Prediabetes: Understanding Pathophysiology, Mechanisms, and Therapeutic Approaches

Prediabetes represents a critical intermediate stage in glucose metabolism between normal homeostasis and diabetes. This condition affects millions globally and is characterized by blood glucose levels that are elevated beyond normal parameters but not high enough to meet diagnostic criteria for diabetes. Current research reveals prediabetes is not merely a "pre-disease" state but a distinct pathophysiological condition with its own metabolic alterations and health risks. Evidence suggests that prediabetes is associated with significant pathophysiological changes across multiple tissues and organs, supporting its recognition as a distinct clinical entity rather than simply a risk factor for diabetes1. Moreover, the vascular complications traditionally associated with diabetes actually begin during this prediabetic phase, emphasizing the importance of early recognition and intervention4. This comprehensive report examines the definition, underlying mechanisms, and evidence-based treatments for prediabetes.

Defining Prediabetes: The Diagnostic Challenge

Prediabetes occupies a position within the continuum of dysglycemia, representing an intermediate stage between normal glucose regulation and overt diabetes. It is characterized by abnormal glucose homeostasis where blood glucose levels exceed normal parameters but fall short of diabetes diagnostic thresholds1. This condition has gained increasing recognition as a distinct pathophysiological state rather than merely a risk factor for future diabetes development. The inclusion of prediabetes and associated billable conditions in recent ICD-10 codes provides additional credence to this position1.

The diagnosis of prediabetes involves several glycemic parameters, with variable cutoff points across different international guidelines. While there is general consensus on the upper boundary between prediabetes and diabetes, considerable ambiguity exists regarding the lower boundary between normal glycemia and prediabetes17. The primary diagnostic criteria include fasting plasma glucose (FPG), 2-hour plasma glucose during an oral glucose tolerance test (OGTT), and glycated hemoglobin (HbA1c). Research analyzing glucose tolerance test results indicates that if the 2-hour post-load glucose is 139 mg/dL, the corresponding upper limit for normal fasting glucose should be 114 mg/dL when using an HbA1c cutoff of 5.9% (as recommended by NICE, Canadian Diabetes Association, and Australian Diabetes Association), or 109 mg/dL when using an HbA1c cutoff of 5.6% (as recommended by the American Diabetes Association)17. These variations in diagnostic thresholds highlight the ongoing effort to standardize prediabetes criteria globally.

The traditional view of prediabetes as a distinct entity separate from diabetes has been challenged by emerging evidence. Current understanding suggests that prediabetes and type 2 diabetes exist along a continuum of dysglycemia and vascular risk that progressively increases over time rather than representing separate, discrete conditions4. This conceptual shift emphasizes the importance of viewing glucose dysregulation as a spectrum with compounding risks rather than categorical states with sudden threshold effects.

Heterogeneity in Prediabetes

Recent research indicates that prediabetes is not a homogeneous condition but demonstrates significant phenotypic heterogeneity. A prospective cohort study examining prediabetes in patients with stable coronary heart disease found that different definitions of prediabetes carry varying prognostic values11. This heterogeneity extends beyond diagnostic criteria to include pathophysiological variations, with differences in metabolic pathways observed across various tissues and organs in individuals with prediabetes compared to those with normal glucose tolerance or established diabetes3. This underlying heterogeneity may explain the variable rates of progression to diabetes and suggests the need for more personalized approaches to both risk assessment and treatment.

Pathophysiological Mechanisms: A Complex Interplay

The development of prediabetes involves multiple interconnected pathophysiological mechanisms. Understanding these mechanisms is crucial for developing targeted interventions aimed at preventing progression to diabetes.

Insulin Resistance and Secretion Dysregulation

The core pathophysiological disturbances in prediabetes include decreased insulin secretion and increased insulin resistance, though their relative contributions vary significantly between lean and obese individuals12. In lean subjects with prediabetes, declining insulin secretory capacity appears to be the predominant mechanism, while in obese individuals, rising insulin resistance plays a more substantial role12. A study examining insulin secretion and resistance indices found that all measures were lower in lean compared to obese groups. Furthermore, the decline in insulin secretion and rise in insulin resistance were progressive from normal glucose tolerance to prediabetes and type 2 diabetes in both groups. However, in lean individuals with prediabetes, the declines in insulin secretion were proportionally greater than increases in insulin resistance, whereas in obese individuals with prediabetes, the rises in insulin resistance exceeded the declines in insulin secretion12.

Pancreatic β-cell dysfunction represents a key feature in the pathogenesis of prediabetes. Research has identified that succinate receptor 1 (SUCNR1) is expressed in β-cells and upregulated in hyperglycemic states in both mice and humans6. Succinate, acting as a hormone-like metabolite, stimulates insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human β-cells. Studies have demonstrated that mice with β-cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance6. Interestingly, patients with impaired glucose tolerance show an enhanced nutrition-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration, revealing a GPCR-mediated amplifying pathway for insulin secretion particularly relevant to the hyperinsulinemia observed in prediabetic states6.

