For Medical Professionals

“The key question is not whether insulin signaling is impaired — it is whether hyperglycemia reflects impaired signaling or substrate excess. That distinction changes everything about how we treat.”

— John M. Poothullil, MD, FRCP
Medical Hypotheses, Elsevier · Vol. 209, 2026 · Article 111926

A framework worth examining

We welcome clinicians, endocrinologists, and researchers to engage with this peer-reviewed hypothesis. The observations described here are not disputed — the point of disagreement concerns whether the phenotype we call “insulin resistance” is a primary causal defect, or a predictable consequence of substrate competition under conditions of nutrient excess. We invite you to consider the evidence and decide how to integrate this perspective into practice.

Peer-reviewed publication

Elsevier

Medical Hypotheses ·
Vol. 209

A substrate-competition hypothesis for type 2 diabetes driven by nutrient excess rather than a primary insulin-signaling defect

John M. Poothullil

MD, FRCP · Portland, OR

Journal Medical Hypotheses

Article 111926

Accepted 23 February 2026

Published 23 February 2026

Insulin resistance

Type 2 diabetes

Substrate competition

Fat storage

Refined carbohydrate

Gestational diabetes

Open access · CC BY-NC-ND

DOI: 10.1016/j.mehy.2026.111926

Clinical Q&A · Endocrinology series · Dr. Sara & Dr. John Poothullil

Question 1 of 15

Your article in Medical Hypotheses proposes a different causal framework for type 2 diabetes. Can you briefly explain your hypothesis?

My hypothesis builds on the Randle cycle: when circulating fatty acids are elevated, skeletal muscle preferentially oxidizes fat, which reduces glucose utilization without requiring any defect in insulin receptors or intracellular signaling pathways. In this framework, what is commonly labeled ‘insulin resistance’ is not a primary pathological defect — it is a predictable consequence of substrate competition under conditions of nutrient excess, particularly lipid oversupply derived from dietary carbohydrates. The focus shifts from signaling abnormalities to metabolic flux and substrate availability.

Question 2 of 15

Hyperinsulinemia often precedes hyperglycemia and is typically interpreted as compensation for insulin resistance. How do you explain that sequence?

At diagnosis, many patients have insulin levels that are normal or elevated. That does not require a compensatory explanation. Postprandial glucose is a strong stimulus for insulin secretion, and incretin hormones such as GLP-1, along with amino acids and free fatty acids, further augment insulin release. Hyperinsulinemia is better understood as a physiological response to chronic nutrient excess — an attempt to maintain metabolic balance in an overloaded system, rather than evidence of a primary signaling defect.

Question 3 of 15

A hallmark of type 2 diabetes is persistent hepatic glucose production despite hyperinsulinemia. Doesn’t that indicate impaired insulin-mediated suppression?

Not necessarily. Elevated fatty acid oxidation generates substrates such as glycerol and acetyl-CoA, which directly drive gluconeogenesis. The liver also converts excess amino acids into glucose after meals. Hepatic glucose production in this setting reflects substrate-driven metabolic flux — not a failure of insulin signaling. When glycogen stores are saturated and lipid storage is exceeded, the liver must export excess substrate. Glucose exits via GLUT2 transporters, which are insulin-independent. This is better understood as a flux imbalance rather than a breakdown in insulin action.

Question 4 of 15

What about α-cell dysfunction and hyperglucagonemia, which are usually attributed to defective intra-islet signaling?

Elevated fatty acid metabolites can mimic fasting-state signals, even in the presence of nutrient excess. This can stimulate α-cell glucagon secretion, producing a physiological response that resembles starvation. Hyperglucagonemia may reflect misinterpreted metabolic signaling driven by lipid excess, rather than intrinsic defects in islet cell communication.

Question 5 of 15

Reduced insulin secretion relative to hyperglycemia is typically labeled β-cell failure. How does your model interpret that?

It may represent an adaptive response rather than failure. Chronic hyperinsulinemia has physiological costs, including effects on cellular proliferation. A reduction in insulin output may help preserve long-term β-cell function. Notably, the fact that agents such as sulfonylureas and meglitinides can still stimulate insulin release suggests that secretory capacity is not necessarily lost — which is difficult to reconcile with a true failure model.

Question 6 of 15

Therapies that improve ‘insulin sensitivity’ reduce hepatic glucose output and improve glycemia. How do you account for that within your model?

Measures such as clamp studies and HOMA-IR infer insulin sensitivity indirectly from glucose dynamics — they do not directly demonstrate improved intracellular signaling. Clinical improvements are more consistently explained by reduced substrate availability: caloric restriction, decreased hepatic lipid burden, and altered metabolic flux. These effects do not require restoration of a primary signaling defect, and the distinction matters for how we frame treatment goals.

Question 7 of 15

Is there an established metabolic condition that illustrates your model more clearly?

