Prediabetes and MASLD : An Overlapping Spectrum of Metabolic Risk

Converging Burden of Prediabetes and MASLD: Prediabetes is associated with a nearly 4-fold higher risk of MASLD. (1) Approximately 33% of Indian adults have prediabetes. (2) The burden of MASLD in India is substantial, with 68.2% showing hepatic steatosis (CAP ≥ 238 dB/m) and 33.7% demonstrating fibrosis [LSM ≥ 7 kPa]. (3) Analysis of NHANES III data from 2025 shows that nearly 47% of individuals with prediabetes or diabetes have MASLD. This overlap increases the risk of all-cause mortality 3-fold and cardiovascular mortality over 10-fold, highlighting that prediabetes is a high-risk metabolic state that calls for early identification and proactive intervention.(1)

Pathophysiological Crossroads: Insulin Resistance, Lipotoxicity, and Inflammation:

Insulin resistance (IR) plays a central pathogenic role in both MASLD and prediabetes, driving hepatic fat accumulation via increased lipolysis, FFA flux, and de novo lipogenesis. Lipotoxic intermediates, adipose dysfunction, and pro-inflammatory cytokines such as TNF-α and IL-6 perpetuate systemic inflammation and hepatocellular injury. (5) MASLD may precede T2D, reflecting an early hepatic manifestation of broader metabolic dysfunction.(1,4)

Prediabetes & MASLD - Why the Dual Burden Needs Early Attention? The coexistence of prediabetes and MASLD marks a high-risk metabolic state often linked to silent liver, kidney, and cardiovascular dysfunction, even before diabetes develops. (6) In Indian clinical settings, non-invasive tools such as transient elastography, CAP, and serum biomarkers including ALT, AST, CK-18, and FGF21 offer pragmatic strategies for early hepatic risk stratification in this high-risk population. (7) The FIB-4 score also helps in early identification of patients at high risk of advanced fibrosis; surveillance at 1–2 year intervals may be considered for those with FIB-4 scores between 1.3 and 2.67. (8)

How Metformin Works: Targeting the Liver and Beyond

Metformin primarily reduces hepatic glucose production by inhibiting mitochondrial complex I and activating AMPK, which suppresses gluconeogenesis and hepatic fat accumulation. It also improves insulin sensitivity in muscle, modulates gut microbiota, increases GLP-1 and GDF15, and exerts anti-fibrotic effects.(9)

The figure below summarizes these key mechanisms of metformin in managing insulin resistance and MASLD.

Figure: Mechanism of action of metformin across key organs involved in glucose and lipid metabolism, with implications in MASLD and Chronic Liver Disease (CLD) Adapted from Perazza F, et al. Metabolites. 2024;14(4):186.

Role of Metformin in Insulin Resistance Associated with Prediabetes-MASLD: Evidence-Based Perspective

Effect of Metformin on Hepatic Glucose Output(HGO): Metformin lowers hepatic glucose output and enhances peripheral glucose utilization, improving overall glycemic control in prediabetes. In the Diabetes Prevention Program (DPP), involving 3,234 participants with elevated fasting glucose and impaired glucose tolerance, metformin reduced the risk of progression to T2D by 31% compared to placebo over 2.8 years [HR 0.69; 95% CI: 0.57–0.83; p<0.001]. (10)

Effect of Metformin on Insulin Sensitivity: Metformin enhances insulin responsiveness in the liver and peripheral tissues thus reducing insulin resistance. In an RCT of overweight, non-diabetic NAFLD patients (n=55), metformin with dietary advice reduced HOMA-IR by 30% (P = 0.003) and significantly improved ALT levels from 77 ± 12 to 45 ± 9 IU/L (P < 0.001) over 6 months, outperforming diet alone. (11)

Anti-inflammatory and Anti-fibrotic Effects: Metformin, through AMPK activation, exerts anti-inflammatory and anti-fibrotic effects by inhibiting hepatic stellate cell activation, suppressing pro-inflammatory cytokines, and reducing oxidative stress. (12)

Effect of Metformin in Pediatric MASLD: A 2025 meta-analysis evaluating 8 RCTs in pediatric MASLD showed that metformin significantly reduced ALT by approximately 5.1 IU/L (95% CI: –7.1 to –3.1) and AST by 2.8 IU/L [95% CI: –4.0 to –1.6]. (13)

Metformin – Prediabetes & MASLD: Guideline Recommendations

Key Takeaways

• Prediabetes and MASLD frequently coexist, amplifying the risk of type 2 diabetes, cardiovascular events, and all-cause mortality, indicating the need for early identification and proactive intervention.
• Metformin lowers hepatic glucose output and enhances peripheral glucose utilization, reducing T2D progression by 31% and HOMA-IR by 30% in non-diabetic NAFLD patients.
• Metformin is associated with reductions in hepatic steatosis, with significant improvements in ALT, AST, triglycerides, total cholesterol, and insulin resistance in NAFLD.
• Guidelines from the ADA, EASL, APASL, and Indian Diabetologists’ expert consensus recommend consideration of metformin in prediabetes, MASLD, and T2DM.