Gut Microbiome and Carbohydrate Metabolism

The role of the gut microbiome in prediabetes pathophysiology has gained increasing recognition. Research indicates that gut microbial carbohydrate metabolism contributes significantly to insulin resistance, a key feature of prediabetes2. The intestinal microbiota's influence on host metabolism extends beyond local effects to impact systemic metabolic regulation, including glucose homeostasis. Alterations in gut microbial composition and function may precede the development of insulin resistance and consequently contribute to prediabetes pathogenesis, highlighting the potential for microbiome-targeted interventions in prediabetes management.

Organ-Specific Metabolic Alterations

Prediabetes involves distinct organ-specific metabolic pathways that differentiate it from both normal glycemic states and overt diabetes3. Rather than representing uniform metabolic dysregulation, prediabetes is characterized by tissue-specific alterations in metabolic signaling. These organ-specific changes may explain the variable presentation and progression of prediabetes among individuals and suggest that targeted interventions addressing specific tissue metabolic abnormalities might be more effective than generic approaches.

Inflammatory and Signaling Pathways

Multiple molecular pathways are implicated in prediabetes pathophysiology. Research exploring the mechanisms of vitamin D supplementation in prediabetic rats identified several key signaling molecules involved in insulin resistance, including insulin receptor substrate-1 (IRS-1), peroxisome proliferator-activated receptor gamma (PPARγ), and nuclear factor kappa B (NF-κB)10. These pathways represent potential targets for therapeutic intervention.

Vitamin D deficiency has been frequently associated with insulin resistance and diabetes. Studies in prediabetic rat models have demonstrated that vitamin D supplementation can dose-dependently improve glucose control parameters, including fasting blood glucose, oral glucose tolerance, glycated albumin, and insulin levels10. At the cellular level, vitamin D supplementation reduces degeneration of the islets of Langerhans and modifies the expression of IRS-1 and the PPARγ/NF-κB axis, providing mechanistic insight into its beneficial effects on insulin resistance in prediabetes10.

Evidence-Based Interventions for Prediabetes

Several interventions have demonstrated efficacy in improving glycemic parameters and preventing or delaying progression from prediabetes to diabetes. These approaches include lifestyle modifications, pharmacological interventions, and nutritional strategies.

Lifestyle Interventions: The First-Line Approach

Lifestyle interventions, encompassing dietary modifications, increased physical activity, and weight loss, represent the cornerstone of prediabetes management. Evidence consistently demonstrates that comprehensive lifestyle changes are particularly effective in preventing or delaying the progression from prediabetes to diabetes, though implementation at the population level remains challenging due to resource intensity and adherence difficulties8. While lifestyle interventions have proven more effective than pharmacological approaches in numerous studies, they tend to be more resource-intensive and expensive to implement on a large scale8.

Metformin: The Leading Pharmacological Option

Among pharmacological interventions, metformin has the strongest evidence base for preventing diabetes in high-risk individuals with prediabetes. A meta-analysis of three pivotal studies demonstrated that metformin used for up to three years decreased the likelihood of progression to diabetes8. The beneficial effects of metformin appear to be particularly pronounced in specific subpopulations, with greater efficacy observed in individuals with higher baseline body mass index (BMI) and higher fasting plasma glucose levels compared to leaner counterparts with lower fasting glucose concentrations8.

Beyond its glucose-lowering effects, metformin has demonstrated additional beneficial properties relevant to prediabetes management. Long-term studies indicate that metformin may confer both cancer-protective and cardioprotective effects, providing additional rationale for its use in prediabetes8. These pleiotropic benefits, combined with its long-standing safety profile and tolerability, have led the National Institute for Clinical Excellence in the UK to recommend metformin for preventing type 2 diabetes in high-risk adults who fail to adhere to lifestyle changes8.

Dietary Approaches: Focus on Monounsaturated Fatty Acids

Specific dietary patterns have shown promise in addressing insulin resistance associated with prediabetes. A systematic review examining the effects of diets rich in monounsaturated fatty acids (MUFAs) on insulin resistance in overweight or obese patients found evidence that MUFA-rich diets can improve insulin resistance14. These beneficial effects may be mediated through the anti-inflammatory and anti-oxidative properties of MUFAs. The intervention periods in these studies ranged from as short as one day to as long as 5.2 years, suggesting both immediate and sustained metabolic benefits14.

