This article was reviewed for scientific accuracy by Benjamin Bikman, PhD and Ronald Goldberg, MD

More than 80 percent of American adults are unaware that they have prediabetes (1). Patients with prediabetes do not typically show symptoms, so the only way to detect it is through blood tests. In healthy people, fasting blood sugars fall between 70 milligrams per deciliter (mg/dL) and 99 mg/dL, while values for those with prediabetes fall between 100 mg/dL and 125 mg/dL. Levels at 126 mg/dL or higher indicate type 2 diabetes (2). Although the cutoff values to define these boundaries are arbitrary, they are useful for type 2 diabetes prevention and underscore the importance of regular checkups. “It was recognized that people who were just shy of that diabetes cut off point had a very high risk of going on to develop diabetes,” said Ronald Goldberg, an endocrinologist at the University of Miami. “It was important to identify those individuals for the purpose of saying, ‘, You're at higher risk,’ and intervening appropriately” 

How does prediabetes develop? 

Prediabetes results from dysfunctional insulin-producing beta cells combined with a loss of sensitivity to insulin, also known as insulin resistance. Normally, dietary glucose enters the blood and leads beta cells in the pancreas to release insulin, which binds to insulin receptors on fat cells, skeletal muscle cells, and liver cells, stimulating glucose uptake from the blood (Figure 1) (3).

Insulin resistance can occur when tissue cells do not respond effectively to insulin, resulting in poor glucose uptake (Figure 1) (4). Although not completely understood, most cases of prediabetes result from insulin resistance due to being overweight or obese, which places an increased demand on dysfunctional beta cells. In some cases, individuals with insulin resistance may not develop diabetes because their beta cells can compensate for defects in glucose absorption by releasing more insulin (3). However, in individuals with a limited beta cell reserve, consuming carbohydrates increases their cellular demand for insulin, which their beta cells cannot accommodate, causing their glucose levels to rise. The degree of insulin resistance and beta cell dysfunction varies between individuals,  highlighting the heterogeneity of this condition (5).

As useful as it is to keep tabs on blood glucose levels, “Insulin is an earlier indicator of prediabetes,” said Benjamin Bikman, a cell biologist and physiologist at Brigham Young University. Insulin levels are not a clinical parameter to diagnose prediabetes. However, “By the time glucose levels are high enough to show up in a blood test, insulin has already been fighting a war for perhaps 10 years or more,” Bikman said. High insulin levels in the blood often lead to metabolic syndrome, a cluster of comorbidities that often occur with prediabetes, including high blood pressure, increased fasting glucose, abnormal lipid levels, and increased abdominal fat (6).

The scientific argument for diet and exercise

Consuming large quantities of refined carbohydrates leads to increased glucose and blood sugar levels, which contribute to chronically elevated insulin. Repeated cycles of high blood insulin due to poor diet can eventually make cells less responsive to insulin signals (4). Bikman’s group showed that women with type-2 diabetes who eliminated refined carbohydrates significantly reduced the ratio of triglycerides to high-density lipoprotein (HDL) cholesterol, a marker of insulin resistance (7). “Within 90 days of just dietary intervention, there was no evidence of diabetes anymore,” Bikman said. Eliminating refined carbohydrate intake also normalized hemoglobin A1c levels, a measure of average blood glucose, over three months. 

The centerpiece of reversing prediabetes currently is weight reduction through calorie restriction and increasing physical activity.  In the Diabetes Prevention Program Outcomes Study, researchers from the diabetes prevention program research group asked people with prediabetes to lose weight by reducing calories, which they achieved by eliminating refined carbohydrates and fat, and including 150 minutes of physical activity per week (8). “Those who achieved both goals, the weight loss goal and the exercise goal, prevented diabetes more effectively than those who achieved just the weight loss goal,” said Goldberg who coauthored the study. In some cases, glucose levels can be restored to normal (9).

Exercise has immediate effects on the body. Increased muscle contractions during exercise raise intracellular calcium levels and create an increased demand for energy, which activates adenosine monophosphate-activated protein kinase (AMPK) (10). AMPK phosphorylates the Akt substrate of 160 kDa (AS160) protein, which allows glucose transporter type 4 (GLUT4) to translocate to the outer membranes of muscle cells, where it enhances glucose uptake (Figure 2). This effect occurs even in people with insulin resistance. 

