Reassessing Diabetes’ Dominant Paradigm

Type 2 diabetes mellitus (T2DM) is commonly attributed to insulin resistance, defined as impaired responsiveness of skeletal muscle, adipose tissue, and liver to insulin. Although the concept is deeply embedded in modern metabolic medicine, it remains largely inferential and descriptive. This paper critically examines conceptual, physiological, and epidemiological limitations of the insulin resistance paradigm. It argues the model lacks a demonstrated unifying mechanism capable of coordinating selective impairment across multiple tissues, does not adequately explain preservation of many insulin-mediated functions, and leaves unresolved clinical paradoxes including rapid reversibility of hyperglycemia, metabolically healthy obesity, and diabetes in lean individuals. Reassessment of insulin resistance as a primary causal construct may be necessary for progress in prevention and treatment of type 2 diabetes.

Type 2 diabetes mellitus has become one of the most consequential chronic diseases of modern medicine. Its prevalence has risen sharply within a historically brief period, both in the United States and globally. The prevailing model holds T2DM develops because skeletal muscle, adipose tissue, and liver become resistant to insulin. Muscle fails to take up glucose efficiently, adipose tissue does not adequately suppress lipolysis, and the liver continues to release glucose despite circulating insulin.

Yet the insulin resistance model has masked unresolved problems. The term functions more as interpretation of measured glucose dynamics than as directly demonstrated lesion in cell biology. Measures such as HOMA-IR and clamp studies quantify relationships among glucose uptake, glucose production, and insulin concentration, but do not identify a primary molecular defect. The field observes altered glucose handling and names the observation insulin resistance, then uses that label to explain the same observation. This paper questions whether such observations justify the conclusion that a primary defect in insulin signalling is the central biological driver.

Historical Development  

The concept of insulin resistance emerged from the need to reconcile hyperglycaemia with presence of insulin. The glucose clamp technique gave investigators a rigorous way to compare insulin levels with glucose disposal, and lower-than-expected disposal rates were interpreted as evidence tissues had become resistant. It quantified the phenomenon; it did not settle the cause. Over time, language of insulin resistance acquired status beyond evidence supporting it. It was inferred from outcomes, generalized across tissues, and institutionalized before a unifying biological mechanism had been demonstrated.

Definitional and Conceptual Problems  

A central weakness lies in imprecision. Insulin resistance can refer to reduced whole-body glucose disposal, impaired insulin-stimulated glucose transport, failure of insulin to suppress hepatic glucose production, or a broad syndrome inferred from surrogate indices. A descriptive index is substituted for a mechanism. Hyperglycaemia may be viewed analogous to hypercholesterolemia, in that both are defined by elevated circulating biomarkers that may arise from multiple underlying causes.

Major Biological Inconsistencies  

No unifying mechanism across tissues: The standard account requires skeletal muscle, adipose tissue, and liver all develop diminished insulin responsiveness. Despite decades of research, no established signal has been shown to orchestrate coordinated reduction in insulin responsiveness across all three tissues.

Selective preservation of other insulin functions: In T2DM, glucose handling is said impaired, yet many other insulin-mediated actions remain operative. Protein synthesis continues. Lipogenic processes are not uniformly absent. Basic physiological functions such as maintenance of muscle tone and thermoregulation are preserved. If the primary defect were generalized failure of insulin signalling, broader collapse might be expected. Instead, the picture is one of selective disturbance concentrated around glucose handling. Why should insulin signalling fail specifically in ways that elevate blood glucose while remaining functional for other tasks?

Selective vulnerability versus other hormones: Insulin does not operate in isolation. Glucagon, catecholamines, cortisol, growth hormone, incretins, adipokines, and other signals influence nutrient handling. Yet a dominant model posits resistance focused primarily on insulin. Glucagon continues to stimulate hepatic glucose production. Catecholamines retain lipolytic effects. Cortisol and growth hormones continue to exert major physiological actions. Selective targeting of insulin weakens the idea that T2DM is fundamentally hormone resistance disorder.

The insulin resistance paradigm has become default explanation for T2DM, but conceptual authority exceeds demonstrated mechanistic foundation. It lacks unifying coordinating mechanism across tissues, struggles to explain selective preservation of insulin’s other functions, cannot account for absence of broad parallel hormone resistance, and sits uneasily with rapid reversibility of hyperglycaemia, lean diabetes, metabolically healthy obesity, and speed of modern diabetes epidemic. Reassessing the dominant paradigm may be necessary if progress in prevention and treatment is to match the scale of disease.

(The writer is a retired physician based in Portland of America. Views Personal.)