Patients with type 2 diabetes were more likely to have genetic variations for a key protein regulating cells’ insulin receptors, according to a multinational case-control study.
The variants’ presence could serve as an early predictive marker of insulin resistance and type 2 diabetes, particularly in patients with a family history of the disease, the study’s authors noted.
The investigators examined variations in the high-mobility group A1 protein, or HMGA1, a key regulator of insulin receptor gene expression. The protein’s most frequent functional variant was found in 7.2% of the study’s 3,278 Italian patients with type 2 diabetes, compared with 0.4% and 3.3% of two Italian control groups (2,544 and 784 patients) without diabetes, significant differences resulting in adjusted odds ratios of 15.8 and 2.0, respectively.
In addition, the variant was found in 7.7% of 970 U.S. case patients, compared with 4.7% of 958 U.S. control patients (adjusted odds ratio, 1.6), a significant difference, and in 7.6% of 354 French case patients vs. 0% of 50 French controls, also a significant difference, reported Dr. Eusebio Chiefari of the University of Catanzaro (Italy) and colleagues (JAMA 2011;305:903-12).
Three other functional variants also were observed in the Italian population, although those variants were not studied in the U.S. and French populations because of the relatively small sample sizes.
Overall, when all four variants were analyzed, nearly 10% of Italian patients with type 2 diabetes were found to have HMGA1 defects, compared with less than 1% of controls.
The four functional variants of the HMGA1 gene were also shown to be associated with decreased insulin receptor (INSR) gene and insulin receptor protein expression.
"Because insulin downregulates its own receptor, we performed two different studies to rule out the possibility that the hyperinsulinemia we observed in our patients with HMGA1 gene variants was downregulating the INSR," the researchers said. Both tests ruled out a hyperinsulinemia effect, they added.
"We believe our observation that nearly 10% of individuals with type 2 diabetes have deleterious variations in the gene encoding HMGA1 has important clinical implications," the researchers wrote. In addition to potentially predicting insulin resistance, the variants might predict response to therapy. In addition, patients with HMGA1 variants and type 2 diabetes might have a different clinical course than do other patients with type 2 diabetes, the investigators said. The search for new type 2 diabetes therapies could include agents that upregulate the expression of HMGA1, they added.
More studies of the HMGA1 gene and its variants are needed, the investigators concluded, including studies in other racial types, to improve understanding of the role HMGA1 plays in insulin resistance and type 2 diabetes.
Dr. Chiefari and his colleagues reported no disclosures. Telethon-Italy, MIUR Italy, and the National Institutes of Health providing funding for the study.
Video: Gene Variations Associated With Risk of Type 2 Diabetes, from The JAMA Report