Recent data suggest that nonalcoholic fatty liver disease (NAFLD) has emerged as a worldwide public health problem due to an escalating prevalence as a major cause of liver cirrhosis and association with diverse extrahepatic disorders. NAFLD has been suggested to elicit the insulin resistance that plays a pivotal role in the development of diabetes. And while data have linked NAFLD and diabetes, or impaired fasting glucose (IFG), well-designed prospective studies on this topic remain limited.

The Study

For a prospective study published in Endocrine Practice, Xiang Gao, MD, PhD, Pennsylvania State University, Shouling Wu, MD, Kailuan General Hospital, China, and colleagues examined the association between baseline NAFLD severity and elevated alanine transaminase (ALT), the risk of developing diabetes and IFG, and the annual increase rate of plasma fasting glucose among more than 41,000 patients with negative hepatitis-B surface antigen who were free of alcohol consumption, diabetes, and liver cirrhosis at baseline. Cox proportional models were used to estimate the risk of diabetes after an average of 3.6 years follow-up. NAFLD was assessed with hepatic ultrasonography. ALT was defined as ALT concentrations >19 u/l in women or 30 u/l in men. Diabetes was defined as a fasting glucose ≥ 7.0 mmol/L or treatment with hypoglycemic medication.

Risk Factors

Severity of liver steatosis was significantly associated with higher risks of developing diabetes and impaired fasting glucose (fasting glucose, 5.6-6.9 mmol/L), and faster increase in rate of fasting glucose concentrations, during follow-up. “The severity of NAFLD may be a marker of severity of insulin resistance,” adds Dr. Gao.  Elevated ALT was also associated with incident diabetes adjusting for NAFLD and other covariates.

“This study confirmed the notion that NAFLD and elevated ALT are independent risk factor for diabetes,” says Dr. Gao. “The strengths of this study include its large sample size (~40k), prospective study design, and ultrasonically defined NAFLD (rather than self-report or indirect estimation). We also examined the dose-response relation between NAFLD severity and diabetes risk, which has been examined only in two previous studies that had smaller sample sizes.”

NAFLD & Future Risk

Dr. Gao adds that the study team found a dose-response relation between NAFLD severity and future risk of diabetes and impaired fasting glucose (Table). For example, an individual with severe NAFLD had 3.5-fold higher risk of diabetes, relative to those without NAFLD at the baseline.

“Because both NAFLD and diabetes are associated with age, sex, obesity, and other factors, we thus controlled for these factors in our models,” says Dr. Gao. “That is, we compared diabetes risk between individuals with versus without NAFLD, but with similar age, BMI, blood pressure and other factors.” Since NAFLD and elevated ALT are risk factors for diabetes, Dr. Gao suggests that these elements be integrated into existing diabetes prevention strategies.

“We observed a dose-response association between severity of liver steatosis and incident diabetes, and NAFLD had synergistic effects with impaired fasting glucose or metabolic syndrome on diabetes risk,” says Dr. Gao. “Further, elevated ALT might be independently associated with incident diabetes. These findings might have important clinical and public health implications because both NAFLD and diabetes are prevailing all over the world and have posed a big burden on healthcare.”

Looking Ahead

Although the researchers used ultrasonically defined NAFLD, Dr. Gao stresses that it is not a perfect approach for the assessment of NAFLD severity, adding that it would be of interest to examine the trajectory of NAFLD status over time as well as future risk of diabetes. Another important research question, has says, is whether treatment of NAFLD could lead to reduced diabetes risk.