SAN ANTONIO, Sept. 11, 2025 – Researchers at The University of Texas at San Antonio Health Science Center have discovered that physiological changes leading to Type 2 diabetes occur well before current prediabetes diagnostic thresholds are met. This groundbreaking study, published in The Journal of Clinical and Applied Research and Education: Diabetes Care, introduces a new risk category termed “pre-prediabetes.”
The study challenges conventional thinking about the onset of Type 2 diabetes by revealing that individuals with normal glucose tolerance can already exhibit severe insulin resistance, early beta cell dysfunction, and measurable cardiovascular disease.
“We’ve shown that long before you develop diabetes, and even before you meet the criteria for prediabetes, people can be severely insulin resistant,” said Ralph DeFronzo, MD, professor of medicine and chief of the Diabetes Division at the Health Science Center, and deputy director of the Texas Diabetes Institute. “Diabetes is a continuous disease; you don’t just wake up one day with prediabetes or diabetes.”
Rethinking Diagnostic Criteria
The American Diabetes Association (ADA) currently defines diabetes based on three criteria: fasting glucose levels of ≥126 mg/dL, two-hour glucose during an oral glucose tolerance test (OGTT) of ≥200 mg/dL, and hemoglobin A1c of ≥6.5%. Prediabetes is similarly defined using slightly lower thresholds. However, these measures often fail to identify at-risk patients before the disease progresses.
In this study, DeFronzo’s team, in collaboration with the Translational Research Department of the Dasman Diabetes Institute in Kuwait, examined individuals with normal glucose tolerance by ADA standards. They found that one-hour glucose levels during an OGTT are a superior predictor of future disease. A value between 120 and 155 mg/dL was identified as a marker for individuals likely to develop prediabetes and eventually Type 2 diabetes, years before standard criteria would detect them.
“The one-hour glucose is far superior to the two-hour glucose test for predicting who will progress,” DeFronzo said. “Using this measure, we can see insulin resistance and beta cell problems well before the current definitions kick in.”
The Case for Early Intervention
Despite this evidence, the ADA does not currently recommend routine treatment of prediabetes, and the Food and Drug Administration has not approved any drugs specifically for prediabetes treatment. In high-risk cases, the ADA advises considering metformin, a drug that DeFronzo helped introduce to the United States but now considers outdated.
DeFronzo advocates for newer treatments, such as the insulin sensitizer pioglitazone, which reduces the progression from prediabetes to diabetes by 75%—more than double metformin’s effect. Additionally, GLP-1 receptor agonists and dual agonists like semaglutide and tirzepatide can cut Type 2 diabetes progression rates by up to 85%.
He suggests that high-risk patients, especially those with strong family histories of diabetes or early cardiovascular disease, should be screened early and offered treatment long before they develop Type 2 diabetes.
Early Detection, Early Intervention
Through continued research, patient education, and off-label prescribing by endocrinologists and other specialists, DeFronzo hopes healthcare providers will shift towards earlier detection and intervention for insulin resistance, prediabetes, and Type 2 diabetes. He argues that this study’s findings should encourage more clinicians to consider OGTTs, particularly in high-risk populations, and recognize that significant metabolic and vascular disease can be present long before traditional prediabetes thresholds.
“Insulin resistance can lead to diabetes, beta cell failure, heart failure, atherosclerosis, liver disease, and kidney disease,” he said. “We can see it and measure it years before overt diabetes becomes manifest. The sooner we act, the better prepared we are to prevent these outcomes.”
The study, titled “One-Hour Plasma Glucose Predicts the Progression From Normal Glucose Tolerance to Prediabetes,” was authored by Abdul-Ghani M, Abu-Farha M, Abdul-Ghani T, Chavez-Velazquez A, Merovci A, DeFronzo RA, Alajmi F, Stern M, and Al-Mulla F, and published on July 1, 2025. The full study can be accessed at PubMed.
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