Insulin resistance to incretin agonism: T2D

A review published on 3 September 2026 in Current Medical Research and Opinion maps the pharmacological path from insulin resistance to full type 2 diabetes mellitus (T2DM) in people with obesity, and assesses which drugs can interrupt that journey. The paper, by Teofilovic et al. ^[1], frames the problem bluntly: more than 828 million people worldwide were living with diabetes as of 2022 ^[2], and obesity is the single largest modifiable driver of incident T2DM.

The central argument is that treating obesity-driven insulin resistance early, before the pancreatic beta cells are exhausted, is where the greatest prevention gains sit. The drug classes that now dominate that window are no longer just metformin. Incretin receptor agonists, specifically GLP-1 receptor agonists and dual GIP/GLP-1 agonists, have moved from glycaemic control tools to genuine prevention candidates.

Why the pathway from obesity to T2DM matters

The biological chain is well characterised. Excess adipose tissue, especially visceral fat, produces inflammatory cytokines and free fatty acids that impair insulin signalling at the liver, skeletal muscle and fat tissue. Peripheral insulin resistance forces the pancreatic beta cells to secrete more insulin to maintain glucose in range. When beta-cell capacity is eventually exceeded, glucose rises, first post-meal and then fasting, and T2DM is diagnosed.

Prediabetes (impaired fasting glucose or impaired glucose tolerance) is the clinical warning stage. In people with obesity and prediabetes, the annual conversion rate to T2DM runs at roughly 5 to 10 percent per year in observational datasets, though exact figures vary by population and diagnostic threshold. The Teofilovic review focuses on this window as the target for pharmacological intervention.

The established anchor: metformin

The review confirms that metformin retains the strongest long-term evidence base for T2DM prevention. The Diabetes Prevention Program Outcomes Study (DPPOS) demonstrated sustained reduction in diabetes incidence over more than a decade of follow-up in people with prediabetes. Teofilovic et al. describe metformin's mechanisms as both AMPK-dependent (hepatic glucose output suppression) and AMPK-independent (intestinal GLP-1 secretion, gut microbiome modulation). These are mechanistically distinct from the incretin class, which matters because the two can be used together. For the full semaglutide regulatory picture, see the peptide page.

Where GLP-1 agonists and tirzepatide now fit

Semaglutide and tirzepatide are the two incretin-class medicines the review treats as having the most relevant evidence for obesity-driven T2DM prevention. Both produce weight loss well above the 5 to 7 percent threshold at which meaningful reductions in insulin resistance are observed. The review notes that GLP-1 receptor agonists also have direct beta-cell effects: they increase glucose-stimulated insulin secretion and appear to slow beta-cell apoptosis in animal models, though the human beta-cell preservation evidence is still accumulating.

Tirzepatide's dual GIP and GLP-1 mechanism adds a second incretin axis. GIP receptor activation in adipose tissue may contribute to lipid redistribution independent of weight loss, which is one reason tirzepatide's cardiometabolic markers in the SURPASS and SURMOUNT programmes often exceeded what the weight loss alone would predict.

Retatrutide: the triple agonist in the prevention frame

The Teofilovic review includes retatrutide, the triple GLP-1, GIP and glucagon receptor agonist developed by Eli Lilly, as an emerging agent in the T2DM prevention discussion. Retatrutide is not approved anywhere as of September 2026. It remains investigational. The review cites its mechanism: glucagon receptor co-activation adds an energy-expenditure arm on top of the appetite and beta-cell effects from GLP-1, and GIP receptor activation further modulates lipid metabolism.

The Phase 2 obesity trial (Jastreboff et al., NEJM 2023) reported a mean 24.2% body-weight reduction at 48 weeks on the 12 mg weekly subcutaneous dose in 338 adults with obesity or overweight and no diabetes. ^[3] At that dose, 83% of participants lost at least 15% of body weight, a threshold associated with major reductions in incident T2DM risk in metabolic surgery literature. The Phase 2 type 2 diabetes trial (Rosenstock et al., Lancet 2023) showed HbA1c reductions significantly greater than placebo in all active dose groups, with the 12 mg arm producing approximately a 2 percentage-point reduction at 24 weeks. ^[4]

Whether retatrutide's triple mechanism translates to superior T2DM prevention compared to dual or single incretin agonists is not yet established. No head-to-head prevention trial has been completed. The TRIUMPH Phase 3 programme is ongoing, with TRIUMPH-2 (retatrutide in people with type 2 diabetes and obesity) as the most directly relevant registered trial.

What this is not

This review and the research it summarises are about preventing T2DM in high-risk individuals, not about self-managing obesity without medical oversight. The drugs discussed are either prescription medicines (metformin, semaglutide, tirzepatide) or investigational compounds (retatrutide) with no approved consumer route. The review does not recommend or describe dosing protocols; it maps mechanism and evidence.

Retatrutide's inclusion in a prevention review does not signal that it is available. The compound is investigational, and the FDA, EMA, MHRA and national agencies in all jurisdictions we track list it as such. The detail is on the retatrutide peptide page.

Where this lands

The Teofilovic 2026 review is not presenting new trial data. Its value is synthesis: it places metformin, GLP-1 agonists, dual agonists and the triple-agonist class in a single mechanistic and evidence map, tied to the question of prevention rather than treatment. For anyone following the incretin space, the important takeaway is that obesity-specific pharmacology is increasingly being discussed as T2DM prevention infrastructure, not just a weight or glucose intervention. Whether retatrutide eventually earns a role in that architecture depends on Phase 3 outcomes that are still being collected.

This article is educational. It does not advise on starting, stopping or sourcing any medicine. Consult a clinician before considering any pharmacological intervention for prediabetes or obesity.