The staggering public health impact of type 2 diabetes
Diabetes is the most expensive medical problem in the United States. In 2017, we spent more than $327 billion on it. And, unfairly, there are some groups of people who are especially ravaged by the disease. Women who have had diabetes during pregnancy face a lifetime elevated risk of type 2 diabetes, as do minorities including individuals of Asian, Hispanic, African, and Native American. Rates of type 2 diabetes are also skyrocketing in youth, and for them, oral medications don’t usually work for very long. They rapidly progress to treatment failure and develop early complications. We still don’t really understand how or why these things happen, limiting our ability to intervene to stop them.
The role of microRNAs in diabetes pathogenesis
Epigenetic regulation of gene expression may play an important role in the progression of diabetes and is a promising source of prognostic or predictive biomarkers. For example, non-coding RNAs called microRNAs (miRNAs) regulate insulin signaling and glucose uptake in target tissues; are altered in tissues in the presence of insulin resistance; are actively secreted into the circulation; and are taken up by distant organs. In the pancreas, some of the same miRNAs regulate expression of genes critical to beta-cell proliferation and survival. In the circulation, they are stable in plasma and serum samples for many years and may be endocrine-style mediators of inter-organ cross-talk or markers of tissue level changes in the regulation of gene expression.
Our contribution
We use epidemiological methods to study epigenetic and non-epigenetic factors that might contribute to the development of diabetes in groups of people at high risk of diabetes or with distinctive diabetes risk factors, such as women with diabetes in pregnancy and Asian Americans. Our recent work aims to identify patterns of circulating miRNAs that precede development of diabetes. In pregnant women, we have identified miRNAs in mid-trimester plasma related to the subsequent development of gestational diabetes (GDM), including miRNAs that are related to the development of GDM only in mothers with pre-pregnancy overweight/obesity and mothers carrying male fetuses. For example, circulating miR-517b levels were associated with GDM among pregnancies with males only. This placentally expressed miRNA regulates levels of TNFS15, a pro-inflammatory, anti-angiogenic cytokine, which may reflect a sex-specific placental response to the maternal immune system. We have also identified circulating miRNAs in mid-trimester plasma that may mediate the association of pre-pregnancy BMI with the subsequent development of GDM: miR-155 and miR-21-3p. These two miRNAs are expressed in a variety of tissues and have established roles in the regulation of cellular growth via effects on mechanistic target of rapamycin (mTOR) signaling. In the circulation, exosomes from adipose tissue macrophages in obese mice are enriched in miR-155. When lean, insulin-sensitive mice are given these exosomes, they develop systemic insulin resistance and dysglycemia, with uptake of the exosomes demonstrated in liver, muscle and adipose.
In a pilot study of Japanese Americans at high risk of type 2 diabetes (n=10), we identified 36 miRNAs that were present at baseline at significantly different levels in plasma samples from incident diabetes cases than from controls who did not develop diabetes after 10 years of follow-up, including a number of miRNAs with established roles in skeletal muscle function, such as miR-15a, miR-106b and miR-20b-5p. In addition to the clinical relevance of these findings, this pilot demonstrated that miRNAs can remain stable in samples for more than 30 years and that differences in circulating miRNAs related to development of diabetes can be seen up to a decade prior to the development of overt disease. These findings will lend support to future projects aiming to measure circulating miRNAs in archival datasets from observational studies and clinical trials, a potentially important way to learn more about changes in tissues such as adipose, skeletal muscle, liver and pancreas or changes in miRNA-mediated tissue cross-talk that precede the development diabetes.
Our recent miRNA studies have confirmed miRNAs previously related to the development of diabetes, identified novel miRNAs that precede the onset of disease and extended these findings to new populations. Our next step will be to demonstrate whether profiles of circulating miRNAs including the candidates we have identified predict disease progression or treatment response, and whether they are altered by treatment in a variety of populations.