Dr. Bastarrachea is a Staff Scientist in the SNPRC and the Department of Genetics. His research focuses on the biology and genetics of complex metabolic traits with focus on cardiovascular disease, obesity, and type 2 diabetes. His research has helped to develop and establish the baboon as a non-human primate (NHP) model to study the physiological mechanisms regulating fat tissue metabolism in obesity and diabetes, with a special emphasis on hormone regulation and action.
Inside The Lab
After developing novel sophisticated tracer methods and blood vessel catheterizations to study free fatty acid kinetics in the baboon, we developed a high-fat, high-carbohydrate challenge diet, which showed pronounced and rapid negative effects on a wide range of key metabolic parameters, consistent with the metabolic disruptions seen in humans.
Recently, we established a method of streptozotocin-induced diabetes in conscious tethered baboons. We successfully induced frank diabetes by IV-administering a single dose of streptozotocin safely and without adverse events in conscious tethered baboons. Animals were continuously monitored, using a tether system that allows moment-by-moment monitoring of glucose levels after administration, and continuous intravenous insulin therapy. We described a triphasic response in blood glucose after streptozotocin administration, including a hypoglycemic phase. Hyperglycemia in these animals was associated with low levels of plasma leptin, insulin and C-peptide concentrations, hyperglucagonemia, and elevated non-esterified fatty acids (NEFA) concentrations.
In collaboration with cardiologist Paul Grayburn, M.D. (Director of Cardiology Research, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX), we applied this model to test and implement a state-of-the- art gene-based therapy in the baboon model using a novel gene delivery protocol called UTMD (micro- bubble delivery) for the treatment of type 1 diabetes. We targeted non-viral gene therapy to pancreatic islets using ultrasound targeted microbubble destruction (UTMD) in baboons. Our Preliminary data indicate that gene therapy by UTMD can achieve in vivo normalization of the intravenous (IV ) glucose tolerance test (IVGTT) curves in streptozotocin-induced diabetic baboons. Immunohistochemistry demonstrated evidence of islet regeneration and restoration of β-cell mass.
This recent work is an extension of earlier studies performed in collaboration with Dr. Ralph A. DeFronzo and the Diabetes Division at UT Health Science Center San Antonio, where we established euglycemic-hyperinsulinemic clamping in baboons, widely considered the gold standard for assessing insulin action in vivo.
Fat accumulation in the liver is symptom of a condition called nonalcoholic steatohepatitis (NASH), found in individuals who consume little or no alcohol. Obesity and diabetes are the two strongest risk factors for the development of NASH in humans. We have established stable isotope infusion protocols under the tether system in baboons to measure the relative sources of fats (triglycerides) that are secreted in lipoproteins and stored in the liver.
Overall, we have developed and established a baboon model for the study of diet-induced cardiometabolic syndrome. We have developed tools for detailed physiological characterizations of hormone action, specifically the regulation of fat cell metabolism, and have used the animal model and approaches for a wide range of studies, including dietary intervention studies and gene therapy.
Main Technologies And Methods Used
- Euglycemic-hyperinsulinemic clamping in baboons
- Micro-bubble delivery for gene therapy
- Molecular physiology of insulin and adipokines