References

1. Younossi, Zobair M et al. “Epidemiology of metabolic dysfunction-associated steatotic liver disease.” Clinical and molecular hepatology vol. 31,Suppl (2025): S32-S50. doi:10.3350/cmh.2024.0431

2. Anjana, Ranjit Mohan et al. “Metabolic non-communicable disease health report of India: the ICMR-INDIAB national cross-sectional study (ICMR-INDIAB-17).” The lancet. Diabetes & endocrinology vol. 11,7 (2023): 474-489. doi:10.1016/S2213-8587(23)00119-5

3. Mohan, V., Joshi, S., Kant, S. et al. Prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease: Mapping Across Different Indian Populations (MAP Study). Diabetes Ther 16, 1435–1450 (2025). https://doi.org/10.1007/s13300-025-01748-1

4. Zhang, Y., Wu, J., Li, T. et al. Association of triglyceride-glucose related indices with mortality among individuals with MASLD combined with prediabetes or diabetes. Cardiovasc Diabetol 24, 52 (2025). https://doi.org/10.1186/s12933-025-02616-9

5. Kuchay, Mohammad Shafi, Narendra Singh Choudhary, and Bruno Ramos-Molina. "Pathophysiological underpinnings of metabolic dysfunction-associated steatotic liver disease." American Journal of Physiology-Cell Physiology, vol. 328, no. 5, 2025, pp. C1637–C1666. https://doi.org/10.1152/ajpcell.00011.2024

6. Cusi, Kenneth et al. “Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in People With Diabetes: The Need for Screening and Early Intervention. A Consensus Report of the American Diabetes Association.” Diabetes care vol. 48,7 (2025): 1057-1082. doi:10.2337/dci24-0094

7. Zargar, Abdul Hamid et al. “Management of metabolic dysfunction-associated steatotic liver disease (MASLD)-An expert consensus statement from Indian diabetologists' perspective.” Diabetes, obesity & metabolism vol. 27 Suppl 4,Suppl 4 (2025): 3-20. doi:10.1111/dom.16496

8. Byrne CD, Targher G, Buchanan RM. Type 2 diabetes, prediabetes, and MASLD: who and when to screen and how to treat? Lancet Diabetes Endocrinol. 2025 Jun 19:S2213-8587(25)00189-5. doi: 10.1016/S2213-8587(25)00189-5.

9. Perazza F, Leoni L, Colosimo S, Musio A, Bocedi G, D’Avino M, Agnelli G, Nicastri A, Rossetti C, Sacilotto F, et al. Metformin and the Liver: Unlocking the Full Therapeutic Potential. Metabolites. 2024; 14(4):186. https://doi.org/10.3390/metabo14040186

10. Knowler, William C et al. “Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.” The New England journal of medicine vol. 346,6 (2002): 393-403. doi:10.1056/NEJMoa012512

11. Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100(5):1082-1090. doi:10.1111/j.1572-0241.2005.41583.x

12. Hasanpour Dehkordi A, Abbaszadeh A, Mir S, Hasanvand A. Metformin and its anti-inflammatory and anti-oxidative effects; new concepts. J Renal Inj Prev. 2019;8(1):54-61. DOI: 10.15171/jrip.2019.11

13. Carpi, G.C., Campos, L.R. & Kopacek, C. Metformin seems promising in improving liver enzymes in pediatric MASLD. Eur J Pediatr 184, 443 (2025). https://doi.org/10.1007/s00431-025-06280-9

14. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81(3):492-542. doi:10.1016/j.jhep.2024.04.031

15. Eslam, M., Fan, JG., Yu, ML. et al. The Asian Pacific association for the study of the liver clinical practice guidelines for the diagnosis and management of metabolic dysfunction-associated fatty liver disease. Hepatol Int 19, 261–301 (2025). https://doi.org/10.1007/s12072-024-10774-3

16. American Diabetes Association Professional Practice Committee; 3. Prevention or Delay of Diabetes and Associated Comorbidities: Standards of Care in Diabetes—2025. Diabetes Care 1 January 2025; 48 (Supplement_1): S50–S58. https://doi.org/10.2337/dc25-S003

Abbreviations: ADA – American Diabetes Association, ALT – Alanine Aminotransferase, APASL – Asian Pacific Association for the Study of the Liver, AST – Aspartate Aminotransferase, BMI – Body Mass Index, CAP – Controlled Attenuation Parameter, CI – Confidence Interval, CK-18 – Cytokeratin-18, CKD – Chronic Kidney Disease, DPP – Diabetes Prevention Program, EASL – European Association for the Study of the Liver, EASD – European Association for the Study of Diabetes, EASO – European Association for the Study of Obesity, ESRD – End-Stage Renal Disease, FFA – Free Fatty Acids, FGF21 – Fibroblast Growth Factor 21, HCC – Hepatocellular Carcinoma, HbA1c – Glycated Hemoglobin, HOMA-IR – Homeostasis Model Assessment of Insulin Resistance, LoE – Level of Evidence, MAFLD – Metabolic Dysfunction-Associated Fatty Liver Disease (older term used interchangeably with MASLD in some guidelines), MASLD – Metabolic Dysfunction-Associated Steatotic Liver Disease, NAFLD – Non-Alcoholic Fatty Liver Disease (older term, used in cited studies), RCT – Randomized Controlled Trial, RR – Risk Ratio, T2D – Type 2 Diabetes Mellitus, TC – Total Cholesterol, TNF-α – Tumor Necrosis Factor-alpha