Study Identifies NAFLD-Hypoglycemia Link Among Type 2 Diabetes Patients

Researchers say their results suggest that clinicians should consider nonalcoholic fatty liver disease a risk factor for hypoglycemia among their patients with type 2 diabetes.

While it is well understood that liver cirrhosis is associated with hypoglycemia, less is known about the possible association between nonalcoholic fatty liver disease (NAFLD) and hypoglycemia in noncirrhotic patients with Type 2 diabetes.

Older age, kidney insufficiency, and insulin therapy are known risk factors for hypoglycemia in patients with Type 2 diabetes, wrote Ji-Yeon Lee, M.D., Ph.D., of Yonsei University College of Medicine in Seoul, South Korea, and colleagues in a study published recently in JAMA Network Open.

Other studies have found an association between body mass index (BMI) and the development of severe hypoglycemia. Lee and colleague examined the risk of hypoglycemia further by undertaking a population-based retrospective cohort study of 1.9 million individuals to explore the association of NAFLD with severe hypoglycemia among patients with Type 2 diabetes.

The study included individuals, ages 20 or older, who had undergone a medical health examination between January 2009 and December 2012 and were diagnosed with Type 2 diabetes. They were followed for three years

Lee and colleagues found that the risk of severe hypoglycemia gradually decreased with increasing fatty liver index (FLI).

“However,” they wrote, “after adjustment for age, sex, smoking and alcohol habits, exercise, and BMI … the pattern reversed, and there was a J-shaped association between FLI and severe hypoglycemia.”

The association remained after further adjustment for other variables, including severe hypoglycemia within the previous three years; insulin, sulfonylurea, and glinide use; and history of hypertension, chronic kidney disease (CKD), and cardiovascular disease (CVD).

Participants with FLI of 60 or greater showed an 88% increased risk of severe hypoglycemia compared with those with FLI of less than 30, “suggesting the strong association between NAFLD and severe hypoglycemia in newly diagnosed Type 2 diabetes,” Lee wrote.

Overall, patients with type 2 diabetes and NAFLD without cirrhosis had an approximately 26% increased risk of severe hypoglycemia after adjustment for multiple clinical covariates. The higher risk of severe hypoglycemia in patients with Type 2 diabetes was independent of obesity.

The overall incidence of NAFLD in the participants was 80%. The risk of NAFLD was significantly higher in people with uncontrolled blood glucose levels, abnormal waist circumference, increased aspartate aminotransferase (AST), and elevated triglyceride levels.

Consuming alcohol was the predominant risk factor, “significantly causing NAFLD among the study subjects,” Lee wrote.

Possible mechanisms explaining the association of NAFLD with severe hypoglycemia include altered glucose metabolism in NAFLD, Lee wrote. “Glucagon level is found to be increased in the presence of NAFLD, and hyperglucagonemia might induce downregulation of hepatic glucagon receptor or blunt the counter-regulatory response to hypoglycemic events in hepatic glucose production.”

In addition, NAFLD may be associated with glycemic variability through increased oxidative stress, which is an important determinant of hypoglycemia.

Lee and his colleagues advise clinicians to consider the presence of NAFLD when evaluating vulnerability to hypoglycemia in patients with type 2 diabetes. They can identify which patients might have a high risk of hypoglycemia to “hopefully reduce its incidence and ultimately improve patient safety via individualized therapy,” they noted.