Leslie J. Baier, Ph.D.

Research Goal

The purpose of our research is to identify the heritable basis for type 2 diabetes and obesity among Indigenous people living in the southwestern region of the United States. We believe that understanding and quantifying specific genetically determined susceptibility factors could lead to prevention by identifying individuals who are most at risk and might benefit from early treatment. The research could also identify novel therapeutic and personalized targets, which may lead to treatment improvements. 

Current Research

Escalating rates of obesity and type 2 diabetes are primarily attributed to changes in the environment, coupled with changes in lifestyle. In most developed countries, however, food is now plentiful and lifestyle is generally sedentary. Yet not all people develop obesity, nor do most people with obesity develop type 2 diabetes. Multiple studies have shown that heritable factors underlie a significant portion of the variation in risk for obesity and type 2 diabetes. Environmental variables influence expression of this genetic susceptibility. Type 2 diabetes and obesity adversely and disproportionately impact specific minority populations.  Our branch has built and sustained a multi-generational relationship with members of an Indigenous community in the southwestern United States, and the research focus of my section is to identify and characterize susceptibility genes for type 2 diabetes and obesity among these individuals.

We utilize many genomic techniques to identify determinants of obesity and type 2 diabetes in Indigenous people. Whole-genome sequence data has been analyzed on 428 fully consented Indigenous community members who have been clinically and metabolically characterized for predictors of type 2 diabetes and obesity in our clinical research center. Variation detected in these genomes was used to design a custom single nucleotide polymorphism (SNP) array which captures 92% of all common variation in these community members. This array has been used to genotype DNA from 10,000 Indigenous people for 548,000 SNPs, which provided a scaffold for imputation of >20 million SNPs in these individuals to use in genome-wide association studies (GWASs) of obesity, type 2 diabetes, their physiologic predictors as well as their complications. Creation of this custom genotyping specific array has allowed us to capture important genetic information that would have been missed using commercially available arrays. For example, we recently published a study of a variant in the GPR158 gene that associated with lower rates of energy expenditure and increased body mass index (BMI). The BMI risk allele for this variant is far more common in Indigenous people as compared to other ethnic groups (e.g. the risk allele occurs in 60% of the Indigenous community members and <1% of Caucasians) and thus this variant does not occur on commercial arrays. Overall, variants in/near the KCNQ1 gene provide our strongest genome-wide association with type 2 diabetes, and we have shown that these variants affect diabetes risk via an effect on acute insulin secretion. We have also found variation in the nearby TH gene that provides an independent signal for type 2 diabetes. Since GWASs and/or imputation may not accurately capture rare variants, we have also obtained whole exome sequence data on 8,000 fully consented Indigenous people, such that rare variants can also be analyzed either individually or in combination with other rare variants within the same gene. Variants that associate with type 2 diabetes, obesity or related phenotypes are then functionally characterized. In addition to analyzing variants using standard in vitro systems (e.g. luciferase assays) we are characterizing the role of these variants in beta-like cells differentiated from human induced pluripotent stems cells (iPSs). We have shown that these differentiated cells exhibit first and second phase insulin responses to a dynamic glucose infusion that closely mimics the glucose stimulated insulin response in human pancreatic islets. We have used this model system to characterize the effects of key SNPs on islet differentiation and function, and test specific drugs for personalized, targeted treatment.  

Applying our Research

Although type 2 diabetes is not always the same disease in different people, currently available drugs are “one size fits all.” Identifying genetic differences that increase risk for this disease will allow development of more specific drugs. Such knowledge will allow physicians to select a drug therapy that is best suited for each patient. 

Need for Further Study

As precision medicine becomes a reality in standard medical practice, it is imperative that people across all ethnic groups are given the same opportunities to participate in genomic research. Exclusion of minority populations, who in many cases are disproportionately burdened by metabolic diseases, will only result in an increase in health disparities. 

Research in Plain Language

Indigenous communities suffer from disproportionately high rates of type 2 diabetes. A major risk factor for type 2 diabetes is obesity. Both of these diseases are heritable (run in families) which suggests that genetics has an important role. In recent years we have identified several DNA variants that increase risk for type 2 diabetes or obesity among Indigenous Americans. Most of these DNA variants are also found in people of other ethnicities where they similarly affect risk for these diseases. However, we have found a few variants that have a larger impact on disease risk specifically in Indigenous people as compared to other ethnic groups. We have also identified a few DNA variants that are solely found in Indigenous people that increase risk for these diseases. 

Our goal is to understand exactly how these DNA variants increase risk for disease for the purpose of identifying more effective, targeted treatment.  We are primarily focused on those DNA variants that are either unique to Indigenous people or have a larger effect on disease risk among Indigenous people, with the hope that Indigenous communities with whom we have collaborated for decades will benefit from this work. We have shown that several of the DNA variants that affect risk for type 2 diabetes function in the pancreas and therefore we created a cell model system where we can study these DNA variants in cells that precisely mimic a developing human pancreas. 

We have found that common DNA variation in the gene KCNQ1 (more than 50% of Indigenous people carry this DNA variant) exert its effect specifically during an early stage of pancreas development. At this early stage of development, several genes make the wrong amounts of important proteins, triggering a cascade of effects which ultimately results in a smaller proportion of total pancreatic cells becoming beta cells (cells which produce insulin) and a compensatory increase in other cell types (primarily alpha and delta cells which do not make insulin). Therefore, people with this DNA variant are more likely to develop type 2 because they have fewer insulin-producing beta cells even at birth. There are some drugs which specifically target beta cell proliferation and we will test these drugs in our cell system to see if this could have a positive effect on increasing beta cell mass. 

We have also studied a DNA variant in the gene ABCC8 that is found in 3% of people living in this Community but is not found in other populations. Infants who inherit 2 copies of this variant (one from each parent) are at very high risk for hyperinsulinemia, hypoglycemia of infancy (HHI) which can be fatal if not treated. We have previously told the Community’s Research Review Committee and physicians who are likely to provide care for these Community members about this variant such that if both parents are carriers, their newborn baby can be monitored for potential HHI before being discharged from the hospital. In contrast, Community members who inherit one copy of this ABCC8 gene variant (get the variant from only one parent) don’t get HHI and instead have a doubled risk for type 2 diabetes and are likely to develop diabetes at a younger age and a lower body weight.  We have now modeled how just one copy of this DNA variant doubles the risk for type 2 diabetes in the beta cell. We have identified the biochemical pathway that is affected. and are excited to learn that there is a FDA approved drug that targets this pathway. We are currently testing an FDA approved drug that targets this pathway in our islet model system in hopes of demonstrating that this drug has the potential to specifically benefit Indigenous people who have type 2 diabetes due to this particular DNA variant.

In summary, recent advances in genomics technology, coupled with decades of clinical data, is now allowing us to understand how specific DNA variants increase risk for type 2 diabetes. It is our hope that this information will ultimately provide personalized treatment, and in the future, ease the burden of type 2 diabetes among Indigenous people.