Vitamin D Supplementation: Promising Evidence

Vitamin D deficiency has been consistently linked to insulin resistance and diabetes risk. Experimental studies in prediabetic rat models have demonstrated that vitamin D supplementation alleviates insulin resistance through multiple mechanisms10. Vitamin D3 supplementation dose-dependently improved glucose control parameters, including fasting blood glucose, oral glucose tolerance, glycated albumin, insulin levels, and markers of insulin resistance (HOMA-IR)10. At the histological level, vitamin D supplementation reduced degeneration of the islets of Langerhans, suggesting a protective effect on pancreatic β-cell structure and function10.

The beneficial effects of vitamin D on insulin resistance appear to be mediated through several molecular pathways. Vitamin D modifies the expression of insulin receptor substrate-1 (IRS-1) and influences the PPARγ/NF-κB signaling axis, which plays a crucial role in inflammation and insulin sensitivity10. These findings provide mechanistic support for vitamin D supplementation as a potential adjunctive therapy in prediabetes management, though further clinical studies are needed to establish optimal dosing strategies and target populations.

Approaches with Limited Evidence

While several interventions have demonstrated benefit in prediabetes management, others have shown minimal efficacy or potentially adverse effects.

Statins: Potential Adverse Metabolic Effects

Statins, widely prescribed for cardiovascular risk reduction, may paradoxically increase the risk of developing diabetes, particularly in individuals with existing insulin resistance or prediabetes. An open-label clinical trial examining the effects of atorvastatin 40 mg daily in adults without known cardiovascular disease or diabetes found that statin therapy increased insulin resistance by a median of 8% and insulin secretion by a median of 9% after 10 weeks of treatment20. These findings suggest that while statins effectively reduce cardiovascular risk, they may adversely affect glucose metabolism in susceptible individuals, highlighting the need for careful risk-benefit analysis in patients with prediabetes.

Emerging Pharmacological Approaches

Beyond metformin, evidence for other pharmacological interventions in prediabetes remains limited. Recent research has begun to explore the potential role of newer antidiabetic agents such as SGLT2 inhibitors and GLP-1 receptor agonists in prediabetes management, particularly in individuals with significant cardiovascular comorbidity4. These agents have demonstrated cardiovascular benefits in patients with established diabetes, but their efficacy, safety, and cost-effectiveness in prediabetes remain to be fully established.

Glimepiride, an insulin secretagogue, has shown promise in delaying the onset of type 2 diabetes from prediabetes, particularly in lean subjects where decreased insulin secretion appears to be the predominant pathophysiological mechanism12. However, the long-term safety and efficacy of sulfonylureas in prediabetes prevention require further investigation, especially given concerns about accelerated β-cell exhaustion with prolonged use.

Clinical Implications and Risk Stratification

The management of prediabetes has significant implications for reducing the global burden of diabetes and its associated complications. Recent research has focused on developing more sophisticated risk stratification approaches to identify high-risk individuals who would benefit most from intensive interventions.

A prospective cohort study examining prediabetes in patients with stable coronary heart disease found that prediabetes defined according to World Health Organization/International Expert Committee criteria was associated with significantly increased risk of major adverse cardiovascular events compared to normoglycemia11. Furthermore, the study identified that applying "very-high-risk" criteria according to the 2018 American Heart Association/American College of Cardiology cholesterol guideline could further stratify prediabetic patients into risk categories, with the very-high-risk group exhibiting a substantially elevated risk compared to the non-very-high-risk group11. This approach facilitates more targeted interventions by identifying those at greatest risk of progression to diabetes and cardiovascular complications.

Conclusion

Prediabetes represents a complex metabolic condition characterized by various pathophysiological alterations that precede the development of overt diabetes. The underlying mechanisms include impaired insulin secretion, increased insulin resistance, gut microbial dysregulation, and various molecular signaling disturbances, with their relative contributions varying between lean and obese individuals. Rather than representing a mere risk factor for future diabetes, prediabetes is increasingly recognized as a distinct pathophysiological state associated with early vascular complications.

Evidence-based interventions for prediabetes management include lifestyle modifications focused on diet, physical activity, and weight management, which remain the cornerstone of prevention. Among pharmacological options, metformin has the strongest evidence base, particularly in individuals with obesity and more significant fasting hyperglycemia. Emerging evidence supports the potential benefits of specific dietary patterns rich in monounsaturated fatty acids and vitamin D supplementation. Conversely, statins may adversely affect glucose metabolism despite their cardiovascular benefits, highlighting the complexity of managing cardiometabolic risk in prediabetic individuals.

Future research should focus on developing more precise diagnostic criteria and risk stratification tools to identify high-risk individuals who would benefit most from intensive interventions. Additionally, greater emphasis on personalized approaches based on individual pathophysiological profiles—distinguishing between predominantly insulin resistance versus secretion defects—may enhance treatment efficacy. As our understanding of the molecular mechanisms underlying prediabetes continues to evolve, novel therapeutic targets are likely to emerge, offering hope for more effective prevention strategies to address this growing global health challenge.