Yes — hyperlipidemia provides a close analogy. Elevated cholesterol or triglycerides reflect excess circulating substrates overwhelming metabolic pathways. Similarly, hyperglycemia can be understood as glucose excess exceeding storage and utilization capacity. In both cases, pathology arises from quantitative overload rather than primary regulatory failure. Lipodystrophy offers another parallel: where adipose storage is markedly constrained, ectopic lipid deposition and severe dysglycemia follow — consistent with the premise that constrained lipid buffering promotes downstream metabolic disruption.

Question 8 of 15

What kind of real-world evidence supports your hypothesis?

Population transitions are informative. Native American populations historically had very low rates of type 2 diabetes prior to dietary changes. Following the introduction of refined, grain-based foods, prevalence rose sharply. That pattern is consistent with a model in which dietary composition and substrate excess drive disease — rather than intrinsic cellular defects. The rapid rise in T2D prevalence over recent decades is also difficult to reconcile with evolutionary timescales if a primary genetic or signaling defect is the operative mechanism.

Question 9 of 15

If insulin resistance is not the primary issue, what is the role of insulin therapy in type 2 diabetes?

Exogenous insulin lowers glucose by forcing it into storage pathways, including glycogen and triglyceride synthesis. That controls hyperglycemia, but it does not address the underlying substrate imbalance and may increase lipid storage over time. Within this framework, insulin is effective for symptom control but is not disease-modifying. The distinction matters — particularly when we consider why complications can still progress despite pharmacologic glucose normalization.

Question 10 of 15

How do GLP-1 receptor agonists fit into your model?

Their benefits are entirely consistent with a substrate-overload model. They reduce appetite, caloric intake, and overall metabolic load, which improves glycemia. However, because they do not directly correct underlying dietary patterns, continued use is typically required. The long-term side effects of GLP-1 medications remain unknown — a consideration that reinforces the case for nutrition-centered approaches that address the upstream substrate imbalance directly.

Question 11 of 15

What would you say to clinicians who continue to treat type 2 diabetes primarily as a problem of insulin resistance?

The underlying metabolic observations are not disputed — the point of disagreement concerns whether the observed phenotype warrants attribution to a primary causal state labeled ‘insulin resistance.’ Patients are often taught that glucose control alone equals disease control, but complications can occur despite pharmacologic normalization. Addressing dietary intake — particularly the excessive carbohydrate-driven substrate load — targets the underlying metabolic imbalance more directly. Clinicians must decide how to integrate this perspective into practice.

Question 12 of 15

How does your hypothesis explain diabetes in patients without apparent overnutrition, such as malnutrition-associated diabetes?

Early-life malnutrition can reduce adipocyte number, limiting storage capacity later in life. This aligns with the concept of a ‘personal fat threshold,’ beyond which lipid storage becomes pathogenic even in individuals with normal body weight. In that situation, fatty acids are preferentially oxidized, which suppresses glucose utilization and leads to hyperglycemia despite relatively low caloric intake. It also helps explain why T2D prevalence varies across BMI strata — a pattern that is difficult to explain if a primary insulin-signaling defect is the initiating mechanism.

Question 13 of 15

Can the nutrient overload hypothesis explain the signaling distortions observed in type 2 diabetes?

Two types of signaling distortions are under investigation. Intracellular signal disruptions could be explained as an adaptive mechanism by the cell to prevent entry of unneeded glucose molecules, because the cell already has an alternate fuel for energy — and to limit the entry of water molecules that could interfere with cell metabolism. Organ-to-organ signal distortions could reflect biologic responses to energy and nutrient utilization in an environment of chronic nutrient overload. In both cases, the distortions are downstream consequences, not initiating defects.

Question 14 of 15

If treatment is nutrition-centered, how should clinicians define success?

Success should be defined by prevention of complications — not glucose control measures alone. The behavioral drivers of overconsumption are largely structural: the easy availability and affordability of grain-based foods that often fail to meet the body’s actual nutrient needs. Modifying food intake to restore balance between intake, storage, and utilization produces disease control as evidenced by glucose normalization — but through a mechanism that is disease-modifying, not merely symptomatic. That is a meaningful distinction for long-term patient outcomes.

Question 15 of 15

Finally, what is your core message to clinicians and researchers engaging with this hypothesis?

Type 2 diabetes can be understood as a disorder of nutrient excess and metabolic overflow rather than a primary hormonal defect. This hypothesis yields falsifiable predictions regarding temporal ordering and measurable intermediates, and outlines study designs that allow direct empirical adjudication between this framework and insulin-resistance-first models. It still requires validation — but it provides a coherent, parsimonious explanation for multiple observed phenomena, including boundary cases that are not easily reconciled by the dominant paradigm. Ultimately, clinicians must decide how to integrate this perspective into practice.