Normally, insulin is the key to ushering glucose into muscles after a carbohydrate-rich meal. However, when muscles are active through exercise, they become eager for glucose, and they take it in without insulin’s help. This means that exercise can reduce blood glucose and therefore insulin levels even in people whose cells are less efficient at taking up glucose due to insulin resistance. Increasing muscle mass with exercise also means having more muscle to consume glucose, effectively maintaining balanced glucose and insulin levels (11).

The role of genetics and epigenetics in prediabetes

Although dietary habits are a main player in type 2 diabetes incidence, genetics also plays a modest role. Most of the focus on genetic determinants of prediabetes and diabetes has been on identifying genes associated with increased risk, which include those related to beta cell function, insulin resistance, and adiposity. Genetic factors alone are not sufficient to predict the progression from prediabetes to diabetes, underscoring the importance of considering both genetic and environmental factors in understanding and managing these conditions (12).

Between 5-10 percent of people with prediabetes will develop type 2 diabetes (13). An important factor that influences prediabetes progression is how the body stores fat, particularly the size and number of fat cells. Fat cell size is different among various ethnic groups, with larger fat cells having a higher capacity for fat storage (14). When fat storage capacity maxes out, excess lipids accumulate in non-adipose tissues like the liver, muscle, and pancreas, leading to a range of harmful metabolic effects, including predisposition to type 2 diabetes (15). Conversely, some individuals have a genetic predisposition to produce new fat cells to accommodate increases in fat, allowing them to maintain insulin sensitivity despite weight gain. “Even though they have a lot of fat cells, they are all small, and they are very insulin sensitive,” said Bikman. 

Maternal obesity may also play a role in insulin resistance and type 2 diabetes risk. Maternal obesity induces epigenetic modifications in offspring that affect the expression of critical genes involved in adipocyte differentiation and function, such as zinc finger protein 423 (Zfp423) and peroxisome-proliferator activator receptor γ (Pparγ,) that lead to a preference for increased fat cell size over an increased number of fat cells (16). Epigenetic modifications during maternal obesity can enhance Zfp423 activity, increasing fat mass and adiposity. Similarly, epigenetic modifications to Pparγ expression in pregnant mice lead to hypertrophic adipocytes, inflammation, and insulin resistance in offspring (17).

Developing prediabetes medicine

Metformin is the only approved drug for prediabetes because of its long-term safety record (8). “The idea comes from the fact that drugs used to treat diabetes lower blood sugar. If you are prediabetic and you lower blood sugar, the hypothesis was that would reduce the chance of developing diabetes,” said Goldberg. 

Metformin reduces blood sugar and increases insulin sensitivity by lowering the amount of glucose released into the bloodstream and increasing glucose uptake in skeletal muscle cells (18). Now, researchers are looking at different ways to mitigate prediabetes by targeting other molecular mechanisms involved in its onset, including epigenetic regulation.

One influential epigenetic mechanism is histone modification, which affects DNA accessibility by cellular machinery. Bromodomain and extraterminal proteins (BET) recognize and bind to acetylated lysines on histone tails, which signals that chromatin is open for transcription. The experimental drug Apabetalone (RVX-208) in clinical treatment for prediabetes inhibits BET proteins and prevents them from binding to acetylated histones, which reduces the expression of genes involved in lipid metabolism, inflammation, and plaque formation in arteries (19).  Scientists believe that Apabetalone can increase the levels of HDL, which in turn would reduce blood glucose through increased insulin secretion and enhanced skeletal muscle glucose uptake. In 20 men with prediabetes, treatment with Apabetalone for four weeks increased the number of medium-sized HDL particles and delayed and reduced peak blood sugar levels after a blood sugar challenge (20). 

Another drug currently in clinical development for prediabetes is TOTUM-63, a patented blend of plant-based biomolecules with a high content of polyphenolic compounds, natural compounds that only plants make (21). Polyphenolic compounds lower blood glucose after a meal by reducing glucose transporters in the gut and can protect pancreatic beta cells from damage (22). After six months, TOTUM-63 reduced body weight, waist circumference, fasting blood glucose, and blood pressure in 51 participants with prediabetes or early stage type-2 diabetes (23). TOTUM-63 also reduced blood sugar levels and the insulin response after a carbohydrate-rich meal in a group of overweight men (24).

