Patients with earlier-onset metabolic dysfunction-associated steatotic liver disease (MASLD) had a higher risk of developing type 2 diabetes than age- and sex-matched patients without MASLD, with the highest risk observed among those with MASLD onset before age 40, according to a prospective cohort study published in Clinical Gastroenterology and Hepatology.
Study design and population
Researchers analyzed data from the Kailuan Study, a community-based prospective cohort in China that enrolled 101,510 adults between 2006 and 2007. After excluding patients with prevalent MASLD, heavy alcohol use, viral hepatitis, cirrhosis, missing data or type 2 diabetes diagnosed before MASLD, 29,016 patients developed new-onset MASLD through 2015. Each case was randomly matched one-to-one with a control participant without MASLD by age and sex. After excluding patients who developed type 2 diabetes within the first two years of follow-up, the final analysis included 19,378 patients with new-onset MASLD and 19,483 matched controls. Participants were followed through December 2020 for incident type 2 diabetes.
During a median follow-up of 11.8 years, researchers documented 2,301 cases of incident type 2 diabetes. The incidence rate was 8.36 cases per 1,000 person-years among patients with new-onset MASLD compared with 2.58 cases per 1,000 person-years among controls without MASLD.
Earlier MASLD onset associated with greater diabetes risk
After adjustment for lifestyle factors, socioeconomic status, and family history of diabetes, patients with MASLD onset before age 40 had the highest likelihood of developing type 2 diabetes, with 6.18 times the likelihood of matched controls without MASLD. The association diminished with increasing age at MASLD onset but remained significant across all age groups:
Younger than 40 years: 6.18 times the likelihood
40 to younger than 50 years: 3.29 times the likelihood
50 to younger than 60 years: 3.14 times the likelihood
60 to younger than 70 years: 2.94 times the likelihood
70 years or older: 2.17 times the likelihood
Although the relative risk declined with increasing MASLD onset age, MASLD remained associated with significantly increased risk of type 2 diabetes across all age groups.
Additional adjustment for baseline cardiometabolic factors attenuated the associations, but they remained statistically significant.
Subgroup and sensitivity analyses
Subgroup analyses showed that the association between MASLD onset age and type 2 diabetes varied by sex and certain lifestyle factors. The relationship was stronger among women in the 40- to younger-than-50-year age group. Significant interactions were also observed for smoking and alcohol use, with more pronounced associations among noncurrent smokers in the 40- to younger-than-70-year groups and among noncurrent drinkers in the 40- to younger-than-50-year group. No significant interactions were detected for hypertension status and body mass index across any age strata.
Multiple sensitivity analyses yielded consistent findings after excluding patients taking antihypertensive or lipid-lowering medications, excluding patients with baseline cardiovascular disease, redefining exposure using the previous nonalcoholic fatty liver disease criteria, accounting for death as a competing risk and modeling metabolic variables as time-varying covariates. When MASLD was further categorized by ultrasound-defined steatosis severity, both mild and moderate-to-severe steatosis were associated with increased diabetes risk across all age groups, with stronger associations observed for moderate-to-severe steatosis.
Study limitations
The researchers noted several limitations, including diagnosis of hepatic steatosis by ultrasonography rather than liver biopsy, the observational design, potential residual confounding, inability to assess liver fibrosis because aspartate aminotransferase measurements were unavailable, possible misclassification of participants with resolved MASLD before study entry and limited generalizability because the cohort consisted predominantly of men from northern China.
The researchers reported no competing interests. The study was supported by the National Natural Science Foundation of China and the Beijing Nova Program. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Expert Insight
GI & Hepatology News invited two experts to comment on the study.
Brian DeBosch, MD, PhD, AGAF, professor of pediatrics and co-chief of the division of pediatric gastroenterology, hepatology and nutrition at Indiana University School of Medicine, said while the association between MASLD and type 2 diabetes mellitus is well-established, this new analysis demonstrates an exposure dose-response relationship linking earlier onset MASLD with progressively greater incident type 2 diabetes risk.
“This observation takes on particular importance in light of the fact that MASLD is fastest growing in the young,” he said. “Overall, the data justify earlier screening and prevention, and perhaps more aggressive treatment algorithms for patients with early-onset MASLD.”
Dr. DeBosch also pointed out that the exposure dosage relationship observed provides epidemiological evidence supporting the underlying concept that MASLD and type 2 diabetes share common pathophysiological drivers, such as insulin resistance and chronic systemic inflammation. He added that the sexually dimorphic, age-dependent interactions the study identified point to a multifactorial risk plane linking MASLD and type 2 diabetes.
“This complex gene-environment-time interaction underscores the greater overall need for more detailed, precision stratification and personalized medicine to best address our health needs in metabolic liver disease, and well beyond,” he concluded.
Robert Fontana, MD, professor of medicine and director of the Transplant Hepatology Fellowship Program at the University of Michigan, said the study’s large sample size, regular follow-up and testing every 2 years and conducting adjusted analyses that accounted for other important covariates (risk factors), strengthen confidence in the observed association between MASLD and future type 2 diabetes.
Dr. Fontana noted that smoking, alcohol use, hyperlipidemia and hypertension were important clinical risk factors for developing future diabetes, lending additional support to the study’s findings. “This is very important since physicians and patients can address these lifestyle issues and potentially delay or reduce the future risk of diabetes (but not studied nor proven here),” he explained.
In terms of limitations of the study, Dr. Fontana added that the study didn’t provide data on impact of baseline or serial diet (total calories and type of foods ingested, ultraprocessed foods) and risk of developing diabetes. The study also did not account for physical activity/exercise or sedentary lifestyle.
Dr. Fontana cautioned that epidemiological studies such as this demonstrate association rather than causation. “In China and Asia, the cut-offs for overweight/obesity differ from those used in the United States,” he explained. “Therefore, the patients studied here are intrinsically different than western patients in the United States or Europe. In addition, the environment, diet and genetics also differ so we need to be careful and thoughtful of extrapolating these findings to a western cohort.” Cohorts such as those enrolled in Framingham, NHANES, nurses study, and other prospective longitudinal groups in the US will be important to see if they have similar or different findings, he explained.
“The bottom line is that detection of MASLD (by a simple ultrasound) may be a bona fide, independent risk factor for developing future diabetes (in addition to known risk factors such as family history, concomitant hypertension, hyperlipidemia and BMI),” Dr. Fontana concluded. “Primary care physicians may need to be looking for this in routine practice, and more importantly, trying to manage and intervene on other lifestyle factors, such as encouraging smoking cessation, reducing alcohol intake, healthy diets and exercise. The study also highlights the importance of early detection since impact was greatest in those < 40 years of age.”