The relationship between diabetes and the cardiovascular system has been extensively studied, but far less is known about how type 1 diabetes (T1D) affects the liver. Adeyinka Taiwo, MBBS, MSc, FRCP, clinical assistant professor in Endocrinology and Metabolism, has published novel research laying the foundation for continued study of T1D comorbidity with the nation’s most common chronic liver disease.
Earlier this summer, Frontiers in Endocrinology published Taiwo’s pilot study—the first to date using comprehensive metabolomic and lipidomics analyses to examine the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) in people with T1D. This study led her to secure a two-year NIH K12 grant in 2024, which funds Taiwo’s continued exploration of metabolic syndrome and abnormal liver changes in T1D.
MASLD, formerly called non-alcoholic fatty liver disease, progresses from fat accumulation in the liver, steatosis, to metabolic dysfunction-associated steatohepatitis (MASH). MASH consists of continued steatosis, hepatocyte ballooning and inflammation, and an increased risk of fibrosis. Unaddressed cases can progress to cirrhosis, which increases the risk of developing hepatocellular carcinoma,
“The thing about MASLD is that it’s a silent disease,” Taiwo said. “It’s like high blood pressure. People can have it and not know until they have a stroke or a heart attack from years of elevated blood pressure.”
Incidences of acute MASH complications and cirrhosis-induced death are expected to increase two to threefold by 2030. Taiwo attributes this projection to rising obesity rates, as obesity causes abnormal fat accumulation in the liver, leading to MASLD. People with T2D and T1D are vulnerable to MASLD, with prevalence rates of 51-70% and 22%, respectively.
Researchers have conducted numerous studies on the pathogenesis of MASLD in people with T2D, as T2D accounts for 90% of diabetes cases. But Taiwo became aware of the incidence of MASLD in persons with T1D during her Endocrine Clinic training as a UI Health Care Endocrinology fellow from 2018 to 2020. She encountered confirmed T1D patients with insulin doses that exceeded the typical range for people with type 1. She also observed cardiac and liver complications in her T1D patients with MASLD that resembled those of T2D patients with MASLD.
Taiwo’s mentors and fellowship program director encouraged her to review existing research about MASLD in T1D. She found substantial gaps in the literature; studies recognized that MASLD was diagnosable in T1D patients with imaging, but there was limited research on the pathogenesis and treatment of MASLD in this population. Curiosity about the pathogenesis of MASLD in T1D patients led to the development of her pilot study.
“A third of people with T1D are at risk for developing obesity, metabolic syndrome, and liver complications,” Taiwo said. “Everybody knows that T1D patients depend solely on insulin therapy for their management, but once they develop metabolic complications such as MASLD, then this needs to be identified early, and appropriate interventions need to be implemented.”
Taiwo’s research goal is to understand the metabolites and metabolic pathways that contribute to the pathogenesis and severity of MASLD in T1D.
Testing, results, and research reflections
Taiwo developed her three-part hypothesis: 1) Because a growing subset of people with T1D diabetes are overweight or obese, a random sample of participants with T1D would have a high prevalence of MASLD. 2) Participants with MASLD would exhibit metabolites associated with insulin resistance—specifically ceramides, glutamate, branched-chain amino acids, and aromatic amino acids. 3) The measured metabolites would correlate with MASLD severity.
The study sample consisted of 30 participants with T1D recruited from the university’s diabetes outpatient clinics. The team screened each participant for MASLD using FibroScan imaging, identifying 17 MASLD cases. The 13 participants whose imaging did not indicate MASLD served as the control group. Compared to the control group, the case group demonstrated features of insulin resistance, including a higher mean BMI and higher than normal insulin requirements.
Researchers took fasted blood samples from participants, separating the plasma for metabolomics profiling using Gas Chromatography Mass Spectrometry (GC-MS) and liquid chromatography tandem mass spectrometry (LC-MS) for lipidomics and acylcarnitines.
The measurements revealed that the case group had higher levels of aromatic acid, ceramides, and triglycerides than the control group. Amino acids in the blood signify abnormal protein metabolism in the muscles, which occurs in the presence of insulin resistance. The released amino acids enter the bloodstream and are transported to the liver, contributing to the insulin resistance in the liver.
Taiwo said that her pilot study metabolite findings align with those reported in T2D/MASLD studies. The only metabolite in the case group that did not resemble the T2D findings was the branched amino acids.
The pilot findings have prompted further investigation in Taiwo’s ongoing MASLD research. Her extension of the pilot study is already underway, tripling her patient study sample and testing a new estimated insulin sensitivity formula to calculate the degree of T1D participants’ resistance to insulin.
Confronting comorbidities with curiosity and care
In the meantime, Taiwo emphasizes the importance of screening high-risk populations, such as persons with T1D, persons with T2D, and persons with obesity for MASLD using the FIB-4 Score, which takes into consideration the AST, ALT, Age, and Platelets. She believes that early identification of persons with MASLD will lead to early treatment interventions and follow-up. Fortunately, she points out, liver inflammation and stages 1-3 of fibrosis can be reversed with lifestyle modifications such as dietary changes, exercise, and initiation of the various classes of medications shown in studies to be effective in resolving inflammation and fibrosis of the liver.
Taiwo looks forward to learning more in her ongoing research as she strives to improve care for T1D patients with liver complications. “What inspired me was my T1D patients, and my curiosity about how best to treat them, as this group of patients are often excluded from treatment trials,” she said. “I want to inspire all doctors to pursue further investigations of their patients that present in an unusual fashion.”
Taiwo expressed gratitude to all her mentors who encouraged her to pursue this research topic. She especially thanks William Sivitz, MD, emeritus professor in Endocrinology and Metabolism; Ayotunde Dokun, MD, PhD, FACE, director of the Division of Endocrinology and Metabolism; Diana Jalal, MD, professor in Nephrology and Hypertension and director for clinical research in the renal division, and Antonio Sanchez, MD, clinical professor in Gastroenterology and Hepatology and medical director of the Liver Service in UI Health Care’s Digestive Health Center.