, not with insulin or HOMA-IR.

In plain terms: a raised fasting insulin or an elevated HOMA-IR is a signal that merits a medical conversation and a look at the whole picture (glucose, HbA1c, lipid profile, blood pressure, waist circumference), not a diagnostic label and not, on its own, an indication for treatment. If you want the detail on how that number is interpreted and which tests go with it, we set it out in the guide on how insulin resistance is diagnosed.

Why it matters: the risk behind it

This is not a cosmetic concern. People with impaired fasting glucose have a fivefold higher risk of developing diabetes, as well as a higher cardiovascular risk (relative risk 1.19) and higher mortality (relative risk 1.28). And the clock is ticking: between 5 and 10% of people with prediabetes develop type 2 diabetes each year.

Insulin resistance does not travel alone, either. It tends to cluster with abdominal obesity, high blood pressure and lipid abnormalities in what is known as metabolic syndrome, and it frequently shows up in blood tests alongside raised triglycerides.

What is known to work in reversing it

Here the evidence is solid and has been building for decades. The Diabetes Prevention Program, published in the New England Journal of Medicine in 2002, randomised 3,234 high-risk people: the intensive lifestyle intervention reduced the incidence of type 2 diabetes by 58% (95% CI 48-66%) and metformin by 31% (95% CI 17-43%) compared with placebo, over a mean follow-up of 2.8 years. The targets of that intervention were specific: at least 7% weight loss and 150 minutes of physical activity a week. In the DPPOS follow-up, the preventive benefit was maintained up to 15 years after randomisation.

Lifestyle does not just win at the outset, it wins on durability. A meta-analysis included in the review by Cebrián Cuenca puts the reduction in diabetes incidence at 39% with lifestyle measures and 36% with medication, but notes that medication is less effective in the long run, whereas the effect of lifestyle extends beyond the intervention period.

Weight is the most powerful variable

The weight figures are striking. A weight loss of at least 5% at one year was associated with 65% lower diabetes incidence (HR 0.35; 95% CI 0.22-0.56). And keeping it off counts for more than achieving it: sustaining that 5% for 2 and 3 years reduced incidence by 79% and 89% respectively.

The DiRECT trial, published in The Lancet in 2018, went a step further and worked with people who already had type 2 diabetes. It achieved remission in 46% of the intervention group compared with 4% of the control group (OR 19.7; 95% CI 7.8-49.8), with a mean weight loss of 10.0 kg versus 1.0 kg. The gradient according to weight lost is the most instructive part: 0% remission in those who gained weight, 7% with 0-5 kg, 34% with 5-10 kg, 57% with 10-15 kg and 86% with 15 kg or more. At 2 years, 36% of the intervention group (53 of 149) were still in remission in primary care.

The 5-year follow-up adds the essential caveat: it is possible to maintain remission, but maintaining the weight loss is hard. At year 5, mean weight loss was 5.6 kg in the intervention group and 4.6 kg in the control group. The NHS Path to Remission programme, evaluated in 2024, reproduced the signal in the real world: 7.2 kg more weight loss at 12 months compared with control (95% CI 4.9-9.4), with higher remission rates the greater the weight loss. And among those who improve, a proportion return to normal glucose tolerance while around 50% remain in a prediabetic state. Why weight tends to come back and how this is tackled is explained in our piece on weight regain after stopping treatment.

A necessary word of warning about DiRECT: its initial phase used a very low-calorie diet under close medical supervision, within a research protocol. It is not a plan to replicate on your own after reading an article.

Medicines: what is and is not authorised in Spain

This needs saying before any figures: there is no medicine authorised in Spain with the specific indication of insulin resistance. Not one. What does exist are medicines authorised for type 2 diabetes or for weight management, which is a different thing.

Metformin is the case that causes the most confusion. Its summary of product characteristics with the AEMPS indicates the treatment of type 2 diabetes mellitus, particularly in overweight patients, when prescribed diet and exercise alone are not enough. It does not include prediabetes, insulin resistance or obesity as authorised indications, and it requires confirmation of the type 2 diabetes diagnosis before starting treatment. Its use in obesity is explicitly classified as off-label by the Pediamécum of the Spanish Association of Paediatrics. The fact that it often turns up in these contexts reflects individual off-label clinical decisions, not an approved indication.

As for its profile, the product information states that metformin does not cause hypoglycaemia on its own, can improve the lipid profile and is associated with stable weight or weight loss. It is contraindicated in acute metabolic acidosis and diabetic pre-coma, and its maximum dose is 3 g a day split into three doses. These are data from the product information, not a regimen: who takes it and at what dose is decided by a doctor on the basis of a confirmed diagnosis.

On the weight route, semaglutide in its weight-management presentation is authorised by the EMA as an adjunct to diet and exercise in adults with a BMI of 30 or above, or between 27 and 30 with an associated comorbidity (hypertension, dyslipidaemia, sleep apnoea, cardiovascular disease or type 2 diabetes). Tirzepatide is authorised for type 2 diabetes from the age of 10 and for obesity or overweight from a BMI of 27. Neither of them carries the label insulin resistance: they are prescribed, where appropriate, for obesity or for diabetes, and always after medical assessment. If you want to understand how this family of medicines works and who it is aimed at, we set it out in detail in the guide to Ozempic in Spain.

And if I cannot lose weight however hard I try

It is one of the most frequently repeated sentences in the consulting room and it has a real basis: the accumulation of ectopic fat and compensatory hyperinsulinaemia create a metabolic context that is not on your side. But the data from DPP and DiRECT were obtained in people in exactly that situation, and the DiRECT gradient shows that even intermediate losses of 5 to 10 kg moved the needle (34% remission). The message is not that a heroic figure is needed, but that the benefit grows with the amount lost and, above all, with maintenance.

When well-executed lifestyle change is not enough, the next decision is a clinical one: review the full diagnosis, rule out other causes, assess whether criteria for prediabetes or diabetes are met and whether the conditions for any authorised indication apply. That requires blood tests, a history and a doctor who reads them together. The context of prediabetes and how it is managed helps to place where you are on that path.

What is worth remembering

Insulin resistance is a real and largely reversible mechanism, but it is not diagnosed with a single isolated number and it is not treated with a medicine labelled for it: what has been measured is that losing weight and keeping it off reduces the incidence of diabetes by up to 89% at the third year and can take recent-onset type 2 diabetes into remission. The hard part is not starting, it is sustaining it. For that there is now medical weight-loss treatment available in Spain with prior assessment, prescription by a registered doctor where appropriate and ongoing follow-up, which is what we do at AiON. You can check in a few minutes whether you are eligible.