Fatty Liver Disease in Type 2 Diabetes: The Hidden Role of Portal Insulin and Insulin Resistance

In this episode of MD Newsline, Dr. Mohamed Abu-Farha, Principal Scientist at the Dasman Diabetes Institute in Kuwait, explores groundbreaking research into the relationship between portal insulin exposure, insulin resistance, and metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as fatty liver disease. Drawing from findings presented at ADA 2026, Dr. Abu-Farha explains how C-peptide measurements, ANGPTL8, and advanced metabolic phenotyping may improve clinicians' ability to identify patients at risk for liver fat accumulation without relying solely on imaging. He also discusses the future of predictive algorithms, GLP-1 therapies, insulin sensitizers, and precision medicine for diabetes care. Episode Highlights Understanding Portal Insulin and Liver Fat Dr. Abu-Farha explains why portal insulin concentration—rather than circulating insulin alone—may be a critical driver of liver fat accumulation. Because insulin travels directly from the pancreas to the liver through the portal vein, elevated portal insulin in insulin-resistant individuals may stimulate excessive fat storage in the liver. Why C-Peptide Matters Instead of measuring insulin alone, Dr. Abu-Farha highlights the importance of C-peptide as a more accurate reflection of pancreatic insulin production. Since insulin is partially cleared by the liver while C-peptide is not, C-peptide provides a better estimate of true portal insulin exposure. ANGPTL8 and Fatty Liver Development After more than a decade of research, Dr. Abu-Farha's team believes ANGPTL8 may serve as a biological link between hyperinsulinemia and hepatic fat accumulation. Their work shows strong associations between ANGPTL8, insulin resistance, triglyceride metabolism, and liver fat, opening new avenues for mechanistic and therapeutic research. Comparing Type 1 and Type 2 Diabetes Dr. Abu-Farha discusses why people with Type 1 diabetes generally develop less liver fat than those with early Type 2 diabetes. The difference, he explains, lies in the pattern of insulin delivery—subcutaneous insulin bypasses the portal circulation, whereas endogenous insulin production creates much higher portal insulin concentrations that may promote liver fat accumulation. Predicting Fatty Liver Without MRI One of the most promising aspects of Dr. Abu-Farha's research is the development of a mathematical prediction model capable of estimating liver fat using routine clinical measurements. Early findings show correlations exceeding 90% compared with imaging-based assessments, potentially making liver fat screening faster, less expensive, and more accessible. Practical Tools for Clinicians The research also demonstrates that readily available clinical measurements—including waist circumference and other metabolic indices—can provide strong estimates of fatty liver risk, helping physicians identify patients who may benefit from additional evaluation before advanced imaging is required. Rethinking Diabetes Therapy Dr. Abu-Farha discusses why reducing reliance on insulin, when clinically appropriate, may benefit some patients with Type 2 diabetes. Combining GLP-1 receptor agonists with insulin sensitizers could address the underlying causes of diabetes—obesity and insulin resistance—while potentially reducing long-term complications associated with excessive insulin exposure. The Future of AI and Precision Medicine Looking ahead, Dr. Abu-Farha envisions artificial intelligence and predictive algorithms becoming integrated into routine diabetes care. By combining metabolic biomarkers with simple clinical measurements, physicians could better estimate insulin resistance and fatty liver risk during everyday office visits. Next Steps in Research Future studies aim to directly test the portal insulin hypothesis in humans, including evaluating medications that suppress insulin production to determine their effect on liver fat accumulation. Dr. Abu-Farha believes these studies could provide definitive evidence supporting the proposed mechanism. Advances in Diabetes Treatment Dr. Abu-Farha concludes by highlighting the rapid evolution of diabetes therapies, including GLP-1 receptor agonists, amylin analogs, SGLT2 inhibitors, and emerging peptide-based treatments. He notes that developing safer and more effective insulin sensitizers remains an important unmet need in diabetes management. Key Takeaway Dr. Abu-Farha's research suggests that portal insulin exposure, insulin resistance, and ANGPTL8 signaling may play a central role in the development of MASLD (fatty liver disease). By combining routine clinical measurements, predictive algorithms, and a deeper understanding of disease biology, clinicians may soon be able to identify patients at risk earlier, reduce reliance on expensive imaging, and deliver more personalized diabetes care that targets the underlying mechanisms of metabolic disease.     Resources Website: https://mdnewsline.com/ Newsletter: https://mdnewsline.com/subscribe/ Contact with Dr. Mohamed Abu-Farha: Here