A landmark study has shed new light on the molecular roots of insulin resistance, a hallmark of type 2 diabetes, by mapping protein-level changes in human skeletal muscle.
The findings may pave the way for more precise, individualised approaches to type 2 diabetes treatment.
Researchers used advanced proteomic technology and deep phenotyping techniques to analyse muscle biopsies from people with and without type 2 diabetes.
The goal was to understand why some individuals with type 2 diabetes show severe insulin resistance, while others retain surprising levels of insulin sensitivity.
Type 2 diabetes, affecting over 500 million people globally, is commonly characterised by elevated blood sugar and impaired insulin action in tissues such as the liver, fat, and muscle.
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Skeletal muscle, responsible for the majority of insulin-stimulated glucose uptake, is a critical player. But until now, the exact molecular signatures driving muscle insulin resistance remained poorly understood.
In this study, scientists focused on the vastus lateralis muscle of 77 individuals — 43 with normal glucose tolerance (NGT) and 34 with type 2 diabetes — while controlling for factors like age, sex, and BMI.
Muscle samples were taken before and during a hyperinsulinemic-euglycemic clamp, the gold standard for assessing insulin sensitivity.
The analysis revealed that insulin sensitivity varied significantly even within diagnosis groups. Some participants with type 2 diabetes were more insulin-sensitive than those without the condition, challenging traditional diagnostic boundaries and highlighting the need for more nuanced classification of metabolic health.
One of the most striking findings was the role of mitochondrial proteins. Rather than serving as indicators of diabetes, their levels were directly linked to how sensitive an individual was to insulin, suggesting that muscle energy production capacity could be a better marker for metabolic health than blood sugar alone.
The study also highlighted several molecular pathways tied to insulin resistance. Increased activity in protein degradation systems like the proteasome and disruptions in signalling pathways – such as Wnt, adrenergic, and JNK-p38 kinases — were associated with poorer insulin action.
In contrast, elevated levels of glycolytic enzymes and altered enzyme ratios, such as lactate dehydrogenase (LDHA/LDHB), hinted at metabolic shifts contributing to resistance.
Unexpectedly, the researchers found that protein signalling in the fasting state was more predictive of insulin sensitivity than signalling observed after insulin stimulation.
One key site, AMPKγ3 S65—a protein modification unique to humans—emerged as a strong marker of insulin resistance and a possible therapeutic target.
Sex differences also emerged: men showed higher levels of glucose-metabolism proteins, while women — mostly post-menopausal — had higher lipid-metabolism markers.
Despite these differences, the core molecular patterns of insulin resistance were largely consistent across sexes.
The research offers compelling evidence that insulin resistance is not a uniform dysfunction but rather a selective failure in specific signalling pathways.
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Some key insulin-related functions, such as AKT signalling, remained intact even in individuals with marked resistance.
Although the study’s observational nature limits its ability to establish causality, its insights reinforce the need for precision medicine in diabetes care.
Moving beyond one-size-fits-all treatments, future therapies may be tailored to an individual’s unique muscle protein profile and metabolic response.
As type 2 diabetes rates continue to rise, this study marks a critical step toward understanding the intricate biology behind insulin resistance, and ultimately, toward better-targeted and more effective treatments.
Read the study in the journal Cell.