Prediabetes is not an irreversible condition; lifestyle changes, particularly diet and exercise, are beneficial. “The food we eat is the culprit and the cure,” said Bikman. Goldberg agrees, and advocates for lifestyle adjustments as the primary strategy, particularly for individuals with glucose levels near the lower end of the abnormal range, recommending that those at the higher end of the prediabetes spectrum might require pharmacological support in addition to lifestyle modification. “What we can do for patients with prediabetes is to treat them effectively and efficiently rather than waiting for them to get to a point where they've already developed complications,” he said.  Innovations in epigenetics and pharmacology, such as the development of drugs like Apabetalone and TOTUM-63, offer promising adjuncts to lifestyle interventions by targeting the underlying biological mechanisms to prevent the onset of type 2 diabetes and its complications. 

References

1. CDC. Prediabetes - Your Chance to Prevent Type 2 Diabetes.Cent Dis Control Prev (2021). at 
2. CDC. Diabetes Testing.Cent Dis Control Prev (2023). 
3. Cerf, M. E. Beta Cell Dysfunction and Insulin Resistance. Front Endocrinol 4, 37 (2013).
4. Janssen, J. A. M. J. L. Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer. Int J Mol Sci  22, 7797 (2021).
5. Faerch, K., Hulmán, A. & Solomon, T. P. J. Heterogeneity of Pre-diabetes and Type 2 Diabetes: Implications for Prediction, Prevention and Treatment Responsiveness. Curr Diabetes Rev  12, 30–41 (2016).
6. Van Buren, P. & LeWinter, M. M. in Heart Fail. Companion Braunwalds Heart Dis. Second Ed. (ed. Mann, D. L.) 408–418 (W.B. Saunders, 2011). 
7. Walton, C. M., Perry, K., Hart, R. H., Berry, S. L. & Bikman, B. T. Improvement in Glycemic and Lipid Profiles in Type 2 Diabetics with a 90-Day Ketogenic Diet. J Diabetes Res  2019, 8681959 (2019).
8. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol3, 866–875 (2015).
9. Perreault, L. et al.  Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: results from the Diabetes Prevention Program Outcomes Study. The Lancet  379, 2243–2251 (2012).
10. Spaulding, H. R. & Yan, Z. AMPK and the Adaptation to Exercise. Annu Rev Physiol  84, 209–227 (2022).
11. Shou, J., Chen, P.-J. & Xiao, W.-H. Mechanism of increased risk of insulin resistance in aging skeletal muscle. Diabetol Metab Syndr  12, 14 (2020).
12. Billings, L. K. et al.  Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes. Diabetes db230761 (2024). 
13. Tabák, A. G., Herder, C., Rathmann, W., Brunner, E. J. & Kivimäki, M. Prediabetes: A high-risk state for developing diabetes. Lancet  379, 2279–2290 (2012).
14. Anand, S. S. et al.  Adipocyte Hypertrophy, Fatty Liver and Metabolic Risk Factors in South Asians: The Molecular Study of Health and Risk in Ethnic Groups (mol-SHARE).PLoS ONE  6, e22112 (2011).
15. Snel, M. et al.  Ectopic Fat and Insulin Resistance: Pathophysiology and Effect of Diet and Lifestyle Interventions. Int J Endocrinol  2012, 983814 (2012).
16. Lecoutre, S., Maqdasy, S. & Breton, C. Maternal obesity as a risk factor for developing diabetes in offspring: An epigenetic point of view.World J  Diabetes  12, 366–382 (2021).
17. Lecoutre, S. et al.  Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications. FASEB J Off Publ Fed Am Soc Exp Biol  32, 2768–2778 (2018).
18. Pernicova, I. & Korbonits, M. Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol  10, 143–156 (2014).
19. Suárez, R. et al.  Epigenetics in Obesity and Diabetes Mellitus: New Insights.Nutrients  15, 811 (2023).
20. Siebel, A. L. et al.  Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial. Metabolism  65, 904–914 (2016).
21. Bertelli, A. et al.  Polyphenols: From Theory to Practice. Foods  10, 2595 (2021).
22. Williamson, G. & Sheedy, K. Effects of Polyphenols on Insulin Resistance. Nutrients  12, 3135 (2020).
23. Sirvent, P. et al.  TOTUM-63, a plant-based polyphenol-rich extract, improves glycaemic control in subjects with prediabetes or early stage newly-diagnosed type 2 diabetes in a randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab  24, 2331–2340 (2022).
24. Chavanelle, V. et al.  Effects of Totum-63 on glucose homeostasis and postprandial glycemia: a translational study. Am. J. Physiol. - Endocrinol Metab  320, E1119 (2021).