Insulin resistance does not necessarily begin with high blood glucose. For years, pancreatic beta cells may secrete more insulin to maintain apparently normal glucose concentrations. Beneath that compensation, adipose lipolysis may be inadequately suppressed, liver fat may accumulate and skeletal muscle may dispose of glucose less efficiently.
Adipose tissue is central to this trajectory. When it stores triglycerides safely, it protects other organs. When it becomes hypertrophic, fibrotic, inflamed and insulin resistant, fatty acids and glycerol spill into the circulation and expose the liver, muscle and pancreas to chronic nutrient excess.
Organ-specific insulin resistance
Insulin resistance is neither uniform nor complete.
- In adipose tissue, insulin becomes less effective at suppressing lipolysis.
- In the liver, insulin inadequately suppresses glucose production, while lipogenesis may remain active.
- In skeletal muscle, insulin-stimulated glucose transport and glycogen synthesis decline.
This selective resistance helps explain why fasting glucose can remain normal while triglycerides, liver fat and postprandial insulin rise.
Liver and muscle
Increased delivery of fatty acids and glycerol supports hepatic gluconeogenesis and triglyceride synthesis. Acetyl-CoA generated through fatty-acid oxidation can activate pyruvate carboxylase, while selected membrane diacylglycerols can activate PKCε and disrupt insulin-receptor signalling. VLDL export rises, contributing to an atherogenic lipid profile.
Skeletal muscle is the main site of insulin-stimulated glucose disposal after meals. Lipid intermediates, inactivity, reduced oxidative capacity and inflammation can impair the IRS–PI3K–Akt–GLUT4 pathway. Yet intramyocellular triglyceride is not automatically harmful: endurance athletes store substantial lipid while maintaining high insulin sensitivity. Turnover, subcellular location and mitochondrial capacity matter more than triglyceride quantity alone.
Compensation and beta-cell failure
Initially, beta cells compensate by increasing insulin secretion. Type 2 diabetes develops when secretion can no longer match insulin resistance. Genetics, age, glucolipotoxic stress, islet amyloid, endoplasmic-reticulum stress and loss of beta-cell identity all influence this transition.
Prediabetes is therefore a risk state rather than a sharp biological boundary. Glucose tolerance may worsen first after meals, followed by fasting glucose and HbA1c.
The personal fat threshold
The amount of weight associated with metabolic dysfunction differs between individuals. Some people maintain a large, insulin-sensitive subcutaneous depot and little ectopic fat; others reach their storage limit at a lower BMI. This model helps explain type 2 diabetes in people without conventional obesity, but it does not provide a single measurable clinical threshold.
Detection in practice
No routine test measures insulin sensitivity perfectly. The hyperinsulinaemic–euglycaemic clamp remains a research reference method. Clinical evaluation instead combines waist measures, blood pressure, fasting glucose, HbA1c, lipid profile, liver risk assessment, family history, gestational diabetes, polycystic ovary syndrome, medications and sleep.
Fasting insulin and HOMA-IR may be useful in research or specialist settings, but assay variation and population-dependent thresholds limit individual diagnosis.
Can the trajectory be reversed?
Muscle contraction stimulates glucose uptake through pathways partly independent of insulin. Both aerobic and resistance training improve glucose handling, and resistance exercise helps preserve the muscle mass that serves as a major glucose sink.
Reducing visceral and liver fat improves insulin sensitivity. In early type 2 diabetes, substantial and sustained weight loss can produce remission. DiRECT showed a strong relationship between maintained weight loss and remission, but five-year follow-up also confirmed that relapse is common when weight is regained. Remission is not permanent cure and does not remove the need for cardiovascular follow-up.
Modern incretin-based treatment and metabolic surgery can produce large weight loss and major glycaemic benefits in appropriate patients. Choice and monitoring remain clinical decisions because efficacy, tolerability, contraindications, access and long-term maintenance differ.
Evidence hierarchy
| Claim | Level | Interpretation |
| Visceral and liver fat are strongly related to insulin resistance and type 2 diabetes risk. | A | Convergent metabolic, imaging and prospective evidence. |
| Substantial sustained weight loss can induce remission of recent type 2 diabetes in some people. | A | Randomised trials and long-term follow-up. |
| DAG/PKC and ceramide pathways contribute to insulin resistance. | B | Strong mechanistic evidence with compartment-specific human support. |
| Fasting insulin alone precisely diagnoses individual insulin resistance. | D | Insufficient standardisation and no universal threshold. |
Pathological Adiposity series
1. Pathological adiposity → 2. Metabolic inflammation → 3. Insulin resistance → 4. Ectopic fat → 5. Endothelial dysfunction and hypertension → 6. Reversibility.
Selected references
- Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiological Reviews. 2018. DOI
- Lean MEJ, et al. DiRECT trial. Lancet. 2018. DOI33102-1)
- Lean MEJ, et al. Five-year DiRECT extension. Lancet Diabetes & Endocrinology. 2024. DOI00385-6)
- American Diabetes Association. Standards of Care in Diabetes.
Core updated sources
- Rubino F, et al. Definition and diagnostic criteria of clinical obesity. Lancet Diabetes & Endocrinology. 2025. DOI00316-4)
- World Health Organization. Obesity and overweight: fact sheet. Updated 2025.
- EASL–EASD–EASO. Clinical Practice Guidelines on MASLD. 2024.
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