For decades, “insulin resistance” was viewed as a single, uniform problem—a systemic disorder reflected in blood tests and united under one specific diagnosis. However, new research shows that where insulin resistance develops in the body may be just as important as the presence of the condition itself. Researchers conclude that adipose (fat) tissue insulin resistance may be more closely and consistently linked to worsening metabolic health than skeletal muscle insulin resistance.
A Global Problem, a Specific Question
Obesity has become one of the premier public health challenges of our time. According to World Health Organization data, approximately 2.5 billion adults were overweight in 2022, including more than 890 million living with obesity. This figure accounted for roughly 43% of the world’s adult population, meaning nearly one in every eight people on Earth was affected by obesity.
Excess weight increases the risk of developing cardiovascular diseases, type 2 diabetes, and insulin resistance—a condition in which cells no longer respond effectively to insulin, the hormone responsible for regulating blood sugar levels.
However, insulin resistance does not always manifest identically. It can emerge in different tissues, including the liver, skeletal muscle, adipose tissue, and indirectly in the pancreatic beta cells that produce insulin. Earlier studies indicated that these distinct forms carry different metabolic consequences. Yet, until now, no study had directly investigated what happens when insulin resistance manifests independently in adipose tissue versus skeletal muscle, or whether one poses a greater threat to overall health than the other.
Study Details
Researchers analyzed baseline data from the 12-week Dietary Intervention Study (PERSON) conducted in the Netherlands. The project involved individuals aged 40 to 75 with a body mass index (BMI) ranging from 25 to 40.
The evaluation comprised several components:
An oral glucose tolerance test
Dual-energy X-ray absorptiometry (DXA) to determine body composition
Whole-body magnetic resonance imaging (MRI) to assess fat distribution and visceral adiposity
In a subgroup of 74 individuals, a hyperinsulinemic-euglycemic clamp—a highly precise research method for evaluating insulin sensitivity.
The researchers used calculated indices to determine insulin sensitivity in both adipose tissue and muscle. They then divided the participants into four groups:
Individuals with relatively high insulin sensitivity in both adipose tissue and muscle.
Individuals with relative insulin resistance in both tissues.
Individuals with adipose tissue insulin resistance but relatively preserved muscle sensitivity.
Individuals with muscle insulin resistance but relatively preserved adipose tissue sensitivity.
These categories were based directly on the distribution of data within the study population rather than universally accepted clinical cutoffs. Consequently, they should be viewed as research phenotypes rather than clinical diagnoses.
A Frequent Discordance
The study showed that insulin sensitivity in adipose tissue and muscle does not always change in tandem. Approximately 42% of participants fell into the two discordant groups, meaning their estimated insulin resistance differed between adipose tissue and muscle.
About 21% exhibited adipose tissue insulin resistance alongside relatively preserved muscle sensitivity, while the remaining 21% presented the opposite picture. These results reinforce the notion that insulin resistance is not identical across different tissues.
However, because this classification relied on surrogate markers and arbitrary threshold values, these percentages should not be taken as an exact estimate of the prevalence of these clinical conditions in the general population.
This divergence created the opportunity for a natural experiment: what happens to a person’s metabolic health when the issue affects only one specific tissue type?
Adipose Tissue Resistance
Credit: Steve Gschmeissner/Science Photo Library/Getty Images
Participants identified with adipose tissue insulin resistance generally exhibited a less favorable metabolic profile. They demonstrated higher baseline fasting insulin, HOMA-IR (a standard marker of insulin resistance), and HbA1c levels, greater glycemic variability, lower levels of HDL (“good”) cholesterol, as well as more pronounced abdominal obesity and liver fat accumulation.
Groups with adipose tissue insulin resistance also showed elevated levels of ALT and AST. While these enzymes can accompany hepatic metabolic dysfunction, they are non-specific and do not independently confirm liver injury or fatty liver disease.
Notably, participants with insulin resistance isolated to adipose tissue were metabolically very similar to those who had resistance in both adipose tissue and muscle. Both of these groups differed sharply from the control group, which maintained good insulin sensitivity.
In other words, adding muscle insulin resistance to existing adipose tissue resistance did not substantially worsen the overall picture—it appears that the vast majority of metabolic impairment was driven by the adipose tissue resistance itself. However, it is too early to state this with absolute certainty.
Muscle Resistance
Participants who had muscle insulin resistance but maintained insulin sensitivity in their adipose tissue exhibited low whole-body insulin sensitivity. Despite this, most of their other cardiometabolic parameters did not differ significantly from those of the control group.
This pattern emerged more clearly in women than in men. Specifically, better muscle insulin sensitivity in women was associated with lower hepatic insulin resistance and lower muscle fat content—associations that were not recorded in men. While these sex-specific features are potentially interesting, they should be considered preliminary hypotheses until confirmed by larger-scale studies.
However, deeming muscle insulin resistance “harmless” would be incorrect. Skeletal muscle is the primary site for insulin-stimulated glucose uptake, and muscle resistance remains an important hallmark of metabolic disorders. The study’s result simply indicates that in this specific cohort, this parameter was more weakly associated with risk markers than adipose tissue insulin resistance.
Why the Link Between Adipose Tissue and the Liver is Plausible
When adipose tissue becomes less sensitive to insulin, insulin can no longer effectively suppress the release of fatty acids from fat cells. An increased supply of fatty acids to the liver can promote fat accumulation within the organ and trigger metabolic disruptions.
Adipose tissue also produces signaling molecules and participates in inflammatory and hormonal regulation. Its influence depends partly on the type and location of the fat: visceral and ectopic fat are typically far more closely linked to metabolic risk than total fat mass as a single, uniform category.
Therefore, the term “adipose tissue insulin resistance” should not be interpreted as though all body fat exerts the same biological effect.
What the Study Does Not Show
It is important to consider several limitations:
The analysis was cross-sectional (point-in-time), making it impossible to determine whether adipose tissue insulin resistance directly causes liver fat accumulation, impaired glucose regulation, or other metabolic changes.
The classification of adipose and muscle tissue sensitivity relied primarily on surrogate indices rather than direct tissue measurements in every participant. For example, Adipose Tissue Insulin Resistance Index (ATIRI) evaluates adipose resistance based on fasting insulin and circulating fatty acids; this is not a direct clinical measurement of insulin action within fat tissue.
The study utilized median thresholds from the participants rather than established diagnostic cutoffs.
The study cohort comprised middle-aged and older adults with overweight or obesity, so the results may not generalize to younger individuals, normal-weight adults, or other populations.
The study was not designed to determine whether a specific diet, exercise program, or medication should be selected based on a person’s tissue-specific insulin resistance profile.
Why This Matters
If the findings of this study are confirmed by larger, prospective scientific works, it will prompt researchers to view insulin resistance not as a single, homogenous state, but as a combination of interconnected, tissue-specific characteristics. Ultimately, this could help foster the development of more personalized approaches to nutrition, exercise, and pharmacological treatment.
At this stage, the most grounded and concrete conclusion is as follows: among the 229 adults participating in the study, adipose tissue insulin resistance was more closely and consistently associated with adverse metabolic parameters than skeletal muscle insulin resistance. The study provides a solid foundation for further exploration in this direction, though it does not prove that adipose tissue is the primary cause of metabolic disorders or that muscle insulin resistance is of lesser importance.
Source: Diabetes Research and Clinical